Federal Practitioner

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

This transcript has been edited for clarity.
 

F. Perry Wilson, MD, MSCE: I am joined today by Dr. Ohad Einav. He’s a staff surgeon in orthopedics at Hadassah Medical Center in Jerusalem. He’s with me to talk about an absolutely incredible surgical case, something that is terrifying to most non–orthopedic surgeons and I imagine is fairly scary for spine surgeons like him as well. It’s a case of internal decapitation that has generated a lot of news around the world because it happened to a young boy. But what we don’t have is information about how this works from a medical perspective. So, first of all, Dr. Einav, thank you for taking time to speak with me today.

Ohad Einav, MD: Thank you for having me.

Dr. Wilson: Can you tell us about Suleiman Hassan and what happened to him before he came into your care?

Dr. Einav: Hassan is a 12-year-old child who was riding his bicycle on the West Bank, about 40 minutes from here. Unfortunately, he was involved in a motor vehicle accident and he suffered injuries to his abdomen and cervical spine. He was transported to our service by helicopter from the scene of the accident.

Hadassah Medical Center

Hadassah Medical Center

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

This transcript has been edited for clarity.
 

F. Perry Wilson, MD, MSCE: I am joined today by Dr. Ohad Einav. He’s a staff surgeon in orthopedics at Hadassah Medical Center in Jerusalem. He’s with me to talk about an absolutely incredible surgical case, something that is terrifying to most non–orthopedic surgeons and I imagine is fairly scary for spine surgeons like him as well. It’s a case of internal decapitation that has generated a lot of news around the world because it happened to a young boy. But what we don’t have is information about how this works from a medical perspective. So, first of all, Dr. Einav, thank you for taking time to speak with me today.

Ohad Einav, MD: Thank you for having me.

Dr. Wilson: Can you tell us about Suleiman Hassan and what happened to him before he came into your care?

Dr. Einav: Hassan is a 12-year-old child who was riding his bicycle on the West Bank, about 40 minutes from here. Unfortunately, he was involved in a motor vehicle accident and he suffered injuries to his abdomen and cervical spine. He was transported to our service by helicopter from the scene of the accident.

Hadassah Medical Center

Hadassah Medical Center

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

This transcript has been edited for clarity.
 

F. Perry Wilson, MD, MSCE: I am joined today by Dr. Ohad Einav. He’s a staff surgeon in orthopedics at Hadassah Medical Center in Jerusalem. He’s with me to talk about an absolutely incredible surgical case, something that is terrifying to most non–orthopedic surgeons and I imagine is fairly scary for spine surgeons like him as well. It’s a case of internal decapitation that has generated a lot of news around the world because it happened to a young boy. But what we don’t have is information about how this works from a medical perspective. So, first of all, Dr. Einav, thank you for taking time to speak with me today.

Ohad Einav, MD: Thank you for having me.

Dr. Wilson: Can you tell us about Suleiman Hassan and what happened to him before he came into your care?

Dr. Einav: Hassan is a 12-year-old child who was riding his bicycle on the West Bank, about 40 minutes from here. Unfortunately, he was involved in a motor vehicle accident and he suffered injuries to his abdomen and cervical spine. He was transported to our service by helicopter from the scene of the accident.

Hadassah Medical Center

Hadassah Medical Center

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

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

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

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

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

Low-dose aspirin reduces the risk for type 2 diabetes among older adults and slows the increase in fasting glucose levels over time, new research finds.

The data come from a secondary analysis of ASPREE, a double-blind, placebo-controlled trial of healthy adults aged 65 years or older, showing that 100 mg of aspirin taken daily for about 5 years did not provide a cardiovascular benefit but did significantly raise the risk for bleeding.

This new analysis shows that individuals taking aspirin had a 15% lower risk for developing type 2 diabetes and that the medication slowed the rate of increase in fasting plasma glucose, compared with placebo, during follow-up.

However, lead author Sophia Zoungas, MBBS, PhD, head of the School of Public Health and Preventive Medicine, Monash University, Melbourne, said: “Major prescribing guidelines now recommend older adults take daily aspirin only when there is a medical reason to do so, such as after a heart attack. ... Although these new findings are of interest, they do not change the clinical advice about aspirin use in older people at this time.”

Nonetheless, she said in an interview, “at this time, our findings are exploratory but ignite the debate of the important role that anti-inflammatory approaches may play in preventing diabetes. Further work is currently underway to understand which subpopulations may be better targeted and to understand the balance of risk versus benefit.”

The results are scheduled to be presented at the upcoming meeting of the European Association for the Study of Diabetes, taking place Oct. 2-6 in Hamburg, Germany.
 

New findings not robust enough to change current practice

Asked to comment, Debabrata Mukherjee, MD, said: “Given the post hoc secondary nature of the analysis, the findings should be considered hypothesis generating and not definitive… At this time, based on prospective randomized studies, the risks of aspirin outweigh the benefits for aspirin in older adults.”

Among those studies was an ASPREE substudy showing failure of low-dose aspirin to reduce fracture risk while increasing the risk for serious falls, and two other trials, ARRIVE and ASCEND, also showing that harms of aspirin outweigh the benefits in people with cardiovascular risk but not diabetes, and in those with diabetes, respectively, said Dr. Mukherjee, professor and chair of the department of internal medicine at Texas Tech University Health Sciences Center at El Paso.

And, Mukherjee noted, in 2019 the American College of Cardiology updated its practice guidelines to say that low-dose aspirin should not be administered on a routine basis for the primary prevention of atherosclerotic cardiovascular disease in adults over age 70. In 2021, the American Diabetes Association seconded that recommendation.

Asked whether these newest findings might change current practice for any higher-risk subgroup, such as people with prediabetes, Dr. Mukherjee replied: “Unless there is a prospective randomized trial that validates these findings in those with prediabetes, the findings should not change practice. There are also no data [showing] that another antiplatelet agent would be indicated or would be beneficial. Instead, I would recommend lifestyle changes including regular exercise and a healthy diet to minimize risk of diabetes.”

The 16,209 ASPREE participants were community dwelling and did not have diabetes, cardiovascular disease, or dementia at baseline. They were randomized in a 1:1 ratio to receive 100 mg/d of enteric-coated aspirin or placebo. Over a median follow-up of 4.7 years, the proportions developing type 2 diabetes were 5.7% with aspirin versus 6.6% with placebo (hazard ratio, 0.85; P = .01).

The annual rate of increase in fasting plasma glucose over the follow-up period was slowed by 0.006 mmol/L with aspirin, compared with placebo, also a significant difference (P = .004).

According to Dr. Zoungas, “the potential for anti-inflammatory agents like aspirin to prevent type 2 diabetes or improve glucose levels needs further study.”

The ASPREE trial was supported by the U.S. National Institutes of Health, the National Health and Medical Research Council of Australia, Monash University, and the Victorian Cancer Agency. Dr. Zoungas and Dr. Mukherjee have no disclosures.

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

Crippling symptoms, lost careers, and eroded incomes: This is the harsh reality for doctors suffering with long COVID, according to the first major survey of physicians with the condition.

The survey, conducted by the British Medical Association and the Long COVID Doctors for Action support group, sheds light on the lingering effects of long COVID on more than 600 chronically ill and disabled doctors with the condition. It also spotlights what they describe as a lack of medical and financial support from their government and employers at the National Health Service.

“We feel betrayed and abandoned,” said Kelly Fearnley, MBChB, chair and cofounder of Long COVID Doctors for Action. “At a time of national crisis, when health care workers were asked to step up, we did. When the nation needed us, we stepped up. We put our lives on the line. We put our families’ lives on the line. And now that we are injured after knowingly being unprotected and deliberately and repeatedly exposed to a level 3 biohazard, we now find ourselves in this position.”

Dr. Fearnley fell ill while working in a hospital’s COVID ward in November 2020. She is one of an estimated 2 million people in the United Kingdom – including thousands of NHS employees – with long COVID. She hasn’t been able to return to work in nearly 3 years.

Long COVID affects more than 65 million people worldwide. It is estimated that 1 in 10 people infected with the virus develop long-term symptoms. In the United Kingdom, health care and social care workers are seven times more likely to have had severe COVID-19 than other types of employees.

Doctors responding to the BMA survey reported a wide range of long COVID symptoms, including fatigue, headaches, muscular pain, nerve damage, joint pain, and respiratory problems.

Among the survey’s key findings, 60% of doctors said long COVID has affected their ability to carry out day-to-day tasks on a regular basis. Almost one in five (18%) said they were no longer able to work, while fewer than one in three (31%) were working full time. This compares with more than half (57%) of respondents working full time before the onset of their COVID illness – a decline of 46%.

Nearly half (48%) of respondents said they have experienced some form of loss of earnings as a result of long COVID, and almost half of the doctors were never referred to an NHS long COVID clinic. The survey included the following first-person accounts from doctors living with the condition.

• One doctor said: “I nearly lost my life, my home, my partner and my career. I have received little support to help keep these. The impact on my mental health nearly cost [me] my life again.”
• A senior consulting physician commented: “Life is absolutely miserable. Every day is a struggle. I wake up exhausted, the insomnia and night terrors are horrendous as I live through my worst fears every night. Any activity such as eating meals, washing, etc., will mean I have to go to bed for a few hours. I am unable to look after myself or my child, exercise or maintain social relationships. I have no financial security. Long COVID has totally destroyed my life.”
• A salaried general practitioner said: “I can no longer work, finances are ruined. I didn’t have employment protection so am now unemployed and penniless.”

Calls for action from the BMA include the following:

• Financial support for doctors and health care staff with long COVID.
• The recognition of long COVID as an occupational disease among health care workers, along with a definition of the condition that covers all of the debilitating disease’s symptoms.
• Improved access to physical and mental health services to help comprehensive assessment, investigations, and treatment.
• Greater workplace protection for health care staff who risk their lives for others.
• Better support for long COVID sufferers to return to work safely if they can, including a flexible approach to the use of workplace adjustments.

“One would think, given the circumstances under which we fell ill and current workforce shortages, NHS employers would be eager to do everything to facilitate the return to work of people with long COVID,” said Dr. Fearnley. “However, NHS employers are legally required to implement only ‘reasonable adjustments,’ and so things such as extended phased return or adjustments to shift patterns are not always being facilitated. Instead, an increasing number of employers are choosing to terminate contracts.”

Raymond Agius, the BMA’s occupational medicine committee cochair, also put the blame on inadequate safety measures for doctors. Those inadequate measures persist to this day, inasmuch as U.K. hospitals have dropped masking requirements.

“During the COVID-19 pandemic, doctors were left exposed and unprotected at work,” he said in a BMA press release. “They often did not have access to the right PPE. ... Too many risk assessments of workplaces and especially of vulnerable doctors were not undertaken.”

A small minority of doctors who were surveyed said they had access to respiratory protective equipment about the time they contracted COVID-19. Only 11% had access to an FFP2 respirator (the equivalent of an N95 mask); 16% had an FFP3 respirator (the equivalent of an N99 mask).

To date, the British government hasn’t issued much of a response to the survey, saying only that it has invested more than ₤50 million to better understand long COVID.

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

Crippling symptoms, lost careers, and eroded incomes: This is the harsh reality for doctors suffering with long COVID, according to the first major survey of physicians with the condition.

The survey, conducted by the British Medical Association and the Long COVID Doctors for Action support group, sheds light on the lingering effects of long COVID on more than 600 chronically ill and disabled doctors with the condition. It also spotlights what they describe as a lack of medical and financial support from their government and employers at the National Health Service.

“We feel betrayed and abandoned,” said Kelly Fearnley, MBChB, chair and cofounder of Long COVID Doctors for Action. “At a time of national crisis, when health care workers were asked to step up, we did. When the nation needed us, we stepped up. We put our lives on the line. We put our families’ lives on the line. And now that we are injured after knowingly being unprotected and deliberately and repeatedly exposed to a level 3 biohazard, we now find ourselves in this position.”

Dr. Fearnley fell ill while working in a hospital’s COVID ward in November 2020. She is one of an estimated 2 million people in the United Kingdom – including thousands of NHS employees – with long COVID. She hasn’t been able to return to work in nearly 3 years.

Long COVID affects more than 65 million people worldwide. It is estimated that 1 in 10 people infected with the virus develop long-term symptoms. In the United Kingdom, health care and social care workers are seven times more likely to have had severe COVID-19 than other types of employees.

Doctors responding to the BMA survey reported a wide range of long COVID symptoms, including fatigue, headaches, muscular pain, nerve damage, joint pain, and respiratory problems.

Among the survey’s key findings, 60% of doctors said long COVID has affected their ability to carry out day-to-day tasks on a regular basis. Almost one in five (18%) said they were no longer able to work, while fewer than one in three (31%) were working full time. This compares with more than half (57%) of respondents working full time before the onset of their COVID illness – a decline of 46%.

Nearly half (48%) of respondents said they have experienced some form of loss of earnings as a result of long COVID, and almost half of the doctors were never referred to an NHS long COVID clinic. The survey included the following first-person accounts from doctors living with the condition.

• One doctor said: “I nearly lost my life, my home, my partner and my career. I have received little support to help keep these. The impact on my mental health nearly cost [me] my life again.”
• A senior consulting physician commented: “Life is absolutely miserable. Every day is a struggle. I wake up exhausted, the insomnia and night terrors are horrendous as I live through my worst fears every night. Any activity such as eating meals, washing, etc., will mean I have to go to bed for a few hours. I am unable to look after myself or my child, exercise or maintain social relationships. I have no financial security. Long COVID has totally destroyed my life.”
• A salaried general practitioner said: “I can no longer work, finances are ruined. I didn’t have employment protection so am now unemployed and penniless.”

Calls for action from the BMA include the following:

• Financial support for doctors and health care staff with long COVID.
• The recognition of long COVID as an occupational disease among health care workers, along with a definition of the condition that covers all of the debilitating disease’s symptoms.
• Improved access to physical and mental health services to help comprehensive assessment, investigations, and treatment.
• Greater workplace protection for health care staff who risk their lives for others.
• Better support for long COVID sufferers to return to work safely if they can, including a flexible approach to the use of workplace adjustments.

“One would think, given the circumstances under which we fell ill and current workforce shortages, NHS employers would be eager to do everything to facilitate the return to work of people with long COVID,” said Dr. Fearnley. “However, NHS employers are legally required to implement only ‘reasonable adjustments,’ and so things such as extended phased return or adjustments to shift patterns are not always being facilitated. Instead, an increasing number of employers are choosing to terminate contracts.”

Raymond Agius, the BMA’s occupational medicine committee cochair, also put the blame on inadequate safety measures for doctors. Those inadequate measures persist to this day, inasmuch as U.K. hospitals have dropped masking requirements.

“During the COVID-19 pandemic, doctors were left exposed and unprotected at work,” he said in a BMA press release. “They often did not have access to the right PPE. ... Too many risk assessments of workplaces and especially of vulnerable doctors were not undertaken.”

A small minority of doctors who were surveyed said they had access to respiratory protective equipment about the time they contracted COVID-19. Only 11% had access to an FFP2 respirator (the equivalent of an N95 mask); 16% had an FFP3 respirator (the equivalent of an N99 mask).

To date, the British government hasn’t issued much of a response to the survey, saying only that it has invested more than ₤50 million to better understand long COVID.

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

Crippling symptoms, lost careers, and eroded incomes: This is the harsh reality for doctors suffering with long COVID, according to the first major survey of physicians with the condition.

The survey, conducted by the British Medical Association and the Long COVID Doctors for Action support group, sheds light on the lingering effects of long COVID on more than 600 chronically ill and disabled doctors with the condition. It also spotlights what they describe as a lack of medical and financial support from their government and employers at the National Health Service.

“We feel betrayed and abandoned,” said Kelly Fearnley, MBChB, chair and cofounder of Long COVID Doctors for Action. “At a time of national crisis, when health care workers were asked to step up, we did. When the nation needed us, we stepped up. We put our lives on the line. We put our families’ lives on the line. And now that we are injured after knowingly being unprotected and deliberately and repeatedly exposed to a level 3 biohazard, we now find ourselves in this position.”

Dr. Fearnley fell ill while working in a hospital’s COVID ward in November 2020. She is one of an estimated 2 million people in the United Kingdom – including thousands of NHS employees – with long COVID. She hasn’t been able to return to work in nearly 3 years.

Long COVID affects more than 65 million people worldwide. It is estimated that 1 in 10 people infected with the virus develop long-term symptoms. In the United Kingdom, health care and social care workers are seven times more likely to have had severe COVID-19 than other types of employees.

Doctors responding to the BMA survey reported a wide range of long COVID symptoms, including fatigue, headaches, muscular pain, nerve damage, joint pain, and respiratory problems.

Among the survey’s key findings, 60% of doctors said long COVID has affected their ability to carry out day-to-day tasks on a regular basis. Almost one in five (18%) said they were no longer able to work, while fewer than one in three (31%) were working full time. This compares with more than half (57%) of respondents working full time before the onset of their COVID illness – a decline of 46%.

Nearly half (48%) of respondents said they have experienced some form of loss of earnings as a result of long COVID, and almost half of the doctors were never referred to an NHS long COVID clinic. The survey included the following first-person accounts from doctors living with the condition.

• One doctor said: “I nearly lost my life, my home, my partner and my career. I have received little support to help keep these. The impact on my mental health nearly cost [me] my life again.”
• A senior consulting physician commented: “Life is absolutely miserable. Every day is a struggle. I wake up exhausted, the insomnia and night terrors are horrendous as I live through my worst fears every night. Any activity such as eating meals, washing, etc., will mean I have to go to bed for a few hours. I am unable to look after myself or my child, exercise or maintain social relationships. I have no financial security. Long COVID has totally destroyed my life.”
• A salaried general practitioner said: “I can no longer work, finances are ruined. I didn’t have employment protection so am now unemployed and penniless.”

Calls for action from the BMA include the following:

• Financial support for doctors and health care staff with long COVID.
• The recognition of long COVID as an occupational disease among health care workers, along with a definition of the condition that covers all of the debilitating disease’s symptoms.
• Improved access to physical and mental health services to help comprehensive assessment, investigations, and treatment.
• Greater workplace protection for health care staff who risk their lives for others.
• Better support for long COVID sufferers to return to work safely if they can, including a flexible approach to the use of workplace adjustments.

“One would think, given the circumstances under which we fell ill and current workforce shortages, NHS employers would be eager to do everything to facilitate the return to work of people with long COVID,” said Dr. Fearnley. “However, NHS employers are legally required to implement only ‘reasonable adjustments,’ and so things such as extended phased return or adjustments to shift patterns are not always being facilitated. Instead, an increasing number of employers are choosing to terminate contracts.”

Raymond Agius, the BMA’s occupational medicine committee cochair, also put the blame on inadequate safety measures for doctors. Those inadequate measures persist to this day, inasmuch as U.K. hospitals have dropped masking requirements.

“During the COVID-19 pandemic, doctors were left exposed and unprotected at work,” he said in a BMA press release. “They often did not have access to the right PPE. ... Too many risk assessments of workplaces and especially of vulnerable doctors were not undertaken.”

A small minority of doctors who were surveyed said they had access to respiratory protective equipment about the time they contracted COVID-19. Only 11% had access to an FFP2 respirator (the equivalent of an N95 mask); 16% had an FFP3 respirator (the equivalent of an N99 mask).

To date, the British government hasn’t issued much of a response to the survey, saying only that it has invested more than ₤50 million to better understand long COVID.

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

Researchers in France are warning against the overzealous use of acid-suppressing drugs in infants after finding that the medications are associated with an increase in risk of serious infections later in life.

The focus on the use of proton pump inhibitors (PPIs) during infancy comes as use of the drugs in young children is rising in France, New Zealand, Scandinavia, and the United States. Much of this use is not to manage confirmed cases of gastroesophageal reflux but rather to soothe the jangled nerves of parents of babies in discomfort, according to the researchers, who have studied national prescribing patterns. In addition to concerns about infection, inappropriate or prolonged use of the acid suppressants is also associated with an increase in the risk of such conditions as hospital-acquired acute kidney injury and inflammatory bowel diseases in children.

PPIs such as omeprazole are effective at reducing gastric acid in babies with gastroesophageal reflux disease. But the researchers warned against using the drugs to manage normal spitting up and dribbling that would have resolved of itself anyway.

“In this study, increased risk of serious infections was associated with PPI use in young children, overall and for various sites and pathogens. In this population, PPIs should not be used without a clear indication,” epidemiologist Marion Lassalle, PharmD, PhD, of EPI-PHARE in Saint-Denis, France, and colleagues reported in JAMA Pediatrics.

Drawing on data from a national birth registry, Dr. Lassalle and colleagues compared infection rates among more than 1.2 million infants who received a PPI at an average age of 88 days with infection rates among children who received another kind of acid suppressant (a histamine receptor blocker or antacid) at an average age of 82 days. More than 600,000 children made up each group.

Slightly over half of the participants were boys, and the study followed children to a maximum age of 9 years. Among children who used PPIs rather than another acid suppressant, there was an overall higher rate of serious infections that required hospitalization (adjusted hazard ratio, 1.34; 95% confidence interval, 1.32-1.36). There were higher rates of infections in the digestive tract; the ear, nose, and throat; the kidneys or urinary tract; the lower respiratory tract; and the nervous system.

Serious infections first appeared 9.7 (range, 3.9-21.3) months after a child stopped using a PPI – a date that Dr. Lassalle’s group determined on the basis of there being a delay of at least 90 days in filling a PPI prescription.
 

Possible confounders

“The study shows an association, it does not show causation,” said Rina Sanghavi, MD, a pediatric gastroenterologist at UT Southwestern Medical Center, Dallas. Dr. Sanghavi noted that the children who continued taking PPIs generally were sicker in their first year of life, as shown by the higher rates of respiratory ailments and corticosteroid use. This could mean that the infections they eventually experienced had many causes and not necessarily the PPI.

Similarly, pediatric gastroenterologist Sophia Patel, MD, of the Cleveland Clinic, pointed to the almost 10-month average lag time between stopping a PPI and developing a first serious infection. That interval is long enough that it is possible that the infection was caused by something else, Dr. Patel said.

Despite the limitations of the study, Dr. Sanghavi and Dr. Patel said the findings serve as a good reminder to clinicians to use PPIs only when needed and to limit their use once begun. The overall evidence base for limiting use of PPIs is strong, both physicians noted, even if this study does not show direct causation between PPI use and infection rates.

“Ask: Does this child need a PPI?” Dr. Sanghavi said. If so, she generally prescribes PPIs for a period of 2 weeks to a maximum of 2 months and she never authorizes automatic refills. Through this approach, a parent and child will come back to the clinic frequently, which in most cases allows faster tapering of the drugs.

Dr. Lassalle, Dr. Sanghavi, and Dr. Patel reported no relevant financial conflicts of interest.

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

Researchers in France are warning against the overzealous use of acid-suppressing drugs in infants after finding that the medications are associated with an increase in risk of serious infections later in life.

The focus on the use of proton pump inhibitors (PPIs) during infancy comes as use of the drugs in young children is rising in France, New Zealand, Scandinavia, and the United States. Much of this use is not to manage confirmed cases of gastroesophageal reflux but rather to soothe the jangled nerves of parents of babies in discomfort, according to the researchers, who have studied national prescribing patterns. In addition to concerns about infection, inappropriate or prolonged use of the acid suppressants is also associated with an increase in the risk of such conditions as hospital-acquired acute kidney injury and inflammatory bowel diseases in children.

PPIs such as omeprazole are effective at reducing gastric acid in babies with gastroesophageal reflux disease. But the researchers warned against using the drugs to manage normal spitting up and dribbling that would have resolved of itself anyway.

“In this study, increased risk of serious infections was associated with PPI use in young children, overall and for various sites and pathogens. In this population, PPIs should not be used without a clear indication,” epidemiologist Marion Lassalle, PharmD, PhD, of EPI-PHARE in Saint-Denis, France, and colleagues reported in JAMA Pediatrics.

Drawing on data from a national birth registry, Dr. Lassalle and colleagues compared infection rates among more than 1.2 million infants who received a PPI at an average age of 88 days with infection rates among children who received another kind of acid suppressant (a histamine receptor blocker or antacid) at an average age of 82 days. More than 600,000 children made up each group.

Slightly over half of the participants were boys, and the study followed children to a maximum age of 9 years. Among children who used PPIs rather than another acid suppressant, there was an overall higher rate of serious infections that required hospitalization (adjusted hazard ratio, 1.34; 95% confidence interval, 1.32-1.36). There were higher rates of infections in the digestive tract; the ear, nose, and throat; the kidneys or urinary tract; the lower respiratory tract; and the nervous system.

Serious infections first appeared 9.7 (range, 3.9-21.3) months after a child stopped using a PPI – a date that Dr. Lassalle’s group determined on the basis of there being a delay of at least 90 days in filling a PPI prescription.
 

Possible confounders

“The study shows an association, it does not show causation,” said Rina Sanghavi, MD, a pediatric gastroenterologist at UT Southwestern Medical Center, Dallas. Dr. Sanghavi noted that the children who continued taking PPIs generally were sicker in their first year of life, as shown by the higher rates of respiratory ailments and corticosteroid use. This could mean that the infections they eventually experienced had many causes and not necessarily the PPI.

Similarly, pediatric gastroenterologist Sophia Patel, MD, of the Cleveland Clinic, pointed to the almost 10-month average lag time between stopping a PPI and developing a first serious infection. That interval is long enough that it is possible that the infection was caused by something else, Dr. Patel said.

Despite the limitations of the study, Dr. Sanghavi and Dr. Patel said the findings serve as a good reminder to clinicians to use PPIs only when needed and to limit their use once begun. The overall evidence base for limiting use of PPIs is strong, both physicians noted, even if this study does not show direct causation between PPI use and infection rates.

“Ask: Does this child need a PPI?” Dr. Sanghavi said. If so, she generally prescribes PPIs for a period of 2 weeks to a maximum of 2 months and she never authorizes automatic refills. Through this approach, a parent and child will come back to the clinic frequently, which in most cases allows faster tapering of the drugs.

Dr. Lassalle, Dr. Sanghavi, and Dr. Patel reported no relevant financial conflicts of interest.

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

Researchers in France are warning against the overzealous use of acid-suppressing drugs in infants after finding that the medications are associated with an increase in risk of serious infections later in life.

The focus on the use of proton pump inhibitors (PPIs) during infancy comes as use of the drugs in young children is rising in France, New Zealand, Scandinavia, and the United States. Much of this use is not to manage confirmed cases of gastroesophageal reflux but rather to soothe the jangled nerves of parents of babies in discomfort, according to the researchers, who have studied national prescribing patterns. In addition to concerns about infection, inappropriate or prolonged use of the acid suppressants is also associated with an increase in the risk of such conditions as hospital-acquired acute kidney injury and inflammatory bowel diseases in children.

PPIs such as omeprazole are effective at reducing gastric acid in babies with gastroesophageal reflux disease. But the researchers warned against using the drugs to manage normal spitting up and dribbling that would have resolved of itself anyway.

“In this study, increased risk of serious infections was associated with PPI use in young children, overall and for various sites and pathogens. In this population, PPIs should not be used without a clear indication,” epidemiologist Marion Lassalle, PharmD, PhD, of EPI-PHARE in Saint-Denis, France, and colleagues reported in JAMA Pediatrics.

Drawing on data from a national birth registry, Dr. Lassalle and colleagues compared infection rates among more than 1.2 million infants who received a PPI at an average age of 88 days with infection rates among children who received another kind of acid suppressant (a histamine receptor blocker or antacid) at an average age of 82 days. More than 600,000 children made up each group.

Slightly over half of the participants were boys, and the study followed children to a maximum age of 9 years. Among children who used PPIs rather than another acid suppressant, there was an overall higher rate of serious infections that required hospitalization (adjusted hazard ratio, 1.34; 95% confidence interval, 1.32-1.36). There were higher rates of infections in the digestive tract; the ear, nose, and throat; the kidneys or urinary tract; the lower respiratory tract; and the nervous system.

Serious infections first appeared 9.7 (range, 3.9-21.3) months after a child stopped using a PPI – a date that Dr. Lassalle’s group determined on the basis of there being a delay of at least 90 days in filling a PPI prescription.
 

Possible confounders

“The study shows an association, it does not show causation,” said Rina Sanghavi, MD, a pediatric gastroenterologist at UT Southwestern Medical Center, Dallas. Dr. Sanghavi noted that the children who continued taking PPIs generally were sicker in their first year of life, as shown by the higher rates of respiratory ailments and corticosteroid use. This could mean that the infections they eventually experienced had many causes and not necessarily the PPI.

Similarly, pediatric gastroenterologist Sophia Patel, MD, of the Cleveland Clinic, pointed to the almost 10-month average lag time between stopping a PPI and developing a first serious infection. That interval is long enough that it is possible that the infection was caused by something else, Dr. Patel said.

Despite the limitations of the study, Dr. Sanghavi and Dr. Patel said the findings serve as a good reminder to clinicians to use PPIs only when needed and to limit their use once begun. The overall evidence base for limiting use of PPIs is strong, both physicians noted, even if this study does not show direct causation between PPI use and infection rates.

“Ask: Does this child need a PPI?” Dr. Sanghavi said. If so, she generally prescribes PPIs for a period of 2 weeks to a maximum of 2 months and she never authorizes automatic refills. Through this approach, a parent and child will come back to the clinic frequently, which in most cases allows faster tapering of the drugs.

Dr. Lassalle, Dr. Sanghavi, and Dr. Patel reported no relevant financial conflicts of interest.

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

The Centers for Disease Control and Prevention and the World Health Organization have dubbed the BA 2.86 variant of COVID-19 as a variant to watch. 

So far, only 26 cases of “Pirola,” as the new variant is being called, have been identified: 10 in Denmark, four each in Sweden and the United States, three in South Africa, two in Portugal, and one each the United Kingdom, Israel, and Canada. BA 2.86 is a subvariant of Omicron, but according to reports from the CDC, the strain has many more mutations than the ones that came before it. 

With so many facts still unknown about this new variant, this news organization asked experts what people need to be aware of as it continues to spread.
 

What is unique about the BA 2.86 variant? 

“It is unique in that it has more than three mutations on the spike protein,” said Purvi S. Parikh, MD, an infectious disease expert at New York University’s Langone Health. The virus uses the spike proteins to enter our cells. 

This “may mean it will be more transmissible, cause more severe disease, and/or our vaccines and treatments may not work as well, as compared to other variants,” she said.
 

What do we need to watch with BA 2.86 going forward? 

“We don’t know if this variant will be associated with a change in the disease severity. We currently see increased numbers of cases in general, even though we don’t yet see the BA.2.86 in our system,” said Heba Mostafa, PhD, director of the molecular virology laboratory at Johns Hopkins Hospital in Baltimore. 

“It is important to monitor BA.2.86 (and other variants) and understand how its evolution impacts the number of cases and disease outcomes,” she said. “We should all be aware of the current increase in cases, though, and try to get tested and be treated as soon as possible, as antivirals should be effective against the circulating variants.” 
 

What should doctors know?

Dr. Parikh said doctors should generally expect more COVID cases in their clinics and make sure to screen patients even if their symptoms are mild.

“We have tools that can be used – antivirals like Paxlovid are still efficacious with current dominant strains such as EG.5,” she said. “And encourage your patients to get their boosters, mask, wash hands, and social distance.”
 

How well can our vaccines fight BA 2.86?

“Vaccine coverage for the BA.2.86 is an area of uncertainty right now,” said Dr. Mostafa. 

In its report, the CDC said scientists are still figuring out how well the updated COVID vaccine works. It’s expected to be available in the fall, and for now, they believe the new shot will still make infections less severe, new variants and all. 

Prior vaccinations and infections have created antibodies in many people, and that will likely provide some protection, Dr. Mostafa said. “When we experienced the Omicron wave in December 2021, even though the variant was distant from what circulated before its emergence and was associated with a very large increase in the number of cases, vaccinations were still protective against severe disease.” 
 

What is the most important thing to keep track of when it comes to this variant?

According to Dr. Parikh, “it’s most important to monitor how transmissible [BA 2.86] is, how severe it is, and if our current treatments and vaccines work.” 

Dr. Mostafa said how well the new variants escape existing antibody protection should also be studied and watched closely. 
 

What does this stage of the virus mutation tell us about where we are in the pandemic?

The history of the coronavirus over the past few years shows that variants with many changes evolve and can spread very quickly, Dr. Mostafa said. “Now that the virus is endemic, it is essential to monitor, update vaccinations if necessary, diagnose, treat, and implement infection control measures when necessary.”

With the limited data we have so far, experts seem to agree that while the variant’s makeup raises some red flags, it is too soon to jump to any conclusions about how easy it is to catch it and the ways it may change how the virus impacts those who contract it.
 

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Adults with asthma who were newly prescribed mepolizumab showed significant improvement in symptoms after 1 year regardless of comorbidities, based on data from 822 individuals.

Comorbidities including chronic rhinosinusitis with polyps (CRSwNP), gastroesophageal reflux disease GERD), anxiety and depression, and chronic obstructive pulmonary disorder (COPD) are common in patients with severe asthma and add to the disease burden, wrote Mark C. Liu, MD, of Johns Hopkins University, Baltimore, and colleagues.

“Some comorbidities, such as CRSwNP, share pathophysiological mechanisms with severe asthma, with interleukin-5 (IL-5),” and treatments targeting IL-5 could improve outcomes, they said.

In the real-world REALITI-A study, mepolizumab, a humanized monoclonal antibody that targets IL-5, significantly reduced asthma exacerbation and oral corticosteroid use in severe asthma patients, they said.

To assess the impact of mepolizumab on patients with comorbidities, the researchers conducted a post hoc analysis of 822 adults with severe asthma, including 321 with CRSwNP, 309 with GERD, 203 with depression/anxiety, and 81 with COPD. The findings were published in the Journal of Allergy and Clinical Immunology: In Practice.

The main outcomes were the rate of clinically significant asthma exacerbations (CSEs) between the 12 months before and after mepolizumab initiation, and the changes from baseline in the daily maintenance use of oral corticosteroids (OCS).

Across all comorbidities, the rate of CSEs decreased significantly from the pretreatment period to the follow-up period, from 4.28 events per year to 1.23 events per year.

“A numerically greater reduction in the rate of CSEs was reported for patients with versus without CRSwNP, whereas the reverse was reported for patients with versus without COPD and depression/anxiety, although the confidence intervals were large for the with COPD subgroup,” the researchers wrote.

The median maintenance dose of oral corticosteroids decreased by at least 50% across all comorbidities after mepolizumab treatment; patients with CRSwNP had the greatest reduction (83%).

In addition, scores on the Asthma Control Questionnaire–5 decreased by at least 0.63 points, and least squared (LS) mean changes in forced expiratory volume per second (FEV₁) increased from baseline across all comorbidities after mepolizumab treatment by at least 74 mL.

Although patients with versus without CRSwNP had greater improvements, patients without GERD, depression/anxiety, and COPD had greater improvements than did those without the respective conditions with the exception of greater FEV₁ improvement in patients with vs. without COPD.

“Patients with severe asthma and comorbid CRSwNP are recognized as having a high disease burden, as demonstrated by more frequent exacerbations,” the researchers wrote in their discussion. “Mepolizumab may serve to reduce the disease burden of this high-risk group by targeting the common pathophysiological pathway of IL-5 and eosinophilic-driven inflammation because it has proven clinical benefits in treating asthma and CRSwNP separately and together,” and the current study findings support the use of mepolizumab for this population in particular, they said.

The findings were limited by several factors including the incomplete data for voluntary assessments, the post hoc design and relatively small numbers of patients in various subgroups, notably COPD, and the potential inaccurate diagnosis of COPD, the researchers noted.

“Nevertheless, because the amount of improvement in each outcome following mepolizumab treatment differed depending on the comorbidity in question, our findings highlight the impact that comorbidities and their prevalence and severity have on outcomes,” and the overall success of mepolizumab across clinical characteristics and comorbidities supports the generalizability of the findings to the larger population of adults with severe asthma, they concluded.

The study was supported by GlaxoSmithKline. Dr. Liu disclosed research funding from GSK, Boehringer Ingelheim, and Gossamer Bio, and participation on advisory boards for AstraZeneca, GSK, and Gossamer Bio.

Adults with asthma who were newly prescribed mepolizumab showed significant improvement in symptoms after 1 year regardless of comorbidities, based on data from 822 individuals.

Comorbidities including chronic rhinosinusitis with polyps (CRSwNP), gastroesophageal reflux disease GERD), anxiety and depression, and chronic obstructive pulmonary disorder (COPD) are common in patients with severe asthma and add to the disease burden, wrote Mark C. Liu, MD, of Johns Hopkins University, Baltimore, and colleagues.

“Some comorbidities, such as CRSwNP, share pathophysiological mechanisms with severe asthma, with interleukin-5 (IL-5),” and treatments targeting IL-5 could improve outcomes, they said.

In the real-world REALITI-A study, mepolizumab, a humanized monoclonal antibody that targets IL-5, significantly reduced asthma exacerbation and oral corticosteroid use in severe asthma patients, they said.

To assess the impact of mepolizumab on patients with comorbidities, the researchers conducted a post hoc analysis of 822 adults with severe asthma, including 321 with CRSwNP, 309 with GERD, 203 with depression/anxiety, and 81 with COPD. The findings were published in the Journal of Allergy and Clinical Immunology: In Practice.

The main outcomes were the rate of clinically significant asthma exacerbations (CSEs) between the 12 months before and after mepolizumab initiation, and the changes from baseline in the daily maintenance use of oral corticosteroids (OCS).

Across all comorbidities, the rate of CSEs decreased significantly from the pretreatment period to the follow-up period, from 4.28 events per year to 1.23 events per year.

“A numerically greater reduction in the rate of CSEs was reported for patients with versus without CRSwNP, whereas the reverse was reported for patients with versus without COPD and depression/anxiety, although the confidence intervals were large for the with COPD subgroup,” the researchers wrote.

The median maintenance dose of oral corticosteroids decreased by at least 50% across all comorbidities after mepolizumab treatment; patients with CRSwNP had the greatest reduction (83%).

In addition, scores on the Asthma Control Questionnaire–5 decreased by at least 0.63 points, and least squared (LS) mean changes in forced expiratory volume per second (FEV₁) increased from baseline across all comorbidities after mepolizumab treatment by at least 74 mL.

Although patients with versus without CRSwNP had greater improvements, patients without GERD, depression/anxiety, and COPD had greater improvements than did those without the respective conditions with the exception of greater FEV₁ improvement in patients with vs. without COPD.

“Patients with severe asthma and comorbid CRSwNP are recognized as having a high disease burden, as demonstrated by more frequent exacerbations,” the researchers wrote in their discussion. “Mepolizumab may serve to reduce the disease burden of this high-risk group by targeting the common pathophysiological pathway of IL-5 and eosinophilic-driven inflammation because it has proven clinical benefits in treating asthma and CRSwNP separately and together,” and the current study findings support the use of mepolizumab for this population in particular, they said.

The findings were limited by several factors including the incomplete data for voluntary assessments, the post hoc design and relatively small numbers of patients in various subgroups, notably COPD, and the potential inaccurate diagnosis of COPD, the researchers noted.

“Nevertheless, because the amount of improvement in each outcome following mepolizumab treatment differed depending on the comorbidity in question, our findings highlight the impact that comorbidities and their prevalence and severity have on outcomes,” and the overall success of mepolizumab across clinical characteristics and comorbidities supports the generalizability of the findings to the larger population of adults with severe asthma, they concluded.

The study was supported by GlaxoSmithKline. Dr. Liu disclosed research funding from GSK, Boehringer Ingelheim, and Gossamer Bio, and participation on advisory boards for AstraZeneca, GSK, and Gossamer Bio.

Adults with asthma who were newly prescribed mepolizumab showed significant improvement in symptoms after 1 year regardless of comorbidities, based on data from 822 individuals.

Comorbidities including chronic rhinosinusitis with polyps (CRSwNP), gastroesophageal reflux disease GERD), anxiety and depression, and chronic obstructive pulmonary disorder (COPD) are common in patients with severe asthma and add to the disease burden, wrote Mark C. Liu, MD, of Johns Hopkins University, Baltimore, and colleagues.

“Some comorbidities, such as CRSwNP, share pathophysiological mechanisms with severe asthma, with interleukin-5 (IL-5),” and treatments targeting IL-5 could improve outcomes, they said.

In the real-world REALITI-A study, mepolizumab, a humanized monoclonal antibody that targets IL-5, significantly reduced asthma exacerbation and oral corticosteroid use in severe asthma patients, they said.

To assess the impact of mepolizumab on patients with comorbidities, the researchers conducted a post hoc analysis of 822 adults with severe asthma, including 321 with CRSwNP, 309 with GERD, 203 with depression/anxiety, and 81 with COPD. The findings were published in the Journal of Allergy and Clinical Immunology: In Practice.

The main outcomes were the rate of clinically significant asthma exacerbations (CSEs) between the 12 months before and after mepolizumab initiation, and the changes from baseline in the daily maintenance use of oral corticosteroids (OCS).

Across all comorbidities, the rate of CSEs decreased significantly from the pretreatment period to the follow-up period, from 4.28 events per year to 1.23 events per year.

“A numerically greater reduction in the rate of CSEs was reported for patients with versus without CRSwNP, whereas the reverse was reported for patients with versus without COPD and depression/anxiety, although the confidence intervals were large for the with COPD subgroup,” the researchers wrote.

The median maintenance dose of oral corticosteroids decreased by at least 50% across all comorbidities after mepolizumab treatment; patients with CRSwNP had the greatest reduction (83%).

In addition, scores on the Asthma Control Questionnaire–5 decreased by at least 0.63 points, and least squared (LS) mean changes in forced expiratory volume per second (FEV₁) increased from baseline across all comorbidities after mepolizumab treatment by at least 74 mL.

Although patients with versus without CRSwNP had greater improvements, patients without GERD, depression/anxiety, and COPD had greater improvements than did those without the respective conditions with the exception of greater FEV₁ improvement in patients with vs. without COPD.

“Patients with severe asthma and comorbid CRSwNP are recognized as having a high disease burden, as demonstrated by more frequent exacerbations,” the researchers wrote in their discussion. “Mepolizumab may serve to reduce the disease burden of this high-risk group by targeting the common pathophysiological pathway of IL-5 and eosinophilic-driven inflammation because it has proven clinical benefits in treating asthma and CRSwNP separately and together,” and the current study findings support the use of mepolizumab for this population in particular, they said.

The findings were limited by several factors including the incomplete data for voluntary assessments, the post hoc design and relatively small numbers of patients in various subgroups, notably COPD, and the potential inaccurate diagnosis of COPD, the researchers noted.

“Nevertheless, because the amount of improvement in each outcome following mepolizumab treatment differed depending on the comorbidity in question, our findings highlight the impact that comorbidities and their prevalence and severity have on outcomes,” and the overall success of mepolizumab across clinical characteristics and comorbidities supports the generalizability of the findings to the larger population of adults with severe asthma, they concluded.

The study was supported by GlaxoSmithKline. Dr. Liu disclosed research funding from GSK, Boehringer Ingelheim, and Gossamer Bio, and participation on advisory boards for AstraZeneca, GSK, and Gossamer Bio.