Immunology

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Recent insights into the pathophysiology of Guillain-Barré syndrome (GBS) – which affects 1 or 2 persons for every 100,000 people annually, usually post infection – indicate that classic subtypes represent varying manifestations of a shared disease process. This knowledge is yielding new treatment strategies aimed at halting the illness in its tracks. Promising therapies include inhibitors of complement and, perhaps one day, the calcium-activated protease calpain.

Meanwhile, an association between COVID-19 and GBS has been debunked, whereas a small risk of GBS following adenovirus-vectored COVID vaccination is now accepted and quantified. Regardless of cause, the potential severity of GBS and variability in its presentation demand constant vigilance.
 

Shutting down the disease process

When patients present to an emergency department with sensory symptoms and increasing muscle weakness, “most of the damage has been or is being done,” said Michael P. Lunn, MBBS, MRCP, PhD, professor of clinical neurology, consultant neurologist, and clinical lead in neuroimmunology at University College London Queen Square Institute of Neurology, who spoke at length about GBS with Neurology Reviews 2023 Rare Neurological Disease Special Report. “The crucial reason that GBS treatment has not advanced significantly – and why we’re still slightly stuck where we are in terms of helping people get better more quickly – is that we need something that absolutely turns the disease off as patients come through the door.”

GBS is probably the best-understood autoimmune-mediated neurological disease, in some respects surpassing myasthenia gravis, Dr. Lunn said. “We know very frequently the organisms and stimuli that set off Guillain-Barré syndrome. We understand, to an extent, the immunology and how you break tolerance of the immune system so that an invading organism can provoke an immune response that damages peripheral nerves.”

Shared mechanism

Based on the findings of electrophysiologic studies, Dr. Lunn said, experts traditionally believed that GBS attacked either axons themselves or their myelin sheaths. “That’s where the anti-ganglioside antibodies come in, providing targeting to nerve structures.” The dichotomous classification system, he added, was partially correct.

Then, through the 2010s and 2020s, neurophysiologist Antonio Uncini, MD, recognized, based partly on histologic studies by Ho and colleagues, that the myelin and axonal subtypes are both likely to stem from the same mechanism.² When antibodies and complement damage the node of Ranvier, Dr. Lunn said, “the myelin gets stripped off and the conduction becomes slow. But then the myelin can return, and patients get better.” But if damage is severe, it severs the axon, resulting in unrecoverable motor axonal neuropathy. “It’s basically all the same spectrum of disease,” Dr. Lunn said. “Anti-ganglioside antibodies may account for different GBS ‘flavors,’ but the immunological attack all occurs at the node of Ranvier in one way or another.”

The foregoing insight has focused development efforts on the shared seminal pathway of all GBS subtypes and given rise to the concept of nodo-paranodopathy, which incorporates damage at either the node of Ranvier or nearby paranodes.³

Simultaneously, Spanish and French researchers began elucidating new antibodies responsible for neuropathology at the node of Ranvier.⁴ Anti-ganglioside antibodies have long been loosely associated with acute motor axonal neuropathy and poor outcomes, although, Dr. Lunn said, they fail to tell the full story. Anti-GQ1b antibodies are associated with the Miller-Fisher syndrome subtype, well recognized for its medical features: double vision, loss of tendon reflexes, and arm and leg weakness.

However, Dr. Lunn said, most GBS cases lack anti-ganglioside antibodies. In some GBS cases, antibodies attack neurofascin, contactins, and gliomedin, which are mainly adhesion proteins at nodes of Ranvier.

“Therefore,” Dr. Lunn said, “there must be an antibody-mediated attack of the node of Ranvier or the paranode. That’s an important series of discoveries, primarily because it helps us understand the immunological attack at the node of Ranvier, which goes along with what Dr. Uncini was saying. But it also divides off a group of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) that present acutely and look initially, for all purposes, like GBS.”

Recognizing acute CIDP (A-CIDP) is critically important for clinicians, Dr. Lunn stressed, because it requires treatment with rituximab (the most commonly used option), steroids, or plasma exchange.

Key clues that distinguish A-CIDP from GBS include:

• A high level of cerebrospinal fluid protein.

• Very slow nerve conduction.

• Early muscle wasting (rare in GBS).

Recognizing CIDP and A-CIDP is crucial, said Dr. Lunn, because it begins to bring all the pathology back together to make sense of GBS. Neurologists have known for decades that, if one damages a nerve with antibodies, then binds complement to those antibodies, the complement punches holes in the affected cells, resulting in death. “But it wasn’t quite clear how those cells might die,” Dr. Lunn said.

After complement-induced injury, calcium-activated calpain permanently damages the entire internal axonal structure.⁵ Perhaps more important, a 2022 mouse study showed that complement-mediated damage could be directed to myelin or axons using the genetically programmed presence or absence of gangliosides to understand subsequent calpain-induced destruction in either axons or myelin.⁶

Some of the engineered mouse cells included ganglioside; others did not. “So you can have anti-ganglioside antibodies directed at one cell type or the other, which would, or would not, have calpain within them,” Dr. Lunn said. Investigators also showed that a calpain inhibitor (AK295) or overproduction of an endogenous inhibitor, calpastatin, prevented damage to both cell types.⁶All existing calpain inhibitors are unsuitable for clinical use because they are highly toxic. “But if you could inhibit calpain and stop it from being activated by calcium,” Dr. Lunn explained, “you would have a mechanism for stopping cell degradation during GBS. That would be an important future target for pharmacotherapy. That whole story – from the beginning to the end of GBS – has opened up options for treatment.”

Because complement bound to antibodies, set up by infection, plays a pivotal role, complement inhibitors have become an exciting area of research over the past decade. The 36-patient Japanese Eculizumab Trial for GBS (JET-GBS) trial showed that, after 6 months, significantly more eculizumab-treated patients could run, compared with placebo-treated patients.⁷

“No other trials of complement inhibitors have yet been completed,” Dr. Lunn said. “But several different complement inhibitors work at different places, in a very complicated immune process. One of the complement inhibitors will become transformative in treating GBS – preventing disability and improving recovery – in the not-very-distant future.”

Additional investigational treatments that have demonstrated early promise in eliminating problem antibodies faster include imlifidase (Idefirix [Hansa Biopharma]), which destroys antibodies, and Fc receptor inhibitors such as efgartigimod alfa-fcab (Vyvgart [argenx]), which push antibodies into the natural catabolic pathway.

“We’ve been stuck with plasma exchange and intravenous immunoglobulin (IVIg) for three or four decades,” Dr. Lunn said. “We now have a series of strategies by which we can completely turn off complement and resulting nerve damage. If we can find a calpain inhibitor that turns off the end of that pathway, we will make dramatic improvements. Our understanding of the immunopathology has changed enormously and influences pharmacotherapy going forward.”
 

Recap of diagnosis and treatment

For decades, the diagnosis of GBS has relied on the presence of symptoms, including progressive weakness and loss of reflexes and sensations. Nerve-conduction studies and cerebrospinal fluid evaluation can help confirm the diagnosis.

IVIg shortens recovery, said Dr. Lunn, although nothing cures GBS. “And that’s a common problem: Clinicians think that they’re going to give somebody IVIg, and the patient’s going to get better immediately.” When that doesn’t happen, he said, physicians are tempted to give a second immunoglobulin dose.

However, a study published in 2021 shows that a second IVIg dose does not result in faster or better improvement – only in a significant risk of cardiovascular, cerebrovascular, and other thrombotic events 3 weeks later.⁸ Dr. Lunn noted that, although adverse-event data were “buried” in the supplemental materials of that study, the high cost of IVIg (approximately $12,500 per dose) means that the study has changed practice for the benefit of patients, providers, and health care systems.
 

COVID-19 and GBS triggers

Campylobacter jejuni infection still accounts for 30% to 40% of GBS cases, followed by other bacteria, including Mycoplasma pneumoniae and Haemophilus influenzae, and then by viruses, including cytomegalovirus and, rarely, human immunodeficiency virus. In recent years, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection – COVID-19 – and vaccines against the viral infection have captured headlines for purportedly being a cause of GBS.

The Zika virus epidemic of 2015-2016 has been linked to GBS-like illness. The 2003 severe acute respiratory syndrome (SARS) pandemic and the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic were associated with GBS – although, taken together, SARS and MERS-CoV produced fewer than 10 cases of GBS, Dr. Lunn noted. Nevertheless, heightened awareness of these viruses fueled hypervigilance regarding the prospect that COVID-19 could cause GBS. Following reports of a single such case in Wuhan and hundreds in Italy, worry over pandemic GBS grew worldwide.

Dr. Lunn and colleagues addressed the COVID-19–GBS question in a 2023 publication.⁹ “Because GBS is largely treated only with IVIg, and IVIg costs a lot of money, and the U.K. government insists on every dose of IVIg being logged in a government database, we were able to identify virtually every case of GBS,” he said.

GBS diagnoses were reliable, he added, because each case was confirmed by physicians outside the emergency department. Analysis revealed that, in 2020, U.K. GBS cases actually declined by around one-third. “And even when there was a second wave of COVID-19 at the end of 2020, partly caused by better counting,” Dr. Lunn said, “there was no further increase in GBS cases. We concluded that there was no link between GBS and COVID-19, as the cases simply didn’t appear.”

The foregoing findings have since been corroborated by studies in Singapore, the United States, and South America, he pointed out. Earlier case series suggesting a link between COVID-19 and GBS were selective, Dr. Lunn added, with numbers too small to support robust conclusions.

The lack of a causal link between COVID-19 and GBS suggested to Dr. Lunn that there was no reason COVID-19 vaccination should cause GBS. All COVID-19 vaccines were designed to provoke an immune response either (1) by producing the SARS-CoV-2 spike protein on the surface of virus (through a replication-incompetent adenoviral vector) or (2) through DNA or mRNA transcription, he explained. “The spike protein is only a small part of COVID-19.”
 

GBS: ‘Adverse event of interest’

A link between modern vaccines and GBS first appeared in the 1970s with the hastily developed swine flu vaccine. “In late 1976,” Dr. Lunn explained, “it was identified that patients who were given that vaccine seemed to be developing illnesses consistent with GBS.” By 1980, Dr. Lunn said, the risk level was determined to be only five or six cases for every 1 million doses of vaccine administered. “But the vaccine program was aborted, and swine flu never really happened.” Every year since, “there has been a surveillance program looking at the occurrence of an association of GBS with influenza vaccine.”

Minor fluctuations aside, he said, the overall incidence of GBS with influenza vaccination – 1 GBS case for every 1 million vaccine doses given – has remained consistent over several decades. “Nevertheless, GBS became an adverse event of special interest for any vaccination campaign.”

COVID-19 vaccination. Dr. Lunn and colleagues used the United Kingdom National Health Service (NHS) National Immunoglobulin Database, and other databases, to pinpoint the risk of GBS presented by the first dose of the AstraZeneca ChAdOx1 nCoV-19 adenoviral vaccine.¹⁰ As with U.K. GBS cases, every COVID-19 vaccination is linked to an NHS number. “We identified all the cases of GBS, found their NHS numbers, and went back and found the exact dates they’d been vaccinated, and with which vaccine.” Only the adenoviral-vector vaccine carried an excess risk of GBS – 5.8 cases for every 1 million doses, associated only with the first dose and peaking at approximately 25 days post vaccination – compared with other vaccines used in the United Kingdom.

Researchers looked at data from the Vaccine Adverse Event Reporting System (VAERS), a program of the Centers for Disease Control and Prevention and the Food and Drug Administration, encompassing nearly 500 million COVID-19 vaccine doses given between December 2020 and January 2022. They found that patients who received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson) had a rate of GBS (within 21 and 41 days post vaccination) that was 9 and 12 times higher, respectively, than corresponding rates for the mRNA-1273 (Moderna) and BNT162b2 (Pfizer BioNTech) COVID-19 vaccines.¹¹ Risk was distributed relatively evenly by gender and age. Also at day 21 and day 41, observed event ratios with the adenoviral-vector vaccine (use of which has been suspended in the United States) were 3.79 and 2.34, respectively. Observed-event ratios with the other vaccines mirrored expected background rates.

The VAERS analysis confirms earlier data from the CDC’s Vaccine Safety Datalink, which showed that, among approximately 15 million U.S. vaccine doses given between mid-December 2020 and mid-November 2021, the unadjusted GBS incidence rate for every 100,000 person-years for the adenoviral vaccine, 21 days post exposure, was 32.4, compared with 1.3 for the mRNA vaccine. The adjusted relative risk with the adenoviral vaccine in the first 3 weeks post vaccination, compared to the 3- to 6-week interval post vaccination, was 6.03.¹² In addition, a head-to-head comparison of adenoviral versus mRNA vaccines at 21 days revealed an adjusted rate ratio of 20.56. Mechanistically, some experts theorize that antibodies induced by the Janssen vaccine might cross-react with glycoproteins on the myelin sheath of peripheral nerve axons to cause GBS, but this remains unproven.11

The AstraZeneca vaccine uses a chimpanzee adenovirus; the Janssen vaccine uses a human adenoviral carrier. “The only commonality between the Janssen/Johnson & Johnson and AstraZeneca vaccines, and the only thing that’s different from the other vaccines, is the adenoviral vector packaging,” Dr. Lunn emphasized. “I believe it’s what generates GBS after COVID-19 vaccination. It has nothing to do with the COVID-19 vaccination, the spike protein, the nucleic acid, the DNA, or anything else.”

The adenoviral vector probably also explains why GBS peaks during winter, said Dr. Lunn. “That’s when adenovirus is circulating.” When people contract the common cold, he explained, they don’t visit their family physician and request a swab to isolate the adenovirus. “By the time you get GBS, the adenovirus has been cleared. We’ve all got antibodies to adenovirus all over the place, anyway, because we get it so often.”

It would be difficult to prove conclusively that adenovirus belongs on the list of GBS causes, Dr. Lunn allowed. “But I have a strong suspicion that it does. COVID-19 and COVID-19 vaccination have given us some new avenues into identifying GBS causation potentially in the near future.” More research is needed in this area, he said.

Dr. Lunn has been a principal investigator for argenx (efgartigimod) and an adviser to AstraZeneca (ChAdOx1 nCoV-19). He has received travel grants from CSL Behring.
 

References

1. Ho TW et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(Pt 3):597-605. doi: 10.1093/brain/118.3.597.

2. Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol. 2012;235(2):513-6. doi: 10.1016/j.expneurol.2012.03.023.

3. Uncini A and Kuwabara S. The electrodiagnosis of Guillain-Barré syndrome subtypes: where do we stand? Clin Neurophysiol. 2018;129(12):2586-93. doi: 10.1016/j.clinph.2018.09.025.

4. Delmont E et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain. 2017;140(7):1851-8. doi: 10.1093/brain/awx124.

5. McGonigal R et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944-60. doi: 10.1093/brain/awq119.

6. Cunningham ME et al. Real time imaging of intra-axonal calcium flux in an explant mouse model of axonal Guillain-Barré syndrome. Exp Neurol. 2022 Sep;355:114127. doi: 10.1016/j.expneurol.2022.114127.

7. Misawa S et al; Japanese Eculizumab Trial for GBS (JET-GBS) Study Group. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519-29. doi: 10.1016/S1474-4422(18)30114-5.

8. Walgaard C et al; Dutch GBS Study Group. Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(4):275-83. doi: 10.1016/S1474-4422(20)30494-4.

9. Keddie S et al. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain. 2021;144(2):682-93. doi: 10.1093/brain/awaa433.

10. Keh RYS et al; BPNS/ABN COVID-19 Vaccine GBS Study Group. COVID-19 vaccination and Guillain-Barré syndrome: Analyses using the National Immunoglobulin Database. Brain. 2023;146(2):739-48. doi: 10.1093/brain/awac067.

11. Abara WE et al. Reports of Guillain-Barré syndrome after COVID-19 vaccination in the United States. JAMA Netw Open. 2023;6(2):e2253845. doi: 10.1001/jamanetworkopen.2022.53845.

12. Hanson KE et al. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open. 2022;5(4):e228879. doi: 10.1001/jamanetworkopen.2022.8879.
 

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin condition that typically affects the face (cheeks), neck, arms, and legs but usually spares the groin and axillary regions. AD usually starts in early infancy but also affects some adults. AD is often associated with elevated levels of immunoglobulin E (IgE). That it is the first disease to present in a series of allergic diseases – including food allergy, asthma, and allergic rhinitis, in order – and has given rise to the “atopic march” theory, which suggests that AD is part of a progression that may lead to subsequent allergic disease at other epithelial barrier surfaces.

Here are five things to know about atopic dermatitis.
 

1. Essential features of AD are pruritus and eczema

The diagnosis of AD is primarily observational. It is made on the basis of patient and family history, pattern of lesions, morphology, and clinical signs. No genetic features or biomarkers are specific enough to reliably aid in diagnosis or severity assessment. Many individual findings are used to diagnose AD, as summarized by the American Academy of Dermatology based on essential, important, associated, and exclusionary features:

• Essential features (must be present for diagnosis) are pruritus and eczema (acute, subacute, or chronic) with typical morphology and age-specific patterns and chronic or relapsing history.
• Important features (usually seen in AD and support the diagnosis) are early age of onset, atopy (personal/family history, IgE reactivity), and xerosis.
• Associated features (nonspecific but suggestive) are atypical vascular response (e.g., delayed blanch response); keratosis pilaris (and some others); ocular/periorbital changes; other regional findings (e.g., perioral changes); and perifollicular accentuation, lichenification, or prurigo lesions.
• Exclusionary conditions (must be excluded to make the AD diagnosis) are scabies, seborrheic dermatitis, contact dermatitis, ichthyoses, cutaneous T-cell lymphoma, psoriasis, photosensitivity dermatoses, immune deficiency diseases, and erythroderma due to other causes.

AD should be differentiated from other red, scaly skin conditions. It is often difficult to separate AD from seborrheic dermatitis in infancy, and the two conditions may overlap in this age group. Particularly if the condition is not responding to therapy, the diagnosis of AD should be re-reviewed and other disorders considered, including more serious nutritional, metabolic, and immunologic conditions in children and cutaneous T-cell lymphoma in adults. Allergic contact dermatitis may be both an alternative diagnosis to AD and an exacerbator of AD in some individuals.
 

2. Associated comorbidities of AD may exacerbate the condition and lead to other atopic disorders

Reported comorbidities of AD include other atopic or allergic conditions, autoimmune diseases, infections, metabolic conditions, mental health disorders, and cardiovascular disease. Certain aspects of AD, such as chronic pruritus, psychosocial distress, and inflammation, can lead to anxiety, depression, and suicidality. AD is associated with and may predispose to higher risk for other atopic disorders, including asthma, hay fever, food allergy, and eosinophilic esophagitis.

Persons with AD also appear to be at higher risk for infectious diseases. The prevalence of cutaneous and systemic infections in patients with AD is significantly higher than those without AD. Infectious complications can include skin and soft-tissue infections, bacteremia, eczema herpeticum, osteomyelitis, endocarditis, and septic arthritis.
 

3. Climate change has a profound impact on AD

The incidence of AD has increased over the past several decades, and environmental factors such as climate change have been implicated as a potential mechanism. Climate change–related factors affect the skin’s capacity to maintain homeostasis, leading to various cutaneous diseases. AD, psoriasis, pemphigus, acne vulgaris, melasma, and photoaging are all associated with rising levels of air pollution. Elevated temperatures due to global warming induce disruption of the skin microbiome, thereby affecting AD.

Extreme weather events due to climate change, including floods and wildfires, are implicated in cutaneous injuries, skin infections, and acute worsening of inflammatory skin disorders.
 

4. The impact and appearance of AD varies in different racial groups

It was once believed that AD was just one single disease affecting people of many different races. More recently, it has been proposed that AD is in fact a group of different diseases. Both epidemiologic and genetic factors may play a role in influencing the main features of AD.

Spongiotic processes such as AD that would be pink or erythematous on white skin are often hypopigmented in individuals with darkly pigmented skin. AD has a higher prevalence and severity in Black and mixed-race populations, probably owing to a combination of environmental and intrinsic factors. Black skin has been shown to have increased transepidermal water loss and lower levels of ceramides, which are important components of the lipid barrier in the stratum corneum.

The American College of Allergy, Asthma & Immunology, along with the Allergy & Asthma Network, are partnering to create Eczema in Skin of Color, a website to aid physicians and patients in recognizing eczema in people with all skin types.
 

5. New and emerging therapies are poised to improve outcomes with AD treatment

Ruxolitinib cream, a topical Janus kinase (JAK)-1/JAK2 inhibitor, was approved for AD by the U.S. Food and Drug Administration in September 2021. The approval was based on results from the Topical Ruxolitinib Evaluation in AD (TRuE-AD) clinical trial program, which consisted of phase 3 studies that investigated 1,249 patients aged greater than or equal to 12 years with mild to moderate AD (Investigator’s Global Assessment score of 2-3) with a body surface area of 3%-20% (excluding scalp). The 2023 AAD guidelines for topical treatment recommend ruxolitinib cream for adults with mild to moderate AD.

Tralokinumab is a monoclonal antibody that inhibits the interleukin-13 cytokines, which prevents the release of cytokines, chemokines, and IgE. It was approved by the FDA in 2021 for treatment of moderate to severe AD. It is administered by subcutaneous injection every 2 weeks. Approval was based on the phase 3 trials ECZTRA 1, 2, and 3, which assessed the efficacy of tralokinumab in 1,934 adults.

Abrocitinib is an oral, once-daily JAK1 inhibitor for treatment of adults living with refractory, moderate to severe AD. FDA approval was based on results of five clinical trials from a large-scale trial program of more than 1,600 patients. Across the trials, abrocitinib demonstrated a consistent safety profile and profound improvements in skin clearance, extent of disease, and severity, as well as rapid improvement in itch after 2 weeks, for some people living with AD vs placebo.

Upadacitinib, another oral JAK1 inhibitor, was approved by the FDA in January 2022 for refractory moderate to severe AD. Approval was based on three double-blind phase 3 trials (Measure Up 1, Measure Up 2, AD Up) in which 2,584 patients with moderate to severe AD were randomized to receive oral upadacitinib 15 mg/d and 30 mg/d. In Measure Up 1 and Measure Up 2, upadacitinib was evaluated as monotherapy; in AD Up, upadacitinib was evaluated in combination with topical corticosteroids.
 

On the horizon

Baricitinib, an oral JAK1/2 inhibitor, is not yet approved by the FDA for AD. It is, however, approved for moderate to severe AD treatment in the European Union and many other countries. A 2022 review of studies evaluating baricitinib for the treatment of moderate to severe AD in adults (BREEZE-AD1, -AD2, -AD3, -AD4, -AD5, -AD6) reported that current evidence supports baricitinib, used as monotherapy or in combination with topical corticosteroids, as a safe and effective agent that can be used as an alternative to subcutaneous biologics in adults with moderate to severe AD.

Topical JAK inhibitors

A 2023 systematic review (19 studies, 3,600 participants) reported on several topical JAK inhibitors that are effective for treating AD. It suggests a stronger safety profile and better results, compared with systemic JAK inhibitors. The review focused on topical delgocitinib, tofacitinib, ruxolitinib, cerdulatinib, and ifidancitinib. All agents were effective in treating AD. All of these topical JAK inhibitors had minimal risk for mild to moderate adverse effects.

Biologics

Lebrikizumab was evaluated in a phase 2b, double-blind, placebo-controlled randomized clinical trial. After 16 weeks (280 participants), patients with moderate to severe AD showed a dose-dependent significant improvement in the primary endpoint, compared with placebo. Two phase 3 trials (ADvocate1, ADvocate2) evaluated the safety and efficacy of monotherapy with lebrikizumab in adults and adolescents with moderate to severe AD.

Nemolizumab, assessed in long-term phase 3 trials of AD-associated pruritus, resulted in clinically meaningful improvements from the beginning of treatment to week 68. Nemolizumab is being evaluated in two identical phase 3 studies (Arcadia 1, Arcadia 2) and a long-term extension study.

Dr. Kim is Professor and Vice Chair of Research in the department of dermatology, as well as Director of the Mark Lebwohl Center for Neuroinflammation and Sensation at the Icahn School of Medicine at Mount Sinai, New York. He reported conflicts of interest with 23andMe, Abrax Japan, AbbVie, Almirall, Amgen, and KiiRNA Biotech.

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

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin condition that typically affects the face (cheeks), neck, arms, and legs but usually spares the groin and axillary regions. AD usually starts in early infancy but also affects some adults. AD is often associated with elevated levels of immunoglobulin E (IgE). That it is the first disease to present in a series of allergic diseases – including food allergy, asthma, and allergic rhinitis, in order – and has given rise to the “atopic march” theory, which suggests that AD is part of a progression that may lead to subsequent allergic disease at other epithelial barrier surfaces.

Here are five things to know about atopic dermatitis.
 

1. Essential features of AD are pruritus and eczema

The diagnosis of AD is primarily observational. It is made on the basis of patient and family history, pattern of lesions, morphology, and clinical signs. No genetic features or biomarkers are specific enough to reliably aid in diagnosis or severity assessment. Many individual findings are used to diagnose AD, as summarized by the American Academy of Dermatology based on essential, important, associated, and exclusionary features:

• Essential features (must be present for diagnosis) are pruritus and eczema (acute, subacute, or chronic) with typical morphology and age-specific patterns and chronic or relapsing history.
• Important features (usually seen in AD and support the diagnosis) are early age of onset, atopy (personal/family history, IgE reactivity), and xerosis.
• Associated features (nonspecific but suggestive) are atypical vascular response (e.g., delayed blanch response); keratosis pilaris (and some others); ocular/periorbital changes; other regional findings (e.g., perioral changes); and perifollicular accentuation, lichenification, or prurigo lesions.
• Exclusionary conditions (must be excluded to make the AD diagnosis) are scabies, seborrheic dermatitis, contact dermatitis, ichthyoses, cutaneous T-cell lymphoma, psoriasis, photosensitivity dermatoses, immune deficiency diseases, and erythroderma due to other causes.

AD should be differentiated from other red, scaly skin conditions. It is often difficult to separate AD from seborrheic dermatitis in infancy, and the two conditions may overlap in this age group. Particularly if the condition is not responding to therapy, the diagnosis of AD should be re-reviewed and other disorders considered, including more serious nutritional, metabolic, and immunologic conditions in children and cutaneous T-cell lymphoma in adults. Allergic contact dermatitis may be both an alternative diagnosis to AD and an exacerbator of AD in some individuals.
 

2. Associated comorbidities of AD may exacerbate the condition and lead to other atopic disorders

Reported comorbidities of AD include other atopic or allergic conditions, autoimmune diseases, infections, metabolic conditions, mental health disorders, and cardiovascular disease. Certain aspects of AD, such as chronic pruritus, psychosocial distress, and inflammation, can lead to anxiety, depression, and suicidality. AD is associated with and may predispose to higher risk for other atopic disorders, including asthma, hay fever, food allergy, and eosinophilic esophagitis.

Persons with AD also appear to be at higher risk for infectious diseases. The prevalence of cutaneous and systemic infections in patients with AD is significantly higher than those without AD. Infectious complications can include skin and soft-tissue infections, bacteremia, eczema herpeticum, osteomyelitis, endocarditis, and septic arthritis.
 

3. Climate change has a profound impact on AD

The incidence of AD has increased over the past several decades, and environmental factors such as climate change have been implicated as a potential mechanism. Climate change–related factors affect the skin’s capacity to maintain homeostasis, leading to various cutaneous diseases. AD, psoriasis, pemphigus, acne vulgaris, melasma, and photoaging are all associated with rising levels of air pollution. Elevated temperatures due to global warming induce disruption of the skin microbiome, thereby affecting AD.

Extreme weather events due to climate change, including floods and wildfires, are implicated in cutaneous injuries, skin infections, and acute worsening of inflammatory skin disorders.
 

4. The impact and appearance of AD varies in different racial groups

It was once believed that AD was just one single disease affecting people of many different races. More recently, it has been proposed that AD is in fact a group of different diseases. Both epidemiologic and genetic factors may play a role in influencing the main features of AD.

Spongiotic processes such as AD that would be pink or erythematous on white skin are often hypopigmented in individuals with darkly pigmented skin. AD has a higher prevalence and severity in Black and mixed-race populations, probably owing to a combination of environmental and intrinsic factors. Black skin has been shown to have increased transepidermal water loss and lower levels of ceramides, which are important components of the lipid barrier in the stratum corneum.

The American College of Allergy, Asthma & Immunology, along with the Allergy & Asthma Network, are partnering to create Eczema in Skin of Color, a website to aid physicians and patients in recognizing eczema in people with all skin types.
 

5. New and emerging therapies are poised to improve outcomes with AD treatment

Ruxolitinib cream, a topical Janus kinase (JAK)-1/JAK2 inhibitor, was approved for AD by the U.S. Food and Drug Administration in September 2021. The approval was based on results from the Topical Ruxolitinib Evaluation in AD (TRuE-AD) clinical trial program, which consisted of phase 3 studies that investigated 1,249 patients aged greater than or equal to 12 years with mild to moderate AD (Investigator’s Global Assessment score of 2-3) with a body surface area of 3%-20% (excluding scalp). The 2023 AAD guidelines for topical treatment recommend ruxolitinib cream for adults with mild to moderate AD.

Tralokinumab is a monoclonal antibody that inhibits the interleukin-13 cytokines, which prevents the release of cytokines, chemokines, and IgE. It was approved by the FDA in 2021 for treatment of moderate to severe AD. It is administered by subcutaneous injection every 2 weeks. Approval was based on the phase 3 trials ECZTRA 1, 2, and 3, which assessed the efficacy of tralokinumab in 1,934 adults.

Abrocitinib is an oral, once-daily JAK1 inhibitor for treatment of adults living with refractory, moderate to severe AD. FDA approval was based on results of five clinical trials from a large-scale trial program of more than 1,600 patients. Across the trials, abrocitinib demonstrated a consistent safety profile and profound improvements in skin clearance, extent of disease, and severity, as well as rapid improvement in itch after 2 weeks, for some people living with AD vs placebo.

Upadacitinib, another oral JAK1 inhibitor, was approved by the FDA in January 2022 for refractory moderate to severe AD. Approval was based on three double-blind phase 3 trials (Measure Up 1, Measure Up 2, AD Up) in which 2,584 patients with moderate to severe AD were randomized to receive oral upadacitinib 15 mg/d and 30 mg/d. In Measure Up 1 and Measure Up 2, upadacitinib was evaluated as monotherapy; in AD Up, upadacitinib was evaluated in combination with topical corticosteroids.
 

On the horizon

Baricitinib, an oral JAK1/2 inhibitor, is not yet approved by the FDA for AD. It is, however, approved for moderate to severe AD treatment in the European Union and many other countries. A 2022 review of studies evaluating baricitinib for the treatment of moderate to severe AD in adults (BREEZE-AD1, -AD2, -AD3, -AD4, -AD5, -AD6) reported that current evidence supports baricitinib, used as monotherapy or in combination with topical corticosteroids, as a safe and effective agent that can be used as an alternative to subcutaneous biologics in adults with moderate to severe AD.

Topical JAK inhibitors

A 2023 systematic review (19 studies, 3,600 participants) reported on several topical JAK inhibitors that are effective for treating AD. It suggests a stronger safety profile and better results, compared with systemic JAK inhibitors. The review focused on topical delgocitinib, tofacitinib, ruxolitinib, cerdulatinib, and ifidancitinib. All agents were effective in treating AD. All of these topical JAK inhibitors had minimal risk for mild to moderate adverse effects.

Biologics

Lebrikizumab was evaluated in a phase 2b, double-blind, placebo-controlled randomized clinical trial. After 16 weeks (280 participants), patients with moderate to severe AD showed a dose-dependent significant improvement in the primary endpoint, compared with placebo. Two phase 3 trials (ADvocate1, ADvocate2) evaluated the safety and efficacy of monotherapy with lebrikizumab in adults and adolescents with moderate to severe AD.

Nemolizumab, assessed in long-term phase 3 trials of AD-associated pruritus, resulted in clinically meaningful improvements from the beginning of treatment to week 68. Nemolizumab is being evaluated in two identical phase 3 studies (Arcadia 1, Arcadia 2) and a long-term extension study.

Dr. Kim is Professor and Vice Chair of Research in the department of dermatology, as well as Director of the Mark Lebwohl Center for Neuroinflammation and Sensation at the Icahn School of Medicine at Mount Sinai, New York. He reported conflicts of interest with 23andMe, Abrax Japan, AbbVie, Almirall, Amgen, and KiiRNA Biotech.

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

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin condition that typically affects the face (cheeks), neck, arms, and legs but usually spares the groin and axillary regions. AD usually starts in early infancy but also affects some adults. AD is often associated with elevated levels of immunoglobulin E (IgE). That it is the first disease to present in a series of allergic diseases – including food allergy, asthma, and allergic rhinitis, in order – and has given rise to the “atopic march” theory, which suggests that AD is part of a progression that may lead to subsequent allergic disease at other epithelial barrier surfaces.

Here are five things to know about atopic dermatitis.
 

1. Essential features of AD are pruritus and eczema

The diagnosis of AD is primarily observational. It is made on the basis of patient and family history, pattern of lesions, morphology, and clinical signs. No genetic features or biomarkers are specific enough to reliably aid in diagnosis or severity assessment. Many individual findings are used to diagnose AD, as summarized by the American Academy of Dermatology based on essential, important, associated, and exclusionary features:

• Essential features (must be present for diagnosis) are pruritus and eczema (acute, subacute, or chronic) with typical morphology and age-specific patterns and chronic or relapsing history.
• Important features (usually seen in AD and support the diagnosis) are early age of onset, atopy (personal/family history, IgE reactivity), and xerosis.
• Associated features (nonspecific but suggestive) are atypical vascular response (e.g., delayed blanch response); keratosis pilaris (and some others); ocular/periorbital changes; other regional findings (e.g., perioral changes); and perifollicular accentuation, lichenification, or prurigo lesions.
• Exclusionary conditions (must be excluded to make the AD diagnosis) are scabies, seborrheic dermatitis, contact dermatitis, ichthyoses, cutaneous T-cell lymphoma, psoriasis, photosensitivity dermatoses, immune deficiency diseases, and erythroderma due to other causes.

AD should be differentiated from other red, scaly skin conditions. It is often difficult to separate AD from seborrheic dermatitis in infancy, and the two conditions may overlap in this age group. Particularly if the condition is not responding to therapy, the diagnosis of AD should be re-reviewed and other disorders considered, including more serious nutritional, metabolic, and immunologic conditions in children and cutaneous T-cell lymphoma in adults. Allergic contact dermatitis may be both an alternative diagnosis to AD and an exacerbator of AD in some individuals.
 

2. Associated comorbidities of AD may exacerbate the condition and lead to other atopic disorders

Reported comorbidities of AD include other atopic or allergic conditions, autoimmune diseases, infections, metabolic conditions, mental health disorders, and cardiovascular disease. Certain aspects of AD, such as chronic pruritus, psychosocial distress, and inflammation, can lead to anxiety, depression, and suicidality. AD is associated with and may predispose to higher risk for other atopic disorders, including asthma, hay fever, food allergy, and eosinophilic esophagitis.

Persons with AD also appear to be at higher risk for infectious diseases. The prevalence of cutaneous and systemic infections in patients with AD is significantly higher than those without AD. Infectious complications can include skin and soft-tissue infections, bacteremia, eczema herpeticum, osteomyelitis, endocarditis, and septic arthritis.
 

3. Climate change has a profound impact on AD

The incidence of AD has increased over the past several decades, and environmental factors such as climate change have been implicated as a potential mechanism. Climate change–related factors affect the skin’s capacity to maintain homeostasis, leading to various cutaneous diseases. AD, psoriasis, pemphigus, acne vulgaris, melasma, and photoaging are all associated with rising levels of air pollution. Elevated temperatures due to global warming induce disruption of the skin microbiome, thereby affecting AD.

Extreme weather events due to climate change, including floods and wildfires, are implicated in cutaneous injuries, skin infections, and acute worsening of inflammatory skin disorders.
 

4. The impact and appearance of AD varies in different racial groups

It was once believed that AD was just one single disease affecting people of many different races. More recently, it has been proposed that AD is in fact a group of different diseases. Both epidemiologic and genetic factors may play a role in influencing the main features of AD.

Spongiotic processes such as AD that would be pink or erythematous on white skin are often hypopigmented in individuals with darkly pigmented skin. AD has a higher prevalence and severity in Black and mixed-race populations, probably owing to a combination of environmental and intrinsic factors. Black skin has been shown to have increased transepidermal water loss and lower levels of ceramides, which are important components of the lipid barrier in the stratum corneum.

The American College of Allergy, Asthma & Immunology, along with the Allergy & Asthma Network, are partnering to create Eczema in Skin of Color, a website to aid physicians and patients in recognizing eczema in people with all skin types.
 

5. New and emerging therapies are poised to improve outcomes with AD treatment

Ruxolitinib cream, a topical Janus kinase (JAK)-1/JAK2 inhibitor, was approved for AD by the U.S. Food and Drug Administration in September 2021. The approval was based on results from the Topical Ruxolitinib Evaluation in AD (TRuE-AD) clinical trial program, which consisted of phase 3 studies that investigated 1,249 patients aged greater than or equal to 12 years with mild to moderate AD (Investigator’s Global Assessment score of 2-3) with a body surface area of 3%-20% (excluding scalp). The 2023 AAD guidelines for topical treatment recommend ruxolitinib cream for adults with mild to moderate AD.

Tralokinumab is a monoclonal antibody that inhibits the interleukin-13 cytokines, which prevents the release of cytokines, chemokines, and IgE. It was approved by the FDA in 2021 for treatment of moderate to severe AD. It is administered by subcutaneous injection every 2 weeks. Approval was based on the phase 3 trials ECZTRA 1, 2, and 3, which assessed the efficacy of tralokinumab in 1,934 adults.

Abrocitinib is an oral, once-daily JAK1 inhibitor for treatment of adults living with refractory, moderate to severe AD. FDA approval was based on results of five clinical trials from a large-scale trial program of more than 1,600 patients. Across the trials, abrocitinib demonstrated a consistent safety profile and profound improvements in skin clearance, extent of disease, and severity, as well as rapid improvement in itch after 2 weeks, for some people living with AD vs placebo.

Upadacitinib, another oral JAK1 inhibitor, was approved by the FDA in January 2022 for refractory moderate to severe AD. Approval was based on three double-blind phase 3 trials (Measure Up 1, Measure Up 2, AD Up) in which 2,584 patients with moderate to severe AD were randomized to receive oral upadacitinib 15 mg/d and 30 mg/d. In Measure Up 1 and Measure Up 2, upadacitinib was evaluated as monotherapy; in AD Up, upadacitinib was evaluated in combination with topical corticosteroids.
 

On the horizon

Baricitinib, an oral JAK1/2 inhibitor, is not yet approved by the FDA for AD. It is, however, approved for moderate to severe AD treatment in the European Union and many other countries. A 2022 review of studies evaluating baricitinib for the treatment of moderate to severe AD in adults (BREEZE-AD1, -AD2, -AD3, -AD4, -AD5, -AD6) reported that current evidence supports baricitinib, used as monotherapy or in combination with topical corticosteroids, as a safe and effective agent that can be used as an alternative to subcutaneous biologics in adults with moderate to severe AD.

Topical JAK inhibitors

A 2023 systematic review (19 studies, 3,600 participants) reported on several topical JAK inhibitors that are effective for treating AD. It suggests a stronger safety profile and better results, compared with systemic JAK inhibitors. The review focused on topical delgocitinib, tofacitinib, ruxolitinib, cerdulatinib, and ifidancitinib. All agents were effective in treating AD. All of these topical JAK inhibitors had minimal risk for mild to moderate adverse effects.

Biologics

Lebrikizumab was evaluated in a phase 2b, double-blind, placebo-controlled randomized clinical trial. After 16 weeks (280 participants), patients with moderate to severe AD showed a dose-dependent significant improvement in the primary endpoint, compared with placebo. Two phase 3 trials (ADvocate1, ADvocate2) evaluated the safety and efficacy of monotherapy with lebrikizumab in adults and adolescents with moderate to severe AD.

Nemolizumab, assessed in long-term phase 3 trials of AD-associated pruritus, resulted in clinically meaningful improvements from the beginning of treatment to week 68. Nemolizumab is being evaluated in two identical phase 3 studies (Arcadia 1, Arcadia 2) and a long-term extension study.

Dr. Kim is Professor and Vice Chair of Research in the department of dermatology, as well as Director of the Mark Lebwohl Center for Neuroinflammation and Sensation at the Icahn School of Medicine at Mount Sinai, New York. He reported conflicts of interest with 23andMe, Abrax Japan, AbbVie, Almirall, Amgen, and KiiRNA Biotech.

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

Children with atopic dermatitis (AD) were significantly more likely to have positive patch test results than were children without AD, according to a study of over 900 children evaluated for allergic contact dermatitis (ACD) with patch testing, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.

ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.

Dr. JiaDe Yu

UCHealth

Top allergens

The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.

MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.

Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.

Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).

Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.

The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.

Patch testing availability

Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.

Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”

The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.

Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”

Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.

Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.

The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.

The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.

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

Children with atopic dermatitis (AD) were significantly more likely to have positive patch test results than were children without AD, according to a study of over 900 children evaluated for allergic contact dermatitis (ACD) with patch testing, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.

ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.

Dr. JiaDe Yu

UCHealth

Top allergens

The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.

MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.

Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.

Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).

Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.

The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.

Patch testing availability

Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.

Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”

The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.

Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”

Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.

Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.

The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.

The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.

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

Children with atopic dermatitis (AD) were significantly more likely to have positive patch test results than were children without AD, according to a study of over 900 children evaluated for allergic contact dermatitis (ACD) with patch testing, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.

ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.

Dr. JiaDe Yu

UCHealth

Top allergens

The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.

MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.

Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.

Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).

Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.

The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.

Patch testing availability

Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.

Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”

The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.

Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”

Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.

Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.

The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.

The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.

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

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; [email protected]

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; [email protected]

THE CASE

A 52-year-old man sought care at the emergency department for intermittent fevers that started within 6 days of receiving his second dose of the BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech). After an unremarkable work-up, he was discharged home. Six days later, he returned to the emergency department with a fever of 102 °F and new-onset, progressive tremors in all 4 of his extremities.

The patient had a history of rheumatoid arthritis, for which he was taking oral methotrexate 15 mg once weekly and golimumab 50 mg SQ once monthly, and atrial fibrillation. He’d also had mechanical aortic and mitral valves implanted and was taking warfarin (9 mg/d on weekdays, 6 mg/d on Saturday and Sunday). Aside from his fever, his vital signs were normal. He also had horizontal nystagmus (chronically present) and diffuse tremors/myoclonic movements throughout his upper and lower extremities. The tremors were present at rest and worsened with intention/activity, which affected the patient’s ability to walk and perform activities of daily living.

He was admitted the next day to the family medicine service for further evaluation. Neurology and infectious disease consultations were requested, and a broad initial work-up was undertaken. Hyperreflexia was present in all of his extremities, but his neurologic examination was otherwise normal. Initial laboratory tests demonstrated leukocytosis and elevated liver transaminases. His international normalized ratio (INR) and prothrombin time (PT) also were elevated (> 8 [goal, 2.5-3.5 for mechanical heart valves] and > 90 seconds [normal range, 9.7-13.0 seconds], respectively), thus his warfarin was held and oral vitamin K was started (initial dose of 2.5 mg, which was increased to 5 mg when his INR did not decrease enough).

By Day 2, his INR and PT had normalized enough to reinitiate his warfarin dosing. Results from the viral antibody and polymerase chain reaction testing indicated the presence of cytomegalovirus (CMV) infection with viremia; blood cultures for bacterial infection were negative. Brain magnetic resonance imaging was ordered and identified a small, acute left-side cerebellar stroke. Lumbar puncture also was ordered but deferred until his INR was below 1.5 (on Day 8), at which point it confirmed the absence of CMV or herpes simplex virus in his central nervous system.

THE DIAGNOSIS

The patient started oral valganciclovir 900 mg twice daily to ameliorate his tremors, but he did not tolerate it well, vomiting after dosing. He was switched to IV ganciclovir 5 mg/kg every 12 hours; however, his tremors were not improving, leading the team to suspect an etiology other than viral infection. A presumptive diagnosis of autoimmune movement disorder was made, and serum tests were ordered; the results were positive for antiphospholipid antibodies, including anticardiolipin and anti-ß₂ glycoprotein-I antibodies. A final diagnosis of autoimmune antiphospholipid antibody syndrome (APS)–related movement disorder¹ with coagulopathy was reached, and the patient was started on methylprednisolone 1 g/d IV.

We suspected the CMV viremia was reactivated by the COVID-19 vaccine and caused the APS that led to the movement disorder, coagulopathy, and likely, the thrombotic cerebellar stroke. The case was reported to the Vaccine Adverse Event Reporting System (VAERS).²

DISCUSSION

Clinically evident APS is rare, with an estimated annual incidence of 2.1 per 100,000 according to a 2019 longitudinal cohort study.³ Notably, all identified cases in this cohort had either a venous or arterial thrombotic event—a characterizing feature of APS—with 45% of patients diagnosed with stroke or transient ischemic attack.^3,4

Continue to: The development of antiphospholipid antibodies...

The development of antiphospholipid antibodies has been independently associated with rheumatoid arthritis,⁵ COVID-19,⁶ and CMV infection,⁷ as well as with vaccination for influenza and tetanus.⁸ There also are reports of antiphospholipid antibodies occurring in patients who have received ­adenovirus-vectored and mRNA COVID-19 vaccines.^9-11

Movement disorders occurring with APS are unusual, with approximately 1.3% to 4.5% of patients with APS demonstrating this manifestation.¹² One of multiple autoimmune-related movement disorders, APS-­related movement disorder is most commonly associated with systemic lupus erythematosus (SLE), although it can occur outside an SLE diagnosis.⁴

Limited evidence suggests that COVID-19 vaccination can cause reactivation of dormant herpesviruses.

While APS-related movement disorder occurs with the presence of antiphospholipid antibodies, the pathogenesis of the movement disorder is unclear.⁴ Patients are typically young women, and the associated movements are choreiform. The condition often occurs with coagulopathy and arterial thrombosis.⁴ Psychiatric manifestations also can occur, including changes in behavior—up to and including psychosis.⁴

Evidence of COVID-19 vaccination reactivating herpesviruses exists, although it is rare and usually does not cause serious health outcomes.¹³ The annual incidence of reactivation related to vaccination is estimated to be 0.7 per 100,000 for varicella zoster virus and 0.03 per 100,000 for herpes simplex virus.¹³ The literature also suggests that the occurrence of Bell palsy—the onset of which may be related to the reactivation of a latent virus—may increase in relation to particular COVID-19 vaccines.^14,15 Although there is no confirmed explanation for these reactivation events at this time, different theories related to altering the focus of immune cells from latent disease to the newly generated antigen have been suggested.¹⁶

To date, reactivation has not been demonstrated with CMV specifically. However, based on the literature reviewed here on the reactivation of herpesviruses and the temporal relationship to infection in our patient, we propose that the BNT162b2 mRNA vaccination reactivated his CMV infection and led to his APS-related movement disorder.

Continue to: Treatment is focused on resolved the autoimmune condition

Treatment is focused on resolving the autoimmune condition, usually with corticosteroids. Longer-term treatment of the movement disorder with antiepileptics such as carbamazepine and valproic acid may be necessary.⁴

Our patient received methylprednisolone IV 1 g/d for 3 days and responded quickly to the treatment. He was discharged to a post-acute rehabilitation hospital on Day 16 with a plan for 21 days of antiviral treatment for an acute CMV infection, 1 month of oral steroid taper for the APS, and continued warfarin treatment. This regimen resulted in complete resolution of his movement disorder and negative testing of antiphospholipid antibodies 16 days after he was discharged from the hospital.

THE TAKEAWAY

This case illustrates the possible reactivation of a herpesvirus (CMV) related to COVID-19 vaccination, as well as the development of APS-related movement disorder and coagulopathy related to acute CMV infection with viremia. Vaccination for the COVID-19 virus is seen as the best intervention available for preventing serious illness and death associated with COVID-19 infection. Thus, it is important to be aware of these unusual events when vaccinating large populations. This case also demonstrates the need to understand the interplay of immune status and possible disorders associated with autoimmune conditions. Keeping an open mind when evaluating patients with post-vaccination complaints is beneficial—especially given the volume of distrust and misinformation associated with COVID-19 vaccination.

CORRESPONDENCE
Aaron Lear, MD, MSc, CAQ, Cleveland Clinic Akron General Center for Family Medicine, 1 Akron General Avenue, Building 301, Akron, OH 44307; [email protected]

Maternal pertussis vaccinations, given during pregnancy, prevent an estimated 65% of pertussis infections in infants, new research indicates.

The study, led by Annette K. Regan, PhD, MPH, a perinatal and pediatric infectious disease epidemiologist at Curtin University, Perth, Australia, was published online in Pediatrics.

Dr. Regan – who is also with the University of San Francisco and the University of California, Los Angeles – and colleagues reviewed data on 279,418 infants born to 252,444 mothers in Australia.

There, about 52% of the women in this study received the Tdap vaccine through a maternal pertussis vaccination program.

Duration of effectiveness in infants was one of the main questions the study sought to answer.

The authors wrote that they assessed vaccine effectiveness through 18 months of age. “We observed significant protection against disease until at least 8 months of age, 2 months longer than reported in previous studies.” From 70% to 90% of all pertussis-attributable hospitalizations and death occur in infancy.
 

Answering the ‘blunting’ question

This study also set out to clarify an important clinical question regarding a potential “blunting” effect in infants. Previous work had suggested that maternal antibodies from the vaccination could interfere with the effectiveness of infants’ DtaP (the version of Tdap for infants) and other vaccines.

Dr. Regan and colleagues found that, “although we observed slightly lower VE [vaccine effectiveness] point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs. 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% confidence interval, 0.61-3.39).
 

Best time to give mothers the vaccine

Another clinical debate has centered on when to give the mother the vaccine during pregnancy. The authors concluded: “Our findings support the infant health benefits of recommendations to administer a booster dose of pertussis vaccine near 28 weeks of gestational age.”

That 28-week mark was associated with lower risk of infection in infants through 8 months of age, they wrote.
 

Positive results in the United States

In an invited commentary, Kathryn M. Edwards, MD, with the division of infectious diseases, department of pediatrics, at Vanderbilt University Medical Center, Nashville, Tenn., highlighted similar positive findings for maternal pertussis vaccination in the United States.

The Centers for Disease Control and Prevention did an ecologic study of infant pertussis cases reported between Jan. 1, 2000, and Dec. 31, 2019. Rates were compared for the years before maternal Tdap vaccinations were recommended against the 7-year period after they were implemented.

That study found that in the period before maternal Tdap vaccination, annual pertussis incidence did not change among infants younger than 2 months and increased slightly in infants 6-12 months.

However, during the period after maternal Tdap vaccination had started (2012-2019), pertussis incidence significantly decreased in infants younger than 2 months and was unchanged in infants 6-12 months.

“As with the Australian data, the U.S. data support the overall benefit of the maternal Tdap program and, as with the Australian data, do not suggest that blunting has led to an increase in cases within the first year of life,” Dr. Edwards wrote.

The CDC notes that pertussis cases are rising and outbreaks are happening across the United States.

“On average, about 1,000 infants are hospitalized and typically between 5 and 15 infants die each year in the United States due to pertussis,” the CDC states.
 

Uptake low despite positive data

Dr. Edwards noted that, despite positive data supporting maternal vaccination to reduce pertussis, uptake rates are low – between 50% and 60% in Australia, the United Kingdom, and the United States. “Active engagement to increase these rates should be implemented.”

Maternal vaccination might also be implemented soon to protect against other diseases including respiratory syncytial virus and group B streptococcal disease after promising study data, she said.

As with pertussis, the potential “blunting” effect will need to be carefully monitored, she said, “as was done in the carefully conducted study of pertussis reported in this issue of Pediatrics.”

One coauthor has received institutional honoraria for participation in advisory groups for Merck Sharpe & Dohme and Pfizer unrelated to this work. Another coauthor was supported by scholarships provided by the Wesfarmers Centre of Vaccines and Infectious Disease at the Telethon Kids Institute. Dr. Edwards reported receiving grants from the CDC and consulting for Bionet, Dynavax, and IBM. She is a member of the data safety and monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration.

Maternal pertussis vaccinations, given during pregnancy, prevent an estimated 65% of pertussis infections in infants, new research indicates.

The study, led by Annette K. Regan, PhD, MPH, a perinatal and pediatric infectious disease epidemiologist at Curtin University, Perth, Australia, was published online in Pediatrics.

Dr. Regan – who is also with the University of San Francisco and the University of California, Los Angeles – and colleagues reviewed data on 279,418 infants born to 252,444 mothers in Australia.

There, about 52% of the women in this study received the Tdap vaccine through a maternal pertussis vaccination program.

Duration of effectiveness in infants was one of the main questions the study sought to answer.

The authors wrote that they assessed vaccine effectiveness through 18 months of age. “We observed significant protection against disease until at least 8 months of age, 2 months longer than reported in previous studies.” From 70% to 90% of all pertussis-attributable hospitalizations and death occur in infancy.
 

Answering the ‘blunting’ question

This study also set out to clarify an important clinical question regarding a potential “blunting” effect in infants. Previous work had suggested that maternal antibodies from the vaccination could interfere with the effectiveness of infants’ DtaP (the version of Tdap for infants) and other vaccines.

Dr. Regan and colleagues found that, “although we observed slightly lower VE [vaccine effectiveness] point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs. 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% confidence interval, 0.61-3.39).
 

Best time to give mothers the vaccine

Another clinical debate has centered on when to give the mother the vaccine during pregnancy. The authors concluded: “Our findings support the infant health benefits of recommendations to administer a booster dose of pertussis vaccine near 28 weeks of gestational age.”

That 28-week mark was associated with lower risk of infection in infants through 8 months of age, they wrote.
 

Positive results in the United States

In an invited commentary, Kathryn M. Edwards, MD, with the division of infectious diseases, department of pediatrics, at Vanderbilt University Medical Center, Nashville, Tenn., highlighted similar positive findings for maternal pertussis vaccination in the United States.

The Centers for Disease Control and Prevention did an ecologic study of infant pertussis cases reported between Jan. 1, 2000, and Dec. 31, 2019. Rates were compared for the years before maternal Tdap vaccinations were recommended against the 7-year period after they were implemented.

That study found that in the period before maternal Tdap vaccination, annual pertussis incidence did not change among infants younger than 2 months and increased slightly in infants 6-12 months.

However, during the period after maternal Tdap vaccination had started (2012-2019), pertussis incidence significantly decreased in infants younger than 2 months and was unchanged in infants 6-12 months.

“As with the Australian data, the U.S. data support the overall benefit of the maternal Tdap program and, as with the Australian data, do not suggest that blunting has led to an increase in cases within the first year of life,” Dr. Edwards wrote.

The CDC notes that pertussis cases are rising and outbreaks are happening across the United States.

“On average, about 1,000 infants are hospitalized and typically between 5 and 15 infants die each year in the United States due to pertussis,” the CDC states.
 

Uptake low despite positive data

Dr. Edwards noted that, despite positive data supporting maternal vaccination to reduce pertussis, uptake rates are low – between 50% and 60% in Australia, the United Kingdom, and the United States. “Active engagement to increase these rates should be implemented.”

Maternal vaccination might also be implemented soon to protect against other diseases including respiratory syncytial virus and group B streptococcal disease after promising study data, she said.

As with pertussis, the potential “blunting” effect will need to be carefully monitored, she said, “as was done in the carefully conducted study of pertussis reported in this issue of Pediatrics.”

One coauthor has received institutional honoraria for participation in advisory groups for Merck Sharpe & Dohme and Pfizer unrelated to this work. Another coauthor was supported by scholarships provided by the Wesfarmers Centre of Vaccines and Infectious Disease at the Telethon Kids Institute. Dr. Edwards reported receiving grants from the CDC and consulting for Bionet, Dynavax, and IBM. She is a member of the data safety and monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration.

Maternal pertussis vaccinations, given during pregnancy, prevent an estimated 65% of pertussis infections in infants, new research indicates.

The study, led by Annette K. Regan, PhD, MPH, a perinatal and pediatric infectious disease epidemiologist at Curtin University, Perth, Australia, was published online in Pediatrics.

Dr. Regan – who is also with the University of San Francisco and the University of California, Los Angeles – and colleagues reviewed data on 279,418 infants born to 252,444 mothers in Australia.

There, about 52% of the women in this study received the Tdap vaccine through a maternal pertussis vaccination program.

Duration of effectiveness in infants was one of the main questions the study sought to answer.

The authors wrote that they assessed vaccine effectiveness through 18 months of age. “We observed significant protection against disease until at least 8 months of age, 2 months longer than reported in previous studies.” From 70% to 90% of all pertussis-attributable hospitalizations and death occur in infancy.
 

Answering the ‘blunting’ question

This study also set out to clarify an important clinical question regarding a potential “blunting” effect in infants. Previous work had suggested that maternal antibodies from the vaccination could interfere with the effectiveness of infants’ DtaP (the version of Tdap for infants) and other vaccines.

Dr. Regan and colleagues found that, “although we observed slightly lower VE [vaccine effectiveness] point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs. 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% confidence interval, 0.61-3.39).
 

Best time to give mothers the vaccine

Another clinical debate has centered on when to give the mother the vaccine during pregnancy. The authors concluded: “Our findings support the infant health benefits of recommendations to administer a booster dose of pertussis vaccine near 28 weeks of gestational age.”

That 28-week mark was associated with lower risk of infection in infants through 8 months of age, they wrote.
 

Positive results in the United States

In an invited commentary, Kathryn M. Edwards, MD, with the division of infectious diseases, department of pediatrics, at Vanderbilt University Medical Center, Nashville, Tenn., highlighted similar positive findings for maternal pertussis vaccination in the United States.

The Centers for Disease Control and Prevention did an ecologic study of infant pertussis cases reported between Jan. 1, 2000, and Dec. 31, 2019. Rates were compared for the years before maternal Tdap vaccinations were recommended against the 7-year period after they were implemented.

That study found that in the period before maternal Tdap vaccination, annual pertussis incidence did not change among infants younger than 2 months and increased slightly in infants 6-12 months.

However, during the period after maternal Tdap vaccination had started (2012-2019), pertussis incidence significantly decreased in infants younger than 2 months and was unchanged in infants 6-12 months.

“As with the Australian data, the U.S. data support the overall benefit of the maternal Tdap program and, as with the Australian data, do not suggest that blunting has led to an increase in cases within the first year of life,” Dr. Edwards wrote.

The CDC notes that pertussis cases are rising and outbreaks are happening across the United States.

“On average, about 1,000 infants are hospitalized and typically between 5 and 15 infants die each year in the United States due to pertussis,” the CDC states.
 

Uptake low despite positive data

Dr. Edwards noted that, despite positive data supporting maternal vaccination to reduce pertussis, uptake rates are low – between 50% and 60% in Australia, the United Kingdom, and the United States. “Active engagement to increase these rates should be implemented.”

Maternal vaccination might also be implemented soon to protect against other diseases including respiratory syncytial virus and group B streptococcal disease after promising study data, she said.

As with pertussis, the potential “blunting” effect will need to be carefully monitored, she said, “as was done in the carefully conducted study of pertussis reported in this issue of Pediatrics.”

One coauthor has received institutional honoraria for participation in advisory groups for Merck Sharpe & Dohme and Pfizer unrelated to this work. Another coauthor was supported by scholarships provided by the Wesfarmers Centre of Vaccines and Infectious Disease at the Telethon Kids Institute. Dr. Edwards reported receiving grants from the CDC and consulting for Bionet, Dynavax, and IBM. She is a member of the data safety and monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration.

The Food and Drug Administration has approved the biosimilar tocilizumab-bavi (Tofidence), Biogen, the drug’s manufacturer, announced on Sept. 29.

It is the first tocilizumab biosimilar approved by the FDA. The reference product, Actemra (Genentech), was first approved by the agency in 2010.

“The approval of Tofidence in the U.S. marks another positive step toward helping more people with chronic autoimmune conditions gain access to leading therapies,” Ian Henshaw, global head of biosimilars at Biogen, said in a statement. “With the increasing numbers of approved biosimilars, we expect increased savings and sustainability for health care systems and an increase in physician choice and patient access to biologics.”

Biogen’s pricing for tocilizumab-bavi will be available closer to the product’s launch date, which has yet to be determined, a company spokesman said. The U.S. average monthly cost of Actemra for rheumatoid arthritis, administered intravenously, is $2,134-$4,268 depending on dosage, according to a Genentech spokesperson.

Tocilizumab-bavi is an intravenous formulation (20 mg/mL) indicated for treatment of moderately to severely active RA, polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA). The medication is administered every 4 weeks in RA and PJIA and every 8 weeks in SJIA as a single intravenous drip infusion over 1 hour.

The European Commission approved its first tocilizumab biosimilar, Tyenne (Fresenius Kabi), earlier in 2023 in both subcutaneous and intravenous formulations. Biogen did not comment on whether the company is working on a subcutaneous formulation for tocilizumab-bavi.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has approved the biosimilar tocilizumab-bavi (Tofidence), Biogen, the drug’s manufacturer, announced on Sept. 29.

It is the first tocilizumab biosimilar approved by the FDA. The reference product, Actemra (Genentech), was first approved by the agency in 2010.

“The approval of Tofidence in the U.S. marks another positive step toward helping more people with chronic autoimmune conditions gain access to leading therapies,” Ian Henshaw, global head of biosimilars at Biogen, said in a statement. “With the increasing numbers of approved biosimilars, we expect increased savings and sustainability for health care systems and an increase in physician choice and patient access to biologics.”

Biogen’s pricing for tocilizumab-bavi will be available closer to the product’s launch date, which has yet to be determined, a company spokesman said. The U.S. average monthly cost of Actemra for rheumatoid arthritis, administered intravenously, is $2,134-$4,268 depending on dosage, according to a Genentech spokesperson.

Tocilizumab-bavi is an intravenous formulation (20 mg/mL) indicated for treatment of moderately to severely active RA, polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA). The medication is administered every 4 weeks in RA and PJIA and every 8 weeks in SJIA as a single intravenous drip infusion over 1 hour.

The European Commission approved its first tocilizumab biosimilar, Tyenne (Fresenius Kabi), earlier in 2023 in both subcutaneous and intravenous formulations. Biogen did not comment on whether the company is working on a subcutaneous formulation for tocilizumab-bavi.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has approved the biosimilar tocilizumab-bavi (Tofidence), Biogen, the drug’s manufacturer, announced on Sept. 29.

It is the first tocilizumab biosimilar approved by the FDA. The reference product, Actemra (Genentech), was first approved by the agency in 2010.

“The approval of Tofidence in the U.S. marks another positive step toward helping more people with chronic autoimmune conditions gain access to leading therapies,” Ian Henshaw, global head of biosimilars at Biogen, said in a statement. “With the increasing numbers of approved biosimilars, we expect increased savings and sustainability for health care systems and an increase in physician choice and patient access to biologics.”

Biogen’s pricing for tocilizumab-bavi will be available closer to the product’s launch date, which has yet to be determined, a company spokesman said. The U.S. average monthly cost of Actemra for rheumatoid arthritis, administered intravenously, is $2,134-$4,268 depending on dosage, according to a Genentech spokesperson.

Tocilizumab-bavi is an intravenous formulation (20 mg/mL) indicated for treatment of moderately to severely active RA, polyarticular juvenile idiopathic arthritis (PJIA), and systemic juvenile idiopathic arthritis (SJIA). The medication is administered every 4 weeks in RA and PJIA and every 8 weeks in SJIA as a single intravenous drip infusion over 1 hour.

The European Commission approved its first tocilizumab biosimilar, Tyenne (Fresenius Kabi), earlier in 2023 in both subcutaneous and intravenous formulations. Biogen did not comment on whether the company is working on a subcutaneous formulation for tocilizumab-bavi.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has issued a complete response letter regarding lebrikizumab, an investigational biologic for the treatment of adult and adolescent patients with moderate to severe atopic dermatitis, describing concerns about findings made during an inspection of a third-party contract manufacturer that included the “monoclonal antibody drug substance” for lebrikizumab, Eli Lilly announced in an Oct. 2 press release.

Lebrikizumab is under FDA review for treating atopic dermatitis; a complete response letter indicates that the review has been completed, and highlights issues that need to be addressed before a final decision on approval is made.

The press release noted that the agency did not raise any concerns about the clinical data package, safety, or label for lebrikizumab, an investigational, monoclonal antibody that binds to the cytokine interleukin (IL)-13, and is designed to be administered once per month.

In the press release, the company said it would work with the third-party manufacturer and the FDA to address the feedback “in order to make lebrikizumab available to patients.”

The Food and Drug Administration has issued a complete response letter regarding lebrikizumab, an investigational biologic for the treatment of adult and adolescent patients with moderate to severe atopic dermatitis, describing concerns about findings made during an inspection of a third-party contract manufacturer that included the “monoclonal antibody drug substance” for lebrikizumab, Eli Lilly announced in an Oct. 2 press release.

Lebrikizumab is under FDA review for treating atopic dermatitis; a complete response letter indicates that the review has been completed, and highlights issues that need to be addressed before a final decision on approval is made.

The press release noted that the agency did not raise any concerns about the clinical data package, safety, or label for lebrikizumab, an investigational, monoclonal antibody that binds to the cytokine interleukin (IL)-13, and is designed to be administered once per month.

In the press release, the company said it would work with the third-party manufacturer and the FDA to address the feedback “in order to make lebrikizumab available to patients.”

The Food and Drug Administration has issued a complete response letter regarding lebrikizumab, an investigational biologic for the treatment of adult and adolescent patients with moderate to severe atopic dermatitis, describing concerns about findings made during an inspection of a third-party contract manufacturer that included the “monoclonal antibody drug substance” for lebrikizumab, Eli Lilly announced in an Oct. 2 press release.

Lebrikizumab is under FDA review for treating atopic dermatitis; a complete response letter indicates that the review has been completed, and highlights issues that need to be addressed before a final decision on approval is made.

The press release noted that the agency did not raise any concerns about the clinical data package, safety, or label for lebrikizumab, an investigational, monoclonal antibody that binds to the cytokine interleukin (IL)-13, and is designed to be administered once per month.

In the press release, the company said it would work with the third-party manufacturer and the FDA to address the feedback “in order to make lebrikizumab available to patients.”

The risk for inflammatory bowel disease (IBD) was increased among children and adults with atopic dermatitis (AD), with the risk increasing with AD severity, according to data from a large cohort study published recently in JAMA Dermatology.

The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.

Courtesy Dr. Gelfand

“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.

“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.

UK general practice cohort

AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.

To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.

The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.

In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
 

AD severity linked with IBD risk

The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.

Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.

AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).

Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.

Robust data with cautionary note

“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”

Case Western Reserve University

However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.

Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.

Wake Forest University

But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”

For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.

“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.

Wake Forest University

“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”

The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”

Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.

The Ohio State Wexner Medical Center

“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”

The authors recommend future related studies in more diverse populations.

Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.

A version of this article appeared on Medscape.com.

The risk for inflammatory bowel disease (IBD) was increased among children and adults with atopic dermatitis (AD), with the risk increasing with AD severity, according to data from a large cohort study published recently in JAMA Dermatology.

The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.

Courtesy Dr. Gelfand

“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.

“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.

UK general practice cohort

AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.

To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.

The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.

In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
 

AD severity linked with IBD risk

The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.

Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.

AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).

Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.

Robust data with cautionary note

“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”

Case Western Reserve University

However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.

Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.

Wake Forest University

But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”

For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.

“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.

Wake Forest University

“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”

The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”

Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.

The Ohio State Wexner Medical Center

“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”

The authors recommend future related studies in more diverse populations.

Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.

A version of this article appeared on Medscape.com.

The risk for inflammatory bowel disease (IBD) was increased among children and adults with atopic dermatitis (AD), with the risk increasing with AD severity, according to data from a large cohort study published recently in JAMA Dermatology.

The study also found an increased risk for Crohn’s disease (CD) in adults and children with AD, as well as an increased risk for ulcerative colitis (UC) in adults with AD and in children with severe AD, researchers reported.

“It is imperative for clinicians to understand atopic dermatitis and the trajectory of our patients with it in order to provide the best standard of care,” senior author Joel M. Gelfand, MD, MSCE, professor in clinical investigation with the department of dermatology at the University of Pennsylvania, Philadelphia, said in a news release.

Courtesy Dr. Gelfand

“There are new and better treatments for AD today, and there will likely continue to be more,” continued Dr. Gelfand. “But providers have to understand how those treatments could impact other autoimmune diseases. For patients with AD and another autoimmune disease, some currently available medications can exacerbate symptoms of their other disease or can help treat two immune diseases at the same time.”

The study results support the idea that AD and IBD may have some common underlying causes, said Sheilagh Maguiness, MD, pediatric dermatologist and associate professor in the department of dermatology at the University of Minnesota, Minneapolis, who was asked to comment on the findings.

“As the pathogenesis of AD is becoming better understood, we are recognizing that, rather than simply a cutaneous disease, the underlying inflammation and immune dysregulation that leads to AD best categorizes it as a systemic inflammatory disease with significant comorbidities,” she told this news organization. “I will be more likely to ask patients and families about GI symptoms, and if positive, may plan to refer to GI more readily than in the past,” added Dr. Maguiness, who was not involved in the study.

UK general practice cohort

AD has been associated with an increasing number of comorbidities, including IBD, but studies linking AD with IBD, including UC, have had mixed results, the authors wrote. And few studies have separately examined how AD or AD severity may be linked with UC or CD risk.

To examine the risk for new-onset IBD, UC, and CD in children and adults with atopic dermatitis, the researchers conducted a population-based cohort study using the THIN (The Health Improvement Network) electronic medical record database of patients registered with United Kingdom general practices. They used 21 years of data collected from January 1994 to February 2015.

The researchers matched each patient who had AD with up to five controls based on age, practice, and index date. Because THIN does not capture AD severity, they used treatment exposure assessed by dermatologic referrals and treatments patients received as proxy for severity. The authors used logistic regression to examine the risks for IBD, UC, and CD in children (aged 1-10) with AD, and in adults (aged 30-68) with AD, and they compared their outcomes with the outcomes for controls.

In the pediatric cohort, the team compared 409,431 children who had AD with 1.8 million children without AD. Slightly more than half were boys. In the adult cohort, they compared 625,083 people who had AD with 2.68 million controls, and slightly more than half were women. Data on race or ethnicity were not available, the authors wrote, but the THIN database is considered to be representative of the UK population.
 

AD severity linked with IBD risk

The risk for new-onset inflammatory bowel disease appears to be higher in children and adults with AD, and the risk varies based on age, AD severity, and subtype of inflammatory bowel disease, the authors reported.

Overall, AD in children was associated with a 44% increased risk for IBD (adjusted hazard ratio (HR), 1.44; 95% confidence interval [CI], 1.31-1.58) compared with controls, the authors reported. They found a 74% increased risk for CD in children with AD compared with controls (HR, 1.74; 95% CI, 1.54-1.97). More severe AD was linked with increased risk for both IBD and CD.

AD did not appear to increase risk for UC in children, except those with severe AD (HR, 1.65; 95% CI, 1.02-2.67).

Overall, adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk for IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk for CD, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk for UC, with risk increasing with increased AD severity.

Robust data with cautionary note

“This study provides the most robust data to date on the association between IBD and AD. It provides clear evidence for an association that most dermatologists or primary care providers are not typically taught in training,” Kelly Scarberry, MD, assistant professor of dermatology at Case Western Reserve University in Cleveland, told this news organization. “I will be much more likely to pursue diagnostic workup in my AD patients who have GI complaints.”

Case Western Reserve University

However, AD severity was measured by proxy, added Dr. Scarberry, who was not involved in the study, and the study lacked important racial and ethnic data.

Lindsay C. Strowd, MD, associate professor of dermatology at Wake Forest University, Winston-Salem, N.C., also not involved in the study, said in an interview that she found the size of the cohort and the longitudinal data to be strengths of the study.

Wake Forest University

But, she added, the “lack of family IBD history, race and ethnicity, and comorbidities, are limitations, as is treatment exposure used as a proxy for disease severity, given that physician treatment practices differ.”

For Steven R. Feldman, MD, PhD, professor of dermatology at Wake Forest, “the most important conclusion, and it is a definitive finding, [is] that IBD is uncommon, even in patients with AD.

“The findings could be misinterpreted,” cautioned Dr. Feldman, who was not involved in the study. “While there is an increased relative risk, the absolute risk is small.” The study found that “the highest relative risk group is children with severe AD, who have a roughly fivefold increased risk for CD.” However, he added, the incidence rates of CD were 0.68 per 1,000 person-years in children with severe AD and 0.08 per 1,000 person-years in controls.

Wake Forest University

“Basically, because Crohn’s disease and IBD don’t happen very often, the modest increase in relative risk the investigators found doesn’t amount to much we’d have to worry about,” he said. “The findings do not show any need to screen patients with atopic dermatitis for IBD any more than we’d need to screen patients without atopic dermatitis.”

The increased relative risk “could be a clue to possible genetic connections between diseases,” he added. “But when we’re making clinical decisions, those decisions should be based on the absolute risk that some event may occur.”

Susan Massick, MD, dermatologist and associate professor at The Ohio State University in Columbus, who was not involved with the study, said in an interview, “We are still scratching the surface of the complexity of the immune and inflammatory pathways in AD and IBD.

The Ohio State Wexner Medical Center

“It is important to remember that correlation does not mean causation,” Dr. Massick said. “It would be premature to draw direct conclusions based on this study alone.”

The authors recommend future related studies in more diverse populations.

Dr. Gelfand and two coauthors reported ties with Pfizer, which supported the study. Dr. Gelfand and three coauthors reported ties with other pharmaceutical companies. Dr. Maguiness, Dr. Scarberry, Dr. Strowd, and Dr. Massick reported having no relevant disclosures. Dr. Feldman reported ties with Pfizer and other pharmaceutical companies.

A version of this article appeared on Medscape.com.

Nearly 70% of adolescents and young adults stop taking oral 5-aminosalicylic acid (5-ASA) maintenance therapy within 12 months of ulcerative colitis (UC) diagnosis, new research from the United Kingdom indicates.

“This is concerning as they are at risk of their condition returning and further complications. It can also lead to severe complications such as surgery to remove part of the gut,” Sonia Saxena, MBBS, director, Imperial Child Health Unit, School of Public Health, Imperial College London, said in a news release.

The study “highlights the importance of counseling and education of patients at diagnosis as this is a critical window that influences long-term health behavior,” Ashwin Ananthakrishnan, MD, MPH, a gastroenterologist with Massachusetts General Hospital and Harvard Medical School, both in Boston, said in an interview.

“It has not been my experience in U.S.-based practice that the rates of discontinuation are that high, but it would be important to examine this in different locations,” added Dr. Ananthakrishnan, who wasn’t involved with the study.

The study was published online in the British Journal of General Practice.
 

Cases on the rise

Globally, the incidence of UC is increasing fastest in younger populations. It’s estimated that up to 30% of individuals with UC are diagnosed in childhood or young adulthood, and these individuals are more likely to have a severe disease course and years living with disability, compared with peers diagnosed later in life. This makes achieving disease control and maintaining remission “paramount” for those diagnosed in early life, Dr. Saxena and colleagues write.

International UC guidelines recommend starting therapy with 5-ASA, also known as mesalamine, soon after diagnosis and continuing it long term to maintain remission. However, some prior evidence suggests that adherence to UC medication may be less optimal in younger people – findings supported by the U.K. study.

Leveraging data from the UK Clinical Practice Research Datalink, Dr. Saxena and colleagues analyzed data for 607 children and young adults aged 10-24 years starting oral 5-ASA maintenance therapy for UC.

They found that 152 individuals (25%) stopped 5-ASA treatment after 1 month, and 419 (69%) discontinued it within 1 year of starting treatment. The median time to stopping the anti-inflammatory drug was 162 days.

Discontinuation rates were highest in young adults aged 18-24 years (74%). The transition to adult care and loss of support from caregivers who encourage adherence in adolescents and provide financial and practical support could be one explanation for this, the researchers write.

After accounting for other factors, young adults aged 18-24 years starting 5-ASA were 43% more likely to discontinue it in the first year than adolescents aged 10-14 years.

Individuals living in socioeconomically deprived areas were 46% more likely to stop treatment, compared with those living in more affluent areas, a finding that suggests the need to address socioeconomic disparities that could drive discontinuation, the authors say.

They also found that early corticosteroid use for an acute UC flare was associated with a 32% lower likelihood of stopping 5-ASA therapy.
 

Adherence falls short

In terms of adherence, defined as the proportion of days covered by 5-ASA medication, the mean was 72%, equivalent to just under 9 months. Adherence fell with older age at initiation of therapy. Adherence was 80% among those 10-14 years, 78% among those 15-17 years, and 69% among those 18-24 years. Prior research has shown that nonadherence to UC medication – defined as proportion of days covered less than 80% – has been associated with a five-fold risk of disease, compared with adherence above 80%, the investigators note.

“If clinicians are unaware of suboptimal adherence to first-line medication, they may incorrectly assume therapy has failed, which may lead to unnecessary escalation in treatment and avoidable steroid use that remains high in UC,” the researchers write.

Psychiatric comorbidity (depression, anxiety, or antidepressant use) was not associated with discontinuation or adherence to treatment.

“As doctors, this study shows we need to be keeping a close eye on patients, particularly within that first year of starting medication,” Dr. Saxena said in the release.

“We should check if these patients are getting their medications and whether they have difficulty paying for them. We should also use the opportunity to talk through any recurring symptoms and how to access advice from providers such as a nurse specialist,” Dr. Saxena said.
 

Effectiveness of therapy in young adults

Reached for comment, Michael Dolinger, MD, assistant professor of pediatric gastroenterology, Icahn School of Medicine and Mount Sinai Kravis Children’s Hospital, both in New York, said he has seen 5-ASA stoppage among his younger patients.

“Generally, what we see is that the majority of patients over time are not able to be sustained on oral mesalamine treatment, and they need a more advanced therapy,” Dr. Dolinger said in an interview.

And while the U.K. study did not delve into the reasons for discontinuation, ineffectiveness of therapy is likely a main cause, Dr. Dolinger said.

“We especially see this in our younger adolescent and young adult patients. In these younger patients, the immune system is potentially driving inflammation a bit more than in older patients, often going beyond the inner lining of the colon to the entire bowel wall, even in ulcerative colitis, and therefore mesalamine may be ineffective over the first year,” Dr. Dolinger explained.

When choosing a more advanced therapy, Dr. Dolinger said, “it’s all about having that conversation in a shared decision-making process about what may be the most effective short- and long-term treatment options with the best safety for that patient. It’s a very individualized discussion.”

“One of the main things we preach and talk about is control of inflammation, getting into early deep remission, because the longer you have inflammation, even if it’s just smoldering, the harder it is to get into deep remission,” Dr. Dolinger added.

The study had no commercial funding. Dr. Saxena, Dr. Ananthakrishnan, and Dr. Dolinger have disclosed no relevant financial relationships.

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

Nearly 70% of adolescents and young adults stop taking oral 5-aminosalicylic acid (5-ASA) maintenance therapy within 12 months of ulcerative colitis (UC) diagnosis, new research from the United Kingdom indicates.

“This is concerning as they are at risk of their condition returning and further complications. It can also lead to severe complications such as surgery to remove part of the gut,” Sonia Saxena, MBBS, director, Imperial Child Health Unit, School of Public Health, Imperial College London, said in a news release.

The study “highlights the importance of counseling and education of patients at diagnosis as this is a critical window that influences long-term health behavior,” Ashwin Ananthakrishnan, MD, MPH, a gastroenterologist with Massachusetts General Hospital and Harvard Medical School, both in Boston, said in an interview.

“It has not been my experience in U.S.-based practice that the rates of discontinuation are that high, but it would be important to examine this in different locations,” added Dr. Ananthakrishnan, who wasn’t involved with the study.

The study was published online in the British Journal of General Practice.
 

Cases on the rise

Globally, the incidence of UC is increasing fastest in younger populations. It’s estimated that up to 30% of individuals with UC are diagnosed in childhood or young adulthood, and these individuals are more likely to have a severe disease course and years living with disability, compared with peers diagnosed later in life. This makes achieving disease control and maintaining remission “paramount” for those diagnosed in early life, Dr. Saxena and colleagues write.

International UC guidelines recommend starting therapy with 5-ASA, also known as mesalamine, soon after diagnosis and continuing it long term to maintain remission. However, some prior evidence suggests that adherence to UC medication may be less optimal in younger people – findings supported by the U.K. study.

Leveraging data from the UK Clinical Practice Research Datalink, Dr. Saxena and colleagues analyzed data for 607 children and young adults aged 10-24 years starting oral 5-ASA maintenance therapy for UC.

They found that 152 individuals (25%) stopped 5-ASA treatment after 1 month, and 419 (69%) discontinued it within 1 year of starting treatment. The median time to stopping the anti-inflammatory drug was 162 days.

Discontinuation rates were highest in young adults aged 18-24 years (74%). The transition to adult care and loss of support from caregivers who encourage adherence in adolescents and provide financial and practical support could be one explanation for this, the researchers write.

After accounting for other factors, young adults aged 18-24 years starting 5-ASA were 43% more likely to discontinue it in the first year than adolescents aged 10-14 years.

Individuals living in socioeconomically deprived areas were 46% more likely to stop treatment, compared with those living in more affluent areas, a finding that suggests the need to address socioeconomic disparities that could drive discontinuation, the authors say.

They also found that early corticosteroid use for an acute UC flare was associated with a 32% lower likelihood of stopping 5-ASA therapy.
 

Adherence falls short

In terms of adherence, defined as the proportion of days covered by 5-ASA medication, the mean was 72%, equivalent to just under 9 months. Adherence fell with older age at initiation of therapy. Adherence was 80% among those 10-14 years, 78% among those 15-17 years, and 69% among those 18-24 years. Prior research has shown that nonadherence to UC medication – defined as proportion of days covered less than 80% – has been associated with a five-fold risk of disease, compared with adherence above 80%, the investigators note.

“If clinicians are unaware of suboptimal adherence to first-line medication, they may incorrectly assume therapy has failed, which may lead to unnecessary escalation in treatment and avoidable steroid use that remains high in UC,” the researchers write.

Psychiatric comorbidity (depression, anxiety, or antidepressant use) was not associated with discontinuation or adherence to treatment.

“As doctors, this study shows we need to be keeping a close eye on patients, particularly within that first year of starting medication,” Dr. Saxena said in the release.

“We should check if these patients are getting their medications and whether they have difficulty paying for them. We should also use the opportunity to talk through any recurring symptoms and how to access advice from providers such as a nurse specialist,” Dr. Saxena said.
 

Effectiveness of therapy in young adults

Reached for comment, Michael Dolinger, MD, assistant professor of pediatric gastroenterology, Icahn School of Medicine and Mount Sinai Kravis Children’s Hospital, both in New York, said he has seen 5-ASA stoppage among his younger patients.

“Generally, what we see is that the majority of patients over time are not able to be sustained on oral mesalamine treatment, and they need a more advanced therapy,” Dr. Dolinger said in an interview.

And while the U.K. study did not delve into the reasons for discontinuation, ineffectiveness of therapy is likely a main cause, Dr. Dolinger said.

“We especially see this in our younger adolescent and young adult patients. In these younger patients, the immune system is potentially driving inflammation a bit more than in older patients, often going beyond the inner lining of the colon to the entire bowel wall, even in ulcerative colitis, and therefore mesalamine may be ineffective over the first year,” Dr. Dolinger explained.

When choosing a more advanced therapy, Dr. Dolinger said, “it’s all about having that conversation in a shared decision-making process about what may be the most effective short- and long-term treatment options with the best safety for that patient. It’s a very individualized discussion.”

“One of the main things we preach and talk about is control of inflammation, getting into early deep remission, because the longer you have inflammation, even if it’s just smoldering, the harder it is to get into deep remission,” Dr. Dolinger added.

The study had no commercial funding. Dr. Saxena, Dr. Ananthakrishnan, and Dr. Dolinger have disclosed no relevant financial relationships.

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

Nearly 70% of adolescents and young adults stop taking oral 5-aminosalicylic acid (5-ASA) maintenance therapy within 12 months of ulcerative colitis (UC) diagnosis, new research from the United Kingdom indicates.

“This is concerning as they are at risk of their condition returning and further complications. It can also lead to severe complications such as surgery to remove part of the gut,” Sonia Saxena, MBBS, director, Imperial Child Health Unit, School of Public Health, Imperial College London, said in a news release.

The study “highlights the importance of counseling and education of patients at diagnosis as this is a critical window that influences long-term health behavior,” Ashwin Ananthakrishnan, MD, MPH, a gastroenterologist with Massachusetts General Hospital and Harvard Medical School, both in Boston, said in an interview.

“It has not been my experience in U.S.-based practice that the rates of discontinuation are that high, but it would be important to examine this in different locations,” added Dr. Ananthakrishnan, who wasn’t involved with the study.

The study was published online in the British Journal of General Practice.
 

Cases on the rise

Globally, the incidence of UC is increasing fastest in younger populations. It’s estimated that up to 30% of individuals with UC are diagnosed in childhood or young adulthood, and these individuals are more likely to have a severe disease course and years living with disability, compared with peers diagnosed later in life. This makes achieving disease control and maintaining remission “paramount” for those diagnosed in early life, Dr. Saxena and colleagues write.

International UC guidelines recommend starting therapy with 5-ASA, also known as mesalamine, soon after diagnosis and continuing it long term to maintain remission. However, some prior evidence suggests that adherence to UC medication may be less optimal in younger people – findings supported by the U.K. study.

Leveraging data from the UK Clinical Practice Research Datalink, Dr. Saxena and colleagues analyzed data for 607 children and young adults aged 10-24 years starting oral 5-ASA maintenance therapy for UC.

They found that 152 individuals (25%) stopped 5-ASA treatment after 1 month, and 419 (69%) discontinued it within 1 year of starting treatment. The median time to stopping the anti-inflammatory drug was 162 days.

Discontinuation rates were highest in young adults aged 18-24 years (74%). The transition to adult care and loss of support from caregivers who encourage adherence in adolescents and provide financial and practical support could be one explanation for this, the researchers write.

After accounting for other factors, young adults aged 18-24 years starting 5-ASA were 43% more likely to discontinue it in the first year than adolescents aged 10-14 years.

Individuals living in socioeconomically deprived areas were 46% more likely to stop treatment, compared with those living in more affluent areas, a finding that suggests the need to address socioeconomic disparities that could drive discontinuation, the authors say.

They also found that early corticosteroid use for an acute UC flare was associated with a 32% lower likelihood of stopping 5-ASA therapy.
 

Adherence falls short

In terms of adherence, defined as the proportion of days covered by 5-ASA medication, the mean was 72%, equivalent to just under 9 months. Adherence fell with older age at initiation of therapy. Adherence was 80% among those 10-14 years, 78% among those 15-17 years, and 69% among those 18-24 years. Prior research has shown that nonadherence to UC medication – defined as proportion of days covered less than 80% – has been associated with a five-fold risk of disease, compared with adherence above 80%, the investigators note.

“If clinicians are unaware of suboptimal adherence to first-line medication, they may incorrectly assume therapy has failed, which may lead to unnecessary escalation in treatment and avoidable steroid use that remains high in UC,” the researchers write.

Psychiatric comorbidity (depression, anxiety, or antidepressant use) was not associated with discontinuation or adherence to treatment.

“As doctors, this study shows we need to be keeping a close eye on patients, particularly within that first year of starting medication,” Dr. Saxena said in the release.

“We should check if these patients are getting their medications and whether they have difficulty paying for them. We should also use the opportunity to talk through any recurring symptoms and how to access advice from providers such as a nurse specialist,” Dr. Saxena said.
 

Effectiveness of therapy in young adults

Reached for comment, Michael Dolinger, MD, assistant professor of pediatric gastroenterology, Icahn School of Medicine and Mount Sinai Kravis Children’s Hospital, both in New York, said he has seen 5-ASA stoppage among his younger patients.

“Generally, what we see is that the majority of patients over time are not able to be sustained on oral mesalamine treatment, and they need a more advanced therapy,” Dr. Dolinger said in an interview.

And while the U.K. study did not delve into the reasons for discontinuation, ineffectiveness of therapy is likely a main cause, Dr. Dolinger said.

“We especially see this in our younger adolescent and young adult patients. In these younger patients, the immune system is potentially driving inflammation a bit more than in older patients, often going beyond the inner lining of the colon to the entire bowel wall, even in ulcerative colitis, and therefore mesalamine may be ineffective over the first year,” Dr. Dolinger explained.

When choosing a more advanced therapy, Dr. Dolinger said, “it’s all about having that conversation in a shared decision-making process about what may be the most effective short- and long-term treatment options with the best safety for that patient. It’s a very individualized discussion.”

“One of the main things we preach and talk about is control of inflammation, getting into early deep remission, because the longer you have inflammation, even if it’s just smoldering, the harder it is to get into deep remission,” Dr. Dolinger added.

The study had no commercial funding. Dr. Saxena, Dr. Ananthakrishnan, and Dr. Dolinger have disclosed no relevant financial relationships.

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

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .

A century ago, pediatricians began prescribing for children with intractable seizures the “keto diet,” which they also used to treat diabetes in children and adults. The low-carbohydrate, high-fat meals were designed to induce a near hypoglycemic state, forcing the body to use ketones for fuel instead of glucose.

The strategy fell out of favor after the discovery of insulin in the 1920s and the development of better antiseizure medications. But the epidemics of obesity and diabetes in the United States have revived interest in low-carbohydrate, high-fat diets. The global market for the ketogenic diet topped $11 billion in 2022.

Is it just a fad, or has the public – and science – caught up with the 100-year-old approach?

Although scientists still don’t know why the ketogenic diet was effective for controlling seizures, they have documented the effectiveness of ketogenic diets for the treatment of diabetes and metabolic syndrome. An extensive body of literature has documented their use in athletes, but less is known regarding conditions such as heart disease and dementia.

Although the data are promising, much of the research has been conducted with mice or has come from trials of short-term use in humans. But recently, the National Institutes of Health awarded a $3.5 million federal grant for a double-blind, randomized, placebo-controlled clinical trial to understand the effects of the long-term use of ketone ester supplementation on frailty. Developed 20 years ago, ketone esters are precursor molecules that the body quickly breaks down into ketone bodies when carbohydrates aren’t available.

“We’ve learned so much recently about how ketone bodies interact with aging biology,” John Newman, MD, PhD, of the Buck Institute for Research on Aging in Novato, Calif., and the study’s principal investigator, said in an interview. “And we’re only just starting to translate that out of the laboratory and into human studies to see how we can take advantage of ketone bodies to improve people’s health.”

Researchers from the Ohio State University and the University of Connecticut will also participate in the TAKEOFF (Targeting Aging With Ketone Ester in Older Adults for Function in Frailty) trial, which seeks to recruit a total of 180 people across the three sites.

Dr. Newman, assistant professor at the Buck Institute and associate professor in the division of geriatrics at the University of California, San Francisco, said ketone bodies might have helpful applications in a variety of conditions of aging.

One of the common things that happen during aging is that tissues – such as of the heart, brain, and muscle – lose the ability to metabolize glucose effectively. Over time, resistance to insulin can develop.

Researchers can map out areas of the brain affected by Alzheimer’s disease, for example, by assessing where patients’ glucose uptake drops. In heart failure, the heart has difficulty obtaining enough energy from glucose and instead burns fats and ketone bodies.

How might ketones affect frailty in the elderly?

As a practicing geriatrician, Dr. Newman measures frailty by evaluating patients’ strength, endurance, and how they react to stresses. He and his colleagues believe certain molecular and cellular changes may make patients more likely to fall, to recover more slowly from surgery, or to lose mobility.

The main hypothesis of the TAKEOFF study is “that if you target these fundamental mechanisms of aging, you would be able to impact many different diseases of aging across different organ systems.”

Dr. Newman and Brianna Stubbs, DPhil, lead translational scientist at the Buck Institute, are still finishing up the BIKE (Buck Institute Ketone Ester) pilot study, which was the first double-blind, randomized, placebo-controlled study to evaluate the use of ketone ester supplements in adults older than 65 years. “The BIKE study is 12 weeks long. That’s actually the longest that anyone has studied ketone ester supplements in humans,” Dr. Stubbs said. The results will help them firm up the protocol for the TAKEOFF trial, which will likely treat patients for up to 24 weeks.

The primary outcome measure at all three study sites will be leg press strength. Researchers will also assess a variety of secondary outcomes that cover geriatric and cognitive function – measures such as gait speed and walking endurance, cognitive tests, and quality of life. And at the Buck, Dr. Newman and Dr. Stubbs will be evaluating the use of biomarkers that are often available in clinical labs – insulin, C-reactive protein, cystatin, and natriuretic peptide tests – for use as outcome measures that are responsive to treatment interventions and that can be used to track outcomes in future research on aging.

To achieve the goal of looking broadly at different organ systems likely to be affected by ketogenic supplements, they have assembled a team of coinvestigators with wide-ranging expertise in ketone and aging research.

Jeff Volek, PhD, professor in the department of human sciences at the Ohio State University, in Columbus, has contributed extensively to the literature on the use of ketogenic diets and supplements in a variety of populations, such as endurance athletes and patients with insulin resistance or diabetes.

Dr. Volek has demonstrated that ketones can have an anticatabolic effect on muscle tissue. “They could help offset some of the muscle loss with aging, which would in turn improve their physical functioning and ability to do daily activities,” he said.

The anti-inflammatory property of ketones may provide another benefit to older people. They can reduce oxidative stress, which is considered one of the chief pathologic mechanisms responsible for conditions such as heart disease, Alzheimer’s disease, asthma, and arthritis.

In addition to the main study outcomes, Dr. Volek’s lab will study muscle physiology by performing biopsies at baseline and after consumption of ketogenic supplements to assess metabolic changes in muscle cells as they consume energy. Study participants will also undergo MRIs to detect subtle changes in muscle size before and after treatment.
 

From elite athletes to everyday agers

As a graduate student in Dr. Volek’s lab, Jenna Bartley, PhD, studied the effects of a ketogenic diet on elite athletes. But her work has taken a turn. Now an assistant professor in the department of immunology and the center on aging at the University of Connecticut in Farmington, she focuses on how immune responses and physical function decline with age.

“Ketogenic diets and the main ketone bodies – mainly beta-hydroxybutyrate – have been shown to have really powerful influences on a lot of things that go wrong with aging,” Dr. Bartley said. The decline in immune function in the elderly is not isolated to one cell type or even one arm of the immune system. There is reason to believe ketone supplementation could improve immune function.

“T cells really love ketones for energy,” Dr. Bartley said. Some data show that production of ketone bodies is impaired in individuals with severe SARS-CoV-2 infection. Mouse models of SARS-CoV-2 infection have found that ketogenic diets led to improvement in the response to antiviral therapy.

In her lab, she’ll assess serum markers of inflammation in patients, as well as cytokine secretion following stimulation of T cells. T cells in culture from older people produce more inflammatory cytokines than those from younger people, leading to a dysfunctional immune response. Dr. Bartley is curious to see whether ketones can fix that. Additional work will include single-cell RNA sequencing of different classes of immune cells to investigate how ketones might change metabolic pathways.

Why use ketogenic supplements instead of having people consume ketogenic diets? “There are no cheat days in the keto diet,” Dr. Bartley said. Administering the diet requires intense supervision of research participants to enforce adherence. Use of supplements will improve compliance and likely make any findings translatable to more of the population, she said.

Drawbacks of the initial formulations of ketone esters, first developed 20 years ago, included high cost and terrible taste. Dr, Stubbs, a former world class rowing champion who competed in the Ironman World Championship last year, has firsthand experience with them as a research participant.

“It tasted like drinking nail polish,” she said. Recent advances in manufacturing have made them cheaper – roughly $5 per day – and more palatable, enabling research studies such as TAKEOFF.

For Dr. Newman, the studies are early building blocks in the emerging field of geroscience, which aims to translate fundamental mechanisms of aging into therapies to treat disease.

“We’re hoping that this will be an example of a proof-of-concept geroscience study that will really help to translate ketone body biology out of the laboratory and hopefully into a diversity of clinical applications,” he said. “There’s a lot we don’t understand still about the molecular mechanisms of frailty.”

Dr. Newman and Dr. Stubbs own stock in BHB Therapeutics Ltd, the company providing the product being studied, and are inventors on patents that relate to the product being studied. The Buck Institute has an ownership interest in BHB Therapeutics. Dr. Bartley and Dr. Volek report no relevant financial relationships.

A version of this article appeared on Medscape.com .