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The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.

“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.

But are these two axioms truly in conflict, or is this a false dichotomy?

 

Occam’s Razor and Simple Diagnoses

Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.

For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.

 

Beyond Hickam’s Dictum and Occam’s Razor

A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.

Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:

1. Incidentaloma: An asymptomatic condition discovered accidentally.

2. Preexisting diagnosis: A known condition in the patient’s medical history.

3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.

4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.

Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.

Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.

Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.

 

Practical Insights

The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.

Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.

 

This story was translated from Univadis Italy 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.

The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.

“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.

But are these two axioms truly in conflict, or is this a false dichotomy?

 

Occam’s Razor and Simple Diagnoses

Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.

For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.

 

Beyond Hickam’s Dictum and Occam’s Razor

A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.

Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:

1. Incidentaloma: An asymptomatic condition discovered accidentally.

2. Preexisting diagnosis: A known condition in the patient’s medical history.

3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.

4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.

Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.

Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.

Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.

 

Practical Insights

The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.

Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.

 

This story was translated from Univadis Italy 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.

The principle of parsimony, often referred to as “Occam’s razor,” favors a unifying explanation over multiple ones, as long as both explain the data equally well. This heuristic, widely used in medical practice, advocates for simpler explanations rather than complex theories. However, its application in modern medicine has sparked debate.

“Hickam’s dictum,” a counterargument to Occam’s razor, asserts that patients — especially as populations grow older and more fragile — can simultaneously have multiple, unrelated diagnoses. These contrasting perspectives on clinical reasoning, balancing diagnostic simplicity and complexity, are both used in daily medical practice.

But are these two axioms truly in conflict, or is this a false dichotomy?

 

Occam’s Razor and Simple Diagnoses

Interpersonal variability in diagnostic approaches, shaped by the subjective nature of many judgments, complicates the formal evaluation of diagnostic parsimony (Occam’s razor). Indirect evidence suggests that prioritizing simplicity in diagnosis can result in under-detection of secondary conditions, particularly in patients with chronic illnesses.

For example, older patients with a known chronic illness were found to have a 30%-60% lower likelihood of being treated for an unrelated secondary diagnosis than matched peers without the chronic condition. Other studies indicate that a readily available, simple diagnosis can lead clinicians to prematurely close their diagnostic reasoning, overlooking other significant illnesses.

 

Beyond Hickam’s Dictum and Occam’s Razor

A recent study explored the phenomenon of multiple diagnoses by examining the supposed conflict between Hickam’s dictum and Occam’s razor, as well as the ambiguities in how they are interpreted and used by physicians in clinical reasoning.

Part 1: Researchers identified articles on PubMed related to Hickam’s dictum or conflicting with Occam’s razor, categorizing instances into four models of Hickam’s dictum:

1. Incidentaloma: An asymptomatic condition discovered accidentally.

2. Preexisting diagnosis: A known condition in the patient’s medical history.

3. Causally related disease: A complication, association, epiphenomenon, or underlying cause connected to the primary diagnosis.

4. Coincidental and independent disease: A symptomatic condition unrelated to the primary diagnosis.

Part 2: Researchers analyzed 220 case records from Massachusetts General Hospital, Boston, and clinical problem-solving reports published in The New England Journal of Medicine between 2017 and 2023. They found no cases where the final diagnosis was not a unifying one.

Part 3: In an online survey of 265 physicians, 79% identified coincidental symptomatic conditions (category 4) as the least likely type of multiple diagnoses. Preexisting conditions (category 2) emerged as the most common, reflecting the tendency to add new diagnoses to a patient’s existing health profile. Almost one third of instances referencing Hickam’s dictum or violations of Occam’s razor fell into category 2.

Causally related diseases (category 3) were probabilistically dependent, meaning that the presence of one condition increased the likelihood of the other, based on the strength (often unknown) of the causal relationship.

 

Practical Insights

The significant finding of this work was that multiple diagnoses occur in predictable patterns, informed by causal connections between conditions, symptom onset timing, and likelihood. The principle of common causation supports the search for a unifying diagnosis for coincidental symptoms. It is not surprising that causally related phenomena often co-occur, as reflected by the fact that 40% of multiple diagnoses in the study’s first part were causally linked.

Thus, understanding multiple diagnoses goes beyond Hickam’s dictum and Occam’s razor. It requires not only identifying diseases but also examining their causal relationships and the timing of symptom onset. A unifying diagnosis is not equivalent to a single diagnosis; rather, it represents a causal pathway linking underlying pathologic changes to acute presentations.

 

This story was translated from Univadis Italy 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.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

The causes of shoulder pain may be as common as a traumatic injury or as rare as a systemic inflammatory condition, according to the American Academy of Orthopaedic Surgeons. The combination of joints, tendons, and muscles that make up the shoulder can present diagnostic and clinical challenges, but several experts shared their tips for management.

Evaluation and Diagnosis

Rotator cuff tendinopathy/tendinitis and subacromial bursitis are typically the most common causes of shoulder pain presenting to a primary care provider, said Jason Kolfenbach, MD, a rheumatologist at UC Health, Denver, Colorado, in an interview. “Other causes of shoulder pain may include acromioclavicular osteoarthritis, biceps tendinitis (often a secondary process in the setting of rotator cuff disease), and true glenohumeral joint osteoarthritis,” he said.

Experts estimate that as much as 80% of shoulder pain involves the muscles, tendons, and ligaments surrounding the joint, rather than true arthritis, said Kolfenbach, who was a co-author of a Medscape slideshow on evaluating shoulder pain. In the slideshow, the authors noted that proper evaluation is needed for successful pain management. Some patients may do well with nonsteroidal anti-inflammatory drugs (NSAIDs), rest, ice, and physical therapy, but more serious conditions may require steroids, disease-modifying antirheumatic drugs, or surgery.

If a patient’s joint pain with active range of motion is relieved when an examiner supports the affected limb (passive range of motion), the cause is more likely related to muscles, tendons, or ligaments, Kolfenbach said.

Primary care providers may not be familiar with examination maneuvers to diagnose shoulder pain, although they are often tasked with evaluating and managing these patients, said Kolfenbach.

Education focused on practical aspects of these maneuvers may help improve primary care confidence in utilizing them and lead to more appropriate ordering of imaging testing and better pain management plans for patients, he said.

However, “If there is concern for a true intra-articular process, plain radiographs are recommended to determine if there is loss of cartilage space and/or other anatomic drivers of pain,” he noted. “Even in conditions of documented intra-articular arthritis, such as osteoarthritis, weakness, and atrophy of the surrounding musculature can contribute to joint disability and pain,” he said. For these patients, referral to physical therapy for periarticular strengthening can provide pain relief, he added.

 

Pinning Down the Pain Point

The many different structures within the shoulder that can cause pain make diagnosis a challenge, Nicole Angelo, DO, MS, a physiatrist at the Hospital for Special Surgery, New York City, said in an interview.

Potential sources of pain include the joint of the shoulder itself, the structures within it (labrum, capsule, and ligaments), and the surrounding rotator cuff muscles and tendons, she said. Patients also may experience overlapping pain referred from the neck (cervical spine) related to nerve irritation (cervical radiculopathy) or arthritis, she noted.

“A patient’s history, including mechanism and acuity of injury, as well as exam, specifically weakness in certain movements,” can help determine whether advanced imaging and surgical intervention may be required,” Angelo told this news organization.

Frozen shoulder is the most missed diagnosis of shoulder pain in primary care, Brian Feeley, MD, chief of sports medicine and shoulder surgery at the University of California, San Francisco (UCSF), said in an interview.

Frozen shoulder, also known as adhesive capsulitis, can mimic many other conditions including rotator cuff problems, shoulder arthritis, and biceps problems, Feeley said. “When people have a loss of active and passive range of motion and no evidence of arthritis on x-rays, their diagnosis is most likely frozen shoulder,” he said.

Another challenge for primary care providers is identifying the severity of rotator cuff problems, Feeley said. “I like to think of rotator cuff problems along a spectrum — impingement is inflammation above the rotator cuff and suggests an imbalance between rotator cuff strength and deltoid strength,” said Feeley. “Partial thickness tears are often normal age-related problems but can be a source of pain,” he added.

However, full-thickness tears encompass a range of problems, from very small asymptomatic holes in the rotator cuff to massive tears that require shoulder replacement, Feeley explained. “Tendinopathy, or changes in the collagen organization in the tendon of the rotator cuff, sounds problematic, but most often is either incidental or part of aging,” he added.

 

When Shoulder Pain Isn’t Caused by the Shoulder

Primary care patients presenting with shoulder pain may in fact have a neck or spine problem instead, Feeley told this news organization. “Pain that is in the shoulder blade area or down the arm and into the fingers is usually coming from the neck/cervical spine,” he said.

In some cases, shoulder pain stems from the joints below the shoulder, including the elbow, because of arthritis, tennis elbow (lateral epicondylopathy), or golfer’s elbow (medial epicondylopathy), said Angelo. “Conditions of the elbow and neck can also affect shoulder mechanics or cause someone to use the joint more or less frequently,” she said. The interconnections between the neck and joints of the upper extremity, including referral patterns, complicate the diagnosis of shoulder pain; therefore, careful history-taking and examination of joints both above and below the shoulder are essential, she added.

 

Conservative Care

Shoulder problems often can be managed conservatively with therapeutic exercise focused on maintaining range of motion of the shoulder and strengthening the musculature around the shoulder, Angelo said. “Often, working with a physical therapist to address the mechanics of how the shoulder is moving and how the muscles are firing can help decrease pain and help patients meet their functional goals,” said Angelo. “Injections into the joint, the bursa adjacent to the rotator cuff, and, at times, into the tendons themselves can also be beneficial in relieving pain and improving function,” she said.

In some cases, a short, consistent course of anti-inflammatory medications can be part of a conservative strategy for the management of shoulder pain, Angelo noted.

“Utilizing these medications on an as-needed basis can also help patients improve their ability to sleep, perform their daily activities, and participate in physical therapy,” she said. A course of physical therapy that promotes maintaining shoulder range of motion, strengthening of the rotator cuff musculature, and working on the mechanics between the scapula and humerus is a good first step for most shoulder conditions, Angelo told this news organization.

“If there is concern due to recent trauma, significant weakness, or new/persistent numbness, referral to a specialist should be considered,” she said. If conservative measures including analgesics and exercise have failed to improve shoulder pain, advanced imaging and further interventional treatment may be necessary, Angelo added.

Most shoulder problems can and should be managed nonoperatively, Feeley said. Surgery should be reserved for patients whose shoulder pain has not improved with nonoperative care in most situations, he said. “It is often surprising for patients to hear, but most things in the shoulder actually get better without surgery, and changes on MRI are often normal for age,” Feeley noted. For example, more than 80% of individuals older than 50 will show signs of a labral tear or arthritis in the acromioclavicular joint, he said. “These are incidental findings that don’t need treatment,” he added.

More research is needed to develop more medications to manage pain for all musculoskeletal conditions, including shoulder pain, said Feeley. “But for now, for patients with shoulder pain, I tend to recommend a combination of Tylenol and an NSAID to improve inflammation and reduce pain, and a guided [physical] therapy program at home or in person. The combination of both usually will be successful,” he said.

 

Postsurgical Shoulder Pain

“For patients who have shoulder surgery, the techniques to manage pain around surgery have improved tremendously over the last decade, particularly with multimodal pain management and nerve blocks,” Feeley told this news organization. These advances have tremendously reduced the need for narcotics for pain management beyond the first 72 hours after surgery, he said. “I strongly recommend patients and primary care doctors to stop all narcotics as soon as possible after shoulder surgery, since they are not nearly as effective for management of pain after the first few days, and they should never be used as a sleep aid,” he emphasized.

Managing pain during recovery from shoulder surgery also involves about 6 weeks in a sling to protect the repair, followed by 6 weeks of active motion but no strengthening, then 3 months of strengthening exercises, he said.

Shoulder pain resources for patients: https://www.hss.edu/condition-list_shoulder-pain-causes.asp

Feeley’s 10-minute video on shoulder examination and pain assessment at the UCSF 14th Annual Primary Care Sports Medicine Conference, 2019: Video on the Essential Shoulder Exam

Kolfenbach disclosed receiving royalties from Elsevier for being the editor of Rheumatology Secrets and Wolters Kluwer for authoring several articles on UpToDate. Feeley and Angelo had no relevant financial conflicts to disclose.

 

A version of this article appeared on Medscape.com.

TOPLINE:

Levonorgestrel intrauterine devices (IUDs) are associated with significantly more reports of acne, alopecia, and hirsutism compared with copper IUDs, with some differences between the available levonorgestrel IUDs.

METHODOLOGY:

• Researchers reviewed the US Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) through December 2023 for adverse events associated with levonorgestrel IUDs where IUDs were the only suspected cause, focusing on acne, alopecia, and hirsutism.
• They included 139,348 reports for the levonorgestrel IUDs (Mirena, Liletta, Kyleena, Skyla) and 50,450 reports for the copper IUD (Paragard).

TAKEAWAY:

• Levonorgestrel IUD users showed higher odds of reporting acne (odds ratio [OR], 3.21), alopecia (OR, 5.96), and hirsutism (OR, 15.48; all P < .0001) than copper IUD users.
• The Kyleena 19.5 mg levonorgestrel IUD was associated with the highest odds of acne reports (OR, 3.42), followed by the Mirena 52 mg (OR, 3.40) and Skyla 13.5 mg (OR, 2.30) levonorgestrel IUDs (all P < .0001).
• The Mirena IUD was associated with the highest odds of alopecia and hirsutism reports (OR, 6.62 and 17.43, respectively), followed by the Kyleena (ORs, 2.90 and 8.17, respectively) and Skyla (ORs, 2.69 and 1.48, respectively) IUDs (all P < .0001).
• Reports of acne, alopecia, and hirsutism were not significantly different between the Liletta 52 mg levonorgestrel IUD and the copper IUD.

IN PRACTICE:

“Overall, we identified significant associations between levonorgestrel IUDs and androgenic cutaneous adverse events,” the authors wrote. “Counseling prior to initiation of levonorgestrel IUDs should include information on possible cutaneous AEs including acne, alopecia, and hirsutism to guide contraceptive shared decision making,” they added.

 

SOURCE:

The study was led by Lydia Cassard, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, and was published online November 3 in Journal of the American Academy of Dermatology.

LIMITATIONS:

FAERS database reports could not be verified, and differences in FDA approval dates for IUDs could have influenced reporting rates. Moreover, a lack of data on prior medication use limits the ability to determine if these AEs are a result of changes in androgenic or antiandrogenic medication use. Cutaneous adverse events associated with copper IUDs may have been underreported because of assumptions that a nonhormonal device would not cause these adverse events.

DISCLOSURES:

The authors did not report any funding source or conflict of interests.

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:

Levonorgestrel intrauterine devices (IUDs) are associated with significantly more reports of acne, alopecia, and hirsutism compared with copper IUDs, with some differences between the available levonorgestrel IUDs.

METHODOLOGY:

• Researchers reviewed the US Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) through December 2023 for adverse events associated with levonorgestrel IUDs where IUDs were the only suspected cause, focusing on acne, alopecia, and hirsutism.
• They included 139,348 reports for the levonorgestrel IUDs (Mirena, Liletta, Kyleena, Skyla) and 50,450 reports for the copper IUD (Paragard).

TAKEAWAY:

• Levonorgestrel IUD users showed higher odds of reporting acne (odds ratio [OR], 3.21), alopecia (OR, 5.96), and hirsutism (OR, 15.48; all P < .0001) than copper IUD users.
• The Kyleena 19.5 mg levonorgestrel IUD was associated with the highest odds of acne reports (OR, 3.42), followed by the Mirena 52 mg (OR, 3.40) and Skyla 13.5 mg (OR, 2.30) levonorgestrel IUDs (all P < .0001).
• The Mirena IUD was associated with the highest odds of alopecia and hirsutism reports (OR, 6.62 and 17.43, respectively), followed by the Kyleena (ORs, 2.90 and 8.17, respectively) and Skyla (ORs, 2.69 and 1.48, respectively) IUDs (all P < .0001).
• Reports of acne, alopecia, and hirsutism were not significantly different between the Liletta 52 mg levonorgestrel IUD and the copper IUD.

IN PRACTICE:

“Overall, we identified significant associations between levonorgestrel IUDs and androgenic cutaneous adverse events,” the authors wrote. “Counseling prior to initiation of levonorgestrel IUDs should include information on possible cutaneous AEs including acne, alopecia, and hirsutism to guide contraceptive shared decision making,” they added.

 

SOURCE:

The study was led by Lydia Cassard, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, and was published online November 3 in Journal of the American Academy of Dermatology.

LIMITATIONS:

FAERS database reports could not be verified, and differences in FDA approval dates for IUDs could have influenced reporting rates. Moreover, a lack of data on prior medication use limits the ability to determine if these AEs are a result of changes in androgenic or antiandrogenic medication use. Cutaneous adverse events associated with copper IUDs may have been underreported because of assumptions that a nonhormonal device would not cause these adverse events.

DISCLOSURES:

The authors did not report any funding source or conflict of interests.

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:

Levonorgestrel intrauterine devices (IUDs) are associated with significantly more reports of acne, alopecia, and hirsutism compared with copper IUDs, with some differences between the available levonorgestrel IUDs.

METHODOLOGY:

• Researchers reviewed the US Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) through December 2023 for adverse events associated with levonorgestrel IUDs where IUDs were the only suspected cause, focusing on acne, alopecia, and hirsutism.
• They included 139,348 reports for the levonorgestrel IUDs (Mirena, Liletta, Kyleena, Skyla) and 50,450 reports for the copper IUD (Paragard).

TAKEAWAY:

• Levonorgestrel IUD users showed higher odds of reporting acne (odds ratio [OR], 3.21), alopecia (OR, 5.96), and hirsutism (OR, 15.48; all P < .0001) than copper IUD users.
• The Kyleena 19.5 mg levonorgestrel IUD was associated with the highest odds of acne reports (OR, 3.42), followed by the Mirena 52 mg (OR, 3.40) and Skyla 13.5 mg (OR, 2.30) levonorgestrel IUDs (all P < .0001).
• The Mirena IUD was associated with the highest odds of alopecia and hirsutism reports (OR, 6.62 and 17.43, respectively), followed by the Kyleena (ORs, 2.90 and 8.17, respectively) and Skyla (ORs, 2.69 and 1.48, respectively) IUDs (all P < .0001).
• Reports of acne, alopecia, and hirsutism were not significantly different between the Liletta 52 mg levonorgestrel IUD and the copper IUD.

IN PRACTICE:

“Overall, we identified significant associations between levonorgestrel IUDs and androgenic cutaneous adverse events,” the authors wrote. “Counseling prior to initiation of levonorgestrel IUDs should include information on possible cutaneous AEs including acne, alopecia, and hirsutism to guide contraceptive shared decision making,” they added.

 

SOURCE:

The study was led by Lydia Cassard, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, and was published online November 3 in Journal of the American Academy of Dermatology.

LIMITATIONS:

FAERS database reports could not be verified, and differences in FDA approval dates for IUDs could have influenced reporting rates. Moreover, a lack of data on prior medication use limits the ability to determine if these AEs are a result of changes in androgenic or antiandrogenic medication use. Cutaneous adverse events associated with copper IUDs may have been underreported because of assumptions that a nonhormonal device would not cause these adverse events.

DISCLOSURES:

The authors did not report any funding source or conflict of interests.

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.

The US Food and Drug Administration (FDA) has approved bimekizumab, a humanized interleukin (IL)-17A and IL-17F antagonist, for the treatment of adults with moderate to severe hidradenitis suppurativa (HS).

Approval was based on results from two phase 3 studies, BE HEARD I and BE HEARD II, which found that bimekizumab improved the signs and symptoms of disease compared with placebo at week 16 and were sustained to week 48, according to a press release from UCB, the drug’s manufacturer. In both trials, a higher proportion of patients treated with bimekizumab achieved Hidradenitis Suppurativa Clinical Response (HiSCR) scores of 50 and 75 compared with those who received placebo.

The company noted that bimekizumab (Bimzelx) is the first and only approved medicine designed to selectively inhibit IL-17F in addition to IL-17A. According to the prescribing information, the recommended dosing for patients with HS is 320 mg administered by subcutaneous injection at week 0, 2, 4, 6, 8, 10, 12, 14, and 16, then every 4 weeks thereafter.

“The approval of bimekizumab for moderate-to-severe HS is tremendous news for people living with HS” and the clinicians who care for them, Jennifer L. Hsiao, MD, director of the HS clinic at the University of Southern California, Los Angeles, told this news organization.

“It is exciting that we already have two-year trial data for bimekizumab in HS and can see that bimekizumab raises the bar in terms of depth and durability of response that we can expect to see in our patients,” she added. “Given the limited treatment options for HS at this time, the addition of bimekizumab to our treatment armamentarium is a huge step forward for the HS community.”

This development marks the fifth approved indication for bimekizumab since it was first approved in October 2023 for the treatment of moderate to severe plaque psoriasis, followed by approvals for active psoriatic arthritis, nonradiographic axial spondyloarthritis, and active ankylosing spondylitis in September 2024. 

According to the prescribing information, certain adverse reactions have been observed with bimekizumab, including suicidal ideation and behavior, infections, liver biochemical abnormalities, and inflammatory bowel disease. A pregnancy exposure registry has been established that monitors pregnancy outcomes in women exposed to bimekizumab. For information, clinicians or patients can contact the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases Study at 1-877-311- 8972 or visit MotherToBaby Pregnancy Studies.

Hsiao disclosed that she is a member of the board of directors for the HS Foundation and has served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, Sanofi, and UCB; a speaker for AbbVie, Galderma, Novartis, Sanofi Regeneron, and UCB; and an investigator for Amgen, Boehringer Ingelheim, and Incyte.

 

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

The US Food and Drug Administration (FDA) has approved bimekizumab, a humanized interleukin (IL)-17A and IL-17F antagonist, for the treatment of adults with moderate to severe hidradenitis suppurativa (HS).

Approval was based on results from two phase 3 studies, BE HEARD I and BE HEARD II, which found that bimekizumab improved the signs and symptoms of disease compared with placebo at week 16 and were sustained to week 48, according to a press release from UCB, the drug’s manufacturer. In both trials, a higher proportion of patients treated with bimekizumab achieved Hidradenitis Suppurativa Clinical Response (HiSCR) scores of 50 and 75 compared with those who received placebo.

The company noted that bimekizumab (Bimzelx) is the first and only approved medicine designed to selectively inhibit IL-17F in addition to IL-17A. According to the prescribing information, the recommended dosing for patients with HS is 320 mg administered by subcutaneous injection at week 0, 2, 4, 6, 8, 10, 12, 14, and 16, then every 4 weeks thereafter.

“The approval of bimekizumab for moderate-to-severe HS is tremendous news for people living with HS” and the clinicians who care for them, Jennifer L. Hsiao, MD, director of the HS clinic at the University of Southern California, Los Angeles, told this news organization.

“It is exciting that we already have two-year trial data for bimekizumab in HS and can see that bimekizumab raises the bar in terms of depth and durability of response that we can expect to see in our patients,” she added. “Given the limited treatment options for HS at this time, the addition of bimekizumab to our treatment armamentarium is a huge step forward for the HS community.”

This development marks the fifth approved indication for bimekizumab since it was first approved in October 2023 for the treatment of moderate to severe plaque psoriasis, followed by approvals for active psoriatic arthritis, nonradiographic axial spondyloarthritis, and active ankylosing spondylitis in September 2024. 

According to the prescribing information, certain adverse reactions have been observed with bimekizumab, including suicidal ideation and behavior, infections, liver biochemical abnormalities, and inflammatory bowel disease. A pregnancy exposure registry has been established that monitors pregnancy outcomes in women exposed to bimekizumab. For information, clinicians or patients can contact the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases Study at 1-877-311- 8972 or visit MotherToBaby Pregnancy Studies.

Hsiao disclosed that she is a member of the board of directors for the HS Foundation and has served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, Sanofi, and UCB; a speaker for AbbVie, Galderma, Novartis, Sanofi Regeneron, and UCB; and an investigator for Amgen, Boehringer Ingelheim, and Incyte.

 

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

The US Food and Drug Administration (FDA) has approved bimekizumab, a humanized interleukin (IL)-17A and IL-17F antagonist, for the treatment of adults with moderate to severe hidradenitis suppurativa (HS).

Approval was based on results from two phase 3 studies, BE HEARD I and BE HEARD II, which found that bimekizumab improved the signs and symptoms of disease compared with placebo at week 16 and were sustained to week 48, according to a press release from UCB, the drug’s manufacturer. In both trials, a higher proportion of patients treated with bimekizumab achieved Hidradenitis Suppurativa Clinical Response (HiSCR) scores of 50 and 75 compared with those who received placebo.

The company noted that bimekizumab (Bimzelx) is the first and only approved medicine designed to selectively inhibit IL-17F in addition to IL-17A. According to the prescribing information, the recommended dosing for patients with HS is 320 mg administered by subcutaneous injection at week 0, 2, 4, 6, 8, 10, 12, 14, and 16, then every 4 weeks thereafter.

“The approval of bimekizumab for moderate-to-severe HS is tremendous news for people living with HS” and the clinicians who care for them, Jennifer L. Hsiao, MD, director of the HS clinic at the University of Southern California, Los Angeles, told this news organization.

“It is exciting that we already have two-year trial data for bimekizumab in HS and can see that bimekizumab raises the bar in terms of depth and durability of response that we can expect to see in our patients,” she added. “Given the limited treatment options for HS at this time, the addition of bimekizumab to our treatment armamentarium is a huge step forward for the HS community.”

This development marks the fifth approved indication for bimekizumab since it was first approved in October 2023 for the treatment of moderate to severe plaque psoriasis, followed by approvals for active psoriatic arthritis, nonradiographic axial spondyloarthritis, and active ankylosing spondylitis in September 2024. 

According to the prescribing information, certain adverse reactions have been observed with bimekizumab, including suicidal ideation and behavior, infections, liver biochemical abnormalities, and inflammatory bowel disease. A pregnancy exposure registry has been established that monitors pregnancy outcomes in women exposed to bimekizumab. For information, clinicians or patients can contact the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases Study at 1-877-311- 8972 or visit MotherToBaby Pregnancy Studies.

Hsiao disclosed that she is a member of the board of directors for the HS Foundation and has served as a consultant for AbbVie, Aclaris, Boehringer Ingelheim, Incyte, Novartis, Sanofi, and UCB; a speaker for AbbVie, Galderma, Novartis, Sanofi Regeneron, and UCB; and an investigator for Amgen, Boehringer Ingelheim, and Incyte.

 

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

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

It was 1996, and Masashi Yanagisawa was on the brink of his next discovery.

The Japanese scientist had arrived at the University of Texas Southwestern in Dallas 5 years earlier, setting up his own lab at age 31. After earning his medical degree, he’d gained notoriety as a PhD student when he discovered endothelin, the body’s most potent vasoconstrictor.

Yanagisawa was about to prove this wasn’t a first-timer’s fluke.

His focus was G-protein–coupled receptors (GPCRs), cell surface receptors that respond to a range of molecules and a popular target for drug discovery. The Human Genome Project had just revealed a slew of newly discovered receptors, or “orphan” GPCRs, and identifying an activating molecule could yield a new drug. (That vasoconstrictor endothelin was one such success story, leading to four new drug approvals in the United States over the past quarter century.) 

Yanagisawa and his team created 50 cell lines, each expressing one orphan receptor. They applied animal tissue to every line, along with a calcium-sensitive dye. If the cells glowed under the microscope, they had a hit.

“He was basically doing an elaborate fishing expedition,” said Jon Willie, MD, PhD, an associate professor of neurosurgery at Washington University School of Medicine in St. Louis, Missouri, who would later join Yanagisawa’s team.

It wasn’t long before the neon-green fluorescence signaled a match. After isolating the activating molecule, the scientists realized they were dealing with two neuropeptides.

No one had ever seen these proteins before. And no one knew their discovery would set off a decades-long journey that would finally solve a century-old medical mystery — and may even fix one of the biggest health crises of our time, as revealed by research published earlier in 2024. It’s a story of strange coincidences, serendipitous discoveries, and quirky details. Most of all, it’s a fascinating example of how basic science can revolutionize medicine — and how true breakthroughs happen over time and in real time.

 

But That’s Basic Science for You

Most basic science studies — the early, foundational research that provides the building blocks for science that follows — don’t lead to medical breakthroughs. But some do, often in surprising ways.

Also called curiosity-driven research, basic science aims to fill knowledge gaps to keep science moving, even if the trajectory isn’t always clear.

“The people working on the basic research that led to discoveries that transformed the modern world had no idea at the time,” said Isobel Ronai, PhD, a postdoctoral fellow in life sciences at Harvard University, Cambridge, Massachusetts. “Often, these stories can only be seen in hindsight,” sometimes decades later.

Case in point: For molecular biology techniques — things like DNA sequencing and gene targeting — the lag between basic science and breakthrough is, on average, 23 years. While many of the resulting techniques have received Nobel Prizes, few of the foundational discoveries have been awarded such accolades.

“The scientific glory is more often associated with the downstream applications,” said Ronai. “The importance of basic research can get lost. But it is the foundation for any future application, such as drug development.”

As funding is increasingly funneled toward applied research, basic science can require a certain persistence. What this under-appreciation can obscure is the pathway to discovery — which is often as compelling as the end result, full of unpredictable twists, turns, and even interpersonal intrigue.

And then there’s the fascinating — and definitely complicated — phenomenon of multiple independent discoveries.

As in: What happens when two independent teams discover the same thing at the same time?

 

Back to Yanagisawa’s Lab ...

... where he and his team learned a few things about those new neuropeptides. Rat brain studies pinpointed the lateral hypothalamus as the peptides’ area of activity — a region often called the brain’s feeding center.

“If you destroy that part of the brain, animals lose appetite,” said Yanagisawa. So these peptides must control feeding, the scientists thought.

Sure enough, injecting the proteins into rat brains led the rodents to start eating.

Satisfied, the team named them “orexin-A” and “orexin-B,” for the Greek word “orexis,” meaning appetite. The brain receptors became “orexin-1” and “orexin-2.” The team prepared to publish its findings in Cell.

But another group beat them to it.

 

Introducing the ‘Hypocretins’

In early January 1998, a team of Scripps Research Institute scientists, led by J. Gregor Sutcliffe, PhD, released a paper in the journal PNAS. They described a gene encoding for the precursor to two neuropeptides

As the peptides were in the hypothalamus and structurally like secretin (a gut hormone), they called them “hypocretins.” The hypocretin peptides excited neurons in the hypothalamus, and later that year, the scientists discovered that the neurons’ branches extended, tentacle-like, throughout the brain. “Many of the connected areas were involved in sleep-wake control,” said Thomas Kilduff, PhD, who joined the Sutcliffe lab just weeks before the hypocretin discovery. At the time, however, the significance of this finding was not yet clear.

Weeks later, in February 1998, Yanagisawa’s paper came out.

Somehow, two groups, over 1000 miles apart, had stumbled on the same neuropeptides at the same time.

“I first heard about [Yanagisawa’s] paper on NBC Nightly News,” recalls Kilduff. “I was skiing in the mountains, so I had to wait until Monday to get back to the lab to see what the paper was all about.”

He realized that Yanagisawa’s orexin was his lab’s hypocretin, although the study didn’t mention another team’s discovery.

“There may have been accusations. But as far as I know, it’s because [Yanagisawa] didn’t know [about the other paper],” said Willie. “This was not something he produced in 2 months. This was clearly years of work.” 

 

‘Multiple Discovery’ Happens More Often Than You Think

In the mid-20th century, sociologist Robert Merton described the phenomenon of “multiple discovery,” where many scientific discoveries or inventions are made independently at roughly the same time.

“This happens much more frequently in scientific research than people suppose,” said David Pendlebury, head of research analysis at Clarivate’s Institute for Scientific Information, the analytics company’s research arm. (Last year, Pendlebury flagged the hypocretin/orexin discovery for Clarivate’s prestigious Citations Laureates award, an honor that aims to predict, often successfully, who will go on to win the Nobel Prize.) 

“People have this idea of the lone researcher making a brilliant discovery,” Pendlebury said. “But more and more, teams find things at the same time.” 

While this can — and does — lead to squabbling about who deserves credit, the desire to be first can also be highly motivating, said Mike Schneider, PhD, an assistant professor of philosophy at the University of Missouri, Columbia, who studies the social dynamics of science, potentially leading to faster scientific advancement.

The downside? If two groups produce the same or similar results, but one publishes first, scientific journals tend to reject the second, citing a lack of novelty.

Yet duplicating research is a key step in confirming the validity of a discovery.

That’s why, in 2018, the journal PLOS Biology created a provision for “scooped” scientists, allowing them to submit their paper within 6 months of the first as a complementary finding. Instead of viewing this as redundancy, the editors believe it adds robustness to the research.

 

‘What the Heck Is This Mouse Doing?’

Even though he’d been scooped, Yanagisawa forged on to the next challenge: Confirming whether orexin regulated feeding.

He began breeding mice missing the orexin gene. His team expected these “knockout” mice to eat less, resulting in a thinner body than other rodents. To the contrary, “they were on average fatter,” said Willie. “They were eating less but weighed more, indicating a slower metabolism.”

The researchers were befuddled. “We were really disappointed, almost desperate about what to do,” said Yanagisawa.

As nocturnal animals eat more at night, he decided they should study the mice after dark. One of his students, Richard Chemelli, MD, bought an infrared video camera from Radio Shack, filming the first 4 hours of the mice’s active period for several nights.

After watching the footage, “Rick called me and said, ‘Let’s get into the lab,’ ” said Willie. “It was four of us on a Saturday looking at these videos, saying, ‘What the heck is this mouse doing?’ ”

While exploring their habitat, the knockout mice would randomly fall over, pop back up after a minute or so, and resume normal activity. This happened over and over — and the scientists were unsure why.

They began monitoring the mice’s brains during these episodes — and made a startling discovery.

The mice weren’t having seizures. They were shifting directly into REM sleep, bypassing the non-REM stage, then quickly toggling back to wake mode.

“That’s when we knew these animals had something akin to narcolepsy,” said Willie.

The team recruited Thomas Scammell, MD, a Harvard neurologist, to investigate whether modafinil — an anti-narcoleptic drug without a clear mechanism — affected orexin neurons.

Two hours after injecting the mice with the medication, the scientists sacrificed them and stained their brains. Remarkably, the number of neurons showing orexin activity had increased ninefold. It seemed modafinil worked by activating the orexin system.

These findings had the potential to crack open the science of narcolepsy, one of the most mysterious sleep disorders.

Unless, of course, another team did it first.

 

The Mystery of Narcolepsy

Yet another multiple discovery, narcolepsy was first described by two scientists — one in Germany, the other in France — within a short span in the late 1800s.

It would be more than a hundred years before anyone understood the disorder’s cause, even though it affects about 1 in 2000 people.

“Patients were often labeled as lazy and malingerers,” said Kilduff, “since they were sleepy all the time and had this weird motor behavior called cataplexy” or the sudden loss of muscle tone.

In the early 1970s, William Dement, MD, PhD — “the father of sleep medicine” — was searching for a narcoleptic cat to study. He couldn’t find a feline, but several colleagues mentioned dogs with narcolepsy-like symptoms.

Dement, who died in 2020, had found his newest research subjects.

In 1973, he started a narcoleptic dog colony at Stanford University in Palo Alto, California. At first, he focused on poodles and beagles. After discovering their narcolepsy wasn’t genetic, he pivoted to dobermans and labradors. Their narcolepsy was inherited, so he could breed them to populate the colony.

Although human narcolepsy is rarely genetic, it’s otherwise a lot like the version in these dogs.

Both involve daytime sleepiness, “pathological” bouts of REM sleep, and the loss of muscle tone in response to emotions, often positive ones.

The researchers hoped the canines could unlock a treatment for human narcolepsy. They began laying out a path of dog kibble, then injecting the dogs with drugs such as selective serotonin reuptake inhibitors. They wanted to see what might help them stay awake as they excitedly chowed down.

Kilduff also started a molecular genetics program, trying to identify the genetic defect behind canine narcolepsy. But after a parvovirus outbreak, Kilduff resigned from the project, drained from the strain of seeing so many dogs die.

A decade after his departure from the dog colony, his work would dramatically intersect with that of his successor, Emmanuel Mignot, MD, PhD.

“I thought I had closed the narcolepsy chapter in my life forever,” said Kilduff. “Then in 1998, we described this novel neuropeptide, hypocretin, that turned out to be the key to understanding the disorder.”

 

Narcoleptic Dogs in California, Mutant Mice in Texas

It was modafinil — the same anti-narcoleptic drug Yanagisawa’s team studied — that brought Emmanuel Mignot to the United States. After training as a pharmacologist in France, his home country sent him to Stanford to study the drug, which was discovered by French scientists, as his required military service.

As Kilduff’s replacement at the dog colony, his goal was to figure out how modafinil worked, hoping to attract a US company to develop the drug.

The plan succeeded. Modafinil became Provigil, a billion-dollar narcolepsy drug, and Mignot became “completely fascinated” with the disorder.

“I realized quickly that there was no way we’d find the cause of narcolepsy by finding the mode of action of this drug,” Mignot said. “Most likely, the drug was acting downstream, not at the cause of the disorder.”

To discover the answer, he needed to become a geneticist. And so began his 11-year odyssey to find the cause of canine narcolepsy.

After mapping the dog genome, Mignot set out to find the smallest stretch of chromosome that the narcoleptic animals had in common. “For a very long time, we were stuck with a relatively large region [of DNA],” he recalls. “It was a no man’s land.” 

Within that region was the gene for the hypocretin/orexin-2 receptor — the same receptor that Yanagisawa had identified in his first orexin paper. Mignot didn’t immediately pursue that gene as a possibility — even though his students suggested it. Why?

“The decision was simply: Should we lose time to test a possible candidate [gene] among many?” Mignot said.

As Mignot studied dog DNA in California, Yanagisawa was creating mutant mice in Texas. Unbeknownst to either scientist, their work was about to converge.

 

What Happened Next Is Somewhat Disputed 

After diagnosing his mice with narcolepsy, Yanagisawa opted not to share this finding with Mignot, though he knew about Mignot’s interest in the condition. Instead, he asked a colleague to find out how far along Mignot was in his genetics research.

According to Yanagisawa, his colleague didn’t realize how quickly DNA sequencing could happen once a target gene was identified. At a sleep meeting, “he showed Emmanuel all of our raw data. Almost accidentally, he disclosed our findings,” he said. “It was a shock for me.” 

Unsure whether he was part of the orexin group, Mignot decided not to reveal that he’d identified the hypocretin/orexin-2 receptor gene as the faulty one in his narcoleptic dogs.

Although he didn’t share this finding, Mignot said he did offer to speak with the lead researcher to see if their findings were the same. If they were, they could jointly submit their articles. But Mignot never heard back.

Meanwhile, back at his lab, Mignot buckled down. While he wasn’t convinced the mouse data proved anything, it did give him the motivation to move faster.

Within weeks, he submitted his findings to Cell, revealing a mutation in the hypocretin/orexin-2 receptor gene as the cause of canine narcolepsy. According to Yanagisawa, the journal’s editor invited him to peer-review the paper, tipping him off to its existence.

“I told him I had a conflict of interest,” said Yanagisawa. “And then we scrambled to finish our manuscript. We wrote up the paper within almost 5 days.”

For a moment, it seemed both papers would be published together in Cell. Instead, on August 6, 1999, Mignot’s study was splashed solo across the journal’s cover.

“At the time, our team was pissed off, but looking back, what else could Emmanuel have done?” said Willie, who was part of Yanagisawa’s team. “The grant he’d been working on for years was at risk. He had it within his power to do the final experiments. Of course he was going to finish.”

Two weeks later, Yanagisawa’s findings followed, also in Cell.

His paper proposed knockout mice as a model for human narcolepsy and orexin as a key regulator of the sleep/wake cycle. With orexin-activated neurons branching into other areas of the brain, the peptide seemed to promote wakefulness by synchronizing several arousal neurotransmitters, such as serotonin, norepinephrine, and histamine.

“If you don’t have orexin, each of those systems can still function, but they’re not as coordinated,” said Willie. “If you have narcolepsy, you’re capable of wakefulness, and you’re capable of sleep. What you can’t do is prevent inappropriately switching between states.”

Together, the two papers painted a clear picture: Narcolepsy was the result of a dysfunction in the hypocretin/orexin system.

After more than a century, the cause of narcolepsy was starting to come into focus.

“This was blockbuster,” said Willie.

By itself, either finding — one in dogs, one in mice — might have been met with skepticism. But in combination, they offered indisputable evidence about narcolepsy’s cause.

 

The Human Brains in Your Fridge Hold Secrets

Jerome Siegel had been searching for the cause of human narcolepsy for years. A PhD and professor at the University of California, Los Angeles, he had managed to acquire four human narcoleptic brains. As laughter is often the trigger for the sudden shift to REM sleep in humans, he focused on the amygdala, an area linked to emotion.

“I looked in the amygdala and didn’t see anything,” he said. “So the brains stayed in my refrigerator for probably 10 years.” 

Then he was invited to review Yanagisawa’s study in Cell. The lightbulb clicked on: Maybe the hypothalamus — not the amygdala — was the area of abnormality. He and his team dug out the decade-old brains.

When they stained the brains, the massive loss of hypocretin-activated neurons was hard to miss: On average, the narcoleptic brains had only about 7000 of the cells versus 70,000 in the average human brain. The scientists also noticed scar tissue in the hypothalamus, indicating that the neurons had at some point died, rather than being absent from birth.

What Siegel didn’t know: Mignot had also acquired a handful of human narcoleptic brains.

Already, he had coauthored a study showing that hypocretin/orexin was undetectable in the cerebrospinal fluid of the majority of the people with narcolepsy his team tested. It seemed clear that the hypocretin/orexin system was flawed — or even broken — in people with the condition.

“It looked like the cause of narcolepsy in humans was indeed this lack of orexin in the brain,” he said. “That was the hypothesis immediately. To me, this is when we established that narcolepsy in humans was due to a lack of orexin. The next thing was to check that the cells were missing.” 

Now he could do exactly that.

As expected, Mignot’s team observed a dramatic loss of hypocretin/orexin cells in the narcoleptic brains. They also noticed that a different cell type in the hypothalamus was unaffected. This implied the damage was specific to the hypocretin-activated cells and supported a hunch they already had: That the deficit was the result not of a genetic defect but of an autoimmune attack. (It’s a hypothesis Mignot has spent the last 15 years proving.)

It wasn’t until a gathering in Hawaii, in late August 2000, that the two realized the overlap of their work.

To celebrate his team’s finding, Mignot had invited a group of researchers to Big Island. With his paper scheduled for publication on September 1, he felt comfortable presenting his findings to his guests, which included Siegel.

Until then, “I didn’t know what he had found, and he didn’t know what I had found, which basically was the same thing,” said Siegel.

In yet another strange twist, the two papers were published just weeks apart, simultaneously revealing that human narcoleptics have a depleted supply of the neurons that bind to hypocretin/orexin. The cause of the disorder was at last a certainty.

“Even if I was first, what does it matter? In the end, you need confirmation,” said Mignot. “You need multiple people to make sure that it’s true. It’s good science when things like this happen.”

 

How All of This Changed Medicine

Since these groundbreaking discoveries, the diagnosis of narcolepsy has become much simpler. Lab tests can now easily measure hypocretin in cerebrospinal fluid, providing a definitive diagnosis.

But the development of narcolepsy treatments has lagged — even though hypocretin/orexin replacement therapy is the obvious answer.

“Almost 25 years have elapsed, and there’s no such therapeutic on the market,” said Kilduff, who now works for SRI International, a non-profit research and development institute.

That’s partly because agonists — drugs that bind to receptors in the brain — are challenging to create, as this requires mimicking the activating molecule’s structure, like copying the grooves of an intricate key.

Antagonists, by comparison, are easier to develop. These act as a gate, blocking access to the receptors. As a result, drugs that promote sleep by thwarting hypocretin/orexin have emerged more quickly, providing a flurry of new options for people with insomnia. The first, suvorexant, was launched in 2014. Two others followed in recent years.

Researchers are hopeful a hypocretin/orexin agonist is on the horizon.

“This is a very hot area of drug development,” said Kilduff. “It’s just a matter of who’s going to get the drug to market first.”

 

One More Hypocretin/Orexin Surprise — and It Could Be The Biggest

Several years ago, Siegel’s lab received what was supposed to be a healthy human brain — one they could use as a comparison for narcoleptic brains. But researcher Thomas Thannickal, PhD, lead author of the UCLA study linking hypocretin loss to human narcolepsy, noticed something strange: This brain had significantly more hypocretin neurons than average.

Was this due to a seizure? A traumatic death? Siegel called the brain bank to request the donor’s records. He was told they were missing.

Years later, Siegel happened to be visiting the brain bank for another project and found himself in a room adjacent to the medical records. “Nobody was there,” he said, “so I just opened a drawer.”

Shuffling through the brain bank’s files, Siegel found the medical records he’d been told were lost. In the file was a note from the donor, explaining that he was a former heroin addict.

“I almost fell out of my chair,” said Siegel. “I realized this guy’s heroin addiction likely had something to do with his very unusual brain.” 

Obviously, opioids affected the orexin system. But how? 

“It’s when people are happy that this peptide is released,” said Siegel. “The hypocretin system is not just related to alertness. It’s related to pleasure.” 

As Yanagisawa observed early on, hypocretin/orexin does indeed play a role in eating — just not the one he initially thought. The peptides prompted pleasure seeking. So the rodents ate. 

In 2018, after acquiring five more brains, Siegel’s group published a study in Translational Medicine showing 54% more detectable hypocretin neurons in the brains of heroin addicts than in those of control individuals.

In 2022, another breakthrough: His team showed that morphine significantly altered the pathways of hypocretin neurons in mice, sending their axons into brain regions associated with addiction. Then, when they removed the mice’s hypocretin neurons and discontinued their daily morphine dose, the rodents showed no symptoms of opioid withdrawal.

This fits the connection with narcolepsy: Among the standard treatments for the condition are amphetamines and other stimulants, which all have addictive potential. Yet, “narcoleptics never abuse these drugs,” Siegel said. “They seem to be uniquely resistant to addiction.”

This could powerfully change the way opioids are administered.

“If you prevent the hypocretin response to opioids, you may be able to prevent opioid addiction,” said Siegel. In other words, blocking the hypocretin system with a drug like those used to treat insomnia may allow patients to experience the pain-relieving benefits of opioids — without the risk for addiction.

His team is currently investigating treatments targeting the hypocretin/orexin system for opioid addiction.

In a study published in July, they found that mice who received suvorexant — the drug for insomnia — didn’t anticipate their daily dose of opioids the way other rodents did. This suggests the medication prevented addiction, without diminishing the pain-relieving effect of opioids.

If it translates to humans, this discovery could potentially save millions of lives.

“I think it’s just us working on this,” said Siegel.

But with hypocretin/orexin, you never know.

A version of this article appeared on Medscape.com.

TOPLINE:

The use of semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), is not associated with an increased risk for nonarteritic anterior ischemic optic neuropathy (NAION) in patients with type 2 diabetes, obesity, or both conditions.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the TriNetX Analytics Network to investigate the potential risk for NAION associated with semaglutide use in a broader population worldwide.
• They included Caucasians aged ≥ 18 years with only type 2 diabetes (n = 37,245) , only obesity (n = 138,391), or both (n = 64,989) who visited healthcare facilities three or more times.
• The participants were further grouped into those prescribed semaglutide and those using non–GLP-1 RA medications.
• Propensity score matching was performed to balance age, sex, body mass index, A1C levels, medications, and underlying comorbidities between the participants using semaglutide or non–GLP-1 RAs.
• The main outcome measure was the occurrence of NAION, evaluated at 1, 2, and 3 years of follow-up.

TAKEAWAY:

• The use of semaglutide vs non–GLP-1 RAs was not associated with an increased risk for NAION in people with only type 2 diabetes during the 1-year (hazard ratio [HR], 2.32; 95% CI, 0.60-8.97), 2-year (HR, 2.31; 95% CI, 0.86-6.17), and 3-year (HR, 1.51; 0.71-3.25) follow-up periods.
• Similarly, in the obesity-only cohort, use of semaglutide was not linked to the development of NAION across 1-year (HR, 0.41; 95% CI, 0.08-2.09), 2-year (HR, 0.67; 95% CI, 0.20-2.24), and 3-year (HR, 0.72; 95% CI, 0.24-2.17) follow-up periods.
• The patients with both diabetes and obesity also showed no significant association between use of semaglutide and the risk for NAION across each follow-up period.
• Sensitivity analysis confirmed the prescription of semaglutide was not associated with an increased risk for NAION compared with non–GLP-1 RA medications.

IN PRACTICE:

“Our large, multinational, population-based, real-world study found that semaglutide is not associated with an increased risk of NAION in the general population,” the authors of the study wrote.

SOURCE:

The study was led by Chien-Chih Chou, MD, PhD, of National Yang Ming Chiao Tung University, in Taipei City, Taiwan, and was published online on November 02, 2024, in Ophthalmology.

LIMITATIONS:

The retrospective nature of the study may have limited the ability to establish causality between the use of semaglutide and the risk for NAION. The reliance on diagnosis coding for NAION may have introduced a potential misclassification of cases. Moreover, approximately half of the healthcare organizations in the TriNetX network are based in the United States, potentially limiting the diversity of the data.

DISCLOSURES:

This study was supported by a grant from Taichung Veterans General Hospital. The authors declared no potential conflicts of interest.

 

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 appeared on Medscape.com.

TOPLINE:

The use of semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), is not associated with an increased risk for nonarteritic anterior ischemic optic neuropathy (NAION) in patients with type 2 diabetes, obesity, or both conditions.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the TriNetX Analytics Network to investigate the potential risk for NAION associated with semaglutide use in a broader population worldwide.
• They included Caucasians aged ≥ 18 years with only type 2 diabetes (n = 37,245) , only obesity (n = 138,391), or both (n = 64,989) who visited healthcare facilities three or more times.
• The participants were further grouped into those prescribed semaglutide and those using non–GLP-1 RA medications.
• Propensity score matching was performed to balance age, sex, body mass index, A1C levels, medications, and underlying comorbidities between the participants using semaglutide or non–GLP-1 RAs.
• The main outcome measure was the occurrence of NAION, evaluated at 1, 2, and 3 years of follow-up.

TAKEAWAY:

• The use of semaglutide vs non–GLP-1 RAs was not associated with an increased risk for NAION in people with only type 2 diabetes during the 1-year (hazard ratio [HR], 2.32; 95% CI, 0.60-8.97), 2-year (HR, 2.31; 95% CI, 0.86-6.17), and 3-year (HR, 1.51; 0.71-3.25) follow-up periods.
• Similarly, in the obesity-only cohort, use of semaglutide was not linked to the development of NAION across 1-year (HR, 0.41; 95% CI, 0.08-2.09), 2-year (HR, 0.67; 95% CI, 0.20-2.24), and 3-year (HR, 0.72; 95% CI, 0.24-2.17) follow-up periods.
• The patients with both diabetes and obesity also showed no significant association between use of semaglutide and the risk for NAION across each follow-up period.
• Sensitivity analysis confirmed the prescription of semaglutide was not associated with an increased risk for NAION compared with non–GLP-1 RA medications.

IN PRACTICE:

“Our large, multinational, population-based, real-world study found that semaglutide is not associated with an increased risk of NAION in the general population,” the authors of the study wrote.

SOURCE:

The study was led by Chien-Chih Chou, MD, PhD, of National Yang Ming Chiao Tung University, in Taipei City, Taiwan, and was published online on November 02, 2024, in Ophthalmology.

LIMITATIONS:

The retrospective nature of the study may have limited the ability to establish causality between the use of semaglutide and the risk for NAION. The reliance on diagnosis coding for NAION may have introduced a potential misclassification of cases. Moreover, approximately half of the healthcare organizations in the TriNetX network are based in the United States, potentially limiting the diversity of the data.

DISCLOSURES:

This study was supported by a grant from Taichung Veterans General Hospital. The authors declared no potential conflicts of interest.

 

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 appeared on Medscape.com.

TOPLINE:

The use of semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1 RA), is not associated with an increased risk for nonarteritic anterior ischemic optic neuropathy (NAION) in patients with type 2 diabetes, obesity, or both conditions.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the TriNetX Analytics Network to investigate the potential risk for NAION associated with semaglutide use in a broader population worldwide.
• They included Caucasians aged ≥ 18 years with only type 2 diabetes (n = 37,245) , only obesity (n = 138,391), or both (n = 64,989) who visited healthcare facilities three or more times.
• The participants were further grouped into those prescribed semaglutide and those using non–GLP-1 RA medications.
• Propensity score matching was performed to balance age, sex, body mass index, A1C levels, medications, and underlying comorbidities between the participants using semaglutide or non–GLP-1 RAs.
• The main outcome measure was the occurrence of NAION, evaluated at 1, 2, and 3 years of follow-up.

TAKEAWAY:

• The use of semaglutide vs non–GLP-1 RAs was not associated with an increased risk for NAION in people with only type 2 diabetes during the 1-year (hazard ratio [HR], 2.32; 95% CI, 0.60-8.97), 2-year (HR, 2.31; 95% CI, 0.86-6.17), and 3-year (HR, 1.51; 0.71-3.25) follow-up periods.
• Similarly, in the obesity-only cohort, use of semaglutide was not linked to the development of NAION across 1-year (HR, 0.41; 95% CI, 0.08-2.09), 2-year (HR, 0.67; 95% CI, 0.20-2.24), and 3-year (HR, 0.72; 95% CI, 0.24-2.17) follow-up periods.
• The patients with both diabetes and obesity also showed no significant association between use of semaglutide and the risk for NAION across each follow-up period.
• Sensitivity analysis confirmed the prescription of semaglutide was not associated with an increased risk for NAION compared with non–GLP-1 RA medications.

IN PRACTICE:

“Our large, multinational, population-based, real-world study found that semaglutide is not associated with an increased risk of NAION in the general population,” the authors of the study wrote.

SOURCE:

The study was led by Chien-Chih Chou, MD, PhD, of National Yang Ming Chiao Tung University, in Taipei City, Taiwan, and was published online on November 02, 2024, in Ophthalmology.

LIMITATIONS:

The retrospective nature of the study may have limited the ability to establish causality between the use of semaglutide and the risk for NAION. The reliance on diagnosis coding for NAION may have introduced a potential misclassification of cases. Moreover, approximately half of the healthcare organizations in the TriNetX network are based in the United States, potentially limiting the diversity of the data.

DISCLOSURES:

This study was supported by a grant from Taichung Veterans General Hospital. The authors declared no potential conflicts of interest.

 

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 appeared on Medscape.com.

TOPLINE:

Consumption of ultraprocessed foods (UPFs), such as carbonated drinks, processed meats, and sweet or savory packaged snacks, is associated with accelerated biological aging, as measured by 36 blood-based biomarkers, and factors other than poor nutritional content may be to blame.

METHODOLOGY:

• Previous studies have reported an association between high consumption of UPFs and some measures of early biological aging, such as shorter telomere length, cognitive decline, and frailty, but the relationship is largely unexplored so far, including exactly how UPFs may harm health.
• To examine the association between UPF consumption and biological aging, researchers conducted a cross-sectional analysis of 22,495 participants (mean chronological age, 55.6 years; 52% women) from the Moli-sani Study in Italy, who were recruited between 2005 and 2010.
• Food intake was assessed with a food frequency questionnaire that covered 188 different food items, each of which was categorized into one of four groups based on the extent of processing, ranging from minimally processed foods, such as fruits, vegetables, meat and fish, to UPFs.
• UPF intake was determined by weight, using the ratio of UPFs to the total weight of food and beverages (g/d), and participants were categorized into sex-specific fifths according to the proportion of UPFs in their total food intake. Diet quality was also evaluated using the Mediterranean Diet Score.
• Biological age was computed using a deep neural network approach based on 36 circulating blood biomarkers, and the mean difference between the mean biological and chronological ages was analyzed.

TAKEAWAY:

• The mean difference between biological and chronological ages of the participants was –0.70 years.
• Higher intake of UPFs was associated with accelerated biological aging compared with the lowest intake (regression coefficient, 0.34; 95% CI, 0.08-0.61), with a mean difference between the biological and chronological ages of −4.1 years and 1.6 years in those with the lowest and highest intakes, respectively.
• The association between UPF consumption and biological aging was nonlinear (P = .049 for nonlinearity). The association tended to be stronger in men than in women, but this was not statistically significant.
• Including the Mediterranean Diet Score in the model slightly attenuated the association by 9.1%, indicating that poor nutritional content was likely to explain a small part of the underlying mechanism.

IN PRACTICE:

“Our results showed that the UPFs–biological aging association was weakly explained by the poor nutritional composition of these highly processed foods, suggesting that biological aging could be mainly influenced by non-nutrient food characteristics, which include altered food matrix, contact materials and neo-formed compounds,” the authors wrote.

 

SOURCE:

The study was led by Simona Esposito, Research Unit of Epidemiology and Prevention, IRCCS Neuromed, Isernia, Italy. It was published online in The American Journal of Clinical Nutrition.

 

LIMITATIONS:

The cross-sectional design of the study limited the ability to determine the temporal directionality of the association, and the observational nature of the study limited the ability to establish the causality between UPF consumption and biological aging. The use of self-reported dietary data may have introduced recall bias. The study population was limited to adults from Central-Southern Italy, which may affect the generalizability of the findings.

 

DISCLOSURES:

The study was developed within the project funded by the Next Generation European Union “Age-It — Ageing well in an ageing society” project, National Recovery and Resilience Plan. The analyses were partially supported by the Italian Ministry of Health. The authors declared no conflicts of interest.

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 appeared on Medscape.com.

TOPLINE:

Consumption of ultraprocessed foods (UPFs), such as carbonated drinks, processed meats, and sweet or savory packaged snacks, is associated with accelerated biological aging, as measured by 36 blood-based biomarkers, and factors other than poor nutritional content may be to blame.

METHODOLOGY:

• Previous studies have reported an association between high consumption of UPFs and some measures of early biological aging, such as shorter telomere length, cognitive decline, and frailty, but the relationship is largely unexplored so far, including exactly how UPFs may harm health.
• To examine the association between UPF consumption and biological aging, researchers conducted a cross-sectional analysis of 22,495 participants (mean chronological age, 55.6 years; 52% women) from the Moli-sani Study in Italy, who were recruited between 2005 and 2010.
• Food intake was assessed with a food frequency questionnaire that covered 188 different food items, each of which was categorized into one of four groups based on the extent of processing, ranging from minimally processed foods, such as fruits, vegetables, meat and fish, to UPFs.
• UPF intake was determined by weight, using the ratio of UPFs to the total weight of food and beverages (g/d), and participants were categorized into sex-specific fifths according to the proportion of UPFs in their total food intake. Diet quality was also evaluated using the Mediterranean Diet Score.
• Biological age was computed using a deep neural network approach based on 36 circulating blood biomarkers, and the mean difference between the mean biological and chronological ages was analyzed.

TAKEAWAY:

• The mean difference between biological and chronological ages of the participants was –0.70 years.
• Higher intake of UPFs was associated with accelerated biological aging compared with the lowest intake (regression coefficient, 0.34; 95% CI, 0.08-0.61), with a mean difference between the biological and chronological ages of −4.1 years and 1.6 years in those with the lowest and highest intakes, respectively.
• The association between UPF consumption and biological aging was nonlinear (P = .049 for nonlinearity). The association tended to be stronger in men than in women, but this was not statistically significant.
• Including the Mediterranean Diet Score in the model slightly attenuated the association by 9.1%, indicating that poor nutritional content was likely to explain a small part of the underlying mechanism.

IN PRACTICE:

“Our results showed that the UPFs–biological aging association was weakly explained by the poor nutritional composition of these highly processed foods, suggesting that biological aging could be mainly influenced by non-nutrient food characteristics, which include altered food matrix, contact materials and neo-formed compounds,” the authors wrote.

 

SOURCE:

The study was led by Simona Esposito, Research Unit of Epidemiology and Prevention, IRCCS Neuromed, Isernia, Italy. It was published online in The American Journal of Clinical Nutrition.

 

LIMITATIONS:

The cross-sectional design of the study limited the ability to determine the temporal directionality of the association, and the observational nature of the study limited the ability to establish the causality between UPF consumption and biological aging. The use of self-reported dietary data may have introduced recall bias. The study population was limited to adults from Central-Southern Italy, which may affect the generalizability of the findings.

 

DISCLOSURES:

The study was developed within the project funded by the Next Generation European Union “Age-It — Ageing well in an ageing society” project, National Recovery and Resilience Plan. The analyses were partially supported by the Italian Ministry of Health. The authors declared no conflicts of interest.

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 appeared on Medscape.com.

TOPLINE:

Consumption of ultraprocessed foods (UPFs), such as carbonated drinks, processed meats, and sweet or savory packaged snacks, is associated with accelerated biological aging, as measured by 36 blood-based biomarkers, and factors other than poor nutritional content may be to blame.

METHODOLOGY:

• Previous studies have reported an association between high consumption of UPFs and some measures of early biological aging, such as shorter telomere length, cognitive decline, and frailty, but the relationship is largely unexplored so far, including exactly how UPFs may harm health.
• To examine the association between UPF consumption and biological aging, researchers conducted a cross-sectional analysis of 22,495 participants (mean chronological age, 55.6 years; 52% women) from the Moli-sani Study in Italy, who were recruited between 2005 and 2010.
• Food intake was assessed with a food frequency questionnaire that covered 188 different food items, each of which was categorized into one of four groups based on the extent of processing, ranging from minimally processed foods, such as fruits, vegetables, meat and fish, to UPFs.
• UPF intake was determined by weight, using the ratio of UPFs to the total weight of food and beverages (g/d), and participants were categorized into sex-specific fifths according to the proportion of UPFs in their total food intake. Diet quality was also evaluated using the Mediterranean Diet Score.
• Biological age was computed using a deep neural network approach based on 36 circulating blood biomarkers, and the mean difference between the mean biological and chronological ages was analyzed.

TAKEAWAY:

• The mean difference between biological and chronological ages of the participants was –0.70 years.
• Higher intake of UPFs was associated with accelerated biological aging compared with the lowest intake (regression coefficient, 0.34; 95% CI, 0.08-0.61), with a mean difference between the biological and chronological ages of −4.1 years and 1.6 years in those with the lowest and highest intakes, respectively.
• The association between UPF consumption and biological aging was nonlinear (P = .049 for nonlinearity). The association tended to be stronger in men than in women, but this was not statistically significant.
• Including the Mediterranean Diet Score in the model slightly attenuated the association by 9.1%, indicating that poor nutritional content was likely to explain a small part of the underlying mechanism.

IN PRACTICE:

“Our results showed that the UPFs–biological aging association was weakly explained by the poor nutritional composition of these highly processed foods, suggesting that biological aging could be mainly influenced by non-nutrient food characteristics, which include altered food matrix, contact materials and neo-formed compounds,” the authors wrote.

 

SOURCE:

The study was led by Simona Esposito, Research Unit of Epidemiology and Prevention, IRCCS Neuromed, Isernia, Italy. It was published online in The American Journal of Clinical Nutrition.

 

LIMITATIONS:

The cross-sectional design of the study limited the ability to determine the temporal directionality of the association, and the observational nature of the study limited the ability to establish the causality between UPF consumption and biological aging. The use of self-reported dietary data may have introduced recall bias. The study population was limited to adults from Central-Southern Italy, which may affect the generalizability of the findings.

 

DISCLOSURES:

The study was developed within the project funded by the Next Generation European Union “Age-It — Ageing well in an ageing society” project, National Recovery and Resilience Plan. The analyses were partially supported by the Italian Ministry of Health. The authors declared no conflicts of interest.

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 appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, told this news organization.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other anti-osteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (–0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (–3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

 

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including 2 who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

 

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told this news organization.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati, Ohio.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

 

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Denmark, who was a coauthor on the ECTS position statement, told this news organization that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

 

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added, however, that other reasons for discontinuing denosumab “are not due to ‘need’ but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told this news organization.

“There is a high need to discuss risk versus benefits toward a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.

A version of this article appeared on Medscape.com.

WASHINGTON — An implantable vagus nerve stimulation (VNS) device effectively treats moderate to severe rheumatoid arthritis (RA) in patients who had previously failed at least one biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD), according to results from a phase 3 trial.

Of the 242 patients in the RESET-RA study, all received the VNS device implant but were blinded as to whether the device was turned on. At 12 weeks, 35.2% of patients receiving daily stimulation achieved 20% improvement in American College of Rheumatology response criteria (ACR20) compared with 24.2% of those with an inactive device. The response was more pronounced among patients with exposure to only one prior b/tsDMARD. A greater proportion of patients in the overall treatment group also reached low disease activity or remission compared with those who did not receive stimulation. 

The research was presented as a late-breaking poster at the ACR 2024 Annual Meeting.

“This is a particularly tough-to-treat patient population, since the patients enrolled were considered refractory to biologic therapy,” said Elena Schiopu, MD, professor of medicine in the Division of Rheumatology and director of clinical trials at the Medical College of Georgia at Augusta University. More than one third of patients in the study had tried three or more b/tsDMARDs prior to the study. “I’m pretty excited about these results,” she added. Schiopu was a RESET-RA institutional principal investigator and enrolled two patients in the trial.

These positive results are a first for VNS treatment in rheumatic diseases. Previous studies demonstrating the potential therapeutic effect of this implant approach have largely been open-label, proof-of-concept, or pilot studies. Noninvasive, wearable stimulation devices have also shown promise in open-label studies; however, a sham-controlled trial published in 2023 showed that transcutaneous vagus nerve stimulation on the ear was no more effective than placebo. 

 

But How Does It Work?

The device, developed by SetPoint Medical in Valencia, California, is about the size of a multivitamin and implanted in an outpatient setting. During the 45-minute procedure, surgeons isolate the vagus nerve on the left side of the neck and place the nerve stimulator with a silicone positioning pod to hold it in place.

The device is programmed to deliver stimulation for 1 minute every day and needs charging for only 10 minutes once a week, which is done remotely with a necklace.

The device takes advantage of the vagus nerve’s anti-inflammatory properties, stimulating the nerve to help regulate an overactive immune system of someone with RA, explained David Chernoff, MD, Setpoint Medical’s chief medical officer. 

“We’re recapitulating what nature has developed over millions of years, which is the nexus between the brain and the immune system, which happens to be mediated by the vagus nerve,” he told Medscape Medical News. 

This novel VNS approach also does not have the same immunosuppressive safety concerns as drugs commonly used to treat RA, he said. 

“We’re able to adjust the amount of inflammation, but we don’t cause the host defense issues” that are present with some of these drugs, he continued.

SetPoint Medical’s pilot study of the device in 14 patients showed promising results. Five of 10 patients randomly assigned to active VNS over 12 weeks showed clinical improvements, measured by 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index. In the remaining four patients who received sham stimulation — where the device was implanted but not activated — there were no clinical disease improvements.

 

RESET-RA Details

The most recent, much larger phase 3 study enrolled patients from 41 sites in the United States. Patients were on average 56 years old and had a body mass index of 30; 86% were women. A total of 39% had previously tried one b/tsDMARD, 22% had tried two, and 39% had tried three or more. Patients, on average, had 15 tender joints and 10 swollen joints. Patients discontinued their prior b/tsDMARD before the procedure and remained on conventional DMARDS during the trial, including methotrexate, hydroxychloroquine, and sulfasalazine.

The researchers randomly assigned patients 1:1 to active (treatment) or nonactive (control) stimulation. 

“The perception of stimulation varies from patient to patient, which itself is helpful in blinding as there is no expected perception of whether or how stimulation will be felt,” Chernoff explained. The 1-minute stimulation was scheduled in the early hours of the morning, when a patient typically would be asleep, he said.

Patients were excluded from the analysis if they were rescued by steroids or b/tsDMARDs through week 12. After week 12, the control group was switched to stimulation and efficacy was reassessed at week 24.

 

Higher ACR20 Response Rate, Lower Disease Activity

Beyond meeting the primary endpoint of ACR20 response, patients on the active stimulation group showed lower disease activity at week 12. Compared with 15.8% of patients in the control group, 27% of those in the treatment group achieved a DAS28-CRP ≤ 3.2. 

The active stimulation was particularly effective in patients who had experience with only one prior b/tsDMARD. In this subset of patients, 44.2% in the treatment group achieved ACR20 compared with 19.0% in the control group.

During this sham-controlled trial period, 13.1% of patients in the treatment group and 18.3% of patients in the control group reported an adverse event (AE) related to the procedure or device, most commonly vocal cord paresis or dysphonia. In the treatment group, 8.2% reported stimulation-related AEs, most commonly mild/moderate pain that was managed by adjusting the stimulation level. 

Serious adverse events (SAEs) were relatively rare, with four treatment-related SAEs across both study groups. No AEs led to study discontinuation through week 24.

The 12-week results mirror those of the initial Humira and Enbrel trials in the late 1990s and early 2000s, Schiopu said, although in those trials, the patients were naive to biologics, and some were naive to methotrexate. A more appropriate comparison, she said, would be biologic-experienced populations.

At week 24, the percentage of patients achieving ACR20 further increased to 51.5% in the treatment group and to 53.1% in the previous control group who were now crossed over to active stimulation. In this secondary period, patients could add any additional therapies like steroids or b/tsDMARDs. At 24 weeks, 81% of patients remained on stimulation without needing additional medication, beyond their continued background DMARDs. 

The results also show “a continuum of improvement over time,” Schiopu said, where response rates climbed through week 24. 

Schiopu is particularly excited about the potential to use this stimulation device in older patients, who have perhaps been on immunosuppressant drugs for decades. 

“Aside from being chronically immunosuppressed, their immune system is more tired [due to age],” she said. With VNS therapies like SetPoint’s, “we could offer [these patients] a lesser immunosuppressive alternative that is still immune-modular enough to manage their RA.”

Schiopu is a consultant for Johnson & Johnson and reported receiving research funding for serving as an institutional principal investigator for SetPoint, Galapagos, Johnson & Johnson, Boehringer Ingelheim, Lilly, argenx, EMD Serono, Priovant, Novartis, Bristol Myers Squibb, Zena Pharmaceuticals, and Horizon/Amgen.

 

A version of this article appeared on Medscape.com.

WASHINGTON — An implantable vagus nerve stimulation (VNS) device effectively treats moderate to severe rheumatoid arthritis (RA) in patients who had previously failed at least one biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD), according to results from a phase 3 trial.

Of the 242 patients in the RESET-RA study, all received the VNS device implant but were blinded as to whether the device was turned on. At 12 weeks, 35.2% of patients receiving daily stimulation achieved 20% improvement in American College of Rheumatology response criteria (ACR20) compared with 24.2% of those with an inactive device. The response was more pronounced among patients with exposure to only one prior b/tsDMARD. A greater proportion of patients in the overall treatment group also reached low disease activity or remission compared with those who did not receive stimulation. 

The research was presented as a late-breaking poster at the ACR 2024 Annual Meeting.

“This is a particularly tough-to-treat patient population, since the patients enrolled were considered refractory to biologic therapy,” said Elena Schiopu, MD, professor of medicine in the Division of Rheumatology and director of clinical trials at the Medical College of Georgia at Augusta University. More than one third of patients in the study had tried three or more b/tsDMARDs prior to the study. “I’m pretty excited about these results,” she added. Schiopu was a RESET-RA institutional principal investigator and enrolled two patients in the trial.

These positive results are a first for VNS treatment in rheumatic diseases. Previous studies demonstrating the potential therapeutic effect of this implant approach have largely been open-label, proof-of-concept, or pilot studies. Noninvasive, wearable stimulation devices have also shown promise in open-label studies; however, a sham-controlled trial published in 2023 showed that transcutaneous vagus nerve stimulation on the ear was no more effective than placebo. 

 

But How Does It Work?

The device, developed by SetPoint Medical in Valencia, California, is about the size of a multivitamin and implanted in an outpatient setting. During the 45-minute procedure, surgeons isolate the vagus nerve on the left side of the neck and place the nerve stimulator with a silicone positioning pod to hold it in place.

The device is programmed to deliver stimulation for 1 minute every day and needs charging for only 10 minutes once a week, which is done remotely with a necklace.

The device takes advantage of the vagus nerve’s anti-inflammatory properties, stimulating the nerve to help regulate an overactive immune system of someone with RA, explained David Chernoff, MD, Setpoint Medical’s chief medical officer. 

“We’re recapitulating what nature has developed over millions of years, which is the nexus between the brain and the immune system, which happens to be mediated by the vagus nerve,” he told Medscape Medical News. 

This novel VNS approach also does not have the same immunosuppressive safety concerns as drugs commonly used to treat RA, he said. 

“We’re able to adjust the amount of inflammation, but we don’t cause the host defense issues” that are present with some of these drugs, he continued.

SetPoint Medical’s pilot study of the device in 14 patients showed promising results. Five of 10 patients randomly assigned to active VNS over 12 weeks showed clinical improvements, measured by 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index. In the remaining four patients who received sham stimulation — where the device was implanted but not activated — there were no clinical disease improvements.

 

RESET-RA Details

The most recent, much larger phase 3 study enrolled patients from 41 sites in the United States. Patients were on average 56 years old and had a body mass index of 30; 86% were women. A total of 39% had previously tried one b/tsDMARD, 22% had tried two, and 39% had tried three or more. Patients, on average, had 15 tender joints and 10 swollen joints. Patients discontinued their prior b/tsDMARD before the procedure and remained on conventional DMARDS during the trial, including methotrexate, hydroxychloroquine, and sulfasalazine.

The researchers randomly assigned patients 1:1 to active (treatment) or nonactive (control) stimulation. 

“The perception of stimulation varies from patient to patient, which itself is helpful in blinding as there is no expected perception of whether or how stimulation will be felt,” Chernoff explained. The 1-minute stimulation was scheduled in the early hours of the morning, when a patient typically would be asleep, he said.

Patients were excluded from the analysis if they were rescued by steroids or b/tsDMARDs through week 12. After week 12, the control group was switched to stimulation and efficacy was reassessed at week 24.

 

Higher ACR20 Response Rate, Lower Disease Activity

Beyond meeting the primary endpoint of ACR20 response, patients on the active stimulation group showed lower disease activity at week 12. Compared with 15.8% of patients in the control group, 27% of those in the treatment group achieved a DAS28-CRP ≤ 3.2. 

The active stimulation was particularly effective in patients who had experience with only one prior b/tsDMARD. In this subset of patients, 44.2% in the treatment group achieved ACR20 compared with 19.0% in the control group.

During this sham-controlled trial period, 13.1% of patients in the treatment group and 18.3% of patients in the control group reported an adverse event (AE) related to the procedure or device, most commonly vocal cord paresis or dysphonia. In the treatment group, 8.2% reported stimulation-related AEs, most commonly mild/moderate pain that was managed by adjusting the stimulation level. 

Serious adverse events (SAEs) were relatively rare, with four treatment-related SAEs across both study groups. No AEs led to study discontinuation through week 24.

The 12-week results mirror those of the initial Humira and Enbrel trials in the late 1990s and early 2000s, Schiopu said, although in those trials, the patients were naive to biologics, and some were naive to methotrexate. A more appropriate comparison, she said, would be biologic-experienced populations.

At week 24, the percentage of patients achieving ACR20 further increased to 51.5% in the treatment group and to 53.1% in the previous control group who were now crossed over to active stimulation. In this secondary period, patients could add any additional therapies like steroids or b/tsDMARDs. At 24 weeks, 81% of patients remained on stimulation without needing additional medication, beyond their continued background DMARDs. 

The results also show “a continuum of improvement over time,” Schiopu said, where response rates climbed through week 24. 

Schiopu is particularly excited about the potential to use this stimulation device in older patients, who have perhaps been on immunosuppressant drugs for decades. 

“Aside from being chronically immunosuppressed, their immune system is more tired [due to age],” she said. With VNS therapies like SetPoint’s, “we could offer [these patients] a lesser immunosuppressive alternative that is still immune-modular enough to manage their RA.”

Schiopu is a consultant for Johnson & Johnson and reported receiving research funding for serving as an institutional principal investigator for SetPoint, Galapagos, Johnson & Johnson, Boehringer Ingelheim, Lilly, argenx, EMD Serono, Priovant, Novartis, Bristol Myers Squibb, Zena Pharmaceuticals, and Horizon/Amgen.

 

A version of this article appeared on Medscape.com.

WASHINGTON — An implantable vagus nerve stimulation (VNS) device effectively treats moderate to severe rheumatoid arthritis (RA) in patients who had previously failed at least one biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD), according to results from a phase 3 trial.

Of the 242 patients in the RESET-RA study, all received the VNS device implant but were blinded as to whether the device was turned on. At 12 weeks, 35.2% of patients receiving daily stimulation achieved 20% improvement in American College of Rheumatology response criteria (ACR20) compared with 24.2% of those with an inactive device. The response was more pronounced among patients with exposure to only one prior b/tsDMARD. A greater proportion of patients in the overall treatment group also reached low disease activity or remission compared with those who did not receive stimulation. 

The research was presented as a late-breaking poster at the ACR 2024 Annual Meeting.

“This is a particularly tough-to-treat patient population, since the patients enrolled were considered refractory to biologic therapy,” said Elena Schiopu, MD, professor of medicine in the Division of Rheumatology and director of clinical trials at the Medical College of Georgia at Augusta University. More than one third of patients in the study had tried three or more b/tsDMARDs prior to the study. “I’m pretty excited about these results,” she added. Schiopu was a RESET-RA institutional principal investigator and enrolled two patients in the trial.

These positive results are a first for VNS treatment in rheumatic diseases. Previous studies demonstrating the potential therapeutic effect of this implant approach have largely been open-label, proof-of-concept, or pilot studies. Noninvasive, wearable stimulation devices have also shown promise in open-label studies; however, a sham-controlled trial published in 2023 showed that transcutaneous vagus nerve stimulation on the ear was no more effective than placebo. 

 

But How Does It Work?

The device, developed by SetPoint Medical in Valencia, California, is about the size of a multivitamin and implanted in an outpatient setting. During the 45-minute procedure, surgeons isolate the vagus nerve on the left side of the neck and place the nerve stimulator with a silicone positioning pod to hold it in place.

The device is programmed to deliver stimulation for 1 minute every day and needs charging for only 10 minutes once a week, which is done remotely with a necklace.

The device takes advantage of the vagus nerve’s anti-inflammatory properties, stimulating the nerve to help regulate an overactive immune system of someone with RA, explained David Chernoff, MD, Setpoint Medical’s chief medical officer. 

“We’re recapitulating what nature has developed over millions of years, which is the nexus between the brain and the immune system, which happens to be mediated by the vagus nerve,” he told Medscape Medical News. 

This novel VNS approach also does not have the same immunosuppressive safety concerns as drugs commonly used to treat RA, he said. 

“We’re able to adjust the amount of inflammation, but we don’t cause the host defense issues” that are present with some of these drugs, he continued.

SetPoint Medical’s pilot study of the device in 14 patients showed promising results. Five of 10 patients randomly assigned to active VNS over 12 weeks showed clinical improvements, measured by 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) and the Clinical Disease Activity Index. In the remaining four patients who received sham stimulation — where the device was implanted but not activated — there were no clinical disease improvements.

 

RESET-RA Details

The most recent, much larger phase 3 study enrolled patients from 41 sites in the United States. Patients were on average 56 years old and had a body mass index of 30; 86% were women. A total of 39% had previously tried one b/tsDMARD, 22% had tried two, and 39% had tried three or more. Patients, on average, had 15 tender joints and 10 swollen joints. Patients discontinued their prior b/tsDMARD before the procedure and remained on conventional DMARDS during the trial, including methotrexate, hydroxychloroquine, and sulfasalazine.

The researchers randomly assigned patients 1:1 to active (treatment) or nonactive (control) stimulation. 

“The perception of stimulation varies from patient to patient, which itself is helpful in blinding as there is no expected perception of whether or how stimulation will be felt,” Chernoff explained. The 1-minute stimulation was scheduled in the early hours of the morning, when a patient typically would be asleep, he said.

Patients were excluded from the analysis if they were rescued by steroids or b/tsDMARDs through week 12. After week 12, the control group was switched to stimulation and efficacy was reassessed at week 24.

 

Higher ACR20 Response Rate, Lower Disease Activity

Beyond meeting the primary endpoint of ACR20 response, patients on the active stimulation group showed lower disease activity at week 12. Compared with 15.8% of patients in the control group, 27% of those in the treatment group achieved a DAS28-CRP ≤ 3.2. 

The active stimulation was particularly effective in patients who had experience with only one prior b/tsDMARD. In this subset of patients, 44.2% in the treatment group achieved ACR20 compared with 19.0% in the control group.

During this sham-controlled trial period, 13.1% of patients in the treatment group and 18.3% of patients in the control group reported an adverse event (AE) related to the procedure or device, most commonly vocal cord paresis or dysphonia. In the treatment group, 8.2% reported stimulation-related AEs, most commonly mild/moderate pain that was managed by adjusting the stimulation level. 

Serious adverse events (SAEs) were relatively rare, with four treatment-related SAEs across both study groups. No AEs led to study discontinuation through week 24.

The 12-week results mirror those of the initial Humira and Enbrel trials in the late 1990s and early 2000s, Schiopu said, although in those trials, the patients were naive to biologics, and some were naive to methotrexate. A more appropriate comparison, she said, would be biologic-experienced populations.

At week 24, the percentage of patients achieving ACR20 further increased to 51.5% in the treatment group and to 53.1% in the previous control group who were now crossed over to active stimulation. In this secondary period, patients could add any additional therapies like steroids or b/tsDMARDs. At 24 weeks, 81% of patients remained on stimulation without needing additional medication, beyond their continued background DMARDs. 

The results also show “a continuum of improvement over time,” Schiopu said, where response rates climbed through week 24. 

Schiopu is particularly excited about the potential to use this stimulation device in older patients, who have perhaps been on immunosuppressant drugs for decades. 

“Aside from being chronically immunosuppressed, their immune system is more tired [due to age],” she said. With VNS therapies like SetPoint’s, “we could offer [these patients] a lesser immunosuppressive alternative that is still immune-modular enough to manage their RA.”

Schiopu is a consultant for Johnson & Johnson and reported receiving research funding for serving as an institutional principal investigator for SetPoint, Galapagos, Johnson & Johnson, Boehringer Ingelheim, Lilly, argenx, EMD Serono, Priovant, Novartis, Bristol Myers Squibb, Zena Pharmaceuticals, and Horizon/Amgen.

 

A version of this article appeared on Medscape.com.