Rare Diseases

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.”

CORRECTED April 16, 2024 // An earlier version of this article stated incorrect percentages of patients who never received any biologics during the study's 3-year period but improved rapidly or moderately.

Early initiation of biologics — within the first 2 months of symptom presentation — appears to have a significant impact on how rapidly patients with juvenile idiopathic arthritis (JIA) improve, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

“Our study provides evidence that early use of biologics can significantly alter the disease trajectory of patients with JIA,” Mei-Sing Ong, PhD, of Harvard Medical School, Boston, told attendees. At the same time, however, not all patients who improved rapidly during a 3-year follow-up period needed biologics, a finding that Ong said the researchers are continuing to investigate.

Marinka Twilt, MD, MScE, PhD, chair of CARRA’s JIA Research Committee and a pediatric rheumatologist and clinician scientist at Alberta Children’s Hospital in Calgary, Canada, was not involved in the research but said the continued sustained remission in patients who improved rapidly is very reassuring.

Dr. Twilt

“We always wonder if initial response will be sustained or if patients tend to flare after the initial treatment,” Dr. Twilt told this news organization. “To see the sustained response up to 3 years is fantastic.” She added that it would be enlightening to see more information about patients who rapidly improved over 3 years, including whether they were still taking a [conventional disease-modifying antirheumatic drug (DMARD)] and/or biologic.

“A new diagnosis can be overwhelming for families, and this sometimes leads to step-up therapy to not overwhelm them more with information on new drugs,” Dr. Twilt said. “This study shows that an earlier start is beneficial, and this should be discussed with families early on so there is less delay in early treatment.”

Canada and many US states currently require 3 months of conventional DMARD treatment before patients can start a biologic, Dr. Twilt said, yet “this study shows the additive benefit of using a biologic within 2 months of starting a DMARD, which hopefully will lead to insurance companies adopting this threshold.”

The STOP-JIA study is a prospective observational study that compares the effectiveness of three different treatment plans for JIA. A Step-Up cohort of 257 patients received conventional antirheumatic monotherapy initially, with a biologic added at 3 months or later as needed. The Early Combination cohort of 100 patients received conventional antirheumatic therapy with a biologic from the start. The Biologic First cohort of 43 patients began taking a biologic as a first-line therapy.

In previously reported results of the study at 12 months’ follow-up, there was no significant difference between the Step-Up and Biologic First groups, but there were significant differences between the Step-Up and Early Combination groups. Significantly more patients in the Early Combination group (58.8%) than in the Step-Up group (42.8%) had inactive disease, based on the clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS-10) (P = .03). Similarly, 81% of Early Combination patients achieved the American College of Rheumatology 70% improvement criteria, compared with 62% of the Step-Up patients (P = .01).

To learn whether the timing of starting a biologic influenced the disease trajectory over time, the researchers compared subgroups of patients with similar trajectories.

“Assessing treatment outcomes at a single point in time does not give us a complete picture of the effects of treatment on disease trajectory, which is an important outcome given that JIA is characterized by a relapsing-remitting course,” Dr. Ong told attendees.

Patients were sorted in the slow, moderate, or rapid improvement trajectories. In previously reported data at 12 months’ follow-up, patients’ odds of achieving rapid improvement were 3.6 times greater if they had started a biologic within 3 months.

This study compared patients’ trajectories over 3 years in the 259 patients (65% of the original cohort) who had at least one cJADAS-10 assessment in each year of follow-up. Most patients (66.8%) were in the rapid improvement class, with 25.9% in the moderate improvement class and 7.3% in the slow improvement class.

Patients in the rapid improvement group achieved inactive disease (cJADAS-10 of 2.5 or less) within 1 year and maintained inactive disease through the second and third years. The moderate and low improvement groups both had higher disease activity at baseline, but the moderate group continued to improve in years 2 and 3, with minimal disease by year 3, on the basis of the cJADAS-10 scores of 2.5-5. The slow group continued to experience moderate disease activity during years 2 and 3.

The findings also revealed that the earlier patients began a biologic, the more likely they were to be in the rapid improvement group than the slow improvement group. Participants who started a biologic in the first month had more than five times greater odds of being in the rapid improvement group than in the slow improvement group (odds ratio [OR], 5.33; P = .017).

Those who started a biologic in the second month were also more likely to be in the rapid improvement group (OR, 2.67; P = .032). For those who began a biologic by the third month, the odds of improving rapidly were not statistically significant, though Ong noted that could have been because of the small sample size. There was also no significant difference between those who improved moderately vs slowly based on when a biologic was initiated.

It would be helpful to learn whether any of the patients in the rapid improvement group were able to stop medications or whether they all continued treatment during the 3 years of follow-up, Dr. Twilt said. “Does early treatment with biologics not only lead to early remission after initiation but also to the possibility of stopping treatment earlier and remaining in remission?” she asked.

The researchers also found that not all patients needed biologics to end up in the rapid improvement group. Among patients who never received any biologics during the 3-year period, 83% improved rapidly and 17% improved moderately. Yet the researchers identified no significant differences in demographics or clinical factors between patients who received biologics and those who did not.

“The fact that there is a group of patients in the rapid response group who never need a biologic is of great interest, as we always want to treat patients early with the medications they need, but we also want to avoid overtreating patients,” Dr. Twilt said. It’s important to find out what differentiates those patients and whether it is possible to predict which patients do not need biologics early on, she said.

Dr. Ong said the research team is working to develop machine learning methods to improve risk stratification in hopes of addressing that question.

Dr. Ong and Dr. Twilt reported no disclosures. The research was funded by CARRA and the Patient-Centered Outcomes Research Institute.
 

A version of this article appeared on Medscape.com .

CORRECTED April 16, 2024 // An earlier version of this article stated incorrect percentages of patients who never received any biologics during the study's 3-year period but improved rapidly or moderately.

Early initiation of biologics — within the first 2 months of symptom presentation — appears to have a significant impact on how rapidly patients with juvenile idiopathic arthritis (JIA) improve, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

“Our study provides evidence that early use of biologics can significantly alter the disease trajectory of patients with JIA,” Mei-Sing Ong, PhD, of Harvard Medical School, Boston, told attendees. At the same time, however, not all patients who improved rapidly during a 3-year follow-up period needed biologics, a finding that Ong said the researchers are continuing to investigate.

Marinka Twilt, MD, MScE, PhD, chair of CARRA’s JIA Research Committee and a pediatric rheumatologist and clinician scientist at Alberta Children’s Hospital in Calgary, Canada, was not involved in the research but said the continued sustained remission in patients who improved rapidly is very reassuring.

Dr. Twilt

“We always wonder if initial response will be sustained or if patients tend to flare after the initial treatment,” Dr. Twilt told this news organization. “To see the sustained response up to 3 years is fantastic.” She added that it would be enlightening to see more information about patients who rapidly improved over 3 years, including whether they were still taking a [conventional disease-modifying antirheumatic drug (DMARD)] and/or biologic.

“A new diagnosis can be overwhelming for families, and this sometimes leads to step-up therapy to not overwhelm them more with information on new drugs,” Dr. Twilt said. “This study shows that an earlier start is beneficial, and this should be discussed with families early on so there is less delay in early treatment.”

Canada and many US states currently require 3 months of conventional DMARD treatment before patients can start a biologic, Dr. Twilt said, yet “this study shows the additive benefit of using a biologic within 2 months of starting a DMARD, which hopefully will lead to insurance companies adopting this threshold.”

The STOP-JIA study is a prospective observational study that compares the effectiveness of three different treatment plans for JIA. A Step-Up cohort of 257 patients received conventional antirheumatic monotherapy initially, with a biologic added at 3 months or later as needed. The Early Combination cohort of 100 patients received conventional antirheumatic therapy with a biologic from the start. The Biologic First cohort of 43 patients began taking a biologic as a first-line therapy.

In previously reported results of the study at 12 months’ follow-up, there was no significant difference between the Step-Up and Biologic First groups, but there were significant differences between the Step-Up and Early Combination groups. Significantly more patients in the Early Combination group (58.8%) than in the Step-Up group (42.8%) had inactive disease, based on the clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS-10) (P = .03). Similarly, 81% of Early Combination patients achieved the American College of Rheumatology 70% improvement criteria, compared with 62% of the Step-Up patients (P = .01).

To learn whether the timing of starting a biologic influenced the disease trajectory over time, the researchers compared subgroups of patients with similar trajectories.

“Assessing treatment outcomes at a single point in time does not give us a complete picture of the effects of treatment on disease trajectory, which is an important outcome given that JIA is characterized by a relapsing-remitting course,” Dr. Ong told attendees.

Patients were sorted in the slow, moderate, or rapid improvement trajectories. In previously reported data at 12 months’ follow-up, patients’ odds of achieving rapid improvement were 3.6 times greater if they had started a biologic within 3 months.

This study compared patients’ trajectories over 3 years in the 259 patients (65% of the original cohort) who had at least one cJADAS-10 assessment in each year of follow-up. Most patients (66.8%) were in the rapid improvement class, with 25.9% in the moderate improvement class and 7.3% in the slow improvement class.

Patients in the rapid improvement group achieved inactive disease (cJADAS-10 of 2.5 or less) within 1 year and maintained inactive disease through the second and third years. The moderate and low improvement groups both had higher disease activity at baseline, but the moderate group continued to improve in years 2 and 3, with minimal disease by year 3, on the basis of the cJADAS-10 scores of 2.5-5. The slow group continued to experience moderate disease activity during years 2 and 3.

The findings also revealed that the earlier patients began a biologic, the more likely they were to be in the rapid improvement group than the slow improvement group. Participants who started a biologic in the first month had more than five times greater odds of being in the rapid improvement group than in the slow improvement group (odds ratio [OR], 5.33; P = .017).

Those who started a biologic in the second month were also more likely to be in the rapid improvement group (OR, 2.67; P = .032). For those who began a biologic by the third month, the odds of improving rapidly were not statistically significant, though Ong noted that could have been because of the small sample size. There was also no significant difference between those who improved moderately vs slowly based on when a biologic was initiated.

It would be helpful to learn whether any of the patients in the rapid improvement group were able to stop medications or whether they all continued treatment during the 3 years of follow-up, Dr. Twilt said. “Does early treatment with biologics not only lead to early remission after initiation but also to the possibility of stopping treatment earlier and remaining in remission?” she asked.

The researchers also found that not all patients needed biologics to end up in the rapid improvement group. Among patients who never received any biologics during the 3-year period, 83% improved rapidly and 17% improved moderately. Yet the researchers identified no significant differences in demographics or clinical factors between patients who received biologics and those who did not.

“The fact that there is a group of patients in the rapid response group who never need a biologic is of great interest, as we always want to treat patients early with the medications they need, but we also want to avoid overtreating patients,” Dr. Twilt said. It’s important to find out what differentiates those patients and whether it is possible to predict which patients do not need biologics early on, she said.

Dr. Ong said the research team is working to develop machine learning methods to improve risk stratification in hopes of addressing that question.

Dr. Ong and Dr. Twilt reported no disclosures. The research was funded by CARRA and the Patient-Centered Outcomes Research Institute.
 

A version of this article appeared on Medscape.com .

CORRECTED April 16, 2024 // An earlier version of this article stated incorrect percentages of patients who never received any biologics during the study's 3-year period but improved rapidly or moderately.

Early initiation of biologics — within the first 2 months of symptom presentation — appears to have a significant impact on how rapidly patients with juvenile idiopathic arthritis (JIA) improve, according to findings presented at the annual scientific meeting of the Childhood Arthritis and Rheumatology Research Alliance.

“Our study provides evidence that early use of biologics can significantly alter the disease trajectory of patients with JIA,” Mei-Sing Ong, PhD, of Harvard Medical School, Boston, told attendees. At the same time, however, not all patients who improved rapidly during a 3-year follow-up period needed biologics, a finding that Ong said the researchers are continuing to investigate.

Marinka Twilt, MD, MScE, PhD, chair of CARRA’s JIA Research Committee and a pediatric rheumatologist and clinician scientist at Alberta Children’s Hospital in Calgary, Canada, was not involved in the research but said the continued sustained remission in patients who improved rapidly is very reassuring.

Dr. Twilt

“We always wonder if initial response will be sustained or if patients tend to flare after the initial treatment,” Dr. Twilt told this news organization. “To see the sustained response up to 3 years is fantastic.” She added that it would be enlightening to see more information about patients who rapidly improved over 3 years, including whether they were still taking a [conventional disease-modifying antirheumatic drug (DMARD)] and/or biologic.

“A new diagnosis can be overwhelming for families, and this sometimes leads to step-up therapy to not overwhelm them more with information on new drugs,” Dr. Twilt said. “This study shows that an earlier start is beneficial, and this should be discussed with families early on so there is less delay in early treatment.”

Canada and many US states currently require 3 months of conventional DMARD treatment before patients can start a biologic, Dr. Twilt said, yet “this study shows the additive benefit of using a biologic within 2 months of starting a DMARD, which hopefully will lead to insurance companies adopting this threshold.”

The STOP-JIA study is a prospective observational study that compares the effectiveness of three different treatment plans for JIA. A Step-Up cohort of 257 patients received conventional antirheumatic monotherapy initially, with a biologic added at 3 months or later as needed. The Early Combination cohort of 100 patients received conventional antirheumatic therapy with a biologic from the start. The Biologic First cohort of 43 patients began taking a biologic as a first-line therapy.

In previously reported results of the study at 12 months’ follow-up, there was no significant difference between the Step-Up and Biologic First groups, but there were significant differences between the Step-Up and Early Combination groups. Significantly more patients in the Early Combination group (58.8%) than in the Step-Up group (42.8%) had inactive disease, based on the clinical Juvenile Arthritis Disease Activity Score 10 (cJADAS-10) (P = .03). Similarly, 81% of Early Combination patients achieved the American College of Rheumatology 70% improvement criteria, compared with 62% of the Step-Up patients (P = .01).

To learn whether the timing of starting a biologic influenced the disease trajectory over time, the researchers compared subgroups of patients with similar trajectories.

“Assessing treatment outcomes at a single point in time does not give us a complete picture of the effects of treatment on disease trajectory, which is an important outcome given that JIA is characterized by a relapsing-remitting course,” Dr. Ong told attendees.

Patients were sorted in the slow, moderate, or rapid improvement trajectories. In previously reported data at 12 months’ follow-up, patients’ odds of achieving rapid improvement were 3.6 times greater if they had started a biologic within 3 months.

This study compared patients’ trajectories over 3 years in the 259 patients (65% of the original cohort) who had at least one cJADAS-10 assessment in each year of follow-up. Most patients (66.8%) were in the rapid improvement class, with 25.9% in the moderate improvement class and 7.3% in the slow improvement class.

Patients in the rapid improvement group achieved inactive disease (cJADAS-10 of 2.5 or less) within 1 year and maintained inactive disease through the second and third years. The moderate and low improvement groups both had higher disease activity at baseline, but the moderate group continued to improve in years 2 and 3, with minimal disease by year 3, on the basis of the cJADAS-10 scores of 2.5-5. The slow group continued to experience moderate disease activity during years 2 and 3.

The findings also revealed that the earlier patients began a biologic, the more likely they were to be in the rapid improvement group than the slow improvement group. Participants who started a biologic in the first month had more than five times greater odds of being in the rapid improvement group than in the slow improvement group (odds ratio [OR], 5.33; P = .017).

Those who started a biologic in the second month were also more likely to be in the rapid improvement group (OR, 2.67; P = .032). For those who began a biologic by the third month, the odds of improving rapidly were not statistically significant, though Ong noted that could have been because of the small sample size. There was also no significant difference between those who improved moderately vs slowly based on when a biologic was initiated.

It would be helpful to learn whether any of the patients in the rapid improvement group were able to stop medications or whether they all continued treatment during the 3 years of follow-up, Dr. Twilt said. “Does early treatment with biologics not only lead to early remission after initiation but also to the possibility of stopping treatment earlier and remaining in remission?” she asked.

The researchers also found that not all patients needed biologics to end up in the rapid improvement group. Among patients who never received any biologics during the 3-year period, 83% improved rapidly and 17% improved moderately. Yet the researchers identified no significant differences in demographics or clinical factors between patients who received biologics and those who did not.

“The fact that there is a group of patients in the rapid response group who never need a biologic is of great interest, as we always want to treat patients early with the medications they need, but we also want to avoid overtreating patients,” Dr. Twilt said. It’s important to find out what differentiates those patients and whether it is possible to predict which patients do not need biologics early on, she said.

Dr. Ong said the research team is working to develop machine learning methods to improve risk stratification in hopes of addressing that question.

Dr. Ong and Dr. Twilt reported no disclosures. The research was funded by CARRA and the Patient-Centered Outcomes Research Institute.
 

A version of this article appeared on Medscape.com .

PIK3CA-related overgrowth spectrum (PROS) encompasses a set of rare disorders caused by pathogenic variants in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Under normal circumstances, this pathway is activated by the stimulation of tyrosine kinase receptors that leads to tightly regulated cell growth, proliferation, and migration. However, in PROS, pathogenic variants in the PI3KCA gene lead to an abnormal accumulation of the enzyme at the cell membrane, resulting in persistent activation of the PI3K/AKT/mTOR pathway and dysregulated cell overgrowth.

Excessive cell growth and proliferation leads to the overgrowth of tissues and organs characteristically seen in PROS. Because PIK3CA pathogenic variants are not present in every cell, only certain areas of the body are affected by overgrowth; these can range from isolated digits to whole limbs, the trunk, or one or more tissues or organs.

The diagnosis of PROS is typically confirmed through genetic testing of the PIK3CA gene, which can identify the specific pathogenic variants responsible for the disorder.

Here are five things to know about PROS.

1. PROS comprises a heterogeneous group of rare congenital diseases.

PROS is a term used to describe a group of rare congenital disorders that are characterized by abnormal, segmental, or lateralized growth of various body tissues and regions. These disorders are linked by a common cause: mosaic pathogenic gain-of-function variants in the PIK3CA gene. The genetic pathogenic variants that cause these disorders are not passed down from parent to child but instead result from changes to genes during embryonic development.

PROS encompasses a range of clinical entities, each with its own set of characteristics but sharing phenotypic similarities. These clinical entities include:

• Fibroadipose hyperplasia (also called fibroadipose overgrowth)
• CLOVES syndrome (congenital lipomatosis overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal or spinal abnormalities)
• Klippel-Trenaunay syndrome
• Megalencephaly-capillary malformation (MCAP) syndrome
• Hemihyperplasia‐multiple lipomatosis syndrome
• Dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia
• Facial infiltrating lipomatosis (a congenital disorder that causes overgrowth of one side of the face)
• Macrodactyly
• Isolated tissue dysplasia-overgrowth phenotypes: lymphatic malformations, vascular malformations, venous malformations, lipomatosis
• CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth)

The global epidemiologic characteristics of PROS are not well documented, but it is estimated that each of these conditions individually has a prevalence rate of fewer than 1 case per million population, and the collective prevalence of PROS-related syndromes is 14 cases per million population. Owing to its low prevalence and the variety of diseases it encompasses, PROS is classified as a rare disease.

2. PROS diseases have specific phenotypic features with common characteristics that result in overlapping phenomena.

The severity of clinical presentation varies in patients with PROS; some have tissue-specific distribution whereas others are more pleiotropic. In general, this condition is marked by segmental overgrowth of multiple tissues, including:

• Organs and other tissues: Excessive and asymmetric overgrowth can affect the skin, bones, muscles, and other structures, leading to disfigurement and functional impairments. The overgrowth typically follows a distal to proximal pattern, mostly unilateral and affecting the lower limbs.
• Brain: Enlargement of specific structures, including ventriculomegaly, a thick corpus callosum, or cerebellar tonsillar ectopia, can cause megalencephaly, which can lead to developmental delay, seizures, cortical dysplasia, and/or hydrocephalus.
• Vasculature: Capillary, venous, arteriovenous, and lymphatic malformations are common and occur in about 43% of patients. These abnormalities can contribute to additional complications, including swelling, pain, and increased risk for bleeding.
• Skin: Thickened epidermal nevi and pigmentary anomalies, such as hyperpigmentation or hypopigmentation, are common. These skin manifestations can be early signs of PROS and may aid in diagnosis.
• Skeletal system: Anomalies can include polydactyly, macrodactyly, macrodontia, and scoliosis or other spinal abnormalities.
• Lipomatosis overgrowth: This can occur with or without regional reduction of adipose tissue on the trunk and limbs.
• Lymphatic system: Isolated malformations may include dilated vascular channels lined by lymphatic endothelial cells, which may lead to fluid-filled cysts that usually grow proportionally with the growth of the affected person and may cause pain or significant morbidity if they are infiltrative.

3. Treatment for a PROS disorder may involve targeted options, surgical interventions, and supportive care.

Historically, treatment for overgrowth syndromes such as PROS primarily involved conservative management, focusing on addressing complications through surgical excision, orthopedic surgery, sclerotherapy, embolization, and compressive therapies. However, these strategies often proved insufficient, and patients frequently experienced relapse and progression of the condition. Indeed, PROS is a complex condition that requires a multifaceted treatment approach.

The discovery of the PIK3/AKT/mTOR activation pathway in these syndromes marked a significant therapeutic breakthrough. Targeted therapies, such as the use of mTOR inhibitors like sirolimus, have shown benefits in treating venous and lymphatic malformations in patients with PROS. More recently, a selective PIK3CA inhibitor, alpelisib, has been approved. This drug has demonstrated remarkable improvements in patients with various PROS phenotypes, including reductions in capillary malformations; cessation of chronic gastrointestinal bleeding; and improvements in scoliosis and cognitive function, particularly in patients with MCAP syndrome.

Supportive care is also a critical component of managing PROS. This includes surgical interventions for significant overgrowth, orthopedic care for scoliosis and leg-length discrepancies, and neurosurgical interventions for neurologic complications such as obstructive hydrocephalus and epilepsy. Vascular and lymphatic malformations may be treated with sclerotherapy, laser therapy, or medications such as sirolimus. Additionally, routine treatment for associated conditions such as cardiac and renal abnormalities, intellectual disabilities, polydactyly, coagulopathy, and hypothyroidism is essential. For those with pain, identifying and treating the underlying cause is crucial. In cases of severe persistent hypoglycemia, ongoing treatment, which may include cornstarch administration, is necessary. Owing to the complexity and varied manifestations of PROS, specialized multidisciplinary care for diagnosis, follow-up, and optimal management is recommended.

4. PROS is a heterogeneous condition, and the clinical presentation can vary widely among affected individuals.

PROS is a complex and heterogeneous condition characterized by a wide range of clinical presentations, reflecting the diversity of affected tissues and the extent of overgrowth. Phenotypes within PROS are diverse and can range from a single lesion (ie, solitary macrodactyly) to systemic diseases (ie, Klippel-Trenaunay syndrome and CLOVES syndrome).

This heterogeneity is primarily due to the timing of the onset of the somatic causative PIK3CA pathogenic variants during embryonic and fetal development, influencing the degree of mosaicism and the combination of tissues involved (eg, neural progenitor cell pathogenic variants can lead to postnatal megalencephaly and hydrocephalus). Moreover, different gain-of-function variants in PIK3CA lead to varying levels of hyperactivation of the PI3K/AKT/mTOR pathway, resulting in diverse severity of abnormal proliferation of mesodermal and ectodermal tissues from embryogenesis onward.

This spectrum of symptoms underscores the complexity and variability of PROS, necessitating a tailored approach to diagnosis and management.

5. Regular surveillance is crucial for the effective management of PROS

Comprehensive and regular monitoring is essential to address the diverse and evolving clinical manifestations of PROS. During each medical visit, it is essential to measure growth parameters, including head circumference and the length of arms, hands, legs, and feet. This assessment helps identify any new neurologic symptoms such as seizures, changes in muscle tone, or signs of Chiari malformation.

Additionally, monitoring the patient’s developmental progress, behavior, and motor skills is vital. Clinical assessments for conditions like scoliosis and abdominal examinations for organomegaly or abdominal masses are also recommended.

Imaging plays a significant role in the ongoing evaluation of PROS. Serial head MRI is advised, with the frequency depending on the initial severity of findings and the degree of brain maturation. For patients with central nervous system overgrowth or dysplasia, brain MRI every 6 months until age 2 years, followed by annual scans until age 8 years, is recommended to monitor for progressive hydrocephalus and Chiari malformation.

Further specialized assessments may be required based on individual clinical indications. These include monitoring of vascular and lymphatic malformations, radiographs of limbs in cases of limb overgrowth, and follow-up ultrasonography or MRI for truncal overgrowth. Spinal MRI is necessary for patients with scoliosis or spinal deformities.

In cases of persistent hypoglycemia, particularly those needing ongoing treatment, blood glucose monitoring and evaluation of the hypothalamic-pituitary-adrenal axis are important.

Postsurgical patients, especially those with the CLOVES phenotype or vascular malformations, should have a hematology consultation to assess thrombosis and coagulopathy risks. The use of renal ultrasonography every 3 months until age 8 years is suggested for tumor screening, such as Wilms tumor, although this practice is somewhat controversial.

These comprehensive and tailored approaches are critical in managing the complex and varied aspects of PROS, ensuring optimal care and monitoring for affected individuals.

Dr. Keppler-Noreuil is professor of pediatrics, division of genetics and metabolism, University of Wisconsin School of Medicine and Public Health; clinical director, department of pediatrics, division of genetics and metabolism; program director, medical genetics and genomics residency, Waisman Center & UW Pediatric Specialty Clinics, University of Wisconsin. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

PIK3CA-related overgrowth spectrum (PROS) encompasses a set of rare disorders caused by pathogenic variants in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Under normal circumstances, this pathway is activated by the stimulation of tyrosine kinase receptors that leads to tightly regulated cell growth, proliferation, and migration. However, in PROS, pathogenic variants in the PI3KCA gene lead to an abnormal accumulation of the enzyme at the cell membrane, resulting in persistent activation of the PI3K/AKT/mTOR pathway and dysregulated cell overgrowth.

Excessive cell growth and proliferation leads to the overgrowth of tissues and organs characteristically seen in PROS. Because PIK3CA pathogenic variants are not present in every cell, only certain areas of the body are affected by overgrowth; these can range from isolated digits to whole limbs, the trunk, or one or more tissues or organs.

The diagnosis of PROS is typically confirmed through genetic testing of the PIK3CA gene, which can identify the specific pathogenic variants responsible for the disorder.

Here are five things to know about PROS.

1. PROS comprises a heterogeneous group of rare congenital diseases.

PROS is a term used to describe a group of rare congenital disorders that are characterized by abnormal, segmental, or lateralized growth of various body tissues and regions. These disorders are linked by a common cause: mosaic pathogenic gain-of-function variants in the PIK3CA gene. The genetic pathogenic variants that cause these disorders are not passed down from parent to child but instead result from changes to genes during embryonic development.

PROS encompasses a range of clinical entities, each with its own set of characteristics but sharing phenotypic similarities. These clinical entities include:

• Fibroadipose hyperplasia (also called fibroadipose overgrowth)
• CLOVES syndrome (congenital lipomatosis overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal or spinal abnormalities)
• Klippel-Trenaunay syndrome
• Megalencephaly-capillary malformation (MCAP) syndrome
• Hemihyperplasia‐multiple lipomatosis syndrome
• Dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia
• Facial infiltrating lipomatosis (a congenital disorder that causes overgrowth of one side of the face)
• Macrodactyly
• Isolated tissue dysplasia-overgrowth phenotypes: lymphatic malformations, vascular malformations, venous malformations, lipomatosis
• CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth)

The global epidemiologic characteristics of PROS are not well documented, but it is estimated that each of these conditions individually has a prevalence rate of fewer than 1 case per million population, and the collective prevalence of PROS-related syndromes is 14 cases per million population. Owing to its low prevalence and the variety of diseases it encompasses, PROS is classified as a rare disease.

2. PROS diseases have specific phenotypic features with common characteristics that result in overlapping phenomena.

The severity of clinical presentation varies in patients with PROS; some have tissue-specific distribution whereas others are more pleiotropic. In general, this condition is marked by segmental overgrowth of multiple tissues, including:

• Organs and other tissues: Excessive and asymmetric overgrowth can affect the skin, bones, muscles, and other structures, leading to disfigurement and functional impairments. The overgrowth typically follows a distal to proximal pattern, mostly unilateral and affecting the lower limbs.
• Brain: Enlargement of specific structures, including ventriculomegaly, a thick corpus callosum, or cerebellar tonsillar ectopia, can cause megalencephaly, which can lead to developmental delay, seizures, cortical dysplasia, and/or hydrocephalus.
• Vasculature: Capillary, venous, arteriovenous, and lymphatic malformations are common and occur in about 43% of patients. These abnormalities can contribute to additional complications, including swelling, pain, and increased risk for bleeding.
• Skin: Thickened epidermal nevi and pigmentary anomalies, such as hyperpigmentation or hypopigmentation, are common. These skin manifestations can be early signs of PROS and may aid in diagnosis.
• Skeletal system: Anomalies can include polydactyly, macrodactyly, macrodontia, and scoliosis or other spinal abnormalities.
• Lipomatosis overgrowth: This can occur with or without regional reduction of adipose tissue on the trunk and limbs.
• Lymphatic system: Isolated malformations may include dilated vascular channels lined by lymphatic endothelial cells, which may lead to fluid-filled cysts that usually grow proportionally with the growth of the affected person and may cause pain or significant morbidity if they are infiltrative.

3. Treatment for a PROS disorder may involve targeted options, surgical interventions, and supportive care.

Historically, treatment for overgrowth syndromes such as PROS primarily involved conservative management, focusing on addressing complications through surgical excision, orthopedic surgery, sclerotherapy, embolization, and compressive therapies. However, these strategies often proved insufficient, and patients frequently experienced relapse and progression of the condition. Indeed, PROS is a complex condition that requires a multifaceted treatment approach.

The discovery of the PIK3/AKT/mTOR activation pathway in these syndromes marked a significant therapeutic breakthrough. Targeted therapies, such as the use of mTOR inhibitors like sirolimus, have shown benefits in treating venous and lymphatic malformations in patients with PROS. More recently, a selective PIK3CA inhibitor, alpelisib, has been approved. This drug has demonstrated remarkable improvements in patients with various PROS phenotypes, including reductions in capillary malformations; cessation of chronic gastrointestinal bleeding; and improvements in scoliosis and cognitive function, particularly in patients with MCAP syndrome.

Supportive care is also a critical component of managing PROS. This includes surgical interventions for significant overgrowth, orthopedic care for scoliosis and leg-length discrepancies, and neurosurgical interventions for neurologic complications such as obstructive hydrocephalus and epilepsy. Vascular and lymphatic malformations may be treated with sclerotherapy, laser therapy, or medications such as sirolimus. Additionally, routine treatment for associated conditions such as cardiac and renal abnormalities, intellectual disabilities, polydactyly, coagulopathy, and hypothyroidism is essential. For those with pain, identifying and treating the underlying cause is crucial. In cases of severe persistent hypoglycemia, ongoing treatment, which may include cornstarch administration, is necessary. Owing to the complexity and varied manifestations of PROS, specialized multidisciplinary care for diagnosis, follow-up, and optimal management is recommended.

4. PROS is a heterogeneous condition, and the clinical presentation can vary widely among affected individuals.

PROS is a complex and heterogeneous condition characterized by a wide range of clinical presentations, reflecting the diversity of affected tissues and the extent of overgrowth. Phenotypes within PROS are diverse and can range from a single lesion (ie, solitary macrodactyly) to systemic diseases (ie, Klippel-Trenaunay syndrome and CLOVES syndrome).

This heterogeneity is primarily due to the timing of the onset of the somatic causative PIK3CA pathogenic variants during embryonic and fetal development, influencing the degree of mosaicism and the combination of tissues involved (eg, neural progenitor cell pathogenic variants can lead to postnatal megalencephaly and hydrocephalus). Moreover, different gain-of-function variants in PIK3CA lead to varying levels of hyperactivation of the PI3K/AKT/mTOR pathway, resulting in diverse severity of abnormal proliferation of mesodermal and ectodermal tissues from embryogenesis onward.

This spectrum of symptoms underscores the complexity and variability of PROS, necessitating a tailored approach to diagnosis and management.

5. Regular surveillance is crucial for the effective management of PROS

Comprehensive and regular monitoring is essential to address the diverse and evolving clinical manifestations of PROS. During each medical visit, it is essential to measure growth parameters, including head circumference and the length of arms, hands, legs, and feet. This assessment helps identify any new neurologic symptoms such as seizures, changes in muscle tone, or signs of Chiari malformation.

Additionally, monitoring the patient’s developmental progress, behavior, and motor skills is vital. Clinical assessments for conditions like scoliosis and abdominal examinations for organomegaly or abdominal masses are also recommended.

Imaging plays a significant role in the ongoing evaluation of PROS. Serial head MRI is advised, with the frequency depending on the initial severity of findings and the degree of brain maturation. For patients with central nervous system overgrowth or dysplasia, brain MRI every 6 months until age 2 years, followed by annual scans until age 8 years, is recommended to monitor for progressive hydrocephalus and Chiari malformation.

Further specialized assessments may be required based on individual clinical indications. These include monitoring of vascular and lymphatic malformations, radiographs of limbs in cases of limb overgrowth, and follow-up ultrasonography or MRI for truncal overgrowth. Spinal MRI is necessary for patients with scoliosis or spinal deformities.

In cases of persistent hypoglycemia, particularly those needing ongoing treatment, blood glucose monitoring and evaluation of the hypothalamic-pituitary-adrenal axis are important.

Postsurgical patients, especially those with the CLOVES phenotype or vascular malformations, should have a hematology consultation to assess thrombosis and coagulopathy risks. The use of renal ultrasonography every 3 months until age 8 years is suggested for tumor screening, such as Wilms tumor, although this practice is somewhat controversial.

These comprehensive and tailored approaches are critical in managing the complex and varied aspects of PROS, ensuring optimal care and monitoring for affected individuals.

Dr. Keppler-Noreuil is professor of pediatrics, division of genetics and metabolism, University of Wisconsin School of Medicine and Public Health; clinical director, department of pediatrics, division of genetics and metabolism; program director, medical genetics and genomics residency, Waisman Center & UW Pediatric Specialty Clinics, University of Wisconsin. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

PIK3CA-related overgrowth spectrum (PROS) encompasses a set of rare disorders caused by pathogenic variants in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Under normal circumstances, this pathway is activated by the stimulation of tyrosine kinase receptors that leads to tightly regulated cell growth, proliferation, and migration. However, in PROS, pathogenic variants in the PI3KCA gene lead to an abnormal accumulation of the enzyme at the cell membrane, resulting in persistent activation of the PI3K/AKT/mTOR pathway and dysregulated cell overgrowth.

Excessive cell growth and proliferation leads to the overgrowth of tissues and organs characteristically seen in PROS. Because PIK3CA pathogenic variants are not present in every cell, only certain areas of the body are affected by overgrowth; these can range from isolated digits to whole limbs, the trunk, or one or more tissues or organs.

The diagnosis of PROS is typically confirmed through genetic testing of the PIK3CA gene, which can identify the specific pathogenic variants responsible for the disorder.

Here are five things to know about PROS.

1. PROS comprises a heterogeneous group of rare congenital diseases.

PROS is a term used to describe a group of rare congenital disorders that are characterized by abnormal, segmental, or lateralized growth of various body tissues and regions. These disorders are linked by a common cause: mosaic pathogenic gain-of-function variants in the PIK3CA gene. The genetic pathogenic variants that cause these disorders are not passed down from parent to child but instead result from changes to genes during embryonic development.

PROS encompasses a range of clinical entities, each with its own set of characteristics but sharing phenotypic similarities. These clinical entities include:

• Fibroadipose hyperplasia (also called fibroadipose overgrowth)
• CLOVES syndrome (congenital lipomatosis overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal or spinal abnormalities)
• Klippel-Trenaunay syndrome
• Megalencephaly-capillary malformation (MCAP) syndrome
• Hemihyperplasia‐multiple lipomatosis syndrome
• Dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia
• Facial infiltrating lipomatosis (a congenital disorder that causes overgrowth of one side of the face)
• Macrodactyly
• Isolated tissue dysplasia-overgrowth phenotypes: lymphatic malformations, vascular malformations, venous malformations, lipomatosis
• CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry, and partial/generalized overgrowth)

The global epidemiologic characteristics of PROS are not well documented, but it is estimated that each of these conditions individually has a prevalence rate of fewer than 1 case per million population, and the collective prevalence of PROS-related syndromes is 14 cases per million population. Owing to its low prevalence and the variety of diseases it encompasses, PROS is classified as a rare disease.

2. PROS diseases have specific phenotypic features with common characteristics that result in overlapping phenomena.

The severity of clinical presentation varies in patients with PROS; some have tissue-specific distribution whereas others are more pleiotropic. In general, this condition is marked by segmental overgrowth of multiple tissues, including:

• Organs and other tissues: Excessive and asymmetric overgrowth can affect the skin, bones, muscles, and other structures, leading to disfigurement and functional impairments. The overgrowth typically follows a distal to proximal pattern, mostly unilateral and affecting the lower limbs.
• Brain: Enlargement of specific structures, including ventriculomegaly, a thick corpus callosum, or cerebellar tonsillar ectopia, can cause megalencephaly, which can lead to developmental delay, seizures, cortical dysplasia, and/or hydrocephalus.
• Vasculature: Capillary, venous, arteriovenous, and lymphatic malformations are common and occur in about 43% of patients. These abnormalities can contribute to additional complications, including swelling, pain, and increased risk for bleeding.
• Skin: Thickened epidermal nevi and pigmentary anomalies, such as hyperpigmentation or hypopigmentation, are common. These skin manifestations can be early signs of PROS and may aid in diagnosis.
• Skeletal system: Anomalies can include polydactyly, macrodactyly, macrodontia, and scoliosis or other spinal abnormalities.
• Lipomatosis overgrowth: This can occur with or without regional reduction of adipose tissue on the trunk and limbs.
• Lymphatic system: Isolated malformations may include dilated vascular channels lined by lymphatic endothelial cells, which may lead to fluid-filled cysts that usually grow proportionally with the growth of the affected person and may cause pain or significant morbidity if they are infiltrative.

3. Treatment for a PROS disorder may involve targeted options, surgical interventions, and supportive care.

Historically, treatment for overgrowth syndromes such as PROS primarily involved conservative management, focusing on addressing complications through surgical excision, orthopedic surgery, sclerotherapy, embolization, and compressive therapies. However, these strategies often proved insufficient, and patients frequently experienced relapse and progression of the condition. Indeed, PROS is a complex condition that requires a multifaceted treatment approach.

The discovery of the PIK3/AKT/mTOR activation pathway in these syndromes marked a significant therapeutic breakthrough. Targeted therapies, such as the use of mTOR inhibitors like sirolimus, have shown benefits in treating venous and lymphatic malformations in patients with PROS. More recently, a selective PIK3CA inhibitor, alpelisib, has been approved. This drug has demonstrated remarkable improvements in patients with various PROS phenotypes, including reductions in capillary malformations; cessation of chronic gastrointestinal bleeding; and improvements in scoliosis and cognitive function, particularly in patients with MCAP syndrome.

Supportive care is also a critical component of managing PROS. This includes surgical interventions for significant overgrowth, orthopedic care for scoliosis and leg-length discrepancies, and neurosurgical interventions for neurologic complications such as obstructive hydrocephalus and epilepsy. Vascular and lymphatic malformations may be treated with sclerotherapy, laser therapy, or medications such as sirolimus. Additionally, routine treatment for associated conditions such as cardiac and renal abnormalities, intellectual disabilities, polydactyly, coagulopathy, and hypothyroidism is essential. For those with pain, identifying and treating the underlying cause is crucial. In cases of severe persistent hypoglycemia, ongoing treatment, which may include cornstarch administration, is necessary. Owing to the complexity and varied manifestations of PROS, specialized multidisciplinary care for diagnosis, follow-up, and optimal management is recommended.

4. PROS is a heterogeneous condition, and the clinical presentation can vary widely among affected individuals.

PROS is a complex and heterogeneous condition characterized by a wide range of clinical presentations, reflecting the diversity of affected tissues and the extent of overgrowth. Phenotypes within PROS are diverse and can range from a single lesion (ie, solitary macrodactyly) to systemic diseases (ie, Klippel-Trenaunay syndrome and CLOVES syndrome).

This heterogeneity is primarily due to the timing of the onset of the somatic causative PIK3CA pathogenic variants during embryonic and fetal development, influencing the degree of mosaicism and the combination of tissues involved (eg, neural progenitor cell pathogenic variants can lead to postnatal megalencephaly and hydrocephalus). Moreover, different gain-of-function variants in PIK3CA lead to varying levels of hyperactivation of the PI3K/AKT/mTOR pathway, resulting in diverse severity of abnormal proliferation of mesodermal and ectodermal tissues from embryogenesis onward.

This spectrum of symptoms underscores the complexity and variability of PROS, necessitating a tailored approach to diagnosis and management.

5. Regular surveillance is crucial for the effective management of PROS

Comprehensive and regular monitoring is essential to address the diverse and evolving clinical manifestations of PROS. During each medical visit, it is essential to measure growth parameters, including head circumference and the length of arms, hands, legs, and feet. This assessment helps identify any new neurologic symptoms such as seizures, changes in muscle tone, or signs of Chiari malformation.

Additionally, monitoring the patient’s developmental progress, behavior, and motor skills is vital. Clinical assessments for conditions like scoliosis and abdominal examinations for organomegaly or abdominal masses are also recommended.

Imaging plays a significant role in the ongoing evaluation of PROS. Serial head MRI is advised, with the frequency depending on the initial severity of findings and the degree of brain maturation. For patients with central nervous system overgrowth or dysplasia, brain MRI every 6 months until age 2 years, followed by annual scans until age 8 years, is recommended to monitor for progressive hydrocephalus and Chiari malformation.

Further specialized assessments may be required based on individual clinical indications. These include monitoring of vascular and lymphatic malformations, radiographs of limbs in cases of limb overgrowth, and follow-up ultrasonography or MRI for truncal overgrowth. Spinal MRI is necessary for patients with scoliosis or spinal deformities.

In cases of persistent hypoglycemia, particularly those needing ongoing treatment, blood glucose monitoring and evaluation of the hypothalamic-pituitary-adrenal axis are important.

Postsurgical patients, especially those with the CLOVES phenotype or vascular malformations, should have a hematology consultation to assess thrombosis and coagulopathy risks. The use of renal ultrasonography every 3 months until age 8 years is suggested for tumor screening, such as Wilms tumor, although this practice is somewhat controversial.

These comprehensive and tailored approaches are critical in managing the complex and varied aspects of PROS, ensuring optimal care and monitoring for affected individuals.

Dr. Keppler-Noreuil is professor of pediatrics, division of genetics and metabolism, University of Wisconsin School of Medicine and Public Health; clinical director, department of pediatrics, division of genetics and metabolism; program director, medical genetics and genomics residency, Waisman Center & UW Pediatric Specialty Clinics, University of Wisconsin. She has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

People with essential tremor (ET) have nearly three times increased risk of developing dementia, compared with the general population, new research showed.

In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.

The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.

The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Mild Cognitive Impairment Prevalence Nearly Double

For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.

At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.

During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.

The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.

“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
 

Far From Trivial

Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”

“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.

“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.

The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.

A version of this article appeared on Medscape.com.

A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?

“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.

There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.

“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.

Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
 

Unnoticed Signs

Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.

“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”

Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.

“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”

In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.

In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.

“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.

In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.

“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.
 

Rules and Experience

In an interview, Dr. Fainboim highlighted key factors that should prompt a pediatrician’s suspicion. One is common symptoms expressed in a more intense or complicated way or when many symptoms coexist in the same patient, even if each one separately is benign or not so severe.

Dr. Fainboim also recommended establishing a therapeutic alliance with parents. “We shouldn’t undermine what parents say, especially those who have other children and already know what normal child development is like. This is a very important milestone.

“We have to strengthen the suspicion clue, and for that, we rely on standards and our experience, which we keep refining. As Wilde said, experience is the sum of our mistakes. But there’s no universal answer. Not all families are the same. Not all diseases manifest in the same way. And unless there’s an imminent risk to life or function, one can wait and take the time to evaluate it. For example, if I have a child with slowed developmental milestones, what I have to do is teach how to stimulate them or send them for stimulation with another professional. And I observe the response to this initial basic treatment. If I see no response, the alarms start to grow louder,” said Dr. Fainboim.

Pablo Barvosa, MD, the principal physician in the outpatient area of the Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina, and a member of the Working Group on Genetics and Rare Diseases of the Argentine Society of Pediatrics, told this news organization about other factors that should be considered for detecting these pathologies. Dr. Barvosa did not participate in the online seminar.

“Patients with rare diseases have common symptoms. What needs to be done is to prioritize those symptoms that behave abnormally, that have an unusual evolution compared with normal situations. For example, children who go into a coma after a fasting episode or after eating a certain food,” he said.

Dr. Barvosa also suggested considering when patients belong to certain communities where there is a lot of endogamy, due to the higher incidence of hereditary diseases. “Attention should be heightened when parents are cousins or relatives,” he pointed out.

“My view is that doctors should think more and better, be rational, sequential. If a disease is treated and resolved, but we find out that the child had 26 previous hospitalizations in the last 2 years, something is wrong. We have to look at the patient’s and family’s life histories. If a mother had 15 miscarriages, that’s a warning sign. We have to find a common thread. Be a sharp-witted pediatrician,” said Dr. Barvosa.

The suspicion and diagnosis of a rare disease can be devastating for families and painful for the professional, but even if there is no specific treatment, “something can always be done for patients,” he added.

And in certain circumstances, identifying a rare disease can reverse the ominous “stamp” of a wrong diagnosis. Dr. Barvosa commented on the case of a 7-year-old boy he attended at the hospital in 2014. The boy presented as quadriplegic, with no mobility in his limbs, and the parents were convinced he had that condition because he had fallen from the roof of the house. Although imaging techniques did not show a spinal injury, it was assumed to be a case of spinal cord injury without radiographic abnormality. But something caught Dr. Barvosa’s attention: The boy had well-developed abdominal muscles, as if he were an athlete. So, he requested an electromyogram, and the muscle was found to be in permanent contraction.

“The patient didn’t have a spinal cord injury: He had Isaacs’ syndrome,” said Dr. Barvosa. The syndrome also is known as acquired neuromyotonia, a rare condition of hyperexcitability of peripheral nerves that activate muscle fibers. “That is treated with anticonvulsants, such as phenytoin. Within a week, he was walking again, and shortly after, he was playing soccer. When I presented the case at a conference, I cried with emotion. That’s why the pediatrician must be insistent, be like the gadfly that stings in the ear” when there are clinical elements that don’t quite fit into a clear diagnosis, he added.

In recent publications, Dr. Dubrovsky has reported receiving fees for consultations or research from PTC, Sarepta, Biogen, Sanofi Genzyme, Takeda Avexis, Novartis, Raffo, and Roche. Dr. Nucifora has received fees from Jansen LATAM. Dr. Fainboim reported receiving fees from Sanofi. Dr. Barvosa has declared no relevant financial conflicts of interest. The webinar was organized by Urban Comunicaciones.
 

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

A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?

“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.

There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.

“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.

Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
 

Unnoticed Signs

Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.

“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”

Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.

“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”

In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.

In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.

“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.

In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.

“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.
 

Rules and Experience

In an interview, Dr. Fainboim highlighted key factors that should prompt a pediatrician’s suspicion. One is common symptoms expressed in a more intense or complicated way or when many symptoms coexist in the same patient, even if each one separately is benign or not so severe.

Dr. Fainboim also recommended establishing a therapeutic alliance with parents. “We shouldn’t undermine what parents say, especially those who have other children and already know what normal child development is like. This is a very important milestone.

“We have to strengthen the suspicion clue, and for that, we rely on standards and our experience, which we keep refining. As Wilde said, experience is the sum of our mistakes. But there’s no universal answer. Not all families are the same. Not all diseases manifest in the same way. And unless there’s an imminent risk to life or function, one can wait and take the time to evaluate it. For example, if I have a child with slowed developmental milestones, what I have to do is teach how to stimulate them or send them for stimulation with another professional. And I observe the response to this initial basic treatment. If I see no response, the alarms start to grow louder,” said Dr. Fainboim.

Pablo Barvosa, MD, the principal physician in the outpatient area of the Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina, and a member of the Working Group on Genetics and Rare Diseases of the Argentine Society of Pediatrics, told this news organization about other factors that should be considered for detecting these pathologies. Dr. Barvosa did not participate in the online seminar.

“Patients with rare diseases have common symptoms. What needs to be done is to prioritize those symptoms that behave abnormally, that have an unusual evolution compared with normal situations. For example, children who go into a coma after a fasting episode or after eating a certain food,” he said.

Dr. Barvosa also suggested considering when patients belong to certain communities where there is a lot of endogamy, due to the higher incidence of hereditary diseases. “Attention should be heightened when parents are cousins or relatives,” he pointed out.

“My view is that doctors should think more and better, be rational, sequential. If a disease is treated and resolved, but we find out that the child had 26 previous hospitalizations in the last 2 years, something is wrong. We have to look at the patient’s and family’s life histories. If a mother had 15 miscarriages, that’s a warning sign. We have to find a common thread. Be a sharp-witted pediatrician,” said Dr. Barvosa.

The suspicion and diagnosis of a rare disease can be devastating for families and painful for the professional, but even if there is no specific treatment, “something can always be done for patients,” he added.

And in certain circumstances, identifying a rare disease can reverse the ominous “stamp” of a wrong diagnosis. Dr. Barvosa commented on the case of a 7-year-old boy he attended at the hospital in 2014. The boy presented as quadriplegic, with no mobility in his limbs, and the parents were convinced he had that condition because he had fallen from the roof of the house. Although imaging techniques did not show a spinal injury, it was assumed to be a case of spinal cord injury without radiographic abnormality. But something caught Dr. Barvosa’s attention: The boy had well-developed abdominal muscles, as if he were an athlete. So, he requested an electromyogram, and the muscle was found to be in permanent contraction.

“The patient didn’t have a spinal cord injury: He had Isaacs’ syndrome,” said Dr. Barvosa. The syndrome also is known as acquired neuromyotonia, a rare condition of hyperexcitability of peripheral nerves that activate muscle fibers. “That is treated with anticonvulsants, such as phenytoin. Within a week, he was walking again, and shortly after, he was playing soccer. When I presented the case at a conference, I cried with emotion. That’s why the pediatrician must be insistent, be like the gadfly that stings in the ear” when there are clinical elements that don’t quite fit into a clear diagnosis, he added.

In recent publications, Dr. Dubrovsky has reported receiving fees for consultations or research from PTC, Sarepta, Biogen, Sanofi Genzyme, Takeda Avexis, Novartis, Raffo, and Roche. Dr. Nucifora has received fees from Jansen LATAM. Dr. Fainboim reported receiving fees from Sanofi. Dr. Barvosa has declared no relevant financial conflicts of interest. The webinar was organized by Urban Comunicaciones.
 

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

A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?

“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.

There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.

“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.

Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
 

Unnoticed Signs

Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.

“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”

Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.

“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”

In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.

In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.

“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.

In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.

“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.
 

Rules and Experience

In an interview, Dr. Fainboim highlighted key factors that should prompt a pediatrician’s suspicion. One is common symptoms expressed in a more intense or complicated way or when many symptoms coexist in the same patient, even if each one separately is benign or not so severe.

Dr. Fainboim also recommended establishing a therapeutic alliance with parents. “We shouldn’t undermine what parents say, especially those who have other children and already know what normal child development is like. This is a very important milestone.

“We have to strengthen the suspicion clue, and for that, we rely on standards and our experience, which we keep refining. As Wilde said, experience is the sum of our mistakes. But there’s no universal answer. Not all families are the same. Not all diseases manifest in the same way. And unless there’s an imminent risk to life or function, one can wait and take the time to evaluate it. For example, if I have a child with slowed developmental milestones, what I have to do is teach how to stimulate them or send them for stimulation with another professional. And I observe the response to this initial basic treatment. If I see no response, the alarms start to grow louder,” said Dr. Fainboim.

Pablo Barvosa, MD, the principal physician in the outpatient area of the Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina, and a member of the Working Group on Genetics and Rare Diseases of the Argentine Society of Pediatrics, told this news organization about other factors that should be considered for detecting these pathologies. Dr. Barvosa did not participate in the online seminar.

“Patients with rare diseases have common symptoms. What needs to be done is to prioritize those symptoms that behave abnormally, that have an unusual evolution compared with normal situations. For example, children who go into a coma after a fasting episode or after eating a certain food,” he said.

Dr. Barvosa also suggested considering when patients belong to certain communities where there is a lot of endogamy, due to the higher incidence of hereditary diseases. “Attention should be heightened when parents are cousins or relatives,” he pointed out.

“My view is that doctors should think more and better, be rational, sequential. If a disease is treated and resolved, but we find out that the child had 26 previous hospitalizations in the last 2 years, something is wrong. We have to look at the patient’s and family’s life histories. If a mother had 15 miscarriages, that’s a warning sign. We have to find a common thread. Be a sharp-witted pediatrician,” said Dr. Barvosa.

The suspicion and diagnosis of a rare disease can be devastating for families and painful for the professional, but even if there is no specific treatment, “something can always be done for patients,” he added.

And in certain circumstances, identifying a rare disease can reverse the ominous “stamp” of a wrong diagnosis. Dr. Barvosa commented on the case of a 7-year-old boy he attended at the hospital in 2014. The boy presented as quadriplegic, with no mobility in his limbs, and the parents were convinced he had that condition because he had fallen from the roof of the house. Although imaging techniques did not show a spinal injury, it was assumed to be a case of spinal cord injury without radiographic abnormality. But something caught Dr. Barvosa’s attention: The boy had well-developed abdominal muscles, as if he were an athlete. So, he requested an electromyogram, and the muscle was found to be in permanent contraction.

“The patient didn’t have a spinal cord injury: He had Isaacs’ syndrome,” said Dr. Barvosa. The syndrome also is known as acquired neuromyotonia, a rare condition of hyperexcitability of peripheral nerves that activate muscle fibers. “That is treated with anticonvulsants, such as phenytoin. Within a week, he was walking again, and shortly after, he was playing soccer. When I presented the case at a conference, I cried with emotion. That’s why the pediatrician must be insistent, be like the gadfly that stings in the ear” when there are clinical elements that don’t quite fit into a clear diagnosis, he added.

In recent publications, Dr. Dubrovsky has reported receiving fees for consultations or research from PTC, Sarepta, Biogen, Sanofi Genzyme, Takeda Avexis, Novartis, Raffo, and Roche. Dr. Nucifora has received fees from Jansen LATAM. Dr. Fainboim reported receiving fees from Sanofi. Dr. Barvosa has declared no relevant financial conflicts of interest. The webinar was organized by Urban Comunicaciones.
 

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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

Treatment with the investigational monoclonal antibody drug batoclimab significantly improved symptoms in patients with antibody-positive generalized myasthenia gravis, data from a new phase 3 study showed.

After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.

The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.

“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.

The findings were published online in JAMA Neurology.
 

Unmet Need

A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.

The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.

Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.

“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.

Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.

The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.

The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.

All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
 

Bests Placebo

Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.

Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.

Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).

While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.

In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.

In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).

Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).

Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.

Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
 

Well Tolerated

On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.

The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).

“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.

Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.

High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.

The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.

In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.

The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.

The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
 

Questions Remain

Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.

It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.

The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.

“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.

The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.

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