Caroline Guignot

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

First described in 2020 by researchers from the U.S. National Institutes of Health, VEXAS syndrome is a systemic autoinflammatory disease of undefined origin. Its name is an acronym: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The prevalence of this syndrome is unknown, but it is not so rare. As it is an X-linked disease, men are predominantly affected.

First identification

The NIH team screened the exomes and genomes of 2,560 individuals. Of this group, 1,477 had been referred because of undiagnosed recurrent fevers, systemic inflammation, or both, and 1,083 were affected by atypical, unclassified disorders. The researchers identified 25 men with a somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene, which is involved in the protein ubiquitylation system. This posttranslational modification has a pleiotropic function that likely explains the clinical heterogeneity seen in VEXAS patients: regulation of protein turnover, especially those involved in the cell cycle, cell death, and signal transduction. Ubiquitylation is also involved in nonproteolytic functions, such as assembly of multiprotein complexes, intracellular signaling, inflammatory signaling, and DNA repair.

Clinical presentation

The clinicobiological presentation of VEXAS syndrome is very heterogeneous. Typically, patients present with a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels, and joints. Molecular diagnosis is made by the sequencing of UBA1.

Most patients present with the characteristic clinical signs of other inflammatory diseases, such as polyarteritis nodosa and recurrent polychondritis. But VEXAS patients are at high risk of developing hematologic conditions. Indeed, the following were seen among the 25 participants in the NIH study: macrocytic anemia (96%), venous thromboembolism (44%), myelodysplastic syndrome (24%), and multiple myeloma or monoclonal gammopathy of undetermined significance (20%).

In VEXAS patients, levels of serum inflammatory markers are increased. These markers include tumor necrosis factor, interleukin-8, interleukin-6, interferon-inducible protein-10, interferon-gamma, C-reactive protein. In addition, there is aberrant activation of innate immune-signaling pathways.

In a large-scale analysis of a multicenter case series of 116 French patients, researchers found that VEXAS syndrome primarily affected men. The disease was progressive, and onset occurred after age 50 years. These patients can be divided into three phenotypically distinct clusters on the basis of integration of clinical and biological data. In the 58 cases in which myelodysplastic syndrome was present, the mortality rates were higher. The researchers also reported that the UBA1 p.Met41L mutation was associated with a better prognosis.
 

Treatment data

VEXAS syndrome resists the classical therapeutic arsenal. Patients require high-dose glucocorticoids, and prognosis appears to be poor. The available treatment data are retrospective. Of the 25 participants in the NIH study, 40% died within 5 years from disease-related causes or complications related to treatment. Among the promising therapeutic avenues is the use of inhibitors of the Janus kinase pathway.

This article was translated from Univadis France. A version of this article appeared on Medscape.com.

Although the nausea and vomiting associated with pregnancy are usually mild, they are more severe (hyperemesis gravidarum) in around one-third of women and require hospitalization in the first trimester for 0.3%-3.6% of these women in France. Given the diversity of practical care, a working group from the National College of French Gynecologists and Obstetricians (CNGOF) has established a consensus on the definition and management of these symptoms.

Definition and severity

Nausea and vomiting during pregnancy are defined as those emerging in the first trimester of pregnancy and for which there is no other etiology.

The severity of these symptoms should be assessed through weight loss from the beginning of the pregnancy, clinical signs of dehydration (thirst, skin turgor, hypotension, oliguria, etc.), and modified PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) score. This is a three-question score rated from 0 to 15, available in the full text of the expert consensus.

Severe nausea and vomiting are not considered complicated when weight loss is < 5%, with no clinical signs of dehydration, and combined with a PUQE score of ≤ 6. In contrast, hyperemesis gravidarum is distinguished from nausea and vomiting during pregnancy by weight loss of ≥ 5 % or signs of dehydration or a PUQE score of ≥ 7.
 

Treating hyperemesis gravidarum

A laboratory workup should be ordered, along with an assay of blood potassium, blood sodium ions, and creatinine levels, as well as a complete dipstick urinalysis.

If symptoms persist or worsen despite well-managed treatment, an additional assessment is recommended, including an abdominal ultrasound and laboratory workup (white blood cell count, transaminases, lipase, CRP, TSH, T4).

Hospitalization is proposed when at least one of the following criteria is met: weight loss ≥ 10%, one or more clinical signs of dehydration, PUQE score of ≥ 13, hypokalemia < 3.0 mmol/L, hyponatremia < 120 mmol/L, elevated serum creatinine > 100 micromol/L, or resistance to treatment.
 

Which treatment?

Prenatal vitamins and iron supplementation should be stopped, as the latter seems to make symptoms worse. This step should be taken without stopping folic acid supplementation.

Women are free to adapt their diets and lifestyles according to their symptoms, since no such changes have been reported to improve symptoms.

If the PUQE score is < 6, even in the absence of proof of their benefit, ginger or B6 vitamin can be used. The same applies to acupressure, acupuncture, and electrical stimulation, which should only be considered in women without complications. Aromatherapy is not to be used, because of the potential risks associated with essential oils, and as no efficacy has been demonstrated.

It is proposed that drugs or combinations of drugs associated with the least severe and least frequent side effects should always be chosen in the absence of superiority of one class over another.

To prevent Gayet Wernicke encephalopathy, vitamin B1 must be administered systematically for hyperemesis gravidarum needing parenteral rehydration. Psychological support should be offered to all patients with hyperemesis gravidarum because of the negative impact of this pathology on mental well-being. Patients should be informed that there are patient associations involved in supporting these women and their families.

A version of this article first appeared on Medscape.com and was translated from Univadis France.

Although the nausea and vomiting associated with pregnancy are usually mild, they are more severe (hyperemesis gravidarum) in around one-third of women and require hospitalization in the first trimester for 0.3%-3.6% of these women in France. Given the diversity of practical care, a working group from the National College of French Gynecologists and Obstetricians (CNGOF) has established a consensus on the definition and management of these symptoms.

Definition and severity

Nausea and vomiting during pregnancy are defined as those emerging in the first trimester of pregnancy and for which there is no other etiology.

The severity of these symptoms should be assessed through weight loss from the beginning of the pregnancy, clinical signs of dehydration (thirst, skin turgor, hypotension, oliguria, etc.), and modified PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) score. This is a three-question score rated from 0 to 15, available in the full text of the expert consensus.

Severe nausea and vomiting are not considered complicated when weight loss is < 5%, with no clinical signs of dehydration, and combined with a PUQE score of ≤ 6. In contrast, hyperemesis gravidarum is distinguished from nausea and vomiting during pregnancy by weight loss of ≥ 5 % or signs of dehydration or a PUQE score of ≥ 7.
 

Treating hyperemesis gravidarum

A laboratory workup should be ordered, along with an assay of blood potassium, blood sodium ions, and creatinine levels, as well as a complete dipstick urinalysis.

If symptoms persist or worsen despite well-managed treatment, an additional assessment is recommended, including an abdominal ultrasound and laboratory workup (white blood cell count, transaminases, lipase, CRP, TSH, T4).

Hospitalization is proposed when at least one of the following criteria is met: weight loss ≥ 10%, one or more clinical signs of dehydration, PUQE score of ≥ 13, hypokalemia < 3.0 mmol/L, hyponatremia < 120 mmol/L, elevated serum creatinine > 100 micromol/L, or resistance to treatment.
 

Which treatment?

Prenatal vitamins and iron supplementation should be stopped, as the latter seems to make symptoms worse. This step should be taken without stopping folic acid supplementation.

Women are free to adapt their diets and lifestyles according to their symptoms, since no such changes have been reported to improve symptoms.

If the PUQE score is < 6, even in the absence of proof of their benefit, ginger or B6 vitamin can be used. The same applies to acupressure, acupuncture, and electrical stimulation, which should only be considered in women without complications. Aromatherapy is not to be used, because of the potential risks associated with essential oils, and as no efficacy has been demonstrated.

It is proposed that drugs or combinations of drugs associated with the least severe and least frequent side effects should always be chosen in the absence of superiority of one class over another.

To prevent Gayet Wernicke encephalopathy, vitamin B1 must be administered systematically for hyperemesis gravidarum needing parenteral rehydration. Psychological support should be offered to all patients with hyperemesis gravidarum because of the negative impact of this pathology on mental well-being. Patients should be informed that there are patient associations involved in supporting these women and their families.

A version of this article first appeared on Medscape.com and was translated from Univadis France.

Although the nausea and vomiting associated with pregnancy are usually mild, they are more severe (hyperemesis gravidarum) in around one-third of women and require hospitalization in the first trimester for 0.3%-3.6% of these women in France. Given the diversity of practical care, a working group from the National College of French Gynecologists and Obstetricians (CNGOF) has established a consensus on the definition and management of these symptoms.

Definition and severity

Nausea and vomiting during pregnancy are defined as those emerging in the first trimester of pregnancy and for which there is no other etiology.

The severity of these symptoms should be assessed through weight loss from the beginning of the pregnancy, clinical signs of dehydration (thirst, skin turgor, hypotension, oliguria, etc.), and modified PUQE (Pregnancy-Unique Quantification of Emesis and Nausea) score. This is a three-question score rated from 0 to 15, available in the full text of the expert consensus.

Severe nausea and vomiting are not considered complicated when weight loss is < 5%, with no clinical signs of dehydration, and combined with a PUQE score of ≤ 6. In contrast, hyperemesis gravidarum is distinguished from nausea and vomiting during pregnancy by weight loss of ≥ 5 % or signs of dehydration or a PUQE score of ≥ 7.
 

Treating hyperemesis gravidarum

A laboratory workup should be ordered, along with an assay of blood potassium, blood sodium ions, and creatinine levels, as well as a complete dipstick urinalysis.

If symptoms persist or worsen despite well-managed treatment, an additional assessment is recommended, including an abdominal ultrasound and laboratory workup (white blood cell count, transaminases, lipase, CRP, TSH, T4).

Hospitalization is proposed when at least one of the following criteria is met: weight loss ≥ 10%, one or more clinical signs of dehydration, PUQE score of ≥ 13, hypokalemia < 3.0 mmol/L, hyponatremia < 120 mmol/L, elevated serum creatinine > 100 micromol/L, or resistance to treatment.
 

Which treatment?

Prenatal vitamins and iron supplementation should be stopped, as the latter seems to make symptoms worse. This step should be taken without stopping folic acid supplementation.

Women are free to adapt their diets and lifestyles according to their symptoms, since no such changes have been reported to improve symptoms.

If the PUQE score is < 6, even in the absence of proof of their benefit, ginger or B6 vitamin can be used. The same applies to acupressure, acupuncture, and electrical stimulation, which should only be considered in women without complications. Aromatherapy is not to be used, because of the potential risks associated with essential oils, and as no efficacy has been demonstrated.

It is proposed that drugs or combinations of drugs associated with the least severe and least frequent side effects should always be chosen in the absence of superiority of one class over another.

To prevent Gayet Wernicke encephalopathy, vitamin B1 must be administered systematically for hyperemesis gravidarum needing parenteral rehydration. Psychological support should be offered to all patients with hyperemesis gravidarum because of the negative impact of this pathology on mental well-being. Patients should be informed that there are patient associations involved in supporting these women and their families.

A version of this article first appeared on Medscape.com and was translated from Univadis France.

Results of a meta-analysis carried out by a French team indicate that there is a link between a father’s or mother’s autoimmune disease and their children’s risk of developing certain neurodevelopmental disorders (autism spectrum disorder [ASD] and attention-deficit/hyperactivity disorder). This meta-analysis is the first to separately explore the link between a father’s or mother’s autoimmune disease and the onset of neurodevelopmental disorders in their children.

According to its authors, these associations may result from exposure to environmental factors that contribute to autoimmune disorders, such as exposure to pollutants or cigarette smoke, and/or genetic predisposition, including genes relating to cytokines or to the HLA system.

Research is needed to determine the pathophysiologic links between these associations. This study suggests that there could be a shared mechanism between both parents, even though the maternal route seems to constitute an additional excess risk.
 

Why is this important?

Neurodevelopmental disorders are said to occur because of a close interrelationship between a person’s genes and environment. Immune-mediated adverse reactions may play an important role in triggering such disorders, as has been shown in associated epidemiologic studies and in animal studies. Autoimmune and autoinflammatory disorders are effectively characterized by the activation of the immune system, the circulation of autoantibodies, and the secretion of cytokines that are harmful to certain tissues.

Some relevant studies suggest a link between autoimmune disorders in the family or in the mother and the onset of neurodevelopmental disorders in their children. However, none of the studies have distinguished the influence of each of the parents so as to provide data that can be used to assess whether this association is more likely to be direct, and thus established during pregnancy, or rather genetic or environmental.
 

Main findings

Overall, the meta-analysis involved 14 studies that included 845,411 mothers and 601,148 fathers with an autoimmune disease, 4,984,965 control mothers and 4,992,854 control fathers. There were 182,927 children with neurodevelopmental disorders and 14,168,474 with no such diagnosis.

Globally, autoimmune diseases in mothers (adjusted odds ratio, 1.27 [1.03-1.57]; P = .02; I2 = 65%) and in fathers (AOR, 1.18 [1.07-1.30]; P = .01; I2 = 15.5%) are associated with a diagnosis of ASD in children. Similarly, they are associated with an increased risk of ADHD in children (AOR, 1.31 [1.11-1.55]; P = .001; I2 = 93% and AOR, 1.14 [1.10-1.17]; P < .0001; I2 = 0%, respectively, for mothers and fathers).

In mothers, type 1 diabetes (AOR, 1.60 [1.18-2.18]; P = .002; I2 = 0%), psoriasis (AOR, 1.45 [1.14-1.85]; P = .002; I2 = 0%), and rheumatoid arthritis (AOR, 1.38 [1.14-1.68]; P = .001; I2 = 0.8%) were associated with a risk of ASD in children. These three conditions also predisposed children to the risk of ADHD (AOR, 1.36 [1.24-1.52]; 1.41 [1.29-1.54]; and 1.32 [1.25-1.40], respectively, all P < .0001).

In fathers, type 1 diabetes considered in isolation was associated with a risk of ASD and ADHD in children (AOR, 1.42 [1.10-1.83] and 1.19 [1.08-1.31], respectively), while psoriasis (AOR, 1.18 [1.12-1.24]; P < .0001) is associated with a risk of ADHD in children.

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

Results of a meta-analysis carried out by a French team indicate that there is a link between a father’s or mother’s autoimmune disease and their children’s risk of developing certain neurodevelopmental disorders (autism spectrum disorder [ASD] and attention-deficit/hyperactivity disorder). This meta-analysis is the first to separately explore the link between a father’s or mother’s autoimmune disease and the onset of neurodevelopmental disorders in their children.

According to its authors, these associations may result from exposure to environmental factors that contribute to autoimmune disorders, such as exposure to pollutants or cigarette smoke, and/or genetic predisposition, including genes relating to cytokines or to the HLA system.

Research is needed to determine the pathophysiologic links between these associations. This study suggests that there could be a shared mechanism between both parents, even though the maternal route seems to constitute an additional excess risk.
 

Why is this important?

Neurodevelopmental disorders are said to occur because of a close interrelationship between a person’s genes and environment. Immune-mediated adverse reactions may play an important role in triggering such disorders, as has been shown in associated epidemiologic studies and in animal studies. Autoimmune and autoinflammatory disorders are effectively characterized by the activation of the immune system, the circulation of autoantibodies, and the secretion of cytokines that are harmful to certain tissues.

Some relevant studies suggest a link between autoimmune disorders in the family or in the mother and the onset of neurodevelopmental disorders in their children. However, none of the studies have distinguished the influence of each of the parents so as to provide data that can be used to assess whether this association is more likely to be direct, and thus established during pregnancy, or rather genetic or environmental.
 

Main findings

Overall, the meta-analysis involved 14 studies that included 845,411 mothers and 601,148 fathers with an autoimmune disease, 4,984,965 control mothers and 4,992,854 control fathers. There were 182,927 children with neurodevelopmental disorders and 14,168,474 with no such diagnosis.

Globally, autoimmune diseases in mothers (adjusted odds ratio, 1.27 [1.03-1.57]; P = .02; I2 = 65%) and in fathers (AOR, 1.18 [1.07-1.30]; P = .01; I2 = 15.5%) are associated with a diagnosis of ASD in children. Similarly, they are associated with an increased risk of ADHD in children (AOR, 1.31 [1.11-1.55]; P = .001; I2 = 93% and AOR, 1.14 [1.10-1.17]; P < .0001; I2 = 0%, respectively, for mothers and fathers).

In mothers, type 1 diabetes (AOR, 1.60 [1.18-2.18]; P = .002; I2 = 0%), psoriasis (AOR, 1.45 [1.14-1.85]; P = .002; I2 = 0%), and rheumatoid arthritis (AOR, 1.38 [1.14-1.68]; P = .001; I2 = 0.8%) were associated with a risk of ASD in children. These three conditions also predisposed children to the risk of ADHD (AOR, 1.36 [1.24-1.52]; 1.41 [1.29-1.54]; and 1.32 [1.25-1.40], respectively, all P < .0001).

In fathers, type 1 diabetes considered in isolation was associated with a risk of ASD and ADHD in children (AOR, 1.42 [1.10-1.83] and 1.19 [1.08-1.31], respectively), while psoriasis (AOR, 1.18 [1.12-1.24]; P < .0001) is associated with a risk of ADHD in children.

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

Results of a meta-analysis carried out by a French team indicate that there is a link between a father’s or mother’s autoimmune disease and their children’s risk of developing certain neurodevelopmental disorders (autism spectrum disorder [ASD] and attention-deficit/hyperactivity disorder). This meta-analysis is the first to separately explore the link between a father’s or mother’s autoimmune disease and the onset of neurodevelopmental disorders in their children.

According to its authors, these associations may result from exposure to environmental factors that contribute to autoimmune disorders, such as exposure to pollutants or cigarette smoke, and/or genetic predisposition, including genes relating to cytokines or to the HLA system.

Research is needed to determine the pathophysiologic links between these associations. This study suggests that there could be a shared mechanism between both parents, even though the maternal route seems to constitute an additional excess risk.
 

Why is this important?

Neurodevelopmental disorders are said to occur because of a close interrelationship between a person’s genes and environment. Immune-mediated adverse reactions may play an important role in triggering such disorders, as has been shown in associated epidemiologic studies and in animal studies. Autoimmune and autoinflammatory disorders are effectively characterized by the activation of the immune system, the circulation of autoantibodies, and the secretion of cytokines that are harmful to certain tissues.

Some relevant studies suggest a link between autoimmune disorders in the family or in the mother and the onset of neurodevelopmental disorders in their children. However, none of the studies have distinguished the influence of each of the parents so as to provide data that can be used to assess whether this association is more likely to be direct, and thus established during pregnancy, or rather genetic or environmental.
 

Main findings

Overall, the meta-analysis involved 14 studies that included 845,411 mothers and 601,148 fathers with an autoimmune disease, 4,984,965 control mothers and 4,992,854 control fathers. There were 182,927 children with neurodevelopmental disorders and 14,168,474 with no such diagnosis.

Globally, autoimmune diseases in mothers (adjusted odds ratio, 1.27 [1.03-1.57]; P = .02; I2 = 65%) and in fathers (AOR, 1.18 [1.07-1.30]; P = .01; I2 = 15.5%) are associated with a diagnosis of ASD in children. Similarly, they are associated with an increased risk of ADHD in children (AOR, 1.31 [1.11-1.55]; P = .001; I2 = 93% and AOR, 1.14 [1.10-1.17]; P < .0001; I2 = 0%, respectively, for mothers and fathers).

In mothers, type 1 diabetes (AOR, 1.60 [1.18-2.18]; P = .002; I2 = 0%), psoriasis (AOR, 1.45 [1.14-1.85]; P = .002; I2 = 0%), and rheumatoid arthritis (AOR, 1.38 [1.14-1.68]; P = .001; I2 = 0.8%) were associated with a risk of ASD in children. These three conditions also predisposed children to the risk of ADHD (AOR, 1.36 [1.24-1.52]; 1.41 [1.29-1.54]; and 1.32 [1.25-1.40], respectively, all P < .0001).

In fathers, type 1 diabetes considered in isolation was associated with a risk of ASD and ADHD in children (AOR, 1.42 [1.10-1.83] and 1.19 [1.08-1.31], respectively), while psoriasis (AOR, 1.18 [1.12-1.24]; P < .0001) is associated with a risk of ADHD in children.

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

Key takeaways

Metformin may be associated with a lower risk of neurodegenerative disease, in particular when the drug has been prescribed for at least 4 years, according to a systematic review and meta-analysis of longitudinal data.

However, the heterogeneity between the available studies and the potential heterogeneity of diagnostic criteria may mean that validation studies are needed.
 

Why is this important?

Data suggest that metformin, the most commonly prescribed antidiabetic drug, may be neuroprotective, while diabetes is associated with an excess risk of neurodegenerative disease. Results of studies conducted specifically to investigate the benefit of the antidiabetic drug on cognitive prognosis have been unclear. A meta-analysis was published in 2020, but it included cross-sectional and case-control studies. Given the long observation period needed to measure such an outcome, only cohort studies conducted over several years can provide reliable results. This new meta-analysis attempts to circumvent this limitation.

Methods

The meta-analysis was conducted using studies published up to March 2021 that met the inclusion criteria (population-based cohort studies published in English in which the administration of metformin and associated risk of exposure were reported).

Main results

Twelve studies were included in this analysis, of which eight were retrospective and 11 were considered to be of good methodologic quality. In total, 194,792 patients were included.

Pooled data showed that the relative risk associated with onset of neurodegenerative disease was 0.77 (95% CI, 0.67-0.88) for patients with diabetes taking metformin versus those not taking metformin. However, heterogeneity between studies was high (I2; 78.8%; P < .001).

The effect was greater with longer metformin use, with an RR of 0.29 (95% CI, 0.13-0.44) for those who took metformin for 4 years or more. Similarly, the studies conducted in Asian countries versus other locations suggested an added benefit for this population (RR, 0.69; 95% CI, 0.64-0.74).

Sensitivity analyses confirmed these results, and subtype analyses showed no difference according to the nature of the neurodegenerative disease.

A version of this article first appeared on Univadis.

Key takeaways

Metformin may be associated with a lower risk of neurodegenerative disease, in particular when the drug has been prescribed for at least 4 years, according to a systematic review and meta-analysis of longitudinal data.

However, the heterogeneity between the available studies and the potential heterogeneity of diagnostic criteria may mean that validation studies are needed.
 

Why is this important?

Data suggest that metformin, the most commonly prescribed antidiabetic drug, may be neuroprotective, while diabetes is associated with an excess risk of neurodegenerative disease. Results of studies conducted specifically to investigate the benefit of the antidiabetic drug on cognitive prognosis have been unclear. A meta-analysis was published in 2020, but it included cross-sectional and case-control studies. Given the long observation period needed to measure such an outcome, only cohort studies conducted over several years can provide reliable results. This new meta-analysis attempts to circumvent this limitation.

Methods

The meta-analysis was conducted using studies published up to March 2021 that met the inclusion criteria (population-based cohort studies published in English in which the administration of metformin and associated risk of exposure were reported).

Main results

Twelve studies were included in this analysis, of which eight were retrospective and 11 were considered to be of good methodologic quality. In total, 194,792 patients were included.

Pooled data showed that the relative risk associated with onset of neurodegenerative disease was 0.77 (95% CI, 0.67-0.88) for patients with diabetes taking metformin versus those not taking metformin. However, heterogeneity between studies was high (I2; 78.8%; P < .001).

The effect was greater with longer metformin use, with an RR of 0.29 (95% CI, 0.13-0.44) for those who took metformin for 4 years or more. Similarly, the studies conducted in Asian countries versus other locations suggested an added benefit for this population (RR, 0.69; 95% CI, 0.64-0.74).

Sensitivity analyses confirmed these results, and subtype analyses showed no difference according to the nature of the neurodegenerative disease.

A version of this article first appeared on Univadis.

Key takeaways

Metformin may be associated with a lower risk of neurodegenerative disease, in particular when the drug has been prescribed for at least 4 years, according to a systematic review and meta-analysis of longitudinal data.

However, the heterogeneity between the available studies and the potential heterogeneity of diagnostic criteria may mean that validation studies are needed.
 

Why is this important?

Data suggest that metformin, the most commonly prescribed antidiabetic drug, may be neuroprotective, while diabetes is associated with an excess risk of neurodegenerative disease. Results of studies conducted specifically to investigate the benefit of the antidiabetic drug on cognitive prognosis have been unclear. A meta-analysis was published in 2020, but it included cross-sectional and case-control studies. Given the long observation period needed to measure such an outcome, only cohort studies conducted over several years can provide reliable results. This new meta-analysis attempts to circumvent this limitation.

Methods

The meta-analysis was conducted using studies published up to March 2021 that met the inclusion criteria (population-based cohort studies published in English in which the administration of metformin and associated risk of exposure were reported).

Main results

Twelve studies were included in this analysis, of which eight were retrospective and 11 were considered to be of good methodologic quality. In total, 194,792 patients were included.

Pooled data showed that the relative risk associated with onset of neurodegenerative disease was 0.77 (95% CI, 0.67-0.88) for patients with diabetes taking metformin versus those not taking metformin. However, heterogeneity between studies was high (I2; 78.8%; P < .001).

The effect was greater with longer metformin use, with an RR of 0.29 (95% CI, 0.13-0.44) for those who took metformin for 4 years or more. Similarly, the studies conducted in Asian countries versus other locations suggested an added benefit for this population (RR, 0.69; 95% CI, 0.64-0.74).

Sensitivity analyses confirmed these results, and subtype analyses showed no difference according to the nature of the neurodegenerative disease.

A version of this article first appeared on Univadis.

A French research team has developed a microRNA (miRNA) signature for diagnosing endometriosis through a simple saliva test. Its validation in a larger cohort could soon allow doctors to have a cheap, noninvasive, and accurate tool to use in diagnosing a disease that, for the time being, is difficult to identify with any certainty. The researchers suggest that their methodology could be used as a blueprint to investigate other pathologies, both benign and malignant.

ENDO-miRNA study

miRNAs regulate as much as 60% of gene expression at the posttranscriptional level. In the setting of endometriosis, several authors have evaluated the relevance of a blood-based miRNA signature, but the results are discordant because of methodological and control group issues. Other researchers have also sought to develop a miRNA saliva test. A French team wanted to determine whether it was possible to define a saliva-based diagnostic miRNome signature that would allow patients with and without endometriosis to be differentiated and, from there, develop the first specific diagnostic test for the disease.

The prospective ENDO-miRNA study included saliva samples obtained from women with chronic pelvic pain suggestive of endometriosis. Exploratory procedures were performed to look for lesions. All the patients underwent either a laparoscopic procedure (therapeutic or diagnostic laparoscopy) and/or MRI imaging. For the patients who underwent laparoscopy, diagnosis was confirmed by histology. For the patients diagnosed with endometriosis without laparoscopic evaluation, all had MRI imaging with features of deep endometriosis.

One part of the study involved the identification of a biomarker based on genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing. The second part involved the development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a random forest algorithm.
 

High sensitivity, specificity

Among the 200 patients (mean age, 31 years) enrolled in the study, 76.5% (n = 153) were diagnosed with endometriosis. On average, their pain was statistically more severe than that of the women in the control group. The Visual Analogue Scale (VAS) scores were, respectively: dysmenorrhea 6 versus 5.0 (P < .001), dyspareunia 5.28 versus 4.95 (P < .001), and urinary pain during menstruation 4.35 versus 2.84 (P < .001).

Next-generation sequencing identified an average of 2,561 expressed miRNAs in the saliva samples. The feature selection method generated a subset of 109 miRNAs composing the endometriosis diagnostic signature. Among those miRNAs, 29 were associated with the main signaling pathways of endometriosis: PI3K/AKT, PTEN, Wnt/beta-catenin, HIF1-alpha/NF kappa B, and YAP/TAZ/EGFR.

The accuracy and reproducibility of the signature were tested on several data sets randomly composed of the same proportion of controls and patients with endometriosis. The respective sensitivity, specificity, and area under the curve for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%, respectively.

The study’s results support the use of a saliva-based miRNA signature for diagnosing whether a patient is discordant/complex (chronic pelvic pain suggestive of endometriosis and both negative clinical examination and imaging findings) or has early-stage or advanced-stage endometriosis.

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

A French research team has developed a microRNA (miRNA) signature for diagnosing endometriosis through a simple saliva test. Its validation in a larger cohort could soon allow doctors to have a cheap, noninvasive, and accurate tool to use in diagnosing a disease that, for the time being, is difficult to identify with any certainty. The researchers suggest that their methodology could be used as a blueprint to investigate other pathologies, both benign and malignant.

ENDO-miRNA study

miRNAs regulate as much as 60% of gene expression at the posttranscriptional level. In the setting of endometriosis, several authors have evaluated the relevance of a blood-based miRNA signature, but the results are discordant because of methodological and control group issues. Other researchers have also sought to develop a miRNA saliva test. A French team wanted to determine whether it was possible to define a saliva-based diagnostic miRNome signature that would allow patients with and without endometriosis to be differentiated and, from there, develop the first specific diagnostic test for the disease.

The prospective ENDO-miRNA study included saliva samples obtained from women with chronic pelvic pain suggestive of endometriosis. Exploratory procedures were performed to look for lesions. All the patients underwent either a laparoscopic procedure (therapeutic or diagnostic laparoscopy) and/or MRI imaging. For the patients who underwent laparoscopy, diagnosis was confirmed by histology. For the patients diagnosed with endometriosis without laparoscopic evaluation, all had MRI imaging with features of deep endometriosis.

One part of the study involved the identification of a biomarker based on genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing. The second part involved the development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a random forest algorithm.
 

High sensitivity, specificity

Among the 200 patients (mean age, 31 years) enrolled in the study, 76.5% (n = 153) were diagnosed with endometriosis. On average, their pain was statistically more severe than that of the women in the control group. The Visual Analogue Scale (VAS) scores were, respectively: dysmenorrhea 6 versus 5.0 (P < .001), dyspareunia 5.28 versus 4.95 (P < .001), and urinary pain during menstruation 4.35 versus 2.84 (P < .001).

Next-generation sequencing identified an average of 2,561 expressed miRNAs in the saliva samples. The feature selection method generated a subset of 109 miRNAs composing the endometriosis diagnostic signature. Among those miRNAs, 29 were associated with the main signaling pathways of endometriosis: PI3K/AKT, PTEN, Wnt/beta-catenin, HIF1-alpha/NF kappa B, and YAP/TAZ/EGFR.

The accuracy and reproducibility of the signature were tested on several data sets randomly composed of the same proportion of controls and patients with endometriosis. The respective sensitivity, specificity, and area under the curve for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%, respectively.

The study’s results support the use of a saliva-based miRNA signature for diagnosing whether a patient is discordant/complex (chronic pelvic pain suggestive of endometriosis and both negative clinical examination and imaging findings) or has early-stage or advanced-stage endometriosis.

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

A French research team has developed a microRNA (miRNA) signature for diagnosing endometriosis through a simple saliva test. Its validation in a larger cohort could soon allow doctors to have a cheap, noninvasive, and accurate tool to use in diagnosing a disease that, for the time being, is difficult to identify with any certainty. The researchers suggest that their methodology could be used as a blueprint to investigate other pathologies, both benign and malignant.

ENDO-miRNA study

miRNAs regulate as much as 60% of gene expression at the posttranscriptional level. In the setting of endometriosis, several authors have evaluated the relevance of a blood-based miRNA signature, but the results are discordant because of methodological and control group issues. Other researchers have also sought to develop a miRNA saliva test. A French team wanted to determine whether it was possible to define a saliva-based diagnostic miRNome signature that would allow patients with and without endometriosis to be differentiated and, from there, develop the first specific diagnostic test for the disease.

The prospective ENDO-miRNA study included saliva samples obtained from women with chronic pelvic pain suggestive of endometriosis. Exploratory procedures were performed to look for lesions. All the patients underwent either a laparoscopic procedure (therapeutic or diagnostic laparoscopy) and/or MRI imaging. For the patients who underwent laparoscopy, diagnosis was confirmed by histology. For the patients diagnosed with endometriosis without laparoscopic evaluation, all had MRI imaging with features of deep endometriosis.

One part of the study involved the identification of a biomarker based on genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing. The second part involved the development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a random forest algorithm.
 

High sensitivity, specificity

Among the 200 patients (mean age, 31 years) enrolled in the study, 76.5% (n = 153) were diagnosed with endometriosis. On average, their pain was statistically more severe than that of the women in the control group. The Visual Analogue Scale (VAS) scores were, respectively: dysmenorrhea 6 versus 5.0 (P < .001), dyspareunia 5.28 versus 4.95 (P < .001), and urinary pain during menstruation 4.35 versus 2.84 (P < .001).

Next-generation sequencing identified an average of 2,561 expressed miRNAs in the saliva samples. The feature selection method generated a subset of 109 miRNAs composing the endometriosis diagnostic signature. Among those miRNAs, 29 were associated with the main signaling pathways of endometriosis: PI3K/AKT, PTEN, Wnt/beta-catenin, HIF1-alpha/NF kappa B, and YAP/TAZ/EGFR.

The accuracy and reproducibility of the signature were tested on several data sets randomly composed of the same proportion of controls and patients with endometriosis. The respective sensitivity, specificity, and area under the curve for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%, respectively.

The study’s results support the use of a saliva-based miRNA signature for diagnosing whether a patient is discordant/complex (chronic pelvic pain suggestive of endometriosis and both negative clinical examination and imaging findings) or has early-stage or advanced-stage endometriosis.

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