Pharmacology

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.
 

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.

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.

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.

A year after celebrating the approval of the first treatment for repigmentation of vitiligo, dermatologists describe how topical ruxolitinib has advanced the outlook for patients with the disease and what’s next in the pipeline.

The Food and Drug Administration approved the cream formulation of ruxolitinib (Opzelura), a JAK inhibitor, for repigmentation of nonsegmental vitiligo in July 2022 for people aged 12 years and older.

Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that he likes to use ruxolitinib cream in combination with other treatments.

Dr. Chovatiya

“In the real world with vitiligo patients, we’re oftentimes doing combinatorial therapy anyway. So phototherapy, specifically, narrow-band UVB, is something that we have a lot of clinical evidence for over the years, and it’s a modality that can combine with topical steroids and topical calcineurin inhibitors.”

He said trials to study combinations will yield better guidance on optimal use of ruxolitinib cream. “In general, vitiligo patients can really benefit from phototherapy,” he said in an interview. (Labeling recommends against combination with other JAK inhibitors, biologics, or potent immunosuppressants, such as azathioprine or cyclosporine.)

This first year has shown that ruxolitinib is an effective option, but counseling patients to expect slow improvement is important so that patients stick with it, he noted.

Documenting what treatments patients with vitiligo have used before is important, he said, as is counseling patients that ruxolitinib is approved only for use on up to 10% of a person’s body surface area. (Product labeling recommends that a thin layer be applied twice a day to affected areas up to 10% of body surface area.)

Ruxolitinib has brought a “louder voice” to vitiligo and has opened up options for patients with the disease, Dr. Chovatiya said. “Having the ability to topically treat people who have very extensive disease really gives us a lot more flexibility than we have had before.”
 

Good experiences with payers at safety-net hospital

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, said that real-world experience with topical ruxolitinib will be more evident after its been on the market for 18-24 months.

Dr. Heath said she, too, encourages use of narrow-band UVB phototherapy in conjunction with the treatment.

From an insurance reimbursement standpoint, she said that she is glad that there have been fewer hurdles in getting ruxolitinib to patients than she has experienced with other medications.

In her safety-net hospital, she told this news organization, she sees patients with many types of insurance, but most have Medicaid. “So, I’m always expecting the step therapies, denials, pushbacks, etc.,” she said. But the path has been smoother for ruxolitinib coverage, she noted.

Her colleagues are committed to documenting everything the patient has tried, she added, and that helps with prior authorization.

Dr. Heath said that pointing out to insurers that ruxolitinib is the only approved treatment for repigmentation helps facilitate coverage.

“The science is advancing, and I’m happy to be practicing during a time when we actually have something approved for vitiligo,” she said. But she pointed out that phototherapy often is not covered for vitiligo, “which is horrible, when it is readily approved for psoriasis and atopic dermatitis.”

To document progress, Dr. Heath said that she always takes photographs of her patients with vitiligo because “the pictures remind us how far we have come.”
 

Data spotlight success in adolescents

Data from two trials give a clinical picture of the drug’s safety and efficacy in younger patients.

Adolescents had particularly good results in the first year with ruxolitinib, according to pooled phase 3 data from TRuE-V1 and TRuE-V2, this news organization reported.

The findings, presented at the 25th World Congress of Dermatology in Singapore, indicate that more than half of the participants achieved at least a 50% improvement from baseline in the total Vitiligo Area Scoring Index (T-VASI50) at 52 weeks.

The percentages of young patients aged 12-17 years taking twice-daily ruxolitinib who achieved T-VASI 50 at weeks 12, 24, and 52 were 11.5%, 26.9%, and 57.7%, respectively. The corresponding percentages for all in the study population were 10.7%, 22.7%, and 44.4%, respectively.

At the meeting, the presenter, Julien Seneschal, MD, PhD, professor of dermatology and head of the vitiligo and pigmentary disorders clinic at the University of Bordeaux, France, said, “This suggests that younger patients can respond better to the treatment.” He noted, however, that there were few adolescents in the studies.
 

New excitement in the field

Daniel Gutierrez, MD, assistant professor of dermatology at New York University, said the treatment has brought new excitement to the field.

“Patients with vitiligo are very motivated to treat their disease,” he said, because it typically is on the face and other highly visual areas, which can affect their overall perception of self.

NYU Langone Health

Previously, he noted in an interview, the only FDA-approved treatment was monobenzone, but that was for depigmentation rather than repigmentation.

Otherwise, treatments were being used off label, and patients were receiving compounded formulations that often weren’t covered by insurance and often had shorter shelf life.

He said that he still occasionally gets denials from payers who consider vitiligo a cosmetic condition.

“I’ve had more luck with insurance, at least in the New York State area.” He added that sometimes payers require use of a topical calcineurin inhibitor for about 12 weeks before they will cover ruxolitinib.

Dr. Gutierrez also recommends using phototherapy with topical ruxolitinib “because they work on slightly different pathways.”

When he starts patients on a new therapy such as ruxolitinib, he asks them to come back in 3 months, and often by then, progress is evident. Facial areas show the most response, he said, while hands and feet are less likely to show significant improvement.

He said that it’s important for physicians and patients to know that improvements can take weeks or months to be noticeable. “I tell patients not to give up,” he added.

Showing the patients pictures from the current appointment and comparing them with pictures from previous appointments can help them better understand their progress, he said.
 

Lead investigator adds observations

David Rosmarin, MD, chair of the department of dermatology at Indiana University, Indianapolis, was the lead investigator of the pivotal TruE-V1 and TruE-V2 trials for vitiligo. In that role, he has been treating vitiligo patients with topical ruxolitinib since 2015.

In an interview, he said that many patients “don’t hit their optimal results at 3 months, 6 months, even the year mark. With continued use, many can see continued benefit.”

Other patients, he said, don’t respond within the first 6 months but with continued use may eventually respond, he said.

“Unfortunately, we have no way of knowing, based on clinical characteristics or baseline demographics, whether a patient will be a delayed responder or not or an early responder,” Dr. Rosmarin added.

He provided several observations about people who have stopped taking the medication.

“When people stop,” he said, “some maintain their response, but some start to depigment again. Again, we have no way of predicting who will be in which category.”

He said that once patients have hit their desired response, he usually advises them to taper down to maybe twice a week or to stop treatment, but if they see any recurrence, they should start reusing the medicine.

“We have some patients who have gone 6 or 7 years now before they had a recurrence, but others may start to depigment again in 2 to 3 months,” Dr. Rosmarin said.

As for phototherapy, he said, the combination with topical ruxolitinib is being studied.

“We think the combination is synergistic and better than either alone, but we’re still waiting for data to prove that,” he said.

In his practice, he offers patients the option either to use just ruxolitinib cream or the combination early on. Many patients, because of convenience, say they’ll first try the cream to see if that works.

“The challenge with light [therapy] is that it can be very inconvenient,” he said. Patients have to live close to a phototherapy unit to receive therapy 2-3 times a week or have a phototherapy product in their home.
 

Next in the pipeline

Experts say the progress doesn’t stop with ruxolitinib cream. Current trials of several medications show there’s more to come for patients with vitiligo.

Dr. Chovatiya said that next up may be oral ritlecitinib (Litfulo), a JAK inhibitor that was approved for severe alopecia areata in June for people aged 12 years and older. Phase 2 results have been published for its use with vitiligo.

“This would be an oral medication that may be able to help people with much more extensive disease as far as vitiligo goes,” he said, adding that he expects approval for a vitiligo indication within a few years.

He pointed out that longer-term safety data will be available because it is already on the market for alopecia.

Upadacitinib (Rinvoq), an oral JAK inhibitor, is approved for atopic dermatitis but is being studied for vitiligo as well, he noted. “I’m very excited to see what that holds for patients as well,” Dr. Chovatiya said.

Dr. Gutierrez said that he is excited about oral JAK inhibitors but sees potential in finding new ways to transplant melanocytes into areas where there are none.

The pigmentation field has seen new energy since last year’s approval, he said, particularly among people of color.

“We have new options for vitiligo that were lacking compared with other conditions, such as atopic dermatitis and psoriasis,” he said. “Hopefully, there will be more promising breakthroughs.”

Dr. Rosmarin is the chief investigator for the pivotal trials that led to FDA approval of ruxolitinib. He disclosed ties with AbbVie, Abcuro, AltruBio, Amgen, Arena, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and Viela Bio. Dr. Chovatiya disclosed ties with AbbVie, Arcutis, Arena, Argenx, Beiersdorf, Bristol-Myers Squibb, Dermavant, Eli Lilly, EPI Health, Incyte, LEO Pharma, L’Oréal, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB. Dr. Heath and Dr. Gutierrez report no relevant financial relationships.

A version of this article appeared on Medscape.com.

A year after celebrating the approval of the first treatment for repigmentation of vitiligo, dermatologists describe how topical ruxolitinib has advanced the outlook for patients with the disease and what’s next in the pipeline.

The Food and Drug Administration approved the cream formulation of ruxolitinib (Opzelura), a JAK inhibitor, for repigmentation of nonsegmental vitiligo in July 2022 for people aged 12 years and older.

Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that he likes to use ruxolitinib cream in combination with other treatments.

Dr. Chovatiya

“In the real world with vitiligo patients, we’re oftentimes doing combinatorial therapy anyway. So phototherapy, specifically, narrow-band UVB, is something that we have a lot of clinical evidence for over the years, and it’s a modality that can combine with topical steroids and topical calcineurin inhibitors.”

He said trials to study combinations will yield better guidance on optimal use of ruxolitinib cream. “In general, vitiligo patients can really benefit from phototherapy,” he said in an interview. (Labeling recommends against combination with other JAK inhibitors, biologics, or potent immunosuppressants, such as azathioprine or cyclosporine.)

This first year has shown that ruxolitinib is an effective option, but counseling patients to expect slow improvement is important so that patients stick with it, he noted.

Documenting what treatments patients with vitiligo have used before is important, he said, as is counseling patients that ruxolitinib is approved only for use on up to 10% of a person’s body surface area. (Product labeling recommends that a thin layer be applied twice a day to affected areas up to 10% of body surface area.)

Ruxolitinib has brought a “louder voice” to vitiligo and has opened up options for patients with the disease, Dr. Chovatiya said. “Having the ability to topically treat people who have very extensive disease really gives us a lot more flexibility than we have had before.”
 

Good experiences with payers at safety-net hospital

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, said that real-world experience with topical ruxolitinib will be more evident after its been on the market for 18-24 months.

Dr. Heath said she, too, encourages use of narrow-band UVB phototherapy in conjunction with the treatment.

From an insurance reimbursement standpoint, she said that she is glad that there have been fewer hurdles in getting ruxolitinib to patients than she has experienced with other medications.

In her safety-net hospital, she told this news organization, she sees patients with many types of insurance, but most have Medicaid. “So, I’m always expecting the step therapies, denials, pushbacks, etc.,” she said. But the path has been smoother for ruxolitinib coverage, she noted.

Her colleagues are committed to documenting everything the patient has tried, she added, and that helps with prior authorization.

Dr. Heath said that pointing out to insurers that ruxolitinib is the only approved treatment for repigmentation helps facilitate coverage.

“The science is advancing, and I’m happy to be practicing during a time when we actually have something approved for vitiligo,” she said. But she pointed out that phototherapy often is not covered for vitiligo, “which is horrible, when it is readily approved for psoriasis and atopic dermatitis.”

To document progress, Dr. Heath said that she always takes photographs of her patients with vitiligo because “the pictures remind us how far we have come.”
 

Data spotlight success in adolescents

Data from two trials give a clinical picture of the drug’s safety and efficacy in younger patients.

Adolescents had particularly good results in the first year with ruxolitinib, according to pooled phase 3 data from TRuE-V1 and TRuE-V2, this news organization reported.

The findings, presented at the 25th World Congress of Dermatology in Singapore, indicate that more than half of the participants achieved at least a 50% improvement from baseline in the total Vitiligo Area Scoring Index (T-VASI50) at 52 weeks.

The percentages of young patients aged 12-17 years taking twice-daily ruxolitinib who achieved T-VASI 50 at weeks 12, 24, and 52 were 11.5%, 26.9%, and 57.7%, respectively. The corresponding percentages for all in the study population were 10.7%, 22.7%, and 44.4%, respectively.

At the meeting, the presenter, Julien Seneschal, MD, PhD, professor of dermatology and head of the vitiligo and pigmentary disorders clinic at the University of Bordeaux, France, said, “This suggests that younger patients can respond better to the treatment.” He noted, however, that there were few adolescents in the studies.
 

New excitement in the field

Daniel Gutierrez, MD, assistant professor of dermatology at New York University, said the treatment has brought new excitement to the field.

“Patients with vitiligo are very motivated to treat their disease,” he said, because it typically is on the face and other highly visual areas, which can affect their overall perception of self.

NYU Langone Health

Previously, he noted in an interview, the only FDA-approved treatment was monobenzone, but that was for depigmentation rather than repigmentation.

Otherwise, treatments were being used off label, and patients were receiving compounded formulations that often weren’t covered by insurance and often had shorter shelf life.

He said that he still occasionally gets denials from payers who consider vitiligo a cosmetic condition.

“I’ve had more luck with insurance, at least in the New York State area.” He added that sometimes payers require use of a topical calcineurin inhibitor for about 12 weeks before they will cover ruxolitinib.

Dr. Gutierrez also recommends using phototherapy with topical ruxolitinib “because they work on slightly different pathways.”

When he starts patients on a new therapy such as ruxolitinib, he asks them to come back in 3 months, and often by then, progress is evident. Facial areas show the most response, he said, while hands and feet are less likely to show significant improvement.

He said that it’s important for physicians and patients to know that improvements can take weeks or months to be noticeable. “I tell patients not to give up,” he added.

Showing the patients pictures from the current appointment and comparing them with pictures from previous appointments can help them better understand their progress, he said.
 

Lead investigator adds observations

David Rosmarin, MD, chair of the department of dermatology at Indiana University, Indianapolis, was the lead investigator of the pivotal TruE-V1 and TruE-V2 trials for vitiligo. In that role, he has been treating vitiligo patients with topical ruxolitinib since 2015.

In an interview, he said that many patients “don’t hit their optimal results at 3 months, 6 months, even the year mark. With continued use, many can see continued benefit.”

Other patients, he said, don’t respond within the first 6 months but with continued use may eventually respond, he said.

“Unfortunately, we have no way of knowing, based on clinical characteristics or baseline demographics, whether a patient will be a delayed responder or not or an early responder,” Dr. Rosmarin added.

He provided several observations about people who have stopped taking the medication.

“When people stop,” he said, “some maintain their response, but some start to depigment again. Again, we have no way of predicting who will be in which category.”

He said that once patients have hit their desired response, he usually advises them to taper down to maybe twice a week or to stop treatment, but if they see any recurrence, they should start reusing the medicine.

“We have some patients who have gone 6 or 7 years now before they had a recurrence, but others may start to depigment again in 2 to 3 months,” Dr. Rosmarin said.

As for phototherapy, he said, the combination with topical ruxolitinib is being studied.

“We think the combination is synergistic and better than either alone, but we’re still waiting for data to prove that,” he said.

In his practice, he offers patients the option either to use just ruxolitinib cream or the combination early on. Many patients, because of convenience, say they’ll first try the cream to see if that works.

“The challenge with light [therapy] is that it can be very inconvenient,” he said. Patients have to live close to a phototherapy unit to receive therapy 2-3 times a week or have a phototherapy product in their home.
 

Next in the pipeline

Experts say the progress doesn’t stop with ruxolitinib cream. Current trials of several medications show there’s more to come for patients with vitiligo.

Dr. Chovatiya said that next up may be oral ritlecitinib (Litfulo), a JAK inhibitor that was approved for severe alopecia areata in June for people aged 12 years and older. Phase 2 results have been published for its use with vitiligo.

“This would be an oral medication that may be able to help people with much more extensive disease as far as vitiligo goes,” he said, adding that he expects approval for a vitiligo indication within a few years.

He pointed out that longer-term safety data will be available because it is already on the market for alopecia.

Upadacitinib (Rinvoq), an oral JAK inhibitor, is approved for atopic dermatitis but is being studied for vitiligo as well, he noted. “I’m very excited to see what that holds for patients as well,” Dr. Chovatiya said.

Dr. Gutierrez said that he is excited about oral JAK inhibitors but sees potential in finding new ways to transplant melanocytes into areas where there are none.

The pigmentation field has seen new energy since last year’s approval, he said, particularly among people of color.

“We have new options for vitiligo that were lacking compared with other conditions, such as atopic dermatitis and psoriasis,” he said. “Hopefully, there will be more promising breakthroughs.”

Dr. Rosmarin is the chief investigator for the pivotal trials that led to FDA approval of ruxolitinib. He disclosed ties with AbbVie, Abcuro, AltruBio, Amgen, Arena, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and Viela Bio. Dr. Chovatiya disclosed ties with AbbVie, Arcutis, Arena, Argenx, Beiersdorf, Bristol-Myers Squibb, Dermavant, Eli Lilly, EPI Health, Incyte, LEO Pharma, L’Oréal, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB. Dr. Heath and Dr. Gutierrez report no relevant financial relationships.

A version of this article appeared on Medscape.com.

A year after celebrating the approval of the first treatment for repigmentation of vitiligo, dermatologists describe how topical ruxolitinib has advanced the outlook for patients with the disease and what’s next in the pipeline.

The Food and Drug Administration approved the cream formulation of ruxolitinib (Opzelura), a JAK inhibitor, for repigmentation of nonsegmental vitiligo in July 2022 for people aged 12 years and older.

Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that he likes to use ruxolitinib cream in combination with other treatments.

Dr. Chovatiya

“In the real world with vitiligo patients, we’re oftentimes doing combinatorial therapy anyway. So phototherapy, specifically, narrow-band UVB, is something that we have a lot of clinical evidence for over the years, and it’s a modality that can combine with topical steroids and topical calcineurin inhibitors.”

He said trials to study combinations will yield better guidance on optimal use of ruxolitinib cream. “In general, vitiligo patients can really benefit from phototherapy,” he said in an interview. (Labeling recommends against combination with other JAK inhibitors, biologics, or potent immunosuppressants, such as azathioprine or cyclosporine.)

This first year has shown that ruxolitinib is an effective option, but counseling patients to expect slow improvement is important so that patients stick with it, he noted.

Documenting what treatments patients with vitiligo have used before is important, he said, as is counseling patients that ruxolitinib is approved only for use on up to 10% of a person’s body surface area. (Product labeling recommends that a thin layer be applied twice a day to affected areas up to 10% of body surface area.)

Ruxolitinib has brought a “louder voice” to vitiligo and has opened up options for patients with the disease, Dr. Chovatiya said. “Having the ability to topically treat people who have very extensive disease really gives us a lot more flexibility than we have had before.”
 

Good experiences with payers at safety-net hospital

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, said that real-world experience with topical ruxolitinib will be more evident after its been on the market for 18-24 months.

Dr. Heath said she, too, encourages use of narrow-band UVB phototherapy in conjunction with the treatment.

From an insurance reimbursement standpoint, she said that she is glad that there have been fewer hurdles in getting ruxolitinib to patients than she has experienced with other medications.

In her safety-net hospital, she told this news organization, she sees patients with many types of insurance, but most have Medicaid. “So, I’m always expecting the step therapies, denials, pushbacks, etc.,” she said. But the path has been smoother for ruxolitinib coverage, she noted.

Her colleagues are committed to documenting everything the patient has tried, she added, and that helps with prior authorization.

Dr. Heath said that pointing out to insurers that ruxolitinib is the only approved treatment for repigmentation helps facilitate coverage.

“The science is advancing, and I’m happy to be practicing during a time when we actually have something approved for vitiligo,” she said. But she pointed out that phototherapy often is not covered for vitiligo, “which is horrible, when it is readily approved for psoriasis and atopic dermatitis.”

To document progress, Dr. Heath said that she always takes photographs of her patients with vitiligo because “the pictures remind us how far we have come.”
 

Data spotlight success in adolescents

Data from two trials give a clinical picture of the drug’s safety and efficacy in younger patients.

Adolescents had particularly good results in the first year with ruxolitinib, according to pooled phase 3 data from TRuE-V1 and TRuE-V2, this news organization reported.

The findings, presented at the 25th World Congress of Dermatology in Singapore, indicate that more than half of the participants achieved at least a 50% improvement from baseline in the total Vitiligo Area Scoring Index (T-VASI50) at 52 weeks.

The percentages of young patients aged 12-17 years taking twice-daily ruxolitinib who achieved T-VASI 50 at weeks 12, 24, and 52 were 11.5%, 26.9%, and 57.7%, respectively. The corresponding percentages for all in the study population were 10.7%, 22.7%, and 44.4%, respectively.

At the meeting, the presenter, Julien Seneschal, MD, PhD, professor of dermatology and head of the vitiligo and pigmentary disorders clinic at the University of Bordeaux, France, said, “This suggests that younger patients can respond better to the treatment.” He noted, however, that there were few adolescents in the studies.
 

New excitement in the field

Daniel Gutierrez, MD, assistant professor of dermatology at New York University, said the treatment has brought new excitement to the field.

“Patients with vitiligo are very motivated to treat their disease,” he said, because it typically is on the face and other highly visual areas, which can affect their overall perception of self.

NYU Langone Health

Previously, he noted in an interview, the only FDA-approved treatment was monobenzone, but that was for depigmentation rather than repigmentation.

Otherwise, treatments were being used off label, and patients were receiving compounded formulations that often weren’t covered by insurance and often had shorter shelf life.

He said that he still occasionally gets denials from payers who consider vitiligo a cosmetic condition.

“I’ve had more luck with insurance, at least in the New York State area.” He added that sometimes payers require use of a topical calcineurin inhibitor for about 12 weeks before they will cover ruxolitinib.

Dr. Gutierrez also recommends using phototherapy with topical ruxolitinib “because they work on slightly different pathways.”

When he starts patients on a new therapy such as ruxolitinib, he asks them to come back in 3 months, and often by then, progress is evident. Facial areas show the most response, he said, while hands and feet are less likely to show significant improvement.

He said that it’s important for physicians and patients to know that improvements can take weeks or months to be noticeable. “I tell patients not to give up,” he added.

Showing the patients pictures from the current appointment and comparing them with pictures from previous appointments can help them better understand their progress, he said.
 

Lead investigator adds observations

David Rosmarin, MD, chair of the department of dermatology at Indiana University, Indianapolis, was the lead investigator of the pivotal TruE-V1 and TruE-V2 trials for vitiligo. In that role, he has been treating vitiligo patients with topical ruxolitinib since 2015.

In an interview, he said that many patients “don’t hit their optimal results at 3 months, 6 months, even the year mark. With continued use, many can see continued benefit.”

Other patients, he said, don’t respond within the first 6 months but with continued use may eventually respond, he said.

“Unfortunately, we have no way of knowing, based on clinical characteristics or baseline demographics, whether a patient will be a delayed responder or not or an early responder,” Dr. Rosmarin added.

He provided several observations about people who have stopped taking the medication.

“When people stop,” he said, “some maintain their response, but some start to depigment again. Again, we have no way of predicting who will be in which category.”

He said that once patients have hit their desired response, he usually advises them to taper down to maybe twice a week or to stop treatment, but if they see any recurrence, they should start reusing the medicine.

“We have some patients who have gone 6 or 7 years now before they had a recurrence, but others may start to depigment again in 2 to 3 months,” Dr. Rosmarin said.

As for phototherapy, he said, the combination with topical ruxolitinib is being studied.

“We think the combination is synergistic and better than either alone, but we’re still waiting for data to prove that,” he said.

In his practice, he offers patients the option either to use just ruxolitinib cream or the combination early on. Many patients, because of convenience, say they’ll first try the cream to see if that works.

“The challenge with light [therapy] is that it can be very inconvenient,” he said. Patients have to live close to a phototherapy unit to receive therapy 2-3 times a week or have a phototherapy product in their home.
 

Next in the pipeline

Experts say the progress doesn’t stop with ruxolitinib cream. Current trials of several medications show there’s more to come for patients with vitiligo.

Dr. Chovatiya said that next up may be oral ritlecitinib (Litfulo), a JAK inhibitor that was approved for severe alopecia areata in June for people aged 12 years and older. Phase 2 results have been published for its use with vitiligo.

“This would be an oral medication that may be able to help people with much more extensive disease as far as vitiligo goes,” he said, adding that he expects approval for a vitiligo indication within a few years.

He pointed out that longer-term safety data will be available because it is already on the market for alopecia.

Upadacitinib (Rinvoq), an oral JAK inhibitor, is approved for atopic dermatitis but is being studied for vitiligo as well, he noted. “I’m very excited to see what that holds for patients as well,” Dr. Chovatiya said.

Dr. Gutierrez said that he is excited about oral JAK inhibitors but sees potential in finding new ways to transplant melanocytes into areas where there are none.

The pigmentation field has seen new energy since last year’s approval, he said, particularly among people of color.

“We have new options for vitiligo that were lacking compared with other conditions, such as atopic dermatitis and psoriasis,” he said. “Hopefully, there will be more promising breakthroughs.”

Dr. Rosmarin is the chief investigator for the pivotal trials that led to FDA approval of ruxolitinib. He disclosed ties with AbbVie, Abcuro, AltruBio, Amgen, Arena, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and Viela Bio. Dr. Chovatiya disclosed ties with AbbVie, Arcutis, Arena, Argenx, Beiersdorf, Bristol-Myers Squibb, Dermavant, Eli Lilly, EPI Health, Incyte, LEO Pharma, L’Oréal, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB. Dr. Heath and Dr. Gutierrez report no relevant financial relationships.

A version of this article appeared on Medscape.com.

The glucose-lowering drug class sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to reduce the risk for recurrent gout flares in people with gout and type 2 diabetes, and to lessen excess mortality in those individuals, compared with those who initiated other types of glucose-lowering medications, new data suggest.

Among nearly 6,000 adults with both type 2 diabetes and gout from a U.K. primary care database, initiation of SGLT2 inhibitor treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality.

Moreover, unlike other urate-lowering therapies, there were no apparent transient increases in the risk of gout flares after initiating therapy, Jie Wei, PhD, of Health Management Center, Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in JAMA Network Open.

These results are important because current management of gout is suboptimal. Many patients either don’t receive adequate urate-lowering therapies such as allopurinol or stop taking them, Dr. Wei and colleagues said.

In addition to lowering glucose, SGLT2 inhibitors also reduce the risk for major adverse cardiovascular events and all-cause mortality in people regardless of their diabetes status. Previous studies have also found that SGLT2 inhibitors reduce the risk for developing gout and of gout flares.

Asked to comment, gout specialist John D. FitzGerald, MD, PhD, clinical chief of rheumatology at the University of California, Los Angeles, said in an interview: “I think it’s a well-done paper, with a large dataset. I think it just reinforces the findings from the other papers. Mostly anything that lowers uric acid levels is going to lower recurrent gout attacks, so it all makes sense.”

However, while Dr. FitzGerald thinks the drug class is a good option for people with diabetes or cardiorenal indications for them who also have gout, he doesn’t envision it as first-line for most other patients with gout. “The current treatments are very effective. Allopurinol brings down uric acid levels by 5-7 points. There are patients who fail allopurinol, but those are less than 5%.”

The most common reason patients stop taking allopurinol is the frequent initial gout flare. But that’s preventable, Dr. FitzGerald said, either by titrating up slowly, or by adding colchicine along with it. “By going slowly, you can avoid that flare risk. I think that’s what’s going on with the SGLT2 inhibitor. It’s not a dramatic urate-lowering drug, but it is clinically meaningful. I think that’s what this paper is showing.”

But, he noted, “I think there are so many reasons to start the SGLT2 inhibitors that if somebody also has gout, all the better. And, if somebody is on the margin with diabetes and gout control and can’t go with allopurinol, it would be great to add for both conditions.”

Less gout recurrence, lower mortality

The retrospective study was conducted from Jan. 1, 2013, to March 31, 2022. Among 5,931 patients with both type 2 diabetes and gout, 1,548 (26.1%) initiated an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin), while 4,383 (73.9%) initiated treatment with other active comparators, mostly (92.6%) dipeptidyl peptidase–4 inhibitors.

Gout flares were identified in the charts for a total of 86% of the participants. The weighted incidence rates for the first recurrent flare were 32.4 versus 41.2 per 1,000 person-years in the SGLT2 inhibitor versus comparator groups, with a weighted absolute rate difference of –8.8/1,000 and weighted hazard ratio of 0.81, a significant difference.

All-cause mortality was 18.8 versus 24.9 per 1,000 person-years, respectively, giving an HR of 0.71 at 5-year follow-up.

Dr. FitzGerald, who chaired the American College of Rheumatology’s 2020 gout guidelines, said he anticipates that the SGLT2 inhibitors will be mentioned in the next update to the ACR’s now “living” guidelines, although he was not speaking on the organization’s behalf.

“We talk about losartan in the current [ACR guidelines], about its specific uric acid–lowering effect. Drugs can make uric acid worse or better. For example, thiazides make it higher. I think the SGLT2 [inhibitors] are important, but I don’t think they’re huge. The study is great, and I think the drugs are great, but I don’t think they will change the way gout is managed.”

This work was supported by grants from the National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of National Clinical Research Center for Geriatric Disorders, and from the Natural Science Foundation of Hunan Province. Dr. Wei reported receiving grant funding from Xiangya Hospital Central South University Project Program of National Clinical Research Center for Geriatric Disorders and the Science and Technology Department of Hunan Province, the Natural Science Foundation of Hunan Province, during the conduct of the study. Dr. FitzGerald reported no relevant financial relationships.

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

The glucose-lowering drug class sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to reduce the risk for recurrent gout flares in people with gout and type 2 diabetes, and to lessen excess mortality in those individuals, compared with those who initiated other types of glucose-lowering medications, new data suggest.

Among nearly 6,000 adults with both type 2 diabetes and gout from a U.K. primary care database, initiation of SGLT2 inhibitor treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality.

Moreover, unlike other urate-lowering therapies, there were no apparent transient increases in the risk of gout flares after initiating therapy, Jie Wei, PhD, of Health Management Center, Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in JAMA Network Open.

These results are important because current management of gout is suboptimal. Many patients either don’t receive adequate urate-lowering therapies such as allopurinol or stop taking them, Dr. Wei and colleagues said.

In addition to lowering glucose, SGLT2 inhibitors also reduce the risk for major adverse cardiovascular events and all-cause mortality in people regardless of their diabetes status. Previous studies have also found that SGLT2 inhibitors reduce the risk for developing gout and of gout flares.

Asked to comment, gout specialist John D. FitzGerald, MD, PhD, clinical chief of rheumatology at the University of California, Los Angeles, said in an interview: “I think it’s a well-done paper, with a large dataset. I think it just reinforces the findings from the other papers. Mostly anything that lowers uric acid levels is going to lower recurrent gout attacks, so it all makes sense.”

However, while Dr. FitzGerald thinks the drug class is a good option for people with diabetes or cardiorenal indications for them who also have gout, he doesn’t envision it as first-line for most other patients with gout. “The current treatments are very effective. Allopurinol brings down uric acid levels by 5-7 points. There are patients who fail allopurinol, but those are less than 5%.”

The most common reason patients stop taking allopurinol is the frequent initial gout flare. But that’s preventable, Dr. FitzGerald said, either by titrating up slowly, or by adding colchicine along with it. “By going slowly, you can avoid that flare risk. I think that’s what’s going on with the SGLT2 inhibitor. It’s not a dramatic urate-lowering drug, but it is clinically meaningful. I think that’s what this paper is showing.”

But, he noted, “I think there are so many reasons to start the SGLT2 inhibitors that if somebody also has gout, all the better. And, if somebody is on the margin with diabetes and gout control and can’t go with allopurinol, it would be great to add for both conditions.”

Less gout recurrence, lower mortality

The retrospective study was conducted from Jan. 1, 2013, to March 31, 2022. Among 5,931 patients with both type 2 diabetes and gout, 1,548 (26.1%) initiated an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin), while 4,383 (73.9%) initiated treatment with other active comparators, mostly (92.6%) dipeptidyl peptidase–4 inhibitors.

Gout flares were identified in the charts for a total of 86% of the participants. The weighted incidence rates for the first recurrent flare were 32.4 versus 41.2 per 1,000 person-years in the SGLT2 inhibitor versus comparator groups, with a weighted absolute rate difference of –8.8/1,000 and weighted hazard ratio of 0.81, a significant difference.

All-cause mortality was 18.8 versus 24.9 per 1,000 person-years, respectively, giving an HR of 0.71 at 5-year follow-up.

Dr. FitzGerald, who chaired the American College of Rheumatology’s 2020 gout guidelines, said he anticipates that the SGLT2 inhibitors will be mentioned in the next update to the ACR’s now “living” guidelines, although he was not speaking on the organization’s behalf.

“We talk about losartan in the current [ACR guidelines], about its specific uric acid–lowering effect. Drugs can make uric acid worse or better. For example, thiazides make it higher. I think the SGLT2 [inhibitors] are important, but I don’t think they’re huge. The study is great, and I think the drugs are great, but I don’t think they will change the way gout is managed.”

This work was supported by grants from the National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of National Clinical Research Center for Geriatric Disorders, and from the Natural Science Foundation of Hunan Province. Dr. Wei reported receiving grant funding from Xiangya Hospital Central South University Project Program of National Clinical Research Center for Geriatric Disorders and the Science and Technology Department of Hunan Province, the Natural Science Foundation of Hunan Province, during the conduct of the study. Dr. FitzGerald reported no relevant financial relationships.

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

The glucose-lowering drug class sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to reduce the risk for recurrent gout flares in people with gout and type 2 diabetes, and to lessen excess mortality in those individuals, compared with those who initiated other types of glucose-lowering medications, new data suggest.

Among nearly 6,000 adults with both type 2 diabetes and gout from a U.K. primary care database, initiation of SGLT2 inhibitor treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality.

Moreover, unlike other urate-lowering therapies, there were no apparent transient increases in the risk of gout flares after initiating therapy, Jie Wei, PhD, of Health Management Center, Xiangya Hospital, Central South University, Changsha, China, and colleagues reported in JAMA Network Open.

These results are important because current management of gout is suboptimal. Many patients either don’t receive adequate urate-lowering therapies such as allopurinol or stop taking them, Dr. Wei and colleagues said.

In addition to lowering glucose, SGLT2 inhibitors also reduce the risk for major adverse cardiovascular events and all-cause mortality in people regardless of their diabetes status. Previous studies have also found that SGLT2 inhibitors reduce the risk for developing gout and of gout flares.

Asked to comment, gout specialist John D. FitzGerald, MD, PhD, clinical chief of rheumatology at the University of California, Los Angeles, said in an interview: “I think it’s a well-done paper, with a large dataset. I think it just reinforces the findings from the other papers. Mostly anything that lowers uric acid levels is going to lower recurrent gout attacks, so it all makes sense.”

However, while Dr. FitzGerald thinks the drug class is a good option for people with diabetes or cardiorenal indications for them who also have gout, he doesn’t envision it as first-line for most other patients with gout. “The current treatments are very effective. Allopurinol brings down uric acid levels by 5-7 points. There are patients who fail allopurinol, but those are less than 5%.”

The most common reason patients stop taking allopurinol is the frequent initial gout flare. But that’s preventable, Dr. FitzGerald said, either by titrating up slowly, or by adding colchicine along with it. “By going slowly, you can avoid that flare risk. I think that’s what’s going on with the SGLT2 inhibitor. It’s not a dramatic urate-lowering drug, but it is clinically meaningful. I think that’s what this paper is showing.”

But, he noted, “I think there are so many reasons to start the SGLT2 inhibitors that if somebody also has gout, all the better. And, if somebody is on the margin with diabetes and gout control and can’t go with allopurinol, it would be great to add for both conditions.”

Less gout recurrence, lower mortality

The retrospective study was conducted from Jan. 1, 2013, to March 31, 2022. Among 5,931 patients with both type 2 diabetes and gout, 1,548 (26.1%) initiated an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin), while 4,383 (73.9%) initiated treatment with other active comparators, mostly (92.6%) dipeptidyl peptidase–4 inhibitors.

Gout flares were identified in the charts for a total of 86% of the participants. The weighted incidence rates for the first recurrent flare were 32.4 versus 41.2 per 1,000 person-years in the SGLT2 inhibitor versus comparator groups, with a weighted absolute rate difference of –8.8/1,000 and weighted hazard ratio of 0.81, a significant difference.

All-cause mortality was 18.8 versus 24.9 per 1,000 person-years, respectively, giving an HR of 0.71 at 5-year follow-up.

Dr. FitzGerald, who chaired the American College of Rheumatology’s 2020 gout guidelines, said he anticipates that the SGLT2 inhibitors will be mentioned in the next update to the ACR’s now “living” guidelines, although he was not speaking on the organization’s behalf.

“We talk about losartan in the current [ACR guidelines], about its specific uric acid–lowering effect. Drugs can make uric acid worse or better. For example, thiazides make it higher. I think the SGLT2 [inhibitors] are important, but I don’t think they’re huge. The study is great, and I think the drugs are great, but I don’t think they will change the way gout is managed.”

This work was supported by grants from the National Key Research and Development Plan, the National Natural Science Foundation of China, the Project Program of National Clinical Research Center for Geriatric Disorders, and from the Natural Science Foundation of Hunan Province. Dr. Wei reported receiving grant funding from Xiangya Hospital Central South University Project Program of National Clinical Research Center for Geriatric Disorders and the Science and Technology Department of Hunan Province, the Natural Science Foundation of Hunan Province, during the conduct of the study. Dr. FitzGerald reported no relevant financial relationships.

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

Variability in antimicrobial prescribing among hospital-based physicians is not associated with patient characteristics or clinical outcomes, data suggest. The lowest level of such prescribing within each hospital could be considered a target for antimicrobial stewardship, according to the researchers.

In a multicenter study of 124 physicians responsible for more than 124,000 hospitalized patients, the difference in mean prescribing between the highest and lowest quartiles of prescription volume was 15.8 days of treatment per 100 patient-days.

Baseline patient characteristics were similar across the quartiles, and there were no differences in patient outcomes, including in-hospital deaths, hospital length of stay, intensive care unit transfer, and hospital readmission.

Although the investigators expected variation in prescribing, “what surprised us most was the limited association with any differences in clinical outcomes, particularly when it came to the amount of antimicrobials used,” study author Mark T. McIntyre, PharmD, pharmacotherapy specialist at the Sinai Health System in Toronto, told this news organization.

“Importantly, this is not a study that defines quality of care,” he said. “We looked at natural variation in practice and association with outcomes. So, I don’t want clinicians to think, ‘Well, I’m high, therefore I’m bad,’ or, ‘I’m low, therefore I’m good.’

“This is an early explanatory analysis that asks whether this is an opportunity to optimize prescribing in ways we hadn’t thought of before,” he said. “Now that we don’t have an association with higher or lower prescribing and outcomes, we can look at what else is driving that antimicrobial prescribing and what we can do about it. Comfort level, risk tolerance, and social, cultural, and contextual factors all likely play a role.”

The study was published online in the Canadian Medical Association Journal.
 

Antimicrobial reductions possible

The investigators conducted a retrospective cohort study using the General Medicine Inpatient Initiative database to assess physician-level volume and spectrum of antimicrobial prescribing in adult general medical wards. Four academic hospitals in Toronto were evaluated for the period 2010 to 2019.

The investigators stratified physicians into quartiles by hospital site on the basis of volume of antimicrobial prescribing (specifically, days of therapy per 100 patient-days and antimicrobial-free days) and antibacterial spectrum (modified spectrum score, which assigns a value to each antibacterial agent on the basis of its breadth of coverage).

They also examined potential differences between physician quartiles in patient characteristics, such as age, sex, the Laboratory-Based Acute Physiology Score, discharge diagnosis, and the Charlson Comorbidity Index.

Multilevel modeling allowed the investigators to evaluate the association between clinical outcomes and antimicrobial volume and spectrum.

The primary measure was days of therapy per 100 patient-days.

As noted, the cohort included 124 physicians who were responsible for 124,158 hospital admissions. The median physician-level volume of antimicrobial prescribing was 56.1 days of therapy per 100 patient-days. Patient characteristics were balanced across the quartiles of physician prescribing.

The difference in mean prescribing between physician quartile 4 and quartile 1 was 15.8 days of therapy per 100 patient-days, meaning the median physician in quartile 4 prescribed antimicrobials at a volume that was 30% higher than that of the median physician in quartile 1.

No significant differences were noted for any clinical outcome with regard to quartile of days of therapy, antimicrobial-free days, or modified spectrum score after adjustment for patient-level characteristics.

In addition, no significant differences in the case mix between quartile 4 and quartile 1 were found when the cohort was restricted to patients admitted and discharged by the same most responsible person, nor were differences found in an analysis that was restricted to those without a discharge diagnosis code of palliative care.

In-hospital mortality was higher among patients cared for by prescribers with higher modified spectrum scores (odds ratio, 1.13). “We still can’t fully explain this finding,” Dr. McIntyre acknowledged. “We only saw that in our primary analysis. When we did several sensitivity analyses, that finding didn’t appear.”

The authors concluded, “Ultimately, without discernible benefit in outcomes of patients of physicians who prescribe more frequently, less antimicrobial exposure may be possible, leading to lower risk of antimicrobial resistance.”
 

Decision-making support

Commenting on the study, Lawrence I. Kaplan, MD, section chief of general internal medicine and associate dean for interprofessional education at the Lewis Katz School of Medicine at Temple University in Philadelphia, said, “Trying to get to the lowest quartile would be a goal, and given that physician characteristics are involved, I think there needs to be much better training in clinical management decision-making: how you come about making a decision based on a diagnosis for a particular patient, in or out of the hospital.” Dr. Kaplan was not involved in the research.

“Clinical decision-making tools that can be plugged into the electronic health record can help,” he suggested. “The tools basically ask if a patient meets certain criteria and then might give a prompt that says, for example, ‘These symptoms are not consistent with bacterial sinusitis. The patient should be treated with decongestants, nasal steroids, et cetera, because antibiotics aren’t appropriate.’

“It’s a bit like checkbox medicine, which a lot of physicians bridle at,” he said. “But if it’s really based on evidence, I think that’s an appropriate use of evidence-based medicine.”

Dr. Kaplan said that more research is needed into the best way to get a physician or any provider to step back and say, “Is this the right decision?” or, “I’m doing this but I’m really on shaky ground. What am I missing?’” He noted that the Society for Medical Decision Making publishes research and resources in this area.

“I love the fact that the paper was authored by an interdisciplinary group,” Dr. Kaplan added. “A pharmacist embedded in the team can, for example, help with treatment decision-making and point out potential drug interactions that prescribers might not be aware of.

“We need to stop practicing medicine siloed, which is what we do a lot of ways, both in the hospital and out of the hospital, because it’s the path of least resistance,” Dr. Kaplan added. “But when we can say, ‘Hey, I have a question about this,’ be it to a computer or a colleague, I would argue that we come up with better care.”

No funding was provided for the study. Dr. McIntyre and Dr. Kaplan have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Variability in antimicrobial prescribing among hospital-based physicians is not associated with patient characteristics or clinical outcomes, data suggest. The lowest level of such prescribing within each hospital could be considered a target for antimicrobial stewardship, according to the researchers.

In a multicenter study of 124 physicians responsible for more than 124,000 hospitalized patients, the difference in mean prescribing between the highest and lowest quartiles of prescription volume was 15.8 days of treatment per 100 patient-days.

Baseline patient characteristics were similar across the quartiles, and there were no differences in patient outcomes, including in-hospital deaths, hospital length of stay, intensive care unit transfer, and hospital readmission.

Although the investigators expected variation in prescribing, “what surprised us most was the limited association with any differences in clinical outcomes, particularly when it came to the amount of antimicrobials used,” study author Mark T. McIntyre, PharmD, pharmacotherapy specialist at the Sinai Health System in Toronto, told this news organization.

“Importantly, this is not a study that defines quality of care,” he said. “We looked at natural variation in practice and association with outcomes. So, I don’t want clinicians to think, ‘Well, I’m high, therefore I’m bad,’ or, ‘I’m low, therefore I’m good.’

“This is an early explanatory analysis that asks whether this is an opportunity to optimize prescribing in ways we hadn’t thought of before,” he said. “Now that we don’t have an association with higher or lower prescribing and outcomes, we can look at what else is driving that antimicrobial prescribing and what we can do about it. Comfort level, risk tolerance, and social, cultural, and contextual factors all likely play a role.”

The study was published online in the Canadian Medical Association Journal.
 

Antimicrobial reductions possible

The investigators conducted a retrospective cohort study using the General Medicine Inpatient Initiative database to assess physician-level volume and spectrum of antimicrobial prescribing in adult general medical wards. Four academic hospitals in Toronto were evaluated for the period 2010 to 2019.

The investigators stratified physicians into quartiles by hospital site on the basis of volume of antimicrobial prescribing (specifically, days of therapy per 100 patient-days and antimicrobial-free days) and antibacterial spectrum (modified spectrum score, which assigns a value to each antibacterial agent on the basis of its breadth of coverage).

They also examined potential differences between physician quartiles in patient characteristics, such as age, sex, the Laboratory-Based Acute Physiology Score, discharge diagnosis, and the Charlson Comorbidity Index.

Multilevel modeling allowed the investigators to evaluate the association between clinical outcomes and antimicrobial volume and spectrum.

The primary measure was days of therapy per 100 patient-days.

As noted, the cohort included 124 physicians who were responsible for 124,158 hospital admissions. The median physician-level volume of antimicrobial prescribing was 56.1 days of therapy per 100 patient-days. Patient characteristics were balanced across the quartiles of physician prescribing.

The difference in mean prescribing between physician quartile 4 and quartile 1 was 15.8 days of therapy per 100 patient-days, meaning the median physician in quartile 4 prescribed antimicrobials at a volume that was 30% higher than that of the median physician in quartile 1.

No significant differences were noted for any clinical outcome with regard to quartile of days of therapy, antimicrobial-free days, or modified spectrum score after adjustment for patient-level characteristics.

In addition, no significant differences in the case mix between quartile 4 and quartile 1 were found when the cohort was restricted to patients admitted and discharged by the same most responsible person, nor were differences found in an analysis that was restricted to those without a discharge diagnosis code of palliative care.

In-hospital mortality was higher among patients cared for by prescribers with higher modified spectrum scores (odds ratio, 1.13). “We still can’t fully explain this finding,” Dr. McIntyre acknowledged. “We only saw that in our primary analysis. When we did several sensitivity analyses, that finding didn’t appear.”

The authors concluded, “Ultimately, without discernible benefit in outcomes of patients of physicians who prescribe more frequently, less antimicrobial exposure may be possible, leading to lower risk of antimicrobial resistance.”
 

Decision-making support

Commenting on the study, Lawrence I. Kaplan, MD, section chief of general internal medicine and associate dean for interprofessional education at the Lewis Katz School of Medicine at Temple University in Philadelphia, said, “Trying to get to the lowest quartile would be a goal, and given that physician characteristics are involved, I think there needs to be much better training in clinical management decision-making: how you come about making a decision based on a diagnosis for a particular patient, in or out of the hospital.” Dr. Kaplan was not involved in the research.

“Clinical decision-making tools that can be plugged into the electronic health record can help,” he suggested. “The tools basically ask if a patient meets certain criteria and then might give a prompt that says, for example, ‘These symptoms are not consistent with bacterial sinusitis. The patient should be treated with decongestants, nasal steroids, et cetera, because antibiotics aren’t appropriate.’

“It’s a bit like checkbox medicine, which a lot of physicians bridle at,” he said. “But if it’s really based on evidence, I think that’s an appropriate use of evidence-based medicine.”

Dr. Kaplan said that more research is needed into the best way to get a physician or any provider to step back and say, “Is this the right decision?” or, “I’m doing this but I’m really on shaky ground. What am I missing?’” He noted that the Society for Medical Decision Making publishes research and resources in this area.

“I love the fact that the paper was authored by an interdisciplinary group,” Dr. Kaplan added. “A pharmacist embedded in the team can, for example, help with treatment decision-making and point out potential drug interactions that prescribers might not be aware of.

“We need to stop practicing medicine siloed, which is what we do a lot of ways, both in the hospital and out of the hospital, because it’s the path of least resistance,” Dr. Kaplan added. “But when we can say, ‘Hey, I have a question about this,’ be it to a computer or a colleague, I would argue that we come up with better care.”

No funding was provided for the study. Dr. McIntyre and Dr. Kaplan have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Variability in antimicrobial prescribing among hospital-based physicians is not associated with patient characteristics or clinical outcomes, data suggest. The lowest level of such prescribing within each hospital could be considered a target for antimicrobial stewardship, according to the researchers.

In a multicenter study of 124 physicians responsible for more than 124,000 hospitalized patients, the difference in mean prescribing between the highest and lowest quartiles of prescription volume was 15.8 days of treatment per 100 patient-days.

Baseline patient characteristics were similar across the quartiles, and there were no differences in patient outcomes, including in-hospital deaths, hospital length of stay, intensive care unit transfer, and hospital readmission.

Although the investigators expected variation in prescribing, “what surprised us most was the limited association with any differences in clinical outcomes, particularly when it came to the amount of antimicrobials used,” study author Mark T. McIntyre, PharmD, pharmacotherapy specialist at the Sinai Health System in Toronto, told this news organization.

“Importantly, this is not a study that defines quality of care,” he said. “We looked at natural variation in practice and association with outcomes. So, I don’t want clinicians to think, ‘Well, I’m high, therefore I’m bad,’ or, ‘I’m low, therefore I’m good.’

“This is an early explanatory analysis that asks whether this is an opportunity to optimize prescribing in ways we hadn’t thought of before,” he said. “Now that we don’t have an association with higher or lower prescribing and outcomes, we can look at what else is driving that antimicrobial prescribing and what we can do about it. Comfort level, risk tolerance, and social, cultural, and contextual factors all likely play a role.”

The study was published online in the Canadian Medical Association Journal.
 

Antimicrobial reductions possible

The investigators conducted a retrospective cohort study using the General Medicine Inpatient Initiative database to assess physician-level volume and spectrum of antimicrobial prescribing in adult general medical wards. Four academic hospitals in Toronto were evaluated for the period 2010 to 2019.

The investigators stratified physicians into quartiles by hospital site on the basis of volume of antimicrobial prescribing (specifically, days of therapy per 100 patient-days and antimicrobial-free days) and antibacterial spectrum (modified spectrum score, which assigns a value to each antibacterial agent on the basis of its breadth of coverage).

They also examined potential differences between physician quartiles in patient characteristics, such as age, sex, the Laboratory-Based Acute Physiology Score, discharge diagnosis, and the Charlson Comorbidity Index.

Multilevel modeling allowed the investigators to evaluate the association between clinical outcomes and antimicrobial volume and spectrum.

The primary measure was days of therapy per 100 patient-days.

As noted, the cohort included 124 physicians who were responsible for 124,158 hospital admissions. The median physician-level volume of antimicrobial prescribing was 56.1 days of therapy per 100 patient-days. Patient characteristics were balanced across the quartiles of physician prescribing.

The difference in mean prescribing between physician quartile 4 and quartile 1 was 15.8 days of therapy per 100 patient-days, meaning the median physician in quartile 4 prescribed antimicrobials at a volume that was 30% higher than that of the median physician in quartile 1.

No significant differences were noted for any clinical outcome with regard to quartile of days of therapy, antimicrobial-free days, or modified spectrum score after adjustment for patient-level characteristics.

In addition, no significant differences in the case mix between quartile 4 and quartile 1 were found when the cohort was restricted to patients admitted and discharged by the same most responsible person, nor were differences found in an analysis that was restricted to those without a discharge diagnosis code of palliative care.

In-hospital mortality was higher among patients cared for by prescribers with higher modified spectrum scores (odds ratio, 1.13). “We still can’t fully explain this finding,” Dr. McIntyre acknowledged. “We only saw that in our primary analysis. When we did several sensitivity analyses, that finding didn’t appear.”

The authors concluded, “Ultimately, without discernible benefit in outcomes of patients of physicians who prescribe more frequently, less antimicrobial exposure may be possible, leading to lower risk of antimicrobial resistance.”
 

Decision-making support

Commenting on the study, Lawrence I. Kaplan, MD, section chief of general internal medicine and associate dean for interprofessional education at the Lewis Katz School of Medicine at Temple University in Philadelphia, said, “Trying to get to the lowest quartile would be a goal, and given that physician characteristics are involved, I think there needs to be much better training in clinical management decision-making: how you come about making a decision based on a diagnosis for a particular patient, in or out of the hospital.” Dr. Kaplan was not involved in the research.

“Clinical decision-making tools that can be plugged into the electronic health record can help,” he suggested. “The tools basically ask if a patient meets certain criteria and then might give a prompt that says, for example, ‘These symptoms are not consistent with bacterial sinusitis. The patient should be treated with decongestants, nasal steroids, et cetera, because antibiotics aren’t appropriate.’

“It’s a bit like checkbox medicine, which a lot of physicians bridle at,” he said. “But if it’s really based on evidence, I think that’s an appropriate use of evidence-based medicine.”

Dr. Kaplan said that more research is needed into the best way to get a physician or any provider to step back and say, “Is this the right decision?” or, “I’m doing this but I’m really on shaky ground. What am I missing?’” He noted that the Society for Medical Decision Making publishes research and resources in this area.

“I love the fact that the paper was authored by an interdisciplinary group,” Dr. Kaplan added. “A pharmacist embedded in the team can, for example, help with treatment decision-making and point out potential drug interactions that prescribers might not be aware of.

“We need to stop practicing medicine siloed, which is what we do a lot of ways, both in the hospital and out of the hospital, because it’s the path of least resistance,” Dr. Kaplan added. “But when we can say, ‘Hey, I have a question about this,’ be it to a computer or a colleague, I would argue that we come up with better care.”

No funding was provided for the study. Dr. McIntyre and Dr. Kaplan have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

TOPLINE:

Holding off on palliative chemotherapy until symptoms start appears to improve quality of life (QoL) without affecting survival for asymptomatic patients with advanced cancer.

METHODOLOGY:

• Traditionally, chemotherapy is started immediately when advanced cancer is diagnosed, but delaying chemotherapy until symptoms start could improve QoL.
• To find out, investigators performed a meta-analysis of five studies that explored the timing of palliative chemotherapy. The analysis included three randomized trials in advanced colorectal cancer (CRC), one in advanced ovarian cancer, and a review of patients with stage IV gastric cancer.
• Of the 919 patients, treatment was delayed for 467 patients (50.8%) until symptoms started in the colorectal trials. It was delayed until tumor recurrence in the ovarian cancer trial, and it was delayed until a month or more had passed in the gastric cancer study, regardless of symptoms.
• QoL was assessed largely by the EORTC-QLQ-C30 questionnaire. Median follow-up ranged from 11 to 60 months.

TAKEAWAY:

• The researchers found no significant differences in overall survival between patients for whom chemotherapy was delayed and those for whom chemotherapy began immediately (pooled hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.90-1.22; P = .52).
• Median overall survival was 11.9 to 25.7 months with immediate treatment, vs. 9 to 27.1 months with delayed treatment.
• In the three studies that evaluated QoL, the findings suggested that QoL was largely better among patients whose treatment was delayed. In the CRC studies that assessed QoL, for instance, global health status in the delayed treatment group was higher than that in the immediate treatment group at almost all time points, but not significantly so.
• Rates of grade 3/4 toxicities, evaluated in two studies, did not differ significantly between the groups.

IN PRACTICE:

There is limited evidence on the optimal timing for starting chemotherapy for asymptomatic patients with advanced cancer. In these studies, delaying chemotherapy until symptoms occurred did not result in worse overall survival compared with immediate treatment and may have resulted in better QoL, the researchers concluded. They noted that for asymptomatic patients, delaying the start of systemic therapy should be discussed with the patient.

SOURCE:

The study, led by Simone Augustinus of the University of Amsterdam, was published online Aug. 17 in The Oncologist.

LIMITATIONS:

• Only three types of cancer were included in the analysis, and the findings may not be generalizable to other types of cancer.
• Some of the studies were older and employed out-of-date treatment regimens.
• QoL was only evaluated in three of five studies and could not be evaluated overall in the meta-analysis because of the different time points measured in each trial.

DISCLOSURES:

The study received no external funding. Two investigators have advisory, speaker, and/or research ties to Celgene, Novartis, AstraZeneca, and other companies.

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

TOPLINE:

Holding off on palliative chemotherapy until symptoms start appears to improve quality of life (QoL) without affecting survival for asymptomatic patients with advanced cancer.

METHODOLOGY:

• Traditionally, chemotherapy is started immediately when advanced cancer is diagnosed, but delaying chemotherapy until symptoms start could improve QoL.
• To find out, investigators performed a meta-analysis of five studies that explored the timing of palliative chemotherapy. The analysis included three randomized trials in advanced colorectal cancer (CRC), one in advanced ovarian cancer, and a review of patients with stage IV gastric cancer.
• Of the 919 patients, treatment was delayed for 467 patients (50.8%) until symptoms started in the colorectal trials. It was delayed until tumor recurrence in the ovarian cancer trial, and it was delayed until a month or more had passed in the gastric cancer study, regardless of symptoms.
• QoL was assessed largely by the EORTC-QLQ-C30 questionnaire. Median follow-up ranged from 11 to 60 months.

TAKEAWAY:

• The researchers found no significant differences in overall survival between patients for whom chemotherapy was delayed and those for whom chemotherapy began immediately (pooled hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.90-1.22; P = .52).
• Median overall survival was 11.9 to 25.7 months with immediate treatment, vs. 9 to 27.1 months with delayed treatment.
• In the three studies that evaluated QoL, the findings suggested that QoL was largely better among patients whose treatment was delayed. In the CRC studies that assessed QoL, for instance, global health status in the delayed treatment group was higher than that in the immediate treatment group at almost all time points, but not significantly so.
• Rates of grade 3/4 toxicities, evaluated in two studies, did not differ significantly between the groups.

IN PRACTICE:

There is limited evidence on the optimal timing for starting chemotherapy for asymptomatic patients with advanced cancer. In these studies, delaying chemotherapy until symptoms occurred did not result in worse overall survival compared with immediate treatment and may have resulted in better QoL, the researchers concluded. They noted that for asymptomatic patients, delaying the start of systemic therapy should be discussed with the patient.

SOURCE:

The study, led by Simone Augustinus of the University of Amsterdam, was published online Aug. 17 in The Oncologist.

LIMITATIONS:

• Only three types of cancer were included in the analysis, and the findings may not be generalizable to other types of cancer.
• Some of the studies were older and employed out-of-date treatment regimens.
• QoL was only evaluated in three of five studies and could not be evaluated overall in the meta-analysis because of the different time points measured in each trial.

DISCLOSURES:

The study received no external funding. Two investigators have advisory, speaker, and/or research ties to Celgene, Novartis, AstraZeneca, and other companies.

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

TOPLINE:

Holding off on palliative chemotherapy until symptoms start appears to improve quality of life (QoL) without affecting survival for asymptomatic patients with advanced cancer.

METHODOLOGY:

• Traditionally, chemotherapy is started immediately when advanced cancer is diagnosed, but delaying chemotherapy until symptoms start could improve QoL.
• To find out, investigators performed a meta-analysis of five studies that explored the timing of palliative chemotherapy. The analysis included three randomized trials in advanced colorectal cancer (CRC), one in advanced ovarian cancer, and a review of patients with stage IV gastric cancer.
• Of the 919 patients, treatment was delayed for 467 patients (50.8%) until symptoms started in the colorectal trials. It was delayed until tumor recurrence in the ovarian cancer trial, and it was delayed until a month or more had passed in the gastric cancer study, regardless of symptoms.
• QoL was assessed largely by the EORTC-QLQ-C30 questionnaire. Median follow-up ranged from 11 to 60 months.

TAKEAWAY:

• The researchers found no significant differences in overall survival between patients for whom chemotherapy was delayed and those for whom chemotherapy began immediately (pooled hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.90-1.22; P = .52).
• Median overall survival was 11.9 to 25.7 months with immediate treatment, vs. 9 to 27.1 months with delayed treatment.
• In the three studies that evaluated QoL, the findings suggested that QoL was largely better among patients whose treatment was delayed. In the CRC studies that assessed QoL, for instance, global health status in the delayed treatment group was higher than that in the immediate treatment group at almost all time points, but not significantly so.
• Rates of grade 3/4 toxicities, evaluated in two studies, did not differ significantly between the groups.

IN PRACTICE:

There is limited evidence on the optimal timing for starting chemotherapy for asymptomatic patients with advanced cancer. In these studies, delaying chemotherapy until symptoms occurred did not result in worse overall survival compared with immediate treatment and may have resulted in better QoL, the researchers concluded. They noted that for asymptomatic patients, delaying the start of systemic therapy should be discussed with the patient.

SOURCE:

The study, led by Simone Augustinus of the University of Amsterdam, was published online Aug. 17 in The Oncologist.

LIMITATIONS:

• Only three types of cancer were included in the analysis, and the findings may not be generalizable to other types of cancer.
• Some of the studies were older and employed out-of-date treatment regimens.
• QoL was only evaluated in three of five studies and could not be evaluated overall in the meta-analysis because of the different time points measured in each trial.

DISCLOSURES:

The study received no external funding. Two investigators have advisory, speaker, and/or research ties to Celgene, Novartis, AstraZeneca, and other companies.

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

Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.

“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.

The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.

The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).

For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).

The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.

Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.

While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.

Plasma concentrations of concizumab remained stable over the course of the study.

There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
 

Pause for safety

Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.

The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.

The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
 

Option for hemophilia B important

Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.

A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.

The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.

As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.

Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.

Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.

“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
 

FDA resubmission planned

In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.

“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”

Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.

The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.

Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.

“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.

The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.

The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).

For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).

The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.

Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.

While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.

Plasma concentrations of concizumab remained stable over the course of the study.

There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
 

Pause for safety

Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.

The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.

The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
 

Option for hemophilia B important

Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.

A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.

The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.

As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.

Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.

Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.

“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
 

FDA resubmission planned

In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.

“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”

Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.

The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.

Concizumab (Novo Nordisk), a subcutaneous monoclonal antibody administered once daily, shows significant reductions in annualized bleeding rates in patients with hemophilia A or B with inhibitors, potentially representing the first subcutaneous treatment option for patients with hemophilia B with inhibitors.

“These results demonstrate the potential of concizumab as an efficacious treatment option for people living with hemophilia A or B with inhibitors – the latter a population with severely limited treatment options,” first author Tadashi Matsushita, MD, PhD, of the department of transfusion medicine, Nagoya (Japan) University Hospital, said in an interview regarding the study, published in the New England Journal of Medicine.

The results are from the prospective, multicenter, phase 3 explorer7 trial, involving 133 patients, including 80 with hemophilia A and 53 had hemophilia B, all with inhibitors, a complication of hemophilia therapy in which antibodies ‘inhibit’ clot formation and complicate standard treatment.

The patients, aged 12 or older and all receiving on-demand treatment with bypassing agents, were randomized to receive no prophylaxis for at least 24 weeks (n = 19) or concizumab prophylaxis for at least 32 weeks (n = 33), with the remaining patients nonrandomly assigned to two groups receiving concizumab prophylaxis for at least 24 weeks (n = 81).

For the primary endpoint of the estimated mean annualized bleeding rate, the rate in the no-prophylaxis group was 11.8 episodes versus just 1.7 episodes in the concizumab prophylaxis 32-week group (rate ratio, 0.14; P < .001).

The overall median annualized bleeding rate for patients in all three groups receiving concizumab was zero episodes.

Annualized rates of treated spontaneous, joint, and target joint bleeding episodes were also lower in the concizumab groups versus the no-prophylaxis group, with annualized rate ratios that were similar to the annualized rate ratio for the primary endpoint.

While similar annualized bleeding rates were observed in hemophilia subtypes, the study wasn’t powered to show superiority according the hemophilia A or B, the authors noted.

Plasma concentrations of concizumab remained stable over the course of the study.

There were no significant differences in terms of key secondary endpoints of change in bodily pain and physical functioning scores from the start of treatment to week 24.
 

Pause for safety

Treatment in the study was paused for 6 months from March 2020 to August 2020 following nonfatal thromboembolic events occurring in three patients receiving concizumab, including one in the explorer7 trial and two in the concurrent explorer8 trial, evaluating the drug in patients with hemophilia without inhibitors.

The authors wrote that the three patients had all received concomitant treatment for bleeding and had thrombotic risk factors including obesity and other comorbidities.

The trial resumed following mitigation measures that included revising the dosing regimen to include a 1–mg/kg concizumab loading dose, followed by a subcutaneous once-daily dose of 0.2 mg/kg concizumab. No further thromboembolic events were reported after the pause. Otherwise, adverse events were mainly low grade, with serious events being rare.
 

Option for hemophilia B important

Of the two disease types, hemophilia A is much more common, with an estimated prevalence in the United States of 12 cases per 100,000 males versus hemophilia B, which has a rate of only 3.7 cases per 100,000, according to the Centers for Disease Control and Prevention. Women make up only about 1% of cases with moderate to severe hemophilia.

A standard treatment of hemophilia A or B is prophylaxis with factor replacement therapies allow for improved clotting and reduced bleeding. However, one caveat is the need for intravenous injections, as often as once daily in some cases.

The development of inhibitors in response to replacement therapy may further necessitate the need for treatment with bypassing agents for breakthrough bleeding.

As an alternative, non–factor replacement therapies can promote coagulation, notably the factor VIII mimetic emicizumab, given by subcutaneous injection, and approved by the Food and Drug Administration in 2018 for patients with and without inhibitors.

Emicizumab is recommended by the World Federation on Hemophilia over bypassing agents as prophylaxis for patients with hemophilia A and persistent inhibitors.

Importantly, however, there are no effective prophylactic treatments or easily administered subcutaneous therapies available for hemophilia B with inhibitors, underscoring the potential importance of concizumab, which targets the tissue factor pathway inhibitor protein, linked to coagulation.

“Concizumab has the potential to become the first subcutaneous and first-in-class treatment for hemophilia B with inhibitors,” Dr. Matsushita said. “There are other therapies investigated for hemophilia B with and without inhibitors still in clinical development,” he noted.
 

FDA resubmission planned

In May, Novo Nordisk announced that the FDA had rejected its application for concizumab, requesting more information on the drug’s manufacturing process and its system for the monitoring and dosing of patients to ensure proper drug administration. In a statement, Novo Nordisk reported its plans to move ahead.

“Novo Nordisk has begun addressing the FDA’s feedback and is working closely with the FDA as plans for resubmission continue,” the company reported. “We are confident in the potential of concizumab to address a significant unmet need, particularly for people with hemophilia B with inhibitors who currently have limited prophylactic options and are committed to bringing this important treatment to people with hemophilia with inhibitors living in the U.S.A.”

Meanwhile in Canada, concizumab was approved in March 2023 for the treatment of adolescent and adult patients with hemophilia B with inhibitors and who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

The authors wrote that concizumab continues to be investigated across all hemophilia subtypes, including in the explorer10 study, which is evaluating the drug in children living with hemophilia A or B, with and without inhibitors.

The study was supported by Novo Nordisk. Dr. Matsushita reported speaking for and participating on a scientific advisory board of Novo Nordisk.