Rare Diseases

LIVERPOOL, ENGLAND — The British Society for Rheumatology (BSR) and the British Association of Dermatologists (BAD) have joined forces for the first time to develop the first British guidelines for the management of people living with Behçet’s disease.

The guidelines will also be the first “living guidelines” produced by either society, which means they will be regularly revised and updated when new evidence emerges that warrants inclusion.

With more than 90 recommendations being made, the new guidelines promise to be the most comprehensive and most up-to-date yet for what is regarded as a rare disease. Robert Moots, MBBS, PhD, provided a “sneak peek” of the guidelines at the annual meeting of the British Society for Rheumatology.

Dr. Moots, professor of rheumatology at the University of Liverpool and a consultant rheumatologist for Liverpool University Hospitals NHS Foundation Trust in England, noted that while the European Alliance of Associations for Rheumatology has produced a guideline for Behçet’s disease, this was last updated in 2018 and is not specific for the population for patients that is seen in the United Kingdom.

The British recommendations will cover all possible manifestations of Behçet’s disease and give practical advice on how to manage everything from the most common presentations such as skin lesions, mouth ulcers, and genital ulcers, as well as the potentially more serious eye, neurological, and vascular involvement.

Sara Freeman/Medscape Medical News

Importance of Raising Awareness

“Joint and musculoskeletal problems are actually one of the least complained of symptoms in people with Behçet’s, and they often can’t understand why a rheumatologist is seeing them,” Dr. Moot said. “But of course, people do get joint problems, they can get enthesitis and arthralgia.”

Dr. Moots has been leading one of the three National Health Service (NHS) Centres of Excellence for Behçet’s Syndrome in England for more than a decade and told this news organization that diagnosing patients could be challenging. It can take up to 10 years from the first symptoms appearing to getting a diagnosis, so part of the job of the NHS Centres of Excellence is to raise awareness among both the healthcare profession and the general public.

“It’s a condition that people learn about at medical school. Most doctors will have come across it, but because it was thought to be really rare in the UK, nobody perhaps really expects to see it,” Dr. Moot said.

“But we all have these patients,” he added. “In Liverpool, we’re commissioned to be looking after an anticipated 150 people with Behçet’s — we’ve got 700. With more awareness, there’s more diagnoses being made, and people are being looked after better.”
 

Patient Perspective

Tony Thornburn, OBE, chair of the patient advocacy group Behçet’s UK, agreed in a separate interview that raising awareness of the syndrome was key to improving its management.

“Patients have said that it is a bit like having arthritis, lupus, MS [multiple sclerosis], and Crohn’s [disease] all at once,” Mr. Thorburn said. “So what we need is a guideline to ensure that people know what they’re looking at.”

Mr. Thorburn added, “Guidelines are important for raising awareness but also providing the detailed information that clinicians and GPs [general practitioners] need to have to treat a patient when they come in with this multifaceted condition.”
 

Multifaceted Means Multidisciplinary Management

Because there can be so many different aspects to managing someone with Behçet’s disease, a multispecialty team that was convened to develop the guidelines agreed that multidisciplinary management should be an overarching theme.

“The guideline development group consisted of all the specialties that you would need for a complex multisystem disease like Behçet’s,” Dr. Moot said. He highlighted that working alongside the consultants in adult and pediatric rheumatology were specialists in dermatology, gastroenterology, neurology, ophthalmology, obstetrics and gynecology, and psychology.

“We’re actually looking at psychological interactions and their impact for the first time,” Dr. Moot said, noting that clinicians needed to “take it seriously, and ask about it.”
 

Management of Manifestations

One of the general principles of the guidelines is to assess the involvement of each organ system and target treatment accordingly.

“One of the problems is that the evidence base to tell us what to do is pretty low,” Dr. Moots acknowledged. There have been few good quality randomized trials, so “treatment tends to be eminence-based rather than evidence-based.”

The recommendation wording bears this in mind, stating whether a treatment should or should not be offered, or just considered if there is no strong evidence to back up its use.

With regard to musculoskeletal manifestations, the recommendations say that colchicine should be offered, perhaps as a first-line option, or an intraarticular steroid injection in the case of monoarthritis. An intramuscular depot steroid may also be appropriate to offer, and there was good evidence to offer azathioprine or, as an alternative in refractory cases, a tumor necrosis factor (TNF) inhibitor. Nonsteroidal anti-inflammatory drugs, methotrexate, apremilast, secukinumab, and referral to a physiotherapist could only be considered, however, based on weaker levels of evidence for their use.

To treat mucocutaneous disease, the guidelines advise offering topical steroids in the form of ointment for genital ulcers or mouthwash or ointment for oral ulcers. For skin lesions, it is recommended to offer colchicine, azathioprine, mycophenolate mofetil, or TNF inhibitor and to consider the use of apremilast, secukinumab, or dapsone.
 

Future Work and Revision

“One of the key things we would like to see developing is a national registry,” Dr. Moots said. This would include biobanking samples for future research and possible genomic and phenotyping studies.

More work needs to be done in conducting clinical trials in children and young people with Behçet’s disease, studies to find prognostic factors for neurological disease, and clinical trials of potential new drug approaches such as Janus kinase inhibitors. Importantly, an auditing process needs to be set up to see what effect, if any, the guidelines will actually have onpatient management.

“It’s taken 5 years to today” to develop the guidelines, Dr. Moot said. What form the process of updating them will take still has to be decided, he said in the interview. It is likely that the necessary literature searches will be performed every 6 months or so, but it will be a compromise between the ideal situation and having the staffing time to do it.

“It’s a big ask,” Dr. Moot acknowledged, adding that even if updates were only once a year, it would still be much faster than the 5- or 6-year cycle that it traditionally takes for most guidelines to be updated.

The BSR and BAD’s processes for developing guidelines are accredited by the National Institute for Health and Care Excellence in England. Dr. Moots is the chief investigator for the Secukinumab in Behçet’s trial, which is sponsored by the Liverpool University Hospitals NHS Foundation Trust via grant funding from Novartis.
 

A version of this article appeared on Medscape.com.

LIVERPOOL, ENGLAND — The British Society for Rheumatology (BSR) and the British Association of Dermatologists (BAD) have joined forces for the first time to develop the first British guidelines for the management of people living with Behçet’s disease.

The guidelines will also be the first “living guidelines” produced by either society, which means they will be regularly revised and updated when new evidence emerges that warrants inclusion.

With more than 90 recommendations being made, the new guidelines promise to be the most comprehensive and most up-to-date yet for what is regarded as a rare disease. Robert Moots, MBBS, PhD, provided a “sneak peek” of the guidelines at the annual meeting of the British Society for Rheumatology.

Dr. Moots, professor of rheumatology at the University of Liverpool and a consultant rheumatologist for Liverpool University Hospitals NHS Foundation Trust in England, noted that while the European Alliance of Associations for Rheumatology has produced a guideline for Behçet’s disease, this was last updated in 2018 and is not specific for the population for patients that is seen in the United Kingdom.

The British recommendations will cover all possible manifestations of Behçet’s disease and give practical advice on how to manage everything from the most common presentations such as skin lesions, mouth ulcers, and genital ulcers, as well as the potentially more serious eye, neurological, and vascular involvement.

Sara Freeman/Medscape Medical News

Importance of Raising Awareness

“Joint and musculoskeletal problems are actually one of the least complained of symptoms in people with Behçet’s, and they often can’t understand why a rheumatologist is seeing them,” Dr. Moot said. “But of course, people do get joint problems, they can get enthesitis and arthralgia.”

Dr. Moots has been leading one of the three National Health Service (NHS) Centres of Excellence for Behçet’s Syndrome in England for more than a decade and told this news organization that diagnosing patients could be challenging. It can take up to 10 years from the first symptoms appearing to getting a diagnosis, so part of the job of the NHS Centres of Excellence is to raise awareness among both the healthcare profession and the general public.

“It’s a condition that people learn about at medical school. Most doctors will have come across it, but because it was thought to be really rare in the UK, nobody perhaps really expects to see it,” Dr. Moot said.

“But we all have these patients,” he added. “In Liverpool, we’re commissioned to be looking after an anticipated 150 people with Behçet’s — we’ve got 700. With more awareness, there’s more diagnoses being made, and people are being looked after better.”
 

Patient Perspective

Tony Thornburn, OBE, chair of the patient advocacy group Behçet’s UK, agreed in a separate interview that raising awareness of the syndrome was key to improving its management.

“Patients have said that it is a bit like having arthritis, lupus, MS [multiple sclerosis], and Crohn’s [disease] all at once,” Mr. Thorburn said. “So what we need is a guideline to ensure that people know what they’re looking at.”

Mr. Thorburn added, “Guidelines are important for raising awareness but also providing the detailed information that clinicians and GPs [general practitioners] need to have to treat a patient when they come in with this multifaceted condition.”
 

Multifaceted Means Multidisciplinary Management

Because there can be so many different aspects to managing someone with Behçet’s disease, a multispecialty team that was convened to develop the guidelines agreed that multidisciplinary management should be an overarching theme.

“The guideline development group consisted of all the specialties that you would need for a complex multisystem disease like Behçet’s,” Dr. Moot said. He highlighted that working alongside the consultants in adult and pediatric rheumatology were specialists in dermatology, gastroenterology, neurology, ophthalmology, obstetrics and gynecology, and psychology.

“We’re actually looking at psychological interactions and their impact for the first time,” Dr. Moot said, noting that clinicians needed to “take it seriously, and ask about it.”
 

Management of Manifestations

One of the general principles of the guidelines is to assess the involvement of each organ system and target treatment accordingly.

“One of the problems is that the evidence base to tell us what to do is pretty low,” Dr. Moots acknowledged. There have been few good quality randomized trials, so “treatment tends to be eminence-based rather than evidence-based.”

The recommendation wording bears this in mind, stating whether a treatment should or should not be offered, or just considered if there is no strong evidence to back up its use.

With regard to musculoskeletal manifestations, the recommendations say that colchicine should be offered, perhaps as a first-line option, or an intraarticular steroid injection in the case of monoarthritis. An intramuscular depot steroid may also be appropriate to offer, and there was good evidence to offer azathioprine or, as an alternative in refractory cases, a tumor necrosis factor (TNF) inhibitor. Nonsteroidal anti-inflammatory drugs, methotrexate, apremilast, secukinumab, and referral to a physiotherapist could only be considered, however, based on weaker levels of evidence for their use.

To treat mucocutaneous disease, the guidelines advise offering topical steroids in the form of ointment for genital ulcers or mouthwash or ointment for oral ulcers. For skin lesions, it is recommended to offer colchicine, azathioprine, mycophenolate mofetil, or TNF inhibitor and to consider the use of apremilast, secukinumab, or dapsone.
 

Future Work and Revision

“One of the key things we would like to see developing is a national registry,” Dr. Moots said. This would include biobanking samples for future research and possible genomic and phenotyping studies.

More work needs to be done in conducting clinical trials in children and young people with Behçet’s disease, studies to find prognostic factors for neurological disease, and clinical trials of potential new drug approaches such as Janus kinase inhibitors. Importantly, an auditing process needs to be set up to see what effect, if any, the guidelines will actually have onpatient management.

“It’s taken 5 years to today” to develop the guidelines, Dr. Moot said. What form the process of updating them will take still has to be decided, he said in the interview. It is likely that the necessary literature searches will be performed every 6 months or so, but it will be a compromise between the ideal situation and having the staffing time to do it.

“It’s a big ask,” Dr. Moot acknowledged, adding that even if updates were only once a year, it would still be much faster than the 5- or 6-year cycle that it traditionally takes for most guidelines to be updated.

The BSR and BAD’s processes for developing guidelines are accredited by the National Institute for Health and Care Excellence in England. Dr. Moots is the chief investigator for the Secukinumab in Behçet’s trial, which is sponsored by the Liverpool University Hospitals NHS Foundation Trust via grant funding from Novartis.
 

A version of this article appeared on Medscape.com.

LIVERPOOL, ENGLAND — The British Society for Rheumatology (BSR) and the British Association of Dermatologists (BAD) have joined forces for the first time to develop the first British guidelines for the management of people living with Behçet’s disease.

The guidelines will also be the first “living guidelines” produced by either society, which means they will be regularly revised and updated when new evidence emerges that warrants inclusion.

With more than 90 recommendations being made, the new guidelines promise to be the most comprehensive and most up-to-date yet for what is regarded as a rare disease. Robert Moots, MBBS, PhD, provided a “sneak peek” of the guidelines at the annual meeting of the British Society for Rheumatology.

Dr. Moots, professor of rheumatology at the University of Liverpool and a consultant rheumatologist for Liverpool University Hospitals NHS Foundation Trust in England, noted that while the European Alliance of Associations for Rheumatology has produced a guideline for Behçet’s disease, this was last updated in 2018 and is not specific for the population for patients that is seen in the United Kingdom.

The British recommendations will cover all possible manifestations of Behçet’s disease and give practical advice on how to manage everything from the most common presentations such as skin lesions, mouth ulcers, and genital ulcers, as well as the potentially more serious eye, neurological, and vascular involvement.

Sara Freeman/Medscape Medical News

Importance of Raising Awareness

“Joint and musculoskeletal problems are actually one of the least complained of symptoms in people with Behçet’s, and they often can’t understand why a rheumatologist is seeing them,” Dr. Moot said. “But of course, people do get joint problems, they can get enthesitis and arthralgia.”

Dr. Moots has been leading one of the three National Health Service (NHS) Centres of Excellence for Behçet’s Syndrome in England for more than a decade and told this news organization that diagnosing patients could be challenging. It can take up to 10 years from the first symptoms appearing to getting a diagnosis, so part of the job of the NHS Centres of Excellence is to raise awareness among both the healthcare profession and the general public.

“It’s a condition that people learn about at medical school. Most doctors will have come across it, but because it was thought to be really rare in the UK, nobody perhaps really expects to see it,” Dr. Moot said.

“But we all have these patients,” he added. “In Liverpool, we’re commissioned to be looking after an anticipated 150 people with Behçet’s — we’ve got 700. With more awareness, there’s more diagnoses being made, and people are being looked after better.”
 

Patient Perspective

Tony Thornburn, OBE, chair of the patient advocacy group Behçet’s UK, agreed in a separate interview that raising awareness of the syndrome was key to improving its management.

“Patients have said that it is a bit like having arthritis, lupus, MS [multiple sclerosis], and Crohn’s [disease] all at once,” Mr. Thorburn said. “So what we need is a guideline to ensure that people know what they’re looking at.”

Mr. Thorburn added, “Guidelines are important for raising awareness but also providing the detailed information that clinicians and GPs [general practitioners] need to have to treat a patient when they come in with this multifaceted condition.”
 

Multifaceted Means Multidisciplinary Management

Because there can be so many different aspects to managing someone with Behçet’s disease, a multispecialty team that was convened to develop the guidelines agreed that multidisciplinary management should be an overarching theme.

“The guideline development group consisted of all the specialties that you would need for a complex multisystem disease like Behçet’s,” Dr. Moot said. He highlighted that working alongside the consultants in adult and pediatric rheumatology were specialists in dermatology, gastroenterology, neurology, ophthalmology, obstetrics and gynecology, and psychology.

“We’re actually looking at psychological interactions and their impact for the first time,” Dr. Moot said, noting that clinicians needed to “take it seriously, and ask about it.”
 

Management of Manifestations

One of the general principles of the guidelines is to assess the involvement of each organ system and target treatment accordingly.

“One of the problems is that the evidence base to tell us what to do is pretty low,” Dr. Moots acknowledged. There have been few good quality randomized trials, so “treatment tends to be eminence-based rather than evidence-based.”

The recommendation wording bears this in mind, stating whether a treatment should or should not be offered, or just considered if there is no strong evidence to back up its use.

With regard to musculoskeletal manifestations, the recommendations say that colchicine should be offered, perhaps as a first-line option, or an intraarticular steroid injection in the case of monoarthritis. An intramuscular depot steroid may also be appropriate to offer, and there was good evidence to offer azathioprine or, as an alternative in refractory cases, a tumor necrosis factor (TNF) inhibitor. Nonsteroidal anti-inflammatory drugs, methotrexate, apremilast, secukinumab, and referral to a physiotherapist could only be considered, however, based on weaker levels of evidence for their use.

To treat mucocutaneous disease, the guidelines advise offering topical steroids in the form of ointment for genital ulcers or mouthwash or ointment for oral ulcers. For skin lesions, it is recommended to offer colchicine, azathioprine, mycophenolate mofetil, or TNF inhibitor and to consider the use of apremilast, secukinumab, or dapsone.
 

Future Work and Revision

“One of the key things we would like to see developing is a national registry,” Dr. Moots said. This would include biobanking samples for future research and possible genomic and phenotyping studies.

More work needs to be done in conducting clinical trials in children and young people with Behçet’s disease, studies to find prognostic factors for neurological disease, and clinical trials of potential new drug approaches such as Janus kinase inhibitors. Importantly, an auditing process needs to be set up to see what effect, if any, the guidelines will actually have onpatient management.

“It’s taken 5 years to today” to develop the guidelines, Dr. Moot said. What form the process of updating them will take still has to be decided, he said in the interview. It is likely that the necessary literature searches will be performed every 6 months or so, but it will be a compromise between the ideal situation and having the staffing time to do it.

“It’s a big ask,” Dr. Moot acknowledged, adding that even if updates were only once a year, it would still be much faster than the 5- or 6-year cycle that it traditionally takes for most guidelines to be updated.

The BSR and BAD’s processes for developing guidelines are accredited by the National Institute for Health and Care Excellence in England. Dr. Moots is the chief investigator for the Secukinumab in Behçet’s trial, which is sponsored by the Liverpool University Hospitals NHS Foundation Trust via grant funding from Novartis.
 

A version of this article appeared on Medscape.com.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

Ted Bosworth/MDedge News

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

Ted Bosworth/MDedge News

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — Unlike a first trial of PB&TURSO, which led to regulatory approval of this combination therapy in 2022, a second larger and longer multicenter placebo-controlled study was unable to show any significant benefit on primary or secondary endpoints.

As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.

Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.

Ted Bosworth/MDedge News

PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
 

ALSFRS-R Served as Primary Endpoint in Both Trials

In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).

The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.

In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.

For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.

Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.

As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
 

Differences Between Two Trials Were Evaluated

The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.

When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.

An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.

Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
 

‘Unfortunate’ Results

Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.

Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.

In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.

“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.

However, he believes that the study will still have value for better understanding ALS.

“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”

Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.

DENVER — When combined with rHuPh20, a recombinant DNA-derived human hyaluronidase, efgartigimod, promises a new treatment option for chronic inflammatory demyelinating polyneuropathy (CIDP), according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.

“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.

Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.

Ted Bosworth/MDedge News

ADHERE Called Largest CIDP Trial to Date

In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.

After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.

The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,

The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.

The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.

There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
 

aINCAT Provided Primary Endpoint for CIDP Trial

For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.

By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.

When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.

In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.

On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
 

E-PH20 Is Characterized as Well Tolerated

Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.

“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.

The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.

There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.

“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.

Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.

Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.

DENVER — When combined with rHuPh20, a recombinant DNA-derived human hyaluronidase, efgartigimod, promises a new treatment option for chronic inflammatory demyelinating polyneuropathy (CIDP), according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.

“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.

Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.

Ted Bosworth/MDedge News

ADHERE Called Largest CIDP Trial to Date

In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.

After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.

The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,

The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.

The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.

There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
 

aINCAT Provided Primary Endpoint for CIDP Trial

For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.

By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.

When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.

In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.

On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
 

E-PH20 Is Characterized as Well Tolerated

Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.

“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.

The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.

There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.

“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.

Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.

Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.

DENVER — When combined with rHuPh20, a recombinant DNA-derived human hyaluronidase, efgartigimod, promises a new treatment option for chronic inflammatory demyelinating polyneuropathy (CIDP), according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.

“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.

Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.

Ted Bosworth/MDedge News

ADHERE Called Largest CIDP Trial to Date

In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.

After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.

The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,

The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.

The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.

There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
 

aINCAT Provided Primary Endpoint for CIDP Trial

For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.

By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.

When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.

In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.

On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
 

E-PH20 Is Characterized as Well Tolerated

Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.

“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.

The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.

There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.

“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.

Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.

Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.

According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.

“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.

In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.

“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,

This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
 

The New Focus on Prevention

The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.

There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.

A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.

Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.

Dr. Feldman reported no potential conflicts of interest.

TOPLINE:

Subcutaneous tocilizumab provides durable disease control rates in patients with polyarticular and systemic juvenile idiopathic arthritis (pJIA and sJIA, respectively).

METHODOLOGY:

• This long-term extension (LTE) study included 44 patients with pJIA and 38 patients with sJIA, according to the International League of Associations for Rheumatology criteria, from two 52-week phase 1b trials (NCT01904292 and NCT01904279).
• In the core trials, the dosing frequency of subcutaneous tocilizumab was determined by weight: Every 3 weeks for those < 30 kg in pJIA and every 2 weeks for those ≥ 30 kg; in sJIA, initially every 10 days for those < 30 kg, transitioning to every 2 weeks, and weekly for those ≥ 30 kg.
• Patients who had adequate disease control with subcutaneous tocilizumab, comparable with the use of intravenous tocilizumab in the core trials, continued to receive subcutaneous tocilizumab.
• The study outcome was the change in Juvenile Arthritis Disease Activity Score on 71 joints (JADAS-71, range 0-101).

TAKEAWAY:

• Disease control remained stable in both groups, with sustained improvements in median JADAS-71 scores in pJIA (−0.2 with lower frequency dosing to −0.5 with higher frequency) and sJIA (−0.1 at both dosing frequencies).
• In the pJIA group, 90% and 53% of patients weighing < 30 kg and ≥ 30 kg achieved inactive disease, respectively, whereas in the sJIA group, the respective rates were 91% and 92%.
• A total of five of 15 patients with pJIA weighing ≥ 30 kg who received subcutaneous tocilizumab every 2 weeks achieved clinical remission, whereas in other groups, the clinical remission rates ranged from 74% to 92%.
• Six patients with pJIA reported seven serious adverse events (SAEs), while five patients with sJIA experienced six SAEs. Five patients with pJIA and one patient with sJIA reported serious infections.

IN PRACTICE:

The authors concluded that subcutaneous tocilizumab treatment provided long-term disease control in patients with pJIA or sJIA, with a safety profile consistent with past studies of tocilizumab.

SOURCE:

The study was led by Hermine I. Brunner, MD, director of the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center. It was published online in Rheumatology (Oxford).

LIMITATIONS:

The open-label design and lack of a control group limited the analysis. Only a few patients continued the treatment for 5 years.

DISCLOSURES:

This work was supported by F. Hoffmann-La Roche Ltd. Eight authors reported receiving honoraria and consulting or speaker fees from various pharma sources. The remaining authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Subcutaneous tocilizumab provides durable disease control rates in patients with polyarticular and systemic juvenile idiopathic arthritis (pJIA and sJIA, respectively).

METHODOLOGY:

• This long-term extension (LTE) study included 44 patients with pJIA and 38 patients with sJIA, according to the International League of Associations for Rheumatology criteria, from two 52-week phase 1b trials (NCT01904292 and NCT01904279).
• In the core trials, the dosing frequency of subcutaneous tocilizumab was determined by weight: Every 3 weeks for those < 30 kg in pJIA and every 2 weeks for those ≥ 30 kg; in sJIA, initially every 10 days for those < 30 kg, transitioning to every 2 weeks, and weekly for those ≥ 30 kg.
• Patients who had adequate disease control with subcutaneous tocilizumab, comparable with the use of intravenous tocilizumab in the core trials, continued to receive subcutaneous tocilizumab.
• The study outcome was the change in Juvenile Arthritis Disease Activity Score on 71 joints (JADAS-71, range 0-101).

TAKEAWAY:

• Disease control remained stable in both groups, with sustained improvements in median JADAS-71 scores in pJIA (−0.2 with lower frequency dosing to −0.5 with higher frequency) and sJIA (−0.1 at both dosing frequencies).
• In the pJIA group, 90% and 53% of patients weighing < 30 kg and ≥ 30 kg achieved inactive disease, respectively, whereas in the sJIA group, the respective rates were 91% and 92%.
• A total of five of 15 patients with pJIA weighing ≥ 30 kg who received subcutaneous tocilizumab every 2 weeks achieved clinical remission, whereas in other groups, the clinical remission rates ranged from 74% to 92%.
• Six patients with pJIA reported seven serious adverse events (SAEs), while five patients with sJIA experienced six SAEs. Five patients with pJIA and one patient with sJIA reported serious infections.

IN PRACTICE:

The authors concluded that subcutaneous tocilizumab treatment provided long-term disease control in patients with pJIA or sJIA, with a safety profile consistent with past studies of tocilizumab.

SOURCE:

The study was led by Hermine I. Brunner, MD, director of the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center. It was published online in Rheumatology (Oxford).

LIMITATIONS:

The open-label design and lack of a control group limited the analysis. Only a few patients continued the treatment for 5 years.

DISCLOSURES:

This work was supported by F. Hoffmann-La Roche Ltd. Eight authors reported receiving honoraria and consulting or speaker fees from various pharma sources. The remaining authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Subcutaneous tocilizumab provides durable disease control rates in patients with polyarticular and systemic juvenile idiopathic arthritis (pJIA and sJIA, respectively).

METHODOLOGY:

• This long-term extension (LTE) study included 44 patients with pJIA and 38 patients with sJIA, according to the International League of Associations for Rheumatology criteria, from two 52-week phase 1b trials (NCT01904292 and NCT01904279).
• In the core trials, the dosing frequency of subcutaneous tocilizumab was determined by weight: Every 3 weeks for those < 30 kg in pJIA and every 2 weeks for those ≥ 30 kg; in sJIA, initially every 10 days for those < 30 kg, transitioning to every 2 weeks, and weekly for those ≥ 30 kg.
• Patients who had adequate disease control with subcutaneous tocilizumab, comparable with the use of intravenous tocilizumab in the core trials, continued to receive subcutaneous tocilizumab.
• The study outcome was the change in Juvenile Arthritis Disease Activity Score on 71 joints (JADAS-71, range 0-101).

TAKEAWAY:

• Disease control remained stable in both groups, with sustained improvements in median JADAS-71 scores in pJIA (−0.2 with lower frequency dosing to −0.5 with higher frequency) and sJIA (−0.1 at both dosing frequencies).
• In the pJIA group, 90% and 53% of patients weighing < 30 kg and ≥ 30 kg achieved inactive disease, respectively, whereas in the sJIA group, the respective rates were 91% and 92%.
• A total of five of 15 patients with pJIA weighing ≥ 30 kg who received subcutaneous tocilizumab every 2 weeks achieved clinical remission, whereas in other groups, the clinical remission rates ranged from 74% to 92%.
• Six patients with pJIA reported seven serious adverse events (SAEs), while five patients with sJIA experienced six SAEs. Five patients with pJIA and one patient with sJIA reported serious infections.

IN PRACTICE:

The authors concluded that subcutaneous tocilizumab treatment provided long-term disease control in patients with pJIA or sJIA, with a safety profile consistent with past studies of tocilizumab.

SOURCE:

The study was led by Hermine I. Brunner, MD, director of the Division of Rheumatology at Cincinnati Children’s Hospital Medical Center. It was published online in Rheumatology (Oxford).

LIMITATIONS:

The open-label design and lack of a control group limited the analysis. Only a few patients continued the treatment for 5 years.

DISCLOSURES:

This work was supported by F. Hoffmann-La Roche Ltd. Eight authors reported receiving honoraria and consulting or speaker fees from various pharma sources. The remaining authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the launch of the first clinical trial for chimeric antigen receptor (CAR) T-cell therapy in children with systemic lupus erythematosus.

The trial, called Reversing Autoimmunity through Cell Therapy (REACT-01), will take place at Seattle Children’s Hospital in Washington State and is expected to begin this summer.

The CAR-T therapy will target CD19 positive B-cells, an approach that has had promising results in a small number of adult patients. While the FDA has approved a number of clinical trials using CAR-T therapy to treat autoimmune diseases in adults, this is the first authorization for a CAR T-cell therapy trial to treat autoimmune disease in children.

REACT-01 will enroll 12 individuals under 18 years of age, Shaun W. Jackson, MD, PhD, the principal investigator of the trial and attending physician in Pediatric Nephrology and Pediatric Rheumatology at Seattle Children’s Hospital, told this news organization. 

The trial will be initiated in separate phases, using three age cohorts. The first phase will enroll three individuals aged at least 17 years, before moving to the second phase and enrolling three individuals aged 12-17 years. Then, phase 3 will also include children aged 5-12 years.

To be eligible for the trial, participants must have failed at least two standard immunosuppressive therapies as well as have evidence of active lupus disease affecting a major organ system, such as the heart, lungs, and kidneys.

“Seattle Children’s Hospital will be the only site for this study, although patients can travel to Seattle to receive the therapy and then return back to their primary center for ongoing care,” Dr. Jackson said. 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the launch of the first clinical trial for chimeric antigen receptor (CAR) T-cell therapy in children with systemic lupus erythematosus.

The trial, called Reversing Autoimmunity through Cell Therapy (REACT-01), will take place at Seattle Children’s Hospital in Washington State and is expected to begin this summer.

The CAR-T therapy will target CD19 positive B-cells, an approach that has had promising results in a small number of adult patients. While the FDA has approved a number of clinical trials using CAR-T therapy to treat autoimmune diseases in adults, this is the first authorization for a CAR T-cell therapy trial to treat autoimmune disease in children.

REACT-01 will enroll 12 individuals under 18 years of age, Shaun W. Jackson, MD, PhD, the principal investigator of the trial and attending physician in Pediatric Nephrology and Pediatric Rheumatology at Seattle Children’s Hospital, told this news organization. 

The trial will be initiated in separate phases, using three age cohorts. The first phase will enroll three individuals aged at least 17 years, before moving to the second phase and enrolling three individuals aged 12-17 years. Then, phase 3 will also include children aged 5-12 years.

To be eligible for the trial, participants must have failed at least two standard immunosuppressive therapies as well as have evidence of active lupus disease affecting a major organ system, such as the heart, lungs, and kidneys.

“Seattle Children’s Hospital will be the only site for this study, although patients can travel to Seattle to receive the therapy and then return back to their primary center for ongoing care,” Dr. Jackson said. 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the launch of the first clinical trial for chimeric antigen receptor (CAR) T-cell therapy in children with systemic lupus erythematosus.

The trial, called Reversing Autoimmunity through Cell Therapy (REACT-01), will take place at Seattle Children’s Hospital in Washington State and is expected to begin this summer.

The CAR-T therapy will target CD19 positive B-cells, an approach that has had promising results in a small number of adult patients. While the FDA has approved a number of clinical trials using CAR-T therapy to treat autoimmune diseases in adults, this is the first authorization for a CAR T-cell therapy trial to treat autoimmune disease in children.

REACT-01 will enroll 12 individuals under 18 years of age, Shaun W. Jackson, MD, PhD, the principal investigator of the trial and attending physician in Pediatric Nephrology and Pediatric Rheumatology at Seattle Children’s Hospital, told this news organization. 

The trial will be initiated in separate phases, using three age cohorts. The first phase will enroll three individuals aged at least 17 years, before moving to the second phase and enrolling three individuals aged 12-17 years. Then, phase 3 will also include children aged 5-12 years.

To be eligible for the trial, participants must have failed at least two standard immunosuppressive therapies as well as have evidence of active lupus disease affecting a major organ system, such as the heart, lungs, and kidneys.

“Seattle Children’s Hospital will be the only site for this study, although patients can travel to Seattle to receive the therapy and then return back to their primary center for ongoing care,” Dr. Jackson said. 

A version of this article appeared on Medscape.com.

Images generated by photographic computer software are the first to depict accurate images of facial distortions experienced by patients with prosopometamorphopsia (PMO), a rare visual disorder that is often mistaken for mental illness.

PMO is a rare, often misdiagnosed, visual disorder in which human faces appear distorted in shape, texture, position, or color. Most patients with PMO see these distorted facial features all the time, whether they are looking at a face in person, on a screen, or paper.

For this study, investigators worked with a single patient, a 58-year-old man with a 31-month history of seeing what he describes as “demonic”-looking human faces. Unlike most cases of PMO, the patient reported seeing the distortions only when encountering someone in person but not on a screen or on paper.

This allowed researchers to use editing software to create an image on a computer screen that matched the patient’s distorted view.

“This new information should help healthcare professionals grasp the intensity of facial distortions experienced by people with PMO,” study investigator Brad Duchaine, PhD, professor, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire, told this news organization.

“A substantial number of people we have worked with have been misdiagnosed, often with schizophrenia or some sort of psychotic episode, and some have been put on antipsychotics despite the fact they’ve just had some little tweak in their visual system,” he added.

The report was published online on March 23 in The Lancet.
 

Prevalence Underestimated?

Although fewer than 100 cases of PMO have been reported in the literature, Dr. Duchaine said this is likely an underestimate. Based on a response to a website his team created to recruit affected patients, he said he believes “there are far more cases out there that we realize.”

PMO might be caused by a neurologic event that leads to a lesion in the right temporal lobe, near areas of facial processing, but in many cases, the cause is unclear.

PMO can occur in the context of head trauma, as well as cerebral infarction, epilepsy, migraine, and hallucinogen-persisting perception disorder, researchers noted. The condition can also manifest without detectable structural brain changes.

“We’re hearing from a lot of people through our website who haven’t had, or aren’t aware of having had, a neurologic event that coincided with the onset of face distortions,” Dr. Duchaine noted.

The patient in this study had a significant head injury at age 43 that led to hospitalization. He was exposed to high levels of carbon monoxide about 4 months before his symptoms began, but it’s not clear if the PMO and the incident are related.

He was not prescribed any medications and reported no history of illicit substance use.

The patient also had a history of bipolar affective disorder and posttraumatic stress disorder. His visions of distorted faces were not accompanied by delusional beliefs about the people he encountered, the investigators reported.

Neuropsychological tests were normal, and there were no deficits of visual acuity or color vision. Computer-based face perception tests indicated mild impairment in recognition of facial identity but normal recognition of facial expression.

The patient did not typically see distortions when looking at objects, such as a coffee mug or computer. However, said Dr. Duchaine, “if you get enough text together, the text will start to swirl for him.”
 

Eye-Opening Findings

The patient described the visual facial distortions as “severely stretched features, with deep grooves on the forehead, cheeks, and chin.” Even though these faces were distorted, he was able to recognize the people he saw.

Because the patient reported no distortion when viewing facial images on a screen, researchers asked him to compare what he saw when he looked at the face of a person in the room to a photograph of the same person on a computer screen.

The patient alternated between observing the in-person face, which he perceived as distorted, and the photo on the screen, which he perceived as normal.

Researchers used real-time feedback from the patient and photo-editing software to manipulate the photo on the screen until the photo and the patient’s visual perception of the person in the room matched.

“This is the first time we have actually been able to have a visualization where we are really confident that that’s what someone with PMO is experiencing,” said Dr. Duchaine. “If he were a typical PMO case, he would look at the face in real life and look at the face on the screen and the face on the screen would be distorting as well.”

The researchers discovered that the patient’s distortions are influenced by color; if he looks at faces through a red filter, the distortions are greatly intensified, but if he looks at them through a green filter, the distortions are greatly reduced. He now wears green-filtered glasses in certain situations.

Dr. Duchaine hopes this case will open the eyes of clinicians. “These sorts of visual distortions that your patient is telling you about are probably real, and they’re not a sign of broader mental illness; it’s a problem limited to the visual system,” he said.

The research was funded by the Hitchcock Foundation. The authors reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Images generated by photographic computer software are the first to depict accurate images of facial distortions experienced by patients with prosopometamorphopsia (PMO), a rare visual disorder that is often mistaken for mental illness.

PMO is a rare, often misdiagnosed, visual disorder in which human faces appear distorted in shape, texture, position, or color. Most patients with PMO see these distorted facial features all the time, whether they are looking at a face in person, on a screen, or paper.

For this study, investigators worked with a single patient, a 58-year-old man with a 31-month history of seeing what he describes as “demonic”-looking human faces. Unlike most cases of PMO, the patient reported seeing the distortions only when encountering someone in person but not on a screen or on paper.

This allowed researchers to use editing software to create an image on a computer screen that matched the patient’s distorted view.

“This new information should help healthcare professionals grasp the intensity of facial distortions experienced by people with PMO,” study investigator Brad Duchaine, PhD, professor, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire, told this news organization.

“A substantial number of people we have worked with have been misdiagnosed, often with schizophrenia or some sort of psychotic episode, and some have been put on antipsychotics despite the fact they’ve just had some little tweak in their visual system,” he added.

The report was published online on March 23 in The Lancet.
 

Prevalence Underestimated?

Although fewer than 100 cases of PMO have been reported in the literature, Dr. Duchaine said this is likely an underestimate. Based on a response to a website his team created to recruit affected patients, he said he believes “there are far more cases out there that we realize.”

PMO might be caused by a neurologic event that leads to a lesion in the right temporal lobe, near areas of facial processing, but in many cases, the cause is unclear.

PMO can occur in the context of head trauma, as well as cerebral infarction, epilepsy, migraine, and hallucinogen-persisting perception disorder, researchers noted. The condition can also manifest without detectable structural brain changes.

“We’re hearing from a lot of people through our website who haven’t had, or aren’t aware of having had, a neurologic event that coincided with the onset of face distortions,” Dr. Duchaine noted.

The patient in this study had a significant head injury at age 43 that led to hospitalization. He was exposed to high levels of carbon monoxide about 4 months before his symptoms began, but it’s not clear if the PMO and the incident are related.

He was not prescribed any medications and reported no history of illicit substance use.

The patient also had a history of bipolar affective disorder and posttraumatic stress disorder. His visions of distorted faces were not accompanied by delusional beliefs about the people he encountered, the investigators reported.

Neuropsychological tests were normal, and there were no deficits of visual acuity or color vision. Computer-based face perception tests indicated mild impairment in recognition of facial identity but normal recognition of facial expression.

The patient did not typically see distortions when looking at objects, such as a coffee mug or computer. However, said Dr. Duchaine, “if you get enough text together, the text will start to swirl for him.”
 

Eye-Opening Findings

The patient described the visual facial distortions as “severely stretched features, with deep grooves on the forehead, cheeks, and chin.” Even though these faces were distorted, he was able to recognize the people he saw.

Because the patient reported no distortion when viewing facial images on a screen, researchers asked him to compare what he saw when he looked at the face of a person in the room to a photograph of the same person on a computer screen.

The patient alternated between observing the in-person face, which he perceived as distorted, and the photo on the screen, which he perceived as normal.

Researchers used real-time feedback from the patient and photo-editing software to manipulate the photo on the screen until the photo and the patient’s visual perception of the person in the room matched.

“This is the first time we have actually been able to have a visualization where we are really confident that that’s what someone with PMO is experiencing,” said Dr. Duchaine. “If he were a typical PMO case, he would look at the face in real life and look at the face on the screen and the face on the screen would be distorting as well.”

The researchers discovered that the patient’s distortions are influenced by color; if he looks at faces through a red filter, the distortions are greatly intensified, but if he looks at them through a green filter, the distortions are greatly reduced. He now wears green-filtered glasses in certain situations.

Dr. Duchaine hopes this case will open the eyes of clinicians. “These sorts of visual distortions that your patient is telling you about are probably real, and they’re not a sign of broader mental illness; it’s a problem limited to the visual system,” he said.

The research was funded by the Hitchcock Foundation. The authors reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

Images generated by photographic computer software are the first to depict accurate images of facial distortions experienced by patients with prosopometamorphopsia (PMO), a rare visual disorder that is often mistaken for mental illness.

PMO is a rare, often misdiagnosed, visual disorder in which human faces appear distorted in shape, texture, position, or color. Most patients with PMO see these distorted facial features all the time, whether they are looking at a face in person, on a screen, or paper.

For this study, investigators worked with a single patient, a 58-year-old man with a 31-month history of seeing what he describes as “demonic”-looking human faces. Unlike most cases of PMO, the patient reported seeing the distortions only when encountering someone in person but not on a screen or on paper.

This allowed researchers to use editing software to create an image on a computer screen that matched the patient’s distorted view.

“This new information should help healthcare professionals grasp the intensity of facial distortions experienced by people with PMO,” study investigator Brad Duchaine, PhD, professor, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, New Hampshire, told this news organization.

“A substantial number of people we have worked with have been misdiagnosed, often with schizophrenia or some sort of psychotic episode, and some have been put on antipsychotics despite the fact they’ve just had some little tweak in their visual system,” he added.

The report was published online on March 23 in The Lancet.
 

Prevalence Underestimated?

Although fewer than 100 cases of PMO have been reported in the literature, Dr. Duchaine said this is likely an underestimate. Based on a response to a website his team created to recruit affected patients, he said he believes “there are far more cases out there that we realize.”

PMO might be caused by a neurologic event that leads to a lesion in the right temporal lobe, near areas of facial processing, but in many cases, the cause is unclear.

PMO can occur in the context of head trauma, as well as cerebral infarction, epilepsy, migraine, and hallucinogen-persisting perception disorder, researchers noted. The condition can also manifest without detectable structural brain changes.

“We’re hearing from a lot of people through our website who haven’t had, or aren’t aware of having had, a neurologic event that coincided with the onset of face distortions,” Dr. Duchaine noted.

The patient in this study had a significant head injury at age 43 that led to hospitalization. He was exposed to high levels of carbon monoxide about 4 months before his symptoms began, but it’s not clear if the PMO and the incident are related.

He was not prescribed any medications and reported no history of illicit substance use.

The patient also had a history of bipolar affective disorder and posttraumatic stress disorder. His visions of distorted faces were not accompanied by delusional beliefs about the people he encountered, the investigators reported.

Neuropsychological tests were normal, and there were no deficits of visual acuity or color vision. Computer-based face perception tests indicated mild impairment in recognition of facial identity but normal recognition of facial expression.

The patient did not typically see distortions when looking at objects, such as a coffee mug or computer. However, said Dr. Duchaine, “if you get enough text together, the text will start to swirl for him.”
 

Eye-Opening Findings

The patient described the visual facial distortions as “severely stretched features, with deep grooves on the forehead, cheeks, and chin.” Even though these faces were distorted, he was able to recognize the people he saw.

Because the patient reported no distortion when viewing facial images on a screen, researchers asked him to compare what he saw when he looked at the face of a person in the room to a photograph of the same person on a computer screen.

The patient alternated between observing the in-person face, which he perceived as distorted, and the photo on the screen, which he perceived as normal.

Researchers used real-time feedback from the patient and photo-editing software to manipulate the photo on the screen until the photo and the patient’s visual perception of the person in the room matched.

“This is the first time we have actually been able to have a visualization where we are really confident that that’s what someone with PMO is experiencing,” said Dr. Duchaine. “If he were a typical PMO case, he would look at the face in real life and look at the face on the screen and the face on the screen would be distorting as well.”

The researchers discovered that the patient’s distortions are influenced by color; if he looks at faces through a red filter, the distortions are greatly intensified, but if he looks at them through a green filter, the distortions are greatly reduced. He now wears green-filtered glasses in certain situations.

Dr. Duchaine hopes this case will open the eyes of clinicians. “These sorts of visual distortions that your patient is telling you about are probably real, and they’re not a sign of broader mental illness; it’s a problem limited to the visual system,” he said.

The research was funded by the Hitchcock Foundation. The authors reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Hypoplastic pitted amelogenesis imperfecta may affect patients with the rare genetic disorder Kindler epidermolysis bullosa (KEB).

METHODOLOGY:

• KEB or Kindler syndrome, a genetic skin-blistering disease associated with pathogenic variants in FERMT1, is the rarest type of EB. Early detection and preventive measures can minimize complications, such as gum disease and other oral health issues, that have been reported in patients with KEB.
• Amelogenesis imperfecta is a group of rare genetic developmental conditions characterized by tooth enamel defects and can be associated with hypersensitivity and eruption disturbances in teeth, as well as periodontal conditions.
• Researchers conducted a longitudinal study on 36 patients with KEB (age, 2 weeks to 70 years; 42% female) from two clinics in Germany and Chile from 2003 to 2023, with follow-up times of 1-24 years.
• The primary outcomes were presence of orofacial features, including amelogenesis imperfecta, intraoral wounds,  and periodontal disease, and oral squamous cell carcinoma.

TAKEAWAY:

• All 11 patients with information on enamel structure in their records had pitted enamel anomalies (pitted amelogenesis imperfecta), with variable severity.
• Of patients whose enamel could not be analyzed, three had all teeth crowned in their 20s, suggesting enamel defects, and two had all teeth extracted in their teens or 20s, indicating severe periodontal disease.
• The most common orofacial features were periodontal disease (27 of 36 patients), intraoral lesions (16 of 22 patients), angular cheilitis (24 of 33 patients), and cheilitis (22 of 34 patients), gingival overgrowth (17 of 26 patients), microstomia (14 of 25 patients), and vestibular obliteration (8 of 16 patients).
• Oral squamous cell carcinoma was diagnosed at the site of chronic lip lesions in two patients, with lethal outcomes.

IN PRACTICE:

These findings highlight the extent and severity of oral manifestations in KEB, the authors concluded, adding that “oral care is mandatory” in patients with KEB.

SOURCE:

This report, led by Susanne Krämer, DDS, MSc, of Medical Faculty and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany, was published online in JAMA Dermatology.

LIMITATIONS:

The small sample size and the retrospective nature of the study could limit its generalizability.

DISCLOSURES:

The authors did not disclose any source of funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Hypoplastic pitted amelogenesis imperfecta may affect patients with the rare genetic disorder Kindler epidermolysis bullosa (KEB).

METHODOLOGY:

• KEB or Kindler syndrome, a genetic skin-blistering disease associated with pathogenic variants in FERMT1, is the rarest type of EB. Early detection and preventive measures can minimize complications, such as gum disease and other oral health issues, that have been reported in patients with KEB.
• Amelogenesis imperfecta is a group of rare genetic developmental conditions characterized by tooth enamel defects and can be associated with hypersensitivity and eruption disturbances in teeth, as well as periodontal conditions.
• Researchers conducted a longitudinal study on 36 patients with KEB (age, 2 weeks to 70 years; 42% female) from two clinics in Germany and Chile from 2003 to 2023, with follow-up times of 1-24 years.
• The primary outcomes were presence of orofacial features, including amelogenesis imperfecta, intraoral wounds,  and periodontal disease, and oral squamous cell carcinoma.

TAKEAWAY:

• All 11 patients with information on enamel structure in their records had pitted enamel anomalies (pitted amelogenesis imperfecta), with variable severity.
• Of patients whose enamel could not be analyzed, three had all teeth crowned in their 20s, suggesting enamel defects, and two had all teeth extracted in their teens or 20s, indicating severe periodontal disease.
• The most common orofacial features were periodontal disease (27 of 36 patients), intraoral lesions (16 of 22 patients), angular cheilitis (24 of 33 patients), and cheilitis (22 of 34 patients), gingival overgrowth (17 of 26 patients), microstomia (14 of 25 patients), and vestibular obliteration (8 of 16 patients).
• Oral squamous cell carcinoma was diagnosed at the site of chronic lip lesions in two patients, with lethal outcomes.

IN PRACTICE:

These findings highlight the extent and severity of oral manifestations in KEB, the authors concluded, adding that “oral care is mandatory” in patients with KEB.

SOURCE:

This report, led by Susanne Krämer, DDS, MSc, of Medical Faculty and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany, was published online in JAMA Dermatology.

LIMITATIONS:

The small sample size and the retrospective nature of the study could limit its generalizability.

DISCLOSURES:

The authors did not disclose any source of funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Hypoplastic pitted amelogenesis imperfecta may affect patients with the rare genetic disorder Kindler epidermolysis bullosa (KEB).

METHODOLOGY:

• KEB or Kindler syndrome, a genetic skin-blistering disease associated with pathogenic variants in FERMT1, is the rarest type of EB. Early detection and preventive measures can minimize complications, such as gum disease and other oral health issues, that have been reported in patients with KEB.
• Amelogenesis imperfecta is a group of rare genetic developmental conditions characterized by tooth enamel defects and can be associated with hypersensitivity and eruption disturbances in teeth, as well as periodontal conditions.
• Researchers conducted a longitudinal study on 36 patients with KEB (age, 2 weeks to 70 years; 42% female) from two clinics in Germany and Chile from 2003 to 2023, with follow-up times of 1-24 years.
• The primary outcomes were presence of orofacial features, including amelogenesis imperfecta, intraoral wounds,  and periodontal disease, and oral squamous cell carcinoma.

TAKEAWAY:

• All 11 patients with information on enamel structure in their records had pitted enamel anomalies (pitted amelogenesis imperfecta), with variable severity.
• Of patients whose enamel could not be analyzed, three had all teeth crowned in their 20s, suggesting enamel defects, and two had all teeth extracted in their teens or 20s, indicating severe periodontal disease.
• The most common orofacial features were periodontal disease (27 of 36 patients), intraoral lesions (16 of 22 patients), angular cheilitis (24 of 33 patients), and cheilitis (22 of 34 patients), gingival overgrowth (17 of 26 patients), microstomia (14 of 25 patients), and vestibular obliteration (8 of 16 patients).
• Oral squamous cell carcinoma was diagnosed at the site of chronic lip lesions in two patients, with lethal outcomes.

IN PRACTICE:

These findings highlight the extent and severity of oral manifestations in KEB, the authors concluded, adding that “oral care is mandatory” in patients with KEB.

SOURCE:

This report, led by Susanne Krämer, DDS, MSc, of Medical Faculty and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany, was published online in JAMA Dermatology.

LIMITATIONS:

The small sample size and the retrospective nature of the study could limit its generalizability.

DISCLOSURES:

The authors did not disclose any source of funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

CORRECTED April 7, 2024 // An earlier version of this article misstated the clinical factors of children with CNO that were significantly associated with the need for second-line treatment, as well as the scope of assessments of aspects of disease involvement and their relationship to total number of days on NSAID monotherapy and the odds of needing a second-line treatment.

Children with chronic nonbacterial osteomyelitis (CNO) who had symmetric bone lesions or multiple affected body regions were more likely to need second-line treatment than were patients without these features, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

CNO is an auto-inflammatory condition that results in sterile inflammatory bone lesions and most commonly affects the long bones of people who are skeletally immature. After a first-line treatment of nonsteroidal anti-inflammatory drugs (NSAIDs), second-line treatments per CARRA guidelines typically include methotrexate or sulfasalazine, tumor necrosis factor (TNF)–alpha inhibitors, and bisphosphonates.

“Since it’s common for there to be long delays before diagnosis of CNO, it is important to start an effective treatment promptly,” Katherine D. Nowicki, MD, of Children’s Hospital Colorado, Aurora, told attendees. “While we have guidance on which treatments to use, it remains unclear which patients are most likely to respond to NSAIDs and which patients will require a second-line treatment.”
 

Findings Helpful for Counseling

Melissa S. Oliver, MD, MS, assistant professor of clinical pediatrics in rheumatology at Riley Children’s Health at Indiana University Health, Indianapolis, who was not involved in the research, said the findings of this study are helpful in “counseling families and patients at that initial visit and having a lower threshold to start a second-line agent if NSAID monotherapy is not working well.”

There are no clinical trials on patients with CNO, Dr. Oliver said, so very little data exist for guiding clinicians on the best therapy to use and how long to keep patients on therapy while minimizing risk for flare when coming off therapy.

A key clinical takeaway for clinicians is being able to tell patients with unifocal disease that they may not need to be on NSAIDs for a long period and can still do well, Dr. Oliver said. For patients with multifocal disease with symmetric bone lesions or multiple regions involved with CNO, “pediatric rheumatologists should have a lower threshold to start a second-line therapy for these patients,” she said.

Findings From Largest Single-Center Cohort in North America

Their topline findings revealed that patients with unifocal disease at diagnosis required 47% fewer total days of NSAID monotherapy treatment than those with multifocal disease at diagnosis, Dr. Nowicki told attendees. Having symmetric bone lesions increased the likelihood of needing a second-line therapy by 6.86 times compared with those without symmetric bone lesions, and for each additional region affected by CNO, the odds of needing a second-line therapy increased by a factor of 1.94, she said.

There were no significant differences in patient ages or sex or in mean interval from symptom onset to treatment onset across treatment groups. However, patients who received second-line treatment did have a significantly longer average time from symptom onset to diagnosis (324 days) than those who had a short course (119 days) or long course (270 days) of NSAIDs (P = .023). Mean follow-up was also significantly longer for patients with second-line treatment (3.8 years) or long-course NSAIDs (2.7 years) than for those with short-course NSAIDs (1.2 years; P < .001).

Mean erythrocyte sedimentation rate or C-reactive protein did not differ across treatment groups nor did presence of a CNO lesion on x-rays at presentation. But significantly more patients in the second-line group had a biopsy (94%) than in the long-course (74%) or short-course (69%) NSAID groups (P = .0025). They were also more likely to have one or more whole-body MRIs. Most of the patients on short-course (88%) and long-course (82%) NSAIDs did not undergo a whole-body MRI, whereas most patients (59%) on a second-line treatment underwent at least one and 24% underwent three or more MRIs (P < .001).

More patients on short-course NSAIDs had unifocal disease at diagnosis (72%) than those on long-course NSAIDs (47%) or a second-line treatment (41%; P = .015). Patients on a second-line treatment were also more likely to have symmetric involvement in the same bone (73% vs 16% short-course and 23% long-course NSAIDs) and to have more regions of the body affected (P < .001).

There were significant differences in mean days on NSAID monotherapy and number of NSAIDs trialed. Patients on a second-line treatment had a mean 441 days of NSAID monotherapy compared with 175 days for patients on short-course NSAIDs and 725 for patients on long-course NSAIDs (P < .001). Nearly all the short-course patients (94%) trialed a single NSAID, while more than half the long-course and second-line patients trialed two or more (P < .001).

None of the patients on short-course NSAIDs had complications. More patients on second-line treatments had vertebral height loss (20%) or amplified pain (14%) than long-course patients (13% and 5%, respectively; P = .02).

At the study’s end date, nearly all the patients on short-course NSAIDs were in remission (94%) compared with 71% of patients on long-course NSAIDs and only half of patients (51%) on the second-line treatment (P < .001). None of the patients on short-course NSAIDs had active disease compared with 11% of patients on long-course NSAIDs and 20% of patients on second-line treatments (P = .02).

This study included the largest single-center cohort of patients with CNO in North America, all treated at a multidisciplinary clinic with a protocolized treatment approach, but it remains limited by its retrospective nature and the missing data for 70 patients, Dr. Nowicki said. She noted that whole-body MRI was not systematically performed on all patients, so it was possible patients without a whole-body MRI had undetected asymptomatic lesions.

Despite these limitations, Dr. Oliver said retrospective studies like these can help pediatric rheumatologists get an idea of reasonable therapies to start, how long to keep patients on them, and when to escalate to the next step.

“I hope one day our CNO research will be able to tell us about which is the optimal second-line therapy for patients, such as bisphosphonates vs TNF inhibitors vs DMARDs [disease-modifying antirheumatic drugs],” Dr. Oliver said.

Dr. Nowicki and Dr. Oliver reported no disclosures. Information on study funding was not provided.

A version of this article appeared on Medscape.com .

CORRECTED April 7, 2024 // An earlier version of this article misstated the clinical factors of children with CNO that were significantly associated with the need for second-line treatment, as well as the scope of assessments of aspects of disease involvement and their relationship to total number of days on NSAID monotherapy and the odds of needing a second-line treatment.

Children with chronic nonbacterial osteomyelitis (CNO) who had symmetric bone lesions or multiple affected body regions were more likely to need second-line treatment than were patients without these features, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

CNO is an auto-inflammatory condition that results in sterile inflammatory bone lesions and most commonly affects the long bones of people who are skeletally immature. After a first-line treatment of nonsteroidal anti-inflammatory drugs (NSAIDs), second-line treatments per CARRA guidelines typically include methotrexate or sulfasalazine, tumor necrosis factor (TNF)–alpha inhibitors, and bisphosphonates.

“Since it’s common for there to be long delays before diagnosis of CNO, it is important to start an effective treatment promptly,” Katherine D. Nowicki, MD, of Children’s Hospital Colorado, Aurora, told attendees. “While we have guidance on which treatments to use, it remains unclear which patients are most likely to respond to NSAIDs and which patients will require a second-line treatment.”
 

Findings Helpful for Counseling

Melissa S. Oliver, MD, MS, assistant professor of clinical pediatrics in rheumatology at Riley Children’s Health at Indiana University Health, Indianapolis, who was not involved in the research, said the findings of this study are helpful in “counseling families and patients at that initial visit and having a lower threshold to start a second-line agent if NSAID monotherapy is not working well.”

There are no clinical trials on patients with CNO, Dr. Oliver said, so very little data exist for guiding clinicians on the best therapy to use and how long to keep patients on therapy while minimizing risk for flare when coming off therapy.

A key clinical takeaway for clinicians is being able to tell patients with unifocal disease that they may not need to be on NSAIDs for a long period and can still do well, Dr. Oliver said. For patients with multifocal disease with symmetric bone lesions or multiple regions involved with CNO, “pediatric rheumatologists should have a lower threshold to start a second-line therapy for these patients,” she said.

Findings From Largest Single-Center Cohort in North America

Their topline findings revealed that patients with unifocal disease at diagnosis required 47% fewer total days of NSAID monotherapy treatment than those with multifocal disease at diagnosis, Dr. Nowicki told attendees. Having symmetric bone lesions increased the likelihood of needing a second-line therapy by 6.86 times compared with those without symmetric bone lesions, and for each additional region affected by CNO, the odds of needing a second-line therapy increased by a factor of 1.94, she said.

There were no significant differences in patient ages or sex or in mean interval from symptom onset to treatment onset across treatment groups. However, patients who received second-line treatment did have a significantly longer average time from symptom onset to diagnosis (324 days) than those who had a short course (119 days) or long course (270 days) of NSAIDs (P = .023). Mean follow-up was also significantly longer for patients with second-line treatment (3.8 years) or long-course NSAIDs (2.7 years) than for those with short-course NSAIDs (1.2 years; P < .001).

Mean erythrocyte sedimentation rate or C-reactive protein did not differ across treatment groups nor did presence of a CNO lesion on x-rays at presentation. But significantly more patients in the second-line group had a biopsy (94%) than in the long-course (74%) or short-course (69%) NSAID groups (P = .0025). They were also more likely to have one or more whole-body MRIs. Most of the patients on short-course (88%) and long-course (82%) NSAIDs did not undergo a whole-body MRI, whereas most patients (59%) on a second-line treatment underwent at least one and 24% underwent three or more MRIs (P < .001).

More patients on short-course NSAIDs had unifocal disease at diagnosis (72%) than those on long-course NSAIDs (47%) or a second-line treatment (41%; P = .015). Patients on a second-line treatment were also more likely to have symmetric involvement in the same bone (73% vs 16% short-course and 23% long-course NSAIDs) and to have more regions of the body affected (P < .001).

There were significant differences in mean days on NSAID monotherapy and number of NSAIDs trialed. Patients on a second-line treatment had a mean 441 days of NSAID monotherapy compared with 175 days for patients on short-course NSAIDs and 725 for patients on long-course NSAIDs (P < .001). Nearly all the short-course patients (94%) trialed a single NSAID, while more than half the long-course and second-line patients trialed two or more (P < .001).

None of the patients on short-course NSAIDs had complications. More patients on second-line treatments had vertebral height loss (20%) or amplified pain (14%) than long-course patients (13% and 5%, respectively; P = .02).

At the study’s end date, nearly all the patients on short-course NSAIDs were in remission (94%) compared with 71% of patients on long-course NSAIDs and only half of patients (51%) on the second-line treatment (P < .001). None of the patients on short-course NSAIDs had active disease compared with 11% of patients on long-course NSAIDs and 20% of patients on second-line treatments (P = .02).

This study included the largest single-center cohort of patients with CNO in North America, all treated at a multidisciplinary clinic with a protocolized treatment approach, but it remains limited by its retrospective nature and the missing data for 70 patients, Dr. Nowicki said. She noted that whole-body MRI was not systematically performed on all patients, so it was possible patients without a whole-body MRI had undetected asymptomatic lesions.

Despite these limitations, Dr. Oliver said retrospective studies like these can help pediatric rheumatologists get an idea of reasonable therapies to start, how long to keep patients on them, and when to escalate to the next step.

“I hope one day our CNO research will be able to tell us about which is the optimal second-line therapy for patients, such as bisphosphonates vs TNF inhibitors vs DMARDs [disease-modifying antirheumatic drugs],” Dr. Oliver said.

Dr. Nowicki and Dr. Oliver reported no disclosures. Information on study funding was not provided.

A version of this article appeared on Medscape.com .

CORRECTED April 7, 2024 // An earlier version of this article misstated the clinical factors of children with CNO that were significantly associated with the need for second-line treatment, as well as the scope of assessments of aspects of disease involvement and their relationship to total number of days on NSAID monotherapy and the odds of needing a second-line treatment.

Children with chronic nonbacterial osteomyelitis (CNO) who had symmetric bone lesions or multiple affected body regions were more likely to need second-line treatment than were patients without these features, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

CNO is an auto-inflammatory condition that results in sterile inflammatory bone lesions and most commonly affects the long bones of people who are skeletally immature. After a first-line treatment of nonsteroidal anti-inflammatory drugs (NSAIDs), second-line treatments per CARRA guidelines typically include methotrexate or sulfasalazine, tumor necrosis factor (TNF)–alpha inhibitors, and bisphosphonates.

“Since it’s common for there to be long delays before diagnosis of CNO, it is important to start an effective treatment promptly,” Katherine D. Nowicki, MD, of Children’s Hospital Colorado, Aurora, told attendees. “While we have guidance on which treatments to use, it remains unclear which patients are most likely to respond to NSAIDs and which patients will require a second-line treatment.”
 

Findings Helpful for Counseling

Melissa S. Oliver, MD, MS, assistant professor of clinical pediatrics in rheumatology at Riley Children’s Health at Indiana University Health, Indianapolis, who was not involved in the research, said the findings of this study are helpful in “counseling families and patients at that initial visit and having a lower threshold to start a second-line agent if NSAID monotherapy is not working well.”

There are no clinical trials on patients with CNO, Dr. Oliver said, so very little data exist for guiding clinicians on the best therapy to use and how long to keep patients on therapy while minimizing risk for flare when coming off therapy.

A key clinical takeaway for clinicians is being able to tell patients with unifocal disease that they may not need to be on NSAIDs for a long period and can still do well, Dr. Oliver said. For patients with multifocal disease with symmetric bone lesions or multiple regions involved with CNO, “pediatric rheumatologists should have a lower threshold to start a second-line therapy for these patients,” she said.

Findings From Largest Single-Center Cohort in North America

Their topline findings revealed that patients with unifocal disease at diagnosis required 47% fewer total days of NSAID monotherapy treatment than those with multifocal disease at diagnosis, Dr. Nowicki told attendees. Having symmetric bone lesions increased the likelihood of needing a second-line therapy by 6.86 times compared with those without symmetric bone lesions, and for each additional region affected by CNO, the odds of needing a second-line therapy increased by a factor of 1.94, she said.

There were no significant differences in patient ages or sex or in mean interval from symptom onset to treatment onset across treatment groups. However, patients who received second-line treatment did have a significantly longer average time from symptom onset to diagnosis (324 days) than those who had a short course (119 days) or long course (270 days) of NSAIDs (P = .023). Mean follow-up was also significantly longer for patients with second-line treatment (3.8 years) or long-course NSAIDs (2.7 years) than for those with short-course NSAIDs (1.2 years; P < .001).

Mean erythrocyte sedimentation rate or C-reactive protein did not differ across treatment groups nor did presence of a CNO lesion on x-rays at presentation. But significantly more patients in the second-line group had a biopsy (94%) than in the long-course (74%) or short-course (69%) NSAID groups (P = .0025). They were also more likely to have one or more whole-body MRIs. Most of the patients on short-course (88%) and long-course (82%) NSAIDs did not undergo a whole-body MRI, whereas most patients (59%) on a second-line treatment underwent at least one and 24% underwent three or more MRIs (P < .001).

More patients on short-course NSAIDs had unifocal disease at diagnosis (72%) than those on long-course NSAIDs (47%) or a second-line treatment (41%; P = .015). Patients on a second-line treatment were also more likely to have symmetric involvement in the same bone (73% vs 16% short-course and 23% long-course NSAIDs) and to have more regions of the body affected (P < .001).

There were significant differences in mean days on NSAID monotherapy and number of NSAIDs trialed. Patients on a second-line treatment had a mean 441 days of NSAID monotherapy compared with 175 days for patients on short-course NSAIDs and 725 for patients on long-course NSAIDs (P < .001). Nearly all the short-course patients (94%) trialed a single NSAID, while more than half the long-course and second-line patients trialed two or more (P < .001).

None of the patients on short-course NSAIDs had complications. More patients on second-line treatments had vertebral height loss (20%) or amplified pain (14%) than long-course patients (13% and 5%, respectively; P = .02).

At the study’s end date, nearly all the patients on short-course NSAIDs were in remission (94%) compared with 71% of patients on long-course NSAIDs and only half of patients (51%) on the second-line treatment (P < .001). None of the patients on short-course NSAIDs had active disease compared with 11% of patients on long-course NSAIDs and 20% of patients on second-line treatments (P = .02).

This study included the largest single-center cohort of patients with CNO in North America, all treated at a multidisciplinary clinic with a protocolized treatment approach, but it remains limited by its retrospective nature and the missing data for 70 patients, Dr. Nowicki said. She noted that whole-body MRI was not systematically performed on all patients, so it was possible patients without a whole-body MRI had undetected asymptomatic lesions.

Despite these limitations, Dr. Oliver said retrospective studies like these can help pediatric rheumatologists get an idea of reasonable therapies to start, how long to keep patients on them, and when to escalate to the next step.

“I hope one day our CNO research will be able to tell us about which is the optimal second-line therapy for patients, such as bisphosphonates vs TNF inhibitors vs DMARDs [disease-modifying antirheumatic drugs],” Dr. Oliver said.

Dr. Nowicki and Dr. Oliver reported no disclosures. Information on study funding was not provided.

A version of this article appeared on Medscape.com .

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”

Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.

For years, researchers have worked to determine the reasons for sex-linked differences in immune response and autoimmunity, with environmental factors, sex hormones, and X-chromosome inactivation — the process by which a second X chromosome is silenced — all seen as having roles.

More recently, different groups of researchers have homed in on a long noncoding RNA fragment called X-inactive specific transcript, or Xist, as a potential driver of sex bias in autoimmune disease. Xist, which occurs in female mammals, has been known since the 1990s as the master regulator of X-chromosome inactivation, the process by which the second X chromosome is silenced, averting a fatal double dose of X-linked genes.

The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female’s life, allowing X inactivation to be maintained.

But is it possible that Xist, and the many dozens of proteins it recruits to keep that extra X chromosome silent, can also provoke autoimmunity? This is the question that several teams of researchers have been grappling with, resulting in provocative findings and opening exciting new avenues of discovery.
 

Xist Protein Complexes Make Male Mice Vulnerable to Lupus

In February, researchers Howard Chang, MD, PhD, and Diana Dou, PhD, of Stanford University in Stanford, California, made worldwide news when they published results from an experiment using male mice genetically engineered to carry a non-silencing form of Xist on one of their chromosomes.

Xist acts like a scaffold, recruiting multiple protein complexes to help it do its job. Dr. Dou explained in an interview that her team has been eyeing suspiciously for years the dozens of proteins Xist recruits in the process of X-chromosome inactivation, many of which are known autoantigens.

When the mice were injected with pristane, a chemical that induces lupus-like autoimmunity in mice, the Xist-producing males developed symptoms at a rate similar to that of females, while wild-type male mice did not.

By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. “Everything else about the animal is male,” Dr. Dou commented. “You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles. Is just having the particles present in these animals sufficient to increase their autoimmunity? This is what our paper showed: That just having expression of Xist, the presence of these Xist [ribonucleoproteins], is enough in permissive genetic backgrounds to invoke higher incidence and severity of autoimmune disease development in our pristane-induced lupus model.”

The Stanford group sees the Xist protein complex, which they have studied extensively, as a key to understanding how Xist might provoke autoimmunity. Nonetheless, Dr. Dou said, “It’s important to note that there are other contributing factors, which is why not all females develop autoimmunity, and we had very different results in our autoimmune-resistant mouse strain compared to the more autoimmune-prone strain. Xist is a factor, but many factors are required to subvert the checkpoints in immune balance and allow the progression to full-blown autoimmunity.”
 

Faulty X Inactivation and Gene Escape

The understanding that Xist might be implicated in autoimmune disease — and explain some of its female bias — is not new.

About a decade ago, Montserrat Anguera, PhD, a biologist at the University of Pennsylvania, Philadelphia, began looking at the relationship of X-chromosome inactivation, which by definition involves Xist, and lupus.

University of Pennsylvania

Dr. Anguera hypothesized that imperfect X inactivation allowed for greater escape of genes associated with immunity and autoimmunity. Studying patients with lupus, Dr. Anguera found that the silencing process was abnormal, allowing more of these genes to escape the silenced X — including toll-like receptor 7 (TLR-7) and other genes implicated in the pathogenesis of lupus.

“If you get increased expression of certain genes from the [silenced] X, like TLR-7, it can result in autoimmune disease,” Dr. Anguera said. “So what we think is that in the lupus patients, because the silencing is impacted, you’re going to have more expression happening from the inactive X. And then in conjunction with the active X, that’s going to throw off the dosage [of autoimmunity-linked genes]. You’re changing the dosage of genes, and that’s what’s critical.”

Even among patients with lupus whose symptoms are well controlled with medication, “if you look at their T cells and B cells, they still have messed up X inactivation,” Dr. Anguera said. “The Xist RNA that’s supposed to be tethered to the inactive X in a fluffy cloud is not localized, and instead is dispersed all over the nucleus.”

Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. “You also have a host of hormonal and environmental contributors, such as previous viral infections,” she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.

Dr. Anguera said that, while the findings by the Stanford scientists do not explain the full pathogenesis of lupus and related diseases, they still support a strong role for Xist in sex-biased autoimmune diseases. “It’s sort of another take on it,” she said.
 

Is It the Proteins, the RNA, or Both?

The Stanford team points to the proteins recruited by Xist in the process of X-chromosome inactivation as the likely trigger of autoimmunity. However, a group of researchers at Johns Hopkins University in Baltimore, Maryland, made the case in a 2022 paper that Xist RNA itself was dangerous. They found that numerous short RNA sequences within the Xist molecule serve as ligands for TLR-7. And TLR-7 ligation causes plasmacytoid dendritic cells to overproduce type 1 interferon, a classic hallmark of lupus.

Alexander Girgis

“Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon,” explained Brendan Antiochos, MD. “Lupus is an example of that. Sjögren’s syndrome is another. So there’s always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity. And are there specific pathways which could contribute? One of the key pathways that’s been shown in humans and in mice to be important in lupus is toll-like receptor signaling.” Most convincingly, one recent study showed that people who have a gain-of-function mutation in their TLR-7 gene get a spontaneous form of lupus.

Wes Linda

These findings led Erika Darrah, PhD, and her colleague Dr. Antiochos to begin looking more deeply into which RNAs could be triggering this signaling pathway. “We started to think: Well, there is this sex bias. Could it be that women have unique RNAs that could potentially act as triggers for TLR-7 signaling?” Dr. Darrah said.

Dr. Darrah and Dr. Antiochos looked at publicly available genetic data to identify sex-biased sources of self-RNA containing TLR-7 ligands. Xist, they found, was chock full of them. “Every time we analyzed that data, no matter what filter we applied, Xist kept popping out over and over again as the most highly female skewed RNA, the RNA most likely to contain these TLR-7 binding motifs,” Dr. Darrah said. “We started to formulate the hypothesis that Xist was actually promoting responses that were dangerous and pathogenic in lupus.”

That finding led the team to conduct in-vitro experiments that showed different fragments of Xist can activate TLR-7, resulting in higher interferon production. Finally, they looked at blood and kidney cells from women with lupus and found that higher Xist expression correlated with more interferon production, and higher disease activity. “The more Xist, the sicker people were,” Dr. Darrah said.
 

Xist’s Other Functions

Xist was first studied in the 1990s, and most research has centered on its primary role in X-chromosome inactivation. A research group led by Kathrin Plath, PhD, at the University of California, Los Angeles, has been occupied for years with untangling exactly how Xist does what it does. “It’s a very clever RNA, right? It can silence the whole chromosome,” Dr. Plath said in an interview.

In 2021, Dr. Plath and her colleagues established in detail how Xist executes silencing, setting down pairs of molecules in specific spots along the chromosome and building huge protein clouds around them. “We worked on learning where Xist binds and what proteins it binds, drilling down to understand how these proteins and the RNA are coming together.”

Dr. Plath has long suspected that Xist has other functions besides X inactivation, and she and her colleagues are starting to identify them. Early this year they published the surprising finding that Xist can regulate gene expression in autosomes, or non–sex-linked chromosomes, “which it might well also do in cancer cells and lymphocytes,” Dr. Plath said. “And now there is this new evidence of an autoimmune function,” she said. “It’s a super exciting time.”

The different hypotheses surrounding Xist’s role in sex-biased autoimmunity aren’t mutually exclusive, Dr. Plath said. “There’s a tremendous enrichment of proteins occurring” during X inactivation, she said, supporting the Stanford team’s hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers’ understanding that Xist RNA itself is the trigger, “I’m totally open to that,” she said. “Why can’t it be an autoantigen?”

The other model in the field, Dr. Plath noted, is the one proposed by Dr. Anguera — “that there’s [gene] escape from X-inactivation — that females have more escape expression, and that Xist is more dispersed in the lymphocytes [of patients with lupus]. In fact, Xist becoming a little dispersed might make it a better antigen. So I do think everything is possible.”

The plethora of new findings related to autoimmunity has caused Dr. Plath to consider redirecting her lab’s focus toward more translational work, “because we are obviously good at studying Xist.” Among the mysteries Dr. Plath would like to solve is how some genes manage to escape the Xist cloud.

What is needed, she said, is collaboration. “Everyone will come up with different ideas. So I think it’s good to have more people look at things together. Then the field will achieve a breakthrough treatment.”