Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

BY WILL PASS

Don’t count on a runny nose. Young kids with COVID-19 often have no symptoms at all, even when they have a high viral load, according to a study supported by the Centers for Disease Control and Prevention.

Just 14% of adults who tested positive for SARS-CoV-2 were asymptomatic, versus 37% of children aged 0-4 years, in the paper. This raises concern that parents, childcare providers, and preschools may be underestimating infection in seemingly healthy young kids who have been exposed to COVID, wrote lead author Ruth A. Karron, MD, and colleagues in JAMA Network Open.

Methods

The new research involved 690 individuals from 175 households in Maryland who were monitored closely between November 2020 and October 2021. Every week for 8 months, participants completed online symptom checks and underwent PCR testing using nasal swabs, with symptomatic individuals submitting additional swabs for analysis.

“What was different about our study [compared with previous studies] was the intensity of our collection, and the fact that we collected specimens from asymptomatic people,” said Dr. Karron, a pediatrician and professor in the department of international health, Johns Hopkins University, Baltimore, in an interview. “You shed more virus earlier in the infection than later, and the fact that we were sampling every single week meant that we could pick up those early infections.”

The study also stands out for its focus on young children, Dr. Karron said. Enrollment required all households to have at least one child aged 0-4 years, so 256 out of 690 participants (37.1%) were in this youngest age group. The remainder of the population consisted of 100 older children aged 5-17 years (14.5%) and 334 adults aged 18-74 years (48.4%).

Children 4 and under more than twice as likely to be asymptomatic

By the end of the study, 51 participants had tested positive for SARS-CoV-2, among whom 14 had no symptoms. A closer look showed that children 0-4 years of age who contracted COVID were more than twice as likely to be asymptomatic as infected adults (36.8% vs. 14.3%).

The relationship between symptoms and viral load also differed between adults and young children.

While adults with high viral loads – suggesting greater contagiousness – typically had more severe COVID symptoms, no correlation was found in young kids, meaning children with mild or no symptoms could still be highly contagious.

Dr. Karron said these findings should help parents and other stakeholders make better-informed decisions based on known risks. She recommended testing young, asymptomatic children for COVID if they have been exposed to infected individuals, then acting accordingly based on the results.

“If a family is infected with the virus, and the 2-year-old is asymptomatic, and people are thinking about a visit to elderly grandparents who may be frail, one shouldn’t assume that the 2-year-old is uninfected,” Dr. Karron said. “That child should be tested along with other family members.”

Testing should also be considered for young children exposed to COVID at childcare facilities, she added.

But not every expert consulted for this piece shared these opinions of Dr. Karron.

“I question whether that effort is worth it,” said Dean Blumberg, MD, professor and chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, Calif.

He noted that recent Food and Drug Administration guidance for COVID testing calls for three negative at-home antigen tests to confirm lack of infection.

“That would take 4 days to get those tests done,” he said. “So, it’s a lot of testing. It’s a lot of record keeping, it’s inconvenient, it’s uncomfortable to be tested, and I just question whether it’s worth that effort.”

Applicability of findings to today questioned

Dr. Blumberg also questioned whether the study, which was completed almost a year ago, reflects the current pandemic landscape.

“At the time this study was done, it was predominantly Delta [variant instead of Omicron],” Dr. Blumberg said. “The other issue [with the study] is that … most of the children didn’t have preexisting immunity, so you have to take that into account.”

Preexisting immunity – whether from exposure or vaccination – could lower viral loads, so asymptomatic children today really could be less contagious than they were when the study was done, according to Dr. Blumberg. Kids without symptoms are also less likely to spread the virus, because they aren’t coughing or sneezing, he added.

Sara R. Kim, MD, and Janet A. Englund, MD, of the Seattle Children’s Research Institute, University of Washington, said it’s challenging to know how applicable the findings are, although they sided more with the investigators than Dr. Blumberg.

“Given the higher rate of transmissibility and infectivity of the Omicron variant, it is difficult to make direct associations between findings reported during this study period and those present in the current era during which the Omicron variant is circulating,” they wrote in an accompanying editorial. “However, the higher rates of asymptomatic infection observed among children in this study are likely to be consistent with those observed for current and future viral variants.”

Although the experts offered different interpretations of the findings, they shared similar perspectives on vaccination.

“The most important thing that parents can do is get their kids vaccinated, be vaccinated themselves, and have everybody in the household vaccinated and up to date for all doses that are indicated,” Dr. Blumberg said.

Dr. Karron noted that vaccination will be increasingly important in the coming months.

“Summer is ending; school is starting,” she said. “We’re going to be in large groups indoors again very soon. To keep young children safe, I think it’s really important for them to get vaccinated.”

The study was funded by the CDC. The investigators disclosed no other relationships. Dr. Englund disclosed relationships with AstraZeneca, GlaxoSmithKline, Merck, and others. Dr. Kim and Dr. Blumberg disclosed no relevant conflicts of interest.

BY WILL PASS

Don’t count on a runny nose. Young kids with COVID-19 often have no symptoms at all, even when they have a high viral load, according to a study supported by the Centers for Disease Control and Prevention.

Just 14% of adults who tested positive for SARS-CoV-2 were asymptomatic, versus 37% of children aged 0-4 years, in the paper. This raises concern that parents, childcare providers, and preschools may be underestimating infection in seemingly healthy young kids who have been exposed to COVID, wrote lead author Ruth A. Karron, MD, and colleagues in JAMA Network Open.

Methods

The new research involved 690 individuals from 175 households in Maryland who were monitored closely between November 2020 and October 2021. Every week for 8 months, participants completed online symptom checks and underwent PCR testing using nasal swabs, with symptomatic individuals submitting additional swabs for analysis.

“What was different about our study [compared with previous studies] was the intensity of our collection, and the fact that we collected specimens from asymptomatic people,” said Dr. Karron, a pediatrician and professor in the department of international health, Johns Hopkins University, Baltimore, in an interview. “You shed more virus earlier in the infection than later, and the fact that we were sampling every single week meant that we could pick up those early infections.”

The study also stands out for its focus on young children, Dr. Karron said. Enrollment required all households to have at least one child aged 0-4 years, so 256 out of 690 participants (37.1%) were in this youngest age group. The remainder of the population consisted of 100 older children aged 5-17 years (14.5%) and 334 adults aged 18-74 years (48.4%).

Children 4 and under more than twice as likely to be asymptomatic

By the end of the study, 51 participants had tested positive for SARS-CoV-2, among whom 14 had no symptoms. A closer look showed that children 0-4 years of age who contracted COVID were more than twice as likely to be asymptomatic as infected adults (36.8% vs. 14.3%).

The relationship between symptoms and viral load also differed between adults and young children.

While adults with high viral loads – suggesting greater contagiousness – typically had more severe COVID symptoms, no correlation was found in young kids, meaning children with mild or no symptoms could still be highly contagious.

Dr. Karron said these findings should help parents and other stakeholders make better-informed decisions based on known risks. She recommended testing young, asymptomatic children for COVID if they have been exposed to infected individuals, then acting accordingly based on the results.

“If a family is infected with the virus, and the 2-year-old is asymptomatic, and people are thinking about a visit to elderly grandparents who may be frail, one shouldn’t assume that the 2-year-old is uninfected,” Dr. Karron said. “That child should be tested along with other family members.”

Testing should also be considered for young children exposed to COVID at childcare facilities, she added.

But not every expert consulted for this piece shared these opinions of Dr. Karron.

“I question whether that effort is worth it,” said Dean Blumberg, MD, professor and chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, Calif.

He noted that recent Food and Drug Administration guidance for COVID testing calls for three negative at-home antigen tests to confirm lack of infection.

“That would take 4 days to get those tests done,” he said. “So, it’s a lot of testing. It’s a lot of record keeping, it’s inconvenient, it’s uncomfortable to be tested, and I just question whether it’s worth that effort.”

Applicability of findings to today questioned

Dr. Blumberg also questioned whether the study, which was completed almost a year ago, reflects the current pandemic landscape.

“At the time this study was done, it was predominantly Delta [variant instead of Omicron],” Dr. Blumberg said. “The other issue [with the study] is that … most of the children didn’t have preexisting immunity, so you have to take that into account.”

Preexisting immunity – whether from exposure or vaccination – could lower viral loads, so asymptomatic children today really could be less contagious than they were when the study was done, according to Dr. Blumberg. Kids without symptoms are also less likely to spread the virus, because they aren’t coughing or sneezing, he added.

Sara R. Kim, MD, and Janet A. Englund, MD, of the Seattle Children’s Research Institute, University of Washington, said it’s challenging to know how applicable the findings are, although they sided more with the investigators than Dr. Blumberg.

“Given the higher rate of transmissibility and infectivity of the Omicron variant, it is difficult to make direct associations between findings reported during this study period and those present in the current era during which the Omicron variant is circulating,” they wrote in an accompanying editorial. “However, the higher rates of asymptomatic infection observed among children in this study are likely to be consistent with those observed for current and future viral variants.”

Although the experts offered different interpretations of the findings, they shared similar perspectives on vaccination.

“The most important thing that parents can do is get their kids vaccinated, be vaccinated themselves, and have everybody in the household vaccinated and up to date for all doses that are indicated,” Dr. Blumberg said.

Dr. Karron noted that vaccination will be increasingly important in the coming months.

“Summer is ending; school is starting,” she said. “We’re going to be in large groups indoors again very soon. To keep young children safe, I think it’s really important for them to get vaccinated.”

The study was funded by the CDC. The investigators disclosed no other relationships. Dr. Englund disclosed relationships with AstraZeneca, GlaxoSmithKline, Merck, and others. Dr. Kim and Dr. Blumberg disclosed no relevant conflicts of interest.

BY WILL PASS

Don’t count on a runny nose. Young kids with COVID-19 often have no symptoms at all, even when they have a high viral load, according to a study supported by the Centers for Disease Control and Prevention.

Just 14% of adults who tested positive for SARS-CoV-2 were asymptomatic, versus 37% of children aged 0-4 years, in the paper. This raises concern that parents, childcare providers, and preschools may be underestimating infection in seemingly healthy young kids who have been exposed to COVID, wrote lead author Ruth A. Karron, MD, and colleagues in JAMA Network Open.

Methods

The new research involved 690 individuals from 175 households in Maryland who were monitored closely between November 2020 and October 2021. Every week for 8 months, participants completed online symptom checks and underwent PCR testing using nasal swabs, with symptomatic individuals submitting additional swabs for analysis.

“What was different about our study [compared with previous studies] was the intensity of our collection, and the fact that we collected specimens from asymptomatic people,” said Dr. Karron, a pediatrician and professor in the department of international health, Johns Hopkins University, Baltimore, in an interview. “You shed more virus earlier in the infection than later, and the fact that we were sampling every single week meant that we could pick up those early infections.”

The study also stands out for its focus on young children, Dr. Karron said. Enrollment required all households to have at least one child aged 0-4 years, so 256 out of 690 participants (37.1%) were in this youngest age group. The remainder of the population consisted of 100 older children aged 5-17 years (14.5%) and 334 adults aged 18-74 years (48.4%).

Children 4 and under more than twice as likely to be asymptomatic

By the end of the study, 51 participants had tested positive for SARS-CoV-2, among whom 14 had no symptoms. A closer look showed that children 0-4 years of age who contracted COVID were more than twice as likely to be asymptomatic as infected adults (36.8% vs. 14.3%).

The relationship between symptoms and viral load also differed between adults and young children.

While adults with high viral loads – suggesting greater contagiousness – typically had more severe COVID symptoms, no correlation was found in young kids, meaning children with mild or no symptoms could still be highly contagious.

Dr. Karron said these findings should help parents and other stakeholders make better-informed decisions based on known risks. She recommended testing young, asymptomatic children for COVID if they have been exposed to infected individuals, then acting accordingly based on the results.

“If a family is infected with the virus, and the 2-year-old is asymptomatic, and people are thinking about a visit to elderly grandparents who may be frail, one shouldn’t assume that the 2-year-old is uninfected,” Dr. Karron said. “That child should be tested along with other family members.”

Testing should also be considered for young children exposed to COVID at childcare facilities, she added.

But not every expert consulted for this piece shared these opinions of Dr. Karron.

“I question whether that effort is worth it,” said Dean Blumberg, MD, professor and chief of the division of pediatric infectious diseases at UC Davis Health, Sacramento, Calif.

He noted that recent Food and Drug Administration guidance for COVID testing calls for three negative at-home antigen tests to confirm lack of infection.

“That would take 4 days to get those tests done,” he said. “So, it’s a lot of testing. It’s a lot of record keeping, it’s inconvenient, it’s uncomfortable to be tested, and I just question whether it’s worth that effort.”

Applicability of findings to today questioned

Dr. Blumberg also questioned whether the study, which was completed almost a year ago, reflects the current pandemic landscape.

“At the time this study was done, it was predominantly Delta [variant instead of Omicron],” Dr. Blumberg said. “The other issue [with the study] is that … most of the children didn’t have preexisting immunity, so you have to take that into account.”

Preexisting immunity – whether from exposure or vaccination – could lower viral loads, so asymptomatic children today really could be less contagious than they were when the study was done, according to Dr. Blumberg. Kids without symptoms are also less likely to spread the virus, because they aren’t coughing or sneezing, he added.

Sara R. Kim, MD, and Janet A. Englund, MD, of the Seattle Children’s Research Institute, University of Washington, said it’s challenging to know how applicable the findings are, although they sided more with the investigators than Dr. Blumberg.

“Given the higher rate of transmissibility and infectivity of the Omicron variant, it is difficult to make direct associations between findings reported during this study period and those present in the current era during which the Omicron variant is circulating,” they wrote in an accompanying editorial. “However, the higher rates of asymptomatic infection observed among children in this study are likely to be consistent with those observed for current and future viral variants.”

Although the experts offered different interpretations of the findings, they shared similar perspectives on vaccination.

“The most important thing that parents can do is get their kids vaccinated, be vaccinated themselves, and have everybody in the household vaccinated and up to date for all doses that are indicated,” Dr. Blumberg said.

Dr. Karron noted that vaccination will be increasingly important in the coming months.

“Summer is ending; school is starting,” she said. “We’re going to be in large groups indoors again very soon. To keep young children safe, I think it’s really important for them to get vaccinated.”

The study was funded by the CDC. The investigators disclosed no other relationships. Dr. Englund disclosed relationships with AstraZeneca, GlaxoSmithKline, Merck, and others. Dr. Kim and Dr. Blumberg disclosed no relevant conflicts of interest.

PORTLAND, ORE. – During her dermatology residency training at the University of California, Irvine, Medical Center, Jenny Murase, MD, remembers hearing a colleague say that her most angry patients of the day were adult women with recalcitrant acne who present to the clinic with questions like, “My skin has been clear my whole life! What’s going on?”

Such expressions of frustration may partly stem from the fact that high acne treatment failure rates occur in women over the age of 25. In fact, 82% fail multiple courses of systemic antibiotics and 32% relapse after using isotretinoin, Dr. Murase, director of medical dermatology consultative services and patch testing at the Palo Alto Foundation Medical Group, said at the annual meeting of the Pacific Dermatologic Association.

In her clinical experience, hormonal therapy is a safe long-term option for recalcitrant acne in postmenarcheal females over the age of 14. “Although oral antibiotics are going to be superior to hormonal therapy in the first month or two, when you get to about six months, they have equivalent efficacy,” she said.

Obencem/Thinkstock

Telltale signs of acne associated with androgen excess include the development of nodulocystic papules along the jawline and small comedones over the forehead. Female patients with acne may request that labs be ordered to check their hormone levels, but that often is not necessary, according to Dr. Murase, who is also associate clinical professor of dermatology at the University of California, San Francisco. “There aren’t strict guidelines to indicate when you should perform hormonal testing, but warning signs that warrant further evaluation include hirsutism, androgenetic alopecia, virilization, infertility, oligomenorrhea or amenorrhea, and sudden onset of severe acne. The most common situation that warrants hormonal testing is polycystic ovary syndrome (PCOS).”

When there is a strong suspicion for hyperandrogenism, essential labs include free and total testosterone. Free testosterone is commonly elevated in patients with PCOS and total testosterone levels over 200 ng/dL is suggestive of an ovarian tumor. Other essential labs include 17-hyydroxyprogesterone (values greater than 200 ng/dL indicate congenital adrenal hyperplasia), and dehydroepiandrosterone sulfate (DHEA-S); levels over 8,000 mcg/dL indicate an adrenal tumor, while levels in the 4,000-8,000 mcg/dL range indicate congenital adrenal hyperplasia.

Helpful lab tests to consider include the ratio of luteinizing hormone to follicle-stimulating hormone; a 3:1 ratio or greater is suggestive for PCOS. “Ordering a prolactin level can also help, especially if patients are describing issues with headaches, which could indicate a pituitary tumor,” Dr. Murase added. Measuring sex hormone binding globulin (SHBG) levels can also be helpful. “If a patient has been on oral contraceptives for a long time, it increases their SHBG,” which, in older women, she said, “is inversely related to the development of type 2 diabetes.”

All labs for hyperandrogenism should be performed early in the morning on day 3 of the patient’s menstrual cycle. “If patients are on some kind of hormonal therapy, they need to be off of it for at least 6 weeks in order for you get a relevant test,” she said. Other relevant labs to consider include fasting glucose and lipids, cortisol, and thyroid-stimulating hormone.
 

Oral contraceptives

Estrogen contained in oral contraceptives (OCs) provides the most benefit to acne patients. “It reduces sebum production, decreases free testosterone and DHEA-S by stimulating SHBG synthesis in the liver, inhibits 5-alpha-reductase, which decreases peripheral testosterone conversion, and it decreases the production of ovarian and adrenal androgens,” Dr. Murase explained. “On average, you can get about 40%-70% reduction of lesion count, which is pretty good.”

Progestins with low androgenetic activity are the most helpful for acne, including norgestimate, desogestrel, and drospirenone. FDA-approved OC options include Ortho Tri-Cyclen, EstroStep, Yaz, and Beyaz. None has data showing superior efficacy.

No Pap smear or pelvic exam is required when prescribing OCs, but the risk of clotting should be discussed with patients. According to Dr. Murase, the risk of deep vein thrombosis (DVT) at baseline is about 1 per 10,000 woman-years, while the risk of DVT after 1 year on an OC is 3.4 per 10,000 years.

“This is a very mild increased risk that we’re talking about, but it is relevant in smokers, in those with hypertension, and in those who are diabetic,” she said. As for the risk of cancer associated with the use of OCs, a large collaborative study found a relative risk of 1.24 for developing breast cancer (not dose or duration related), but a risk reduction for endometrial, colorectal, and ovarian cancer.

The most common side effects associated with OCs are unscheduled bleeding, nausea, breast tenderness, and possible weight gain. Concomitant antibiotics can be used, with the exception of CYP3A4 inducers, such as rifampin. “That’s the main antibiotic we have to worry about that could affect the efficacy of the birth control pill,” she said. “It accounts for about three-quarters of pregnancies on antibiotics.”

Tetracyclines do not appear to increase the rate of birth defects with incidental first-trimester exposure, and data are reassuring but “tetracycline should be stopped within the first trimester as soon as the patient discovers she is pregnant,” Dr. Murase said.

Contraindications for OCs include being pregnant or breastfeeding; history of stroke, venous thromboembolism, or MI; history of smoking and being over age 35; uncontrolled hypertension; migraines with focal symptoms/aura; current or past breast cancer; hypercholesterolemia; diabetes with end-organ damage or having diabetes over age 35; liver issues such as a tumor, viral hepatitis, or cirrhosis; and a history of major surgery with prolonged immobilization.
 

Spironolactone

Another treatment option is spironolactone, a potassium-sparing diuretic that blocks aldosterone at a dose of 25 mg/day. At doses of 50-100 mg/day, it blocks androgen. “It can be used in combination with an oral contraceptive, with the rates of efficacy reported to range between 33% and 85%,” Dr. Murase said.

Spironolactone can also reduce hirsutism, improve androgenetic alopecia, and lower blood pressure by about 5 mm Hg systolic and 2.5 mm Hg diastolic. Dr. Murase usually checks blood pressure in patients, and “only if they’re really low I’ll talk about the potential for postural hypotension and the fact that you can get a little bit dizzy when going from a position of lying down to standing up.” Potassium levels should be checked at baseline and 4 weeks in patients older than age 46, in those with cardiac and/or renal disease, or in those on concomitant drospirenone or a third-generation progestin.

Spironolactone is classified as a pregnancy category D drug that could compromise the genital development of a male fetus. “So the onus is on us as providers to have the conversation with our patient,” she said. “If you’re putting a patient on spironolactone and they are of child-bearing age, you need to make sure that you’ve had the conversation with them about the fact that they should not get pregnant while on the medicine.”

Spironolactone also has a boxed warning citing the development of benign tumors in animal studies. That warning is based on studies in rats at doses of 10-150 mg/kg per day, “which is an extremely high dose and would never be given in humans,” said Dr. Murase, who has coauthored CME content regarding the safety of dermatologic medications in pregnancy and lactation.

In humans, there has been no evidence of the development of benign tumors associated with spironolactone therapy, and “there has been a decreased risk of prostate cancer and no association with its use and the development of breast, ovarian, bladder, kidney, gastric, or esophageal cancer,” she said.

Dr. Murase noted that during pregnancy, first-line oral antibiotics include amoxicillin for acne rosacea and cefadroxil for acne vulgaris. Macrolides are a second-line choice because of an increase in atrial/ventricular septal defects and pyloric stenosis that have been reported with first-trimester exposure.

“Erythromycin is the preferred choice over azithromycin and clarithromycin because it has the most data, [but] erythromycin estolate has been associated with increased AST levels in the second trimester,” she said. “It occurs in about 10% of cases and is reversible. Erythromycin base and erythromycin ethylsuccinate do not have this risk, and those are preferable.”

Dr. Murase disclosed that she has been a paid speaker of unbranded medical content for Regeneron and UCB. She is also a member of the advisory board for Leo Pharma, Eli Lilly, UCB, and Genzyme/Sanofi.

PORTLAND, ORE. – During her dermatology residency training at the University of California, Irvine, Medical Center, Jenny Murase, MD, remembers hearing a colleague say that her most angry patients of the day were adult women with recalcitrant acne who present to the clinic with questions like, “My skin has been clear my whole life! What’s going on?”

Such expressions of frustration may partly stem from the fact that high acne treatment failure rates occur in women over the age of 25. In fact, 82% fail multiple courses of systemic antibiotics and 32% relapse after using isotretinoin, Dr. Murase, director of medical dermatology consultative services and patch testing at the Palo Alto Foundation Medical Group, said at the annual meeting of the Pacific Dermatologic Association.

In her clinical experience, hormonal therapy is a safe long-term option for recalcitrant acne in postmenarcheal females over the age of 14. “Although oral antibiotics are going to be superior to hormonal therapy in the first month or two, when you get to about six months, they have equivalent efficacy,” she said.

Obencem/Thinkstock

Telltale signs of acne associated with androgen excess include the development of nodulocystic papules along the jawline and small comedones over the forehead. Female patients with acne may request that labs be ordered to check their hormone levels, but that often is not necessary, according to Dr. Murase, who is also associate clinical professor of dermatology at the University of California, San Francisco. “There aren’t strict guidelines to indicate when you should perform hormonal testing, but warning signs that warrant further evaluation include hirsutism, androgenetic alopecia, virilization, infertility, oligomenorrhea or amenorrhea, and sudden onset of severe acne. The most common situation that warrants hormonal testing is polycystic ovary syndrome (PCOS).”

When there is a strong suspicion for hyperandrogenism, essential labs include free and total testosterone. Free testosterone is commonly elevated in patients with PCOS and total testosterone levels over 200 ng/dL is suggestive of an ovarian tumor. Other essential labs include 17-hyydroxyprogesterone (values greater than 200 ng/dL indicate congenital adrenal hyperplasia), and dehydroepiandrosterone sulfate (DHEA-S); levels over 8,000 mcg/dL indicate an adrenal tumor, while levels in the 4,000-8,000 mcg/dL range indicate congenital adrenal hyperplasia.

Helpful lab tests to consider include the ratio of luteinizing hormone to follicle-stimulating hormone; a 3:1 ratio or greater is suggestive for PCOS. “Ordering a prolactin level can also help, especially if patients are describing issues with headaches, which could indicate a pituitary tumor,” Dr. Murase added. Measuring sex hormone binding globulin (SHBG) levels can also be helpful. “If a patient has been on oral contraceptives for a long time, it increases their SHBG,” which, in older women, she said, “is inversely related to the development of type 2 diabetes.”

All labs for hyperandrogenism should be performed early in the morning on day 3 of the patient’s menstrual cycle. “If patients are on some kind of hormonal therapy, they need to be off of it for at least 6 weeks in order for you get a relevant test,” she said. Other relevant labs to consider include fasting glucose and lipids, cortisol, and thyroid-stimulating hormone.
 

Oral contraceptives

Estrogen contained in oral contraceptives (OCs) provides the most benefit to acne patients. “It reduces sebum production, decreases free testosterone and DHEA-S by stimulating SHBG synthesis in the liver, inhibits 5-alpha-reductase, which decreases peripheral testosterone conversion, and it decreases the production of ovarian and adrenal androgens,” Dr. Murase explained. “On average, you can get about 40%-70% reduction of lesion count, which is pretty good.”

Progestins with low androgenetic activity are the most helpful for acne, including norgestimate, desogestrel, and drospirenone. FDA-approved OC options include Ortho Tri-Cyclen, EstroStep, Yaz, and Beyaz. None has data showing superior efficacy.

No Pap smear or pelvic exam is required when prescribing OCs, but the risk of clotting should be discussed with patients. According to Dr. Murase, the risk of deep vein thrombosis (DVT) at baseline is about 1 per 10,000 woman-years, while the risk of DVT after 1 year on an OC is 3.4 per 10,000 years.

“This is a very mild increased risk that we’re talking about, but it is relevant in smokers, in those with hypertension, and in those who are diabetic,” she said. As for the risk of cancer associated with the use of OCs, a large collaborative study found a relative risk of 1.24 for developing breast cancer (not dose or duration related), but a risk reduction for endometrial, colorectal, and ovarian cancer.

The most common side effects associated with OCs are unscheduled bleeding, nausea, breast tenderness, and possible weight gain. Concomitant antibiotics can be used, with the exception of CYP3A4 inducers, such as rifampin. “That’s the main antibiotic we have to worry about that could affect the efficacy of the birth control pill,” she said. “It accounts for about three-quarters of pregnancies on antibiotics.”

Tetracyclines do not appear to increase the rate of birth defects with incidental first-trimester exposure, and data are reassuring but “tetracycline should be stopped within the first trimester as soon as the patient discovers she is pregnant,” Dr. Murase said.

Contraindications for OCs include being pregnant or breastfeeding; history of stroke, venous thromboembolism, or MI; history of smoking and being over age 35; uncontrolled hypertension; migraines with focal symptoms/aura; current or past breast cancer; hypercholesterolemia; diabetes with end-organ damage or having diabetes over age 35; liver issues such as a tumor, viral hepatitis, or cirrhosis; and a history of major surgery with prolonged immobilization.
 

Spironolactone

Another treatment option is spironolactone, a potassium-sparing diuretic that blocks aldosterone at a dose of 25 mg/day. At doses of 50-100 mg/day, it blocks androgen. “It can be used in combination with an oral contraceptive, with the rates of efficacy reported to range between 33% and 85%,” Dr. Murase said.

Spironolactone can also reduce hirsutism, improve androgenetic alopecia, and lower blood pressure by about 5 mm Hg systolic and 2.5 mm Hg diastolic. Dr. Murase usually checks blood pressure in patients, and “only if they’re really low I’ll talk about the potential for postural hypotension and the fact that you can get a little bit dizzy when going from a position of lying down to standing up.” Potassium levels should be checked at baseline and 4 weeks in patients older than age 46, in those with cardiac and/or renal disease, or in those on concomitant drospirenone or a third-generation progestin.

Spironolactone is classified as a pregnancy category D drug that could compromise the genital development of a male fetus. “So the onus is on us as providers to have the conversation with our patient,” she said. “If you’re putting a patient on spironolactone and they are of child-bearing age, you need to make sure that you’ve had the conversation with them about the fact that they should not get pregnant while on the medicine.”

Spironolactone also has a boxed warning citing the development of benign tumors in animal studies. That warning is based on studies in rats at doses of 10-150 mg/kg per day, “which is an extremely high dose and would never be given in humans,” said Dr. Murase, who has coauthored CME content regarding the safety of dermatologic medications in pregnancy and lactation.

In humans, there has been no evidence of the development of benign tumors associated with spironolactone therapy, and “there has been a decreased risk of prostate cancer and no association with its use and the development of breast, ovarian, bladder, kidney, gastric, or esophageal cancer,” she said.

Dr. Murase noted that during pregnancy, first-line oral antibiotics include amoxicillin for acne rosacea and cefadroxil for acne vulgaris. Macrolides are a second-line choice because of an increase in atrial/ventricular septal defects and pyloric stenosis that have been reported with first-trimester exposure.

“Erythromycin is the preferred choice over azithromycin and clarithromycin because it has the most data, [but] erythromycin estolate has been associated with increased AST levels in the second trimester,” she said. “It occurs in about 10% of cases and is reversible. Erythromycin base and erythromycin ethylsuccinate do not have this risk, and those are preferable.”

Dr. Murase disclosed that she has been a paid speaker of unbranded medical content for Regeneron and UCB. She is also a member of the advisory board for Leo Pharma, Eli Lilly, UCB, and Genzyme/Sanofi.

PORTLAND, ORE. – During her dermatology residency training at the University of California, Irvine, Medical Center, Jenny Murase, MD, remembers hearing a colleague say that her most angry patients of the day were adult women with recalcitrant acne who present to the clinic with questions like, “My skin has been clear my whole life! What’s going on?”

Such expressions of frustration may partly stem from the fact that high acne treatment failure rates occur in women over the age of 25. In fact, 82% fail multiple courses of systemic antibiotics and 32% relapse after using isotretinoin, Dr. Murase, director of medical dermatology consultative services and patch testing at the Palo Alto Foundation Medical Group, said at the annual meeting of the Pacific Dermatologic Association.

In her clinical experience, hormonal therapy is a safe long-term option for recalcitrant acne in postmenarcheal females over the age of 14. “Although oral antibiotics are going to be superior to hormonal therapy in the first month or two, when you get to about six months, they have equivalent efficacy,” she said.

Obencem/Thinkstock

Telltale signs of acne associated with androgen excess include the development of nodulocystic papules along the jawline and small comedones over the forehead. Female patients with acne may request that labs be ordered to check their hormone levels, but that often is not necessary, according to Dr. Murase, who is also associate clinical professor of dermatology at the University of California, San Francisco. “There aren’t strict guidelines to indicate when you should perform hormonal testing, but warning signs that warrant further evaluation include hirsutism, androgenetic alopecia, virilization, infertility, oligomenorrhea or amenorrhea, and sudden onset of severe acne. The most common situation that warrants hormonal testing is polycystic ovary syndrome (PCOS).”

When there is a strong suspicion for hyperandrogenism, essential labs include free and total testosterone. Free testosterone is commonly elevated in patients with PCOS and total testosterone levels over 200 ng/dL is suggestive of an ovarian tumor. Other essential labs include 17-hyydroxyprogesterone (values greater than 200 ng/dL indicate congenital adrenal hyperplasia), and dehydroepiandrosterone sulfate (DHEA-S); levels over 8,000 mcg/dL indicate an adrenal tumor, while levels in the 4,000-8,000 mcg/dL range indicate congenital adrenal hyperplasia.

Helpful lab tests to consider include the ratio of luteinizing hormone to follicle-stimulating hormone; a 3:1 ratio or greater is suggestive for PCOS. “Ordering a prolactin level can also help, especially if patients are describing issues with headaches, which could indicate a pituitary tumor,” Dr. Murase added. Measuring sex hormone binding globulin (SHBG) levels can also be helpful. “If a patient has been on oral contraceptives for a long time, it increases their SHBG,” which, in older women, she said, “is inversely related to the development of type 2 diabetes.”

All labs for hyperandrogenism should be performed early in the morning on day 3 of the patient’s menstrual cycle. “If patients are on some kind of hormonal therapy, they need to be off of it for at least 6 weeks in order for you get a relevant test,” she said. Other relevant labs to consider include fasting glucose and lipids, cortisol, and thyroid-stimulating hormone.
 

Oral contraceptives

Estrogen contained in oral contraceptives (OCs) provides the most benefit to acne patients. “It reduces sebum production, decreases free testosterone and DHEA-S by stimulating SHBG synthesis in the liver, inhibits 5-alpha-reductase, which decreases peripheral testosterone conversion, and it decreases the production of ovarian and adrenal androgens,” Dr. Murase explained. “On average, you can get about 40%-70% reduction of lesion count, which is pretty good.”

Progestins with low androgenetic activity are the most helpful for acne, including norgestimate, desogestrel, and drospirenone. FDA-approved OC options include Ortho Tri-Cyclen, EstroStep, Yaz, and Beyaz. None has data showing superior efficacy.

No Pap smear or pelvic exam is required when prescribing OCs, but the risk of clotting should be discussed with patients. According to Dr. Murase, the risk of deep vein thrombosis (DVT) at baseline is about 1 per 10,000 woman-years, while the risk of DVT after 1 year on an OC is 3.4 per 10,000 years.

“This is a very mild increased risk that we’re talking about, but it is relevant in smokers, in those with hypertension, and in those who are diabetic,” she said. As for the risk of cancer associated with the use of OCs, a large collaborative study found a relative risk of 1.24 for developing breast cancer (not dose or duration related), but a risk reduction for endometrial, colorectal, and ovarian cancer.

The most common side effects associated with OCs are unscheduled bleeding, nausea, breast tenderness, and possible weight gain. Concomitant antibiotics can be used, with the exception of CYP3A4 inducers, such as rifampin. “That’s the main antibiotic we have to worry about that could affect the efficacy of the birth control pill,” she said. “It accounts for about three-quarters of pregnancies on antibiotics.”

Tetracyclines do not appear to increase the rate of birth defects with incidental first-trimester exposure, and data are reassuring but “tetracycline should be stopped within the first trimester as soon as the patient discovers she is pregnant,” Dr. Murase said.

Contraindications for OCs include being pregnant or breastfeeding; history of stroke, venous thromboembolism, or MI; history of smoking and being over age 35; uncontrolled hypertension; migraines with focal symptoms/aura; current or past breast cancer; hypercholesterolemia; diabetes with end-organ damage or having diabetes over age 35; liver issues such as a tumor, viral hepatitis, or cirrhosis; and a history of major surgery with prolonged immobilization.
 

Spironolactone

Another treatment option is spironolactone, a potassium-sparing diuretic that blocks aldosterone at a dose of 25 mg/day. At doses of 50-100 mg/day, it blocks androgen. “It can be used in combination with an oral contraceptive, with the rates of efficacy reported to range between 33% and 85%,” Dr. Murase said.

Spironolactone can also reduce hirsutism, improve androgenetic alopecia, and lower blood pressure by about 5 mm Hg systolic and 2.5 mm Hg diastolic. Dr. Murase usually checks blood pressure in patients, and “only if they’re really low I’ll talk about the potential for postural hypotension and the fact that you can get a little bit dizzy when going from a position of lying down to standing up.” Potassium levels should be checked at baseline and 4 weeks in patients older than age 46, in those with cardiac and/or renal disease, or in those on concomitant drospirenone or a third-generation progestin.

Spironolactone is classified as a pregnancy category D drug that could compromise the genital development of a male fetus. “So the onus is on us as providers to have the conversation with our patient,” she said. “If you’re putting a patient on spironolactone and they are of child-bearing age, you need to make sure that you’ve had the conversation with them about the fact that they should not get pregnant while on the medicine.”

Spironolactone also has a boxed warning citing the development of benign tumors in animal studies. That warning is based on studies in rats at doses of 10-150 mg/kg per day, “which is an extremely high dose and would never be given in humans,” said Dr. Murase, who has coauthored CME content regarding the safety of dermatologic medications in pregnancy and lactation.

In humans, there has been no evidence of the development of benign tumors associated with spironolactone therapy, and “there has been a decreased risk of prostate cancer and no association with its use and the development of breast, ovarian, bladder, kidney, gastric, or esophageal cancer,” she said.

Dr. Murase noted that during pregnancy, first-line oral antibiotics include amoxicillin for acne rosacea and cefadroxil for acne vulgaris. Macrolides are a second-line choice because of an increase in atrial/ventricular septal defects and pyloric stenosis that have been reported with first-trimester exposure.

“Erythromycin is the preferred choice over azithromycin and clarithromycin because it has the most data, [but] erythromycin estolate has been associated with increased AST levels in the second trimester,” she said. “It occurs in about 10% of cases and is reversible. Erythromycin base and erythromycin ethylsuccinate do not have this risk, and those are preferable.”

Dr. Murase disclosed that she has been a paid speaker of unbranded medical content for Regeneron and UCB. She is also a member of the advisory board for Leo Pharma, Eli Lilly, UCB, and Genzyme/Sanofi.

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

New research links the use of glucocorticoids with changes in white matter microstructure – which may explain the development of anxiety, depression, and other neuropsychiatric side effects related to these drugs, investigators say.

Results from a cross-sectional study showed that use of both systemic and inhaled glucocorticoids was associated with widespread reductions in fractional anisotropy (FA) and increases in mean diffusivity.

Glucocorticoids have “a whole catalogue” of adverse events, and effects on brain structure “adds to the list,” co-investigator Onno C. Meijer, PhD, professor of molecular neuroendocrinology of corticosteroids, department of medicine, Leiden University Medical Center, the Netherlands, told this news organization.

Serious side effects

Glucocorticoids, a class of synthetic steroids with immunosuppressive properties, are prescribed for a wide range of conditions, including rheumatoid arthritis and asthma.

However, they are also associated with potentially serious metabolic, cardiovascular, and musculoskeletal side effects as well as neuropsychiatric side effects such as depression, mania, and cognitive impairment.

About 1 in 3 patients exposed to “quite a lot of these drugs” will experience neuropsychiatric symptoms, Dr. Meijer said.

Most previous studies that investigated effects from high levels of glucocorticoids on brain structure have been small and involved selected populations, such as those with Cushing disease.

The new study included participants from the UK Biobank, a large population-based cohort. Participants had undergone imaging and did not have a history of psychiatric disease – although they could have conditions associated with glucocorticoid use, including anxiety, depression, mania, or delirium.

The analysis included 222 patients using oral or parenteral glucocorticoids at the time of imaging (systemic group), 557 using inhaled glucocorticoids, and 24,106 not using glucocorticoids (the control group).

Inhaled steroids target the lungs, whereas a steroid in pill form “travels in the blood and reaches each and every organ and cell in the body and typically requires higher doses,” Dr. Meijer noted.

The groups were similar with respect to sex, education, and smoking status. However, the systemic glucocorticoid group was slightly older (mean age, 66.1 years vs. 63.3 years for inhaled glucocorticoid users and 63.5 years for the control group).

In addition to age, researchers adjusted for sex, education level, head position in the scanner, head size, assessment center, and year of imaging.
 

Imaging analyses

Imaging analyses showed systemic glucocorticoid use was associated with reduced global FA (adjusted mean difference, -3.7e-3; 95% confidence interval, -6.4e-3 to 1.0e-3), and reductions in regional FA in the body and genu of the corpus callosum versus the control group.

Inhaled glucocorticoid use was associated with reduced global FA (AMD, -2.3e-3; 95% CI, -4.0e-3 to -5.7e-4), and lower FA in the splenium of the corpus callosum and the cingulum of the hippocampus.

Global mean diffusivity was higher in systemic glucocorticoid users (AMD, 7.2e-6; 95% CI, 3.2e-6 to 1.1e-5) and inhaled glucocorticoid users (AMD, 2.7e-6; 95% CI, 1.7e-7 to 5.2e-6), compared with the control group.

The effects of glucocorticoids on white matter were “pervasive,” and the “most important finding” of the study, Dr. Meijer said. “We were impressed by the fact white matter is so sensitive to these drugs.”

He noted that it is likely that functional connectivity between brain regions is affected by use of glucocorticoids. “You could say communication between brain regions is probably somewhat impaired or challenged,” he said.

Subgroup analyses among participants using glucocorticoids chronically, defined as reported at two consecutive visits, suggested a potential dose-dependent or duration-dependent effect of glucocorticoids on white matter microstructure.

Systemic glucocorticoid use was also associated with an increase in total and grey matter volume of the caudate nucleus.

In addition, there was a significant association between inhaled glucocorticoid use and decreased grey matter volume of the amygdala, which Dr. Meijer said was surprising because studies have shown that glucocorticoids “can drive amygdala big time.”
 

Move away from ‘one dose for all’?

Another surprise was that the results showed no hippocampal volume differences with steroid use, Dr. Meijer noted.

The modest association between glucocorticoid use and brain volumes could indicate that white matter integrity is more sensitive to glucocorticoids than is grey matter volume, “at least at the structural level,” he said.

He added that longer use or higher doses may be necessary to also induce volumetric changes.

Participants also completed a questionnaire to assess mood over the previous 2 weeks. Systemic glucocorticoid users had more depressive symptoms, disinterest, tenseness/restlessness, and tiredness/lethargy, compared with the control group. Inhaled glucocorticoid users only reported more tiredness/lethargy.

The investigators note that mood-related effects could be linked to the condition for which glucocorticoids were prescribed: for example, rheumatoid arthritis or chronic obstructive pulmonary disease.

In terms of cognition, systemic glucocorticoid users performed significantly worse on the symbol digit substitution task, compared with participants in the control group.

In light of these findings, pharmaceutical companies that make inhaled corticosteroids “should perhaps find out if glucocorticoids can be dosed by kilogram body weight rather than simply one dose fits all,” which is currently the case, Dr. Meijer said.
 

Impressive, but several limitations

Commenting on the findings, E. Sherwood Brown, MD, PhD, Distinguished Chair in Psychiatric Research and professor and vice chair for clinical research, department of psychiatry, The University of Texas Southwestern Medical Center, Dallas, called the study sample size “impressive.”

In addition, the study is the first to look at systemic as well as inhaled corticosteroids, said Dr. Brown, who was not involved with the research. He noted that previously, there had been only case reports of psychiatric symptoms with inhaled corticosteroids.

That results are in the same direction but greater with systemic, compared with inhaled corticosteroids, is “particularly interesting” because this might suggest dose-dependent effects, Dr. Brown said.

He noted that cognitive differences were also only observed with systemic corticosteroids.

Some study observations, such as smaller amygdala volume with inhaled but not systemic corticosteroids, “are harder to understand,” said Dr. Brown.

However, he pointed out some study limitations. For example, data were apparently unavailable for verbal and declarative memory test data, despite corticosteroids probably affecting the hippocampus and causing memory changes.

Other drawbacks were that the dose and duration of corticosteroid use, as well as the medical histories of study participants, were not available, Dr. Brown said.

No study funding was reported. Dr. Meijer has received research grants and honorariums from Corcept Therapeutics and a speakers’ fee from Ipsen. Dr. Brown is on an advisory board for Sage Pharmaceuticals, which is developing neurosteroids (not corticosteroids) for mood disorders. He is also on a Medscape advisory board related to bipolar disorder.

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

In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.

The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.

RogerAshford/Thinkstock

“Our results show that, in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin,” lead investigator Colin Baigent, MD, said.

After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.

Dr. Baigent, who is director of the Population Health Research Unit at the University of Oxford (England), presented the data on Aug. 29 at the European Society of Cardiology 2022 Congress.

It was also simultaneously published online in The Lancet. 

Dr. Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).

The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Dr. Baigent said.  

In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.

“Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo,” Dr. Baigent reported.

Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% confidence interval, 1.01-1.06).

In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1,000 patient-years in those taking a statin, compared with 155 per 1,000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1,000 patients in the first year of statin therapy. 

“The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment,” Dr. Baigent added. 

After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1,000 patient-years.

“Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise,” Dr. Baigent said. “After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all.”

“To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year,” he added.

“Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin.”

The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. “There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year,” Dr. Baigent said.

But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
 

Better patient information needed

Dr. Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.

“We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake,” he commented.

“At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable,” he added. “This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff.”

Dr. Baigent also highlighted the large benefits of statins, compared with the small risk for muscle symptoms.

“While statins may cause 11 patients per 1,000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1,000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1,000 patients each year,” he noted.  

The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1,000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).

In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04-1.13) and 1.02 (95% CI, 1.00-1.05), respectively.
 

‘Reassuring information’

Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.

She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. “So, this was a Herculean task to harmonize this very complicated dataset.”

Dr. Bohula concluded: “I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me, and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins.”

Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Dr. Baigent replied that they also examined those data, which had been accounted for in the analysis.

“That’s really good news,” Dr. Steg commented. “This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health.”

The meta-analysis was funded by the British Heart Foundation, the U.K. Medical Research Council, and the Australian National Health and Medical Research Council.

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

In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.

The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.

RogerAshford/Thinkstock

“Our results show that, in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin,” lead investigator Colin Baigent, MD, said.

After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.

Dr. Baigent, who is director of the Population Health Research Unit at the University of Oxford (England), presented the data on Aug. 29 at the European Society of Cardiology 2022 Congress.

It was also simultaneously published online in The Lancet. 

Dr. Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).

The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Dr. Baigent said.  

In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.

“Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo,” Dr. Baigent reported.

Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% confidence interval, 1.01-1.06).

In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1,000 patient-years in those taking a statin, compared with 155 per 1,000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1,000 patients in the first year of statin therapy. 

“The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment,” Dr. Baigent added. 

After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1,000 patient-years.

“Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise,” Dr. Baigent said. “After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all.”

“To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year,” he added.

“Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin.”

The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. “There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year,” Dr. Baigent said.

But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
 

Better patient information needed

Dr. Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.

“We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake,” he commented.

“At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable,” he added. “This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff.”

Dr. Baigent also highlighted the large benefits of statins, compared with the small risk for muscle symptoms.

“While statins may cause 11 patients per 1,000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1,000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1,000 patients each year,” he noted.  

The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1,000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).

In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04-1.13) and 1.02 (95% CI, 1.00-1.05), respectively.
 

‘Reassuring information’

Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.

She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. “So, this was a Herculean task to harmonize this very complicated dataset.”

Dr. Bohula concluded: “I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me, and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins.”

Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Dr. Baigent replied that they also examined those data, which had been accounted for in the analysis.

“That’s really good news,” Dr. Steg commented. “This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health.”

The meta-analysis was funded by the British Heart Foundation, the U.K. Medical Research Council, and the Australian National Health and Medical Research Council.

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

In the vast majority of people who experience muscle pain or weakness while taking a statin, those symptoms are not related to the statin, a new individual patient data meta-analysis of randomized controlled trials shows.

The Cholesterol Trialists Collaboration meta-analysis examined 19 large randomized double-blind trials that compared statin therapy with placebo and involved almost 124,000 patients.

RogerAshford/Thinkstock

“Our results show that, in people who experience muscle symptoms in the first year of taking a statin, those symptoms are actually due to the statin in only 1 of 15 of those people. For the other 14 of the 15 people who experience muscle symptoms in the first year of taking a statin, that muscle pain is not due to the statin,” lead investigator Colin Baigent, MD, said.

After the first year, there was no difference in muscle symptoms between patients taking a statin or those taking placebo.

Dr. Baigent, who is director of the Population Health Research Unit at the University of Oxford (England), presented the data on Aug. 29 at the European Society of Cardiology 2022 Congress.

It was also simultaneously published online in The Lancet. 

Dr. Baigent explained that statins very rarely cause serious muscle adverse effects with biochemical evidence of cellular damage, such as myopathy (which occurs in less than 1 in 10,000 patients per year) and rhabdomyolysis (which occurs in about 0.2 per 10,000 patients per year).

The effect of statins on other less serious muscle symptoms without biochemical evidence of cellular damage is less clear, but misinformation about the risks have arisen from nonrandomized studies, with social media and press reports suggesting that the risk for muscle symptoms with statins is extremely common, Dr. Baigent said.  

In response to this, the Cholesterol Trialists Collaboration put together a new program of data collection, validation, and analysis to provide reliable information from large double-blind randomized trials that are free from bias and confounding.

“Overall, when we look at all these data, we find there is about a 3% relative increase in the risks of experiencing muscle pain or weakness with a statin versus with placebo,” Dr. Baigent reported.

Muscle pain or weakness was reported by 16,835 of 62,028 patients taking a statin, (27.1%), compared with 16,446 of 61,912 patients taking placebo (26.6%), for a rate ratio of 1.03 (95% confidence interval, 1.01-1.06).

In absolute terms, the results show a rate of 166 reports of muscle symptoms per 1,000 patient-years in those taking a statin, compared with 155 per 1,000-patient-years in those taking placebo in the first year. This gives a rate ratio of 1.07 and an excess of 11 cases of muscle pain or weakness per 1,000 patients in the first year of statin therapy. 

“The very small excess of muscle symptoms in the statin patients were generally mild, with most patients able to continue treatment,” Dr. Baigent added. 

After the first year, the rate of muscle pain or weakness was exactly the same in the statin and placebo groups, at 50 per 1,000 patient-years.

“Therefore, for the vast majority of people who experience muscle pain or weakness on a statin, those symptoms are not due to the statin itself. It is due to something else, which could be ageing, thyroid disease, or exercise,” Dr. Baigent said. “After the first year of taking a statin, there is no excess risk of muscle pain or weakness at all.”

“To summarize, the excess risk of muscle pain or weakness with statin use is tiny, and almost nonexistent after the first year,” he added.

“Muscle pain is very common in the general population, and it was very common in both patients taking a statin and those given placebo in these randomized trials. We can only detect a difference by looking at all the data combined in this enormous study. And we now know for sure that over 90% of cases of muscle symptoms experienced by people taking a statin are not due to the statin.”

The researchers also looked at statin intensity and found that the more intense statins tend to cause slightly more muscle pain. “There was also some evidence, although this was not very clear, that the muscle pain with the more intensive statins may persist for longer than 1 year,” Dr. Baigent said.

But in terms of different moderate-intensity and high-intensity statins, there was no evidence of differences in muscle pain between the individual statin brands, he added.
 

Better patient information needed

Dr. Baigent called for better information in statin package inserts about the real risk for muscle symptoms with these drugs.

“We need to do a better job of communicating the real risk of muscle symptom to patients who are taking statins and to their doctors. At the moment, doctors often stop statins if patients complain of muscle pain, but our data show that in 14 out of 15 times, they would be wrong for doing that. Stopping the statin is nearly always a mistake,” he commented.

“At present, the package inserts include a whole load of rubbish from observational studies, which are completely unreliable,” he added. “This is of no value to patients. They go through this information and find several symptoms they are experiencing, which they attribute to the drugs. We really need to divide up the information into the evidence that we really know for sure and then the more speculative stuff.”

Dr. Baigent also highlighted the large benefits of statins, compared with the small risk for muscle symptoms.

“While statins may cause 11 patients per 1,000 to experience some mild muscle pain in the first year of taking these drugs, and this was reduced to none in subsequent years, statins, when used for the primary prevention of cardiovascular disease, prevent 25 cardiovascular events per 1,000 patients every year they are taken. And for secondary prevention this rises to 50 events prevented per 1,000 patients each year,” he noted.  

The individual participant data meta-analysis involved 23 trials with information on almost 155,000 patients. All trials included at least 1,000 patients and at least 2 years of scheduled treatment. Adverse-event data were collected for all individual participants in 19 large randomized double-blind trials comparing statin therapy with placebo (123,940 patients) and in four randomized double-blind trials comparing more-intensive with less-intensive statin therapy (30,724 patients).

In the four trials of more-intensive versus less-intensive statin therapy, high-intensity regimens (atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily) resulted in a larger relative increase in the rate of muscle pain or weakness than moderate-intensity regimens, with rate ratios of 1.08 (95% CI, 1.04-1.13) and 1.02 (95% CI, 1.00-1.05), respectively.
 

‘Reassuring information’

Discussant of the study at the ESC Hotline session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, said this new analysis had many strengths and used a rigorous approach to look at the issue of muscle symptoms with statins.

She pointed out some challenges, including the fact that the definition of adverse muscle events has changed over time and differed in the various trials, with heterogeneous data capture across trials. “So, this was a Herculean task to harmonize this very complicated dataset.”

Dr. Bohula concluded: “I think this is a very significant undertaking, resulting in a rich dataset that enhances our understanding of muscle symptoms related to statin use. The take-home for me is that muscle symptoms are a common complaint in the general population but are very rarely attributable to statins. This is very reassuring to me, and I hope it is reassuring to patients and can help us encourage them with adherence, given the clear cardiovascular benefits of statins.”

Chair of the ESC Hotline session at which the study was presented, Gabriel Steg, MD, Hôpital Bichat, Paris, asked whether some statin patients who experienced muscle symptoms with the drugs in active run-in periods in the trials may have been excluded from the main trials, so that this information might not have been captured, but Dr. Baigent replied that they also examined those data, which had been accounted for in the analysis.

“That’s really good news,” Dr. Steg commented. “This study is going to be one more tool in our response to statin skeptics and I think, as such, this work is a really a service to public health.”

The meta-analysis was funded by the British Heart Foundation, the U.K. Medical Research Council, and the Australian National Health and Medical Research Council.

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

People who use skin-lightening products that contain hydroquinone may be at an increased risk for skin cancers, an analysis of records from a large research database suggests.

In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”

courtesy John Sealy School of Medicine

The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.

Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.

The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).

Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.

LAGUNA DESIGN/Science Photo Library/Getty Images

The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.

They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)

While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
 

Skin lightening is big business and more research is needed

“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.

Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.

“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.

Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.

The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.

“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?

“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”

These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.

“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.

Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.

Courtesy City of Hope

“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.

“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.

“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.

The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.

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

People who use skin-lightening products that contain hydroquinone may be at an increased risk for skin cancers, an analysis of records from a large research database suggests.

In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”

courtesy John Sealy School of Medicine

The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.

Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.

The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).

Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.

LAGUNA DESIGN/Science Photo Library/Getty Images

The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.

They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)

While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
 

Skin lightening is big business and more research is needed

“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.

Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.

“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.

Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.

The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.

“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?

“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”

These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.

“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.

Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.

Courtesy City of Hope

“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.

“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.

“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.

The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.

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

People who use skin-lightening products that contain hydroquinone may be at an increased risk for skin cancers, an analysis of records from a large research database suggests.

In the study, hydroquinone use was associated with an approximately threefold increase for skin cancer risk, coauthor Brittany Miles, a fourth-year medical student at the University of Texas Medical Branch at Galveston’s John Sealy School of Medicine, told this news organization. “The magnitude of the risk was surprising. Increased risk should be disclosed to patients considering hydroquinone treatment.”

courtesy John Sealy School of Medicine

The results of the study were presented in a poster at the annual meeting of the Society for Investigative Dermatology.

Hydroquinone (multiple brand names), a tyrosinase inhibitor used worldwide for skin lightening because of its inhibition of melanin production, was once considered “generally safe and effective” by the Food and Drug Administration, the authors wrote.

The compound’s use in over-the-counter products in the United States has been restricted based on suspicion of carcinogenicity, but few human studies have been conducted. In April, the FDA issued warning letters to 12 companies that sold hydroquinone in concentrations not generally recognized as safe and effective, because of other concerns including rashes, facial swelling, and ochronosis (skin discoloration).

Ms. Miles and her coauthor, Michael Wilkerson, MD, professor and chair of the department of dermatology at UTMB, analyzed data from TriNetX, the medical research database of anonymized medical record information from 61 million patients in 57 large health care organizations, almost all of them in the United States.

LAGUNA DESIGN/Science Photo Library/Getty Images

The researchers created two cohorts of patients aged 15 years and older with no prior diagnosis of skin cancer: one group had been treated with hydroquinone (medication code 5509 in the TriNetX system), and the other had not been exposed to the drug. Using ICD-10 codes for melanoma, nonmelanoma skin cancer, and all skin cancers, they investigated which groups of people were likely to develop these cancers.

They found that hydroquinone exposure was linked with a significant increase in melanoma (relative risk, 3.0; 95% confidence interval, 1.704-5.281; P < .0001), nonmelanoma skin cancers (RR, 3.6; 95%; CI, 2.815-4.561; P < .0001), and all reported skin cancers combined (relative risk, 3.4; 95% CI, 2.731-4.268; P < .0001)

While “the source of the data and the number of patients in the study are significant strengths,” Ms. Miles said, “the inability to determine how long and how consistently the patients used hydroquinone is likely the biggest weakness.”
 

Skin lightening is big business and more research is needed

“The U.S. market for skin-lightening agents was approximately 330 million dollars in 2021, and 330,000 prescriptions containing hydroquinone were dispensed in 2019,” Ms. Miles said.

Valencia D. Thomas, MD, professor in the department of dermatology of the University of Texas MD Anderson Cancer Center, Houston, said in an email that over-the-counter skin-lightening products containing low-concentration hydroquinone are in widespread use and are commonly used in populations of color.

“Hydroquinone preparations in higher concentrations are unfortunately also available in the United States,” added Dr. Thomas, who was not involved in the study and referred to the FDA warning letter issued in April.

Only one hydroquinone-containing medication – Tri-Luma at 4% concentration, used to treat melasma – is currently FDA-approved, she said.

The data in the study do not show an increased risk for skin cancer with hydroquinone exposure, but do show “an increased risk of cancer in the TriNetX medication code 5509 hydroquinone exposure group, which does not prove causation,” Dr. Thomas commented.

“Because ‘hydroquinone exposure’ is not defined, it is unclear how TriNetX identified the hydroquinone exposure cohort,” she noted. “Does ‘exposure’ count prescriptions written and potentially not used, the use of hydroquinone products of high concentration not approved by the FDA, or the use of over-the-counter hydroquinone products?

“The strength of this study is its size,” Dr. Thomas acknowledged. “This study is a wonderful starting point to further investigate the ‘hydroquinone exposure’ cohort to determine if hydroquinone is a driver of cancer, or if hydroquinone is itself a confounder.”

These results highlight the need to examine the social determinants of health that may explain increased risk for cancer, including race, geography, and poverty, she added.

“Given the global consumption of hydroquinone, multinational collaboration investigating hydroquinone and cancer data will likely be needed to provide insight into this continuing question,” Dr. Thomas advised.

Christiane Querfeld, MD, PhD, associate professor of dermatology and dermatopathology at City of Hope in Duarte, Calif., agreed that the occurrence of skin cancer following use of hydroquinone is largely understudied.

Courtesy City of Hope

“The findings have a huge impact on how we counsel and monitor future patients,” Dr. Querfeld, who also was not involved in the study, said in an email. “There may be a trade-off at the start of treatment: Get rid of melasma but develop a skin cancer or melanoma with potentially severe outcomes.

“It remains to be seen if there is a higher incidence of skin cancer following use of hydroquinone or other voluntary bleaching and depigmentation remedies in ethnic groups such as African American or Hispanic patient populations, who have historically been at low risk of developing skin cancer,” she added. “It also remains to be seen if increased risk is due to direct effects or to indirect effects on already-photodamaged skin.

“These data are critical, and I am sure this will open further investigations to study effects in more detail,” Dr. Querfeld said.

The study authors, Dr. Thomas, and Dr. Querfeld reported no relevant financial relationships. The study did not receive external funding.

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

Abbott Nutrition is resuming production of Similac, its leading baby formula, at a Michigan plant that was shut down earlier in 2022 because of contamination concerns.

The company closed the plant in February, which triggered a national shortage of baby formula amid pandemic-related supply chain issues that created a lack of formula ingredients.

“We know that the nationwide infant formula shortage has been difficult for the families we serve, and while restarting Similac production in Michigan is an important milestone, we won’t rest until this product is back on shelves,” Robert Ford, chairman and CEO of Abbott, said in a statement on Aug. 26.

“Making infant formula is a responsibility we take very seriously, and parents can feel confident in the quality and safety of Similac and other Abbott formulas,” he said. “We are committed to re-earning the trust parents and health care providers have placed in us for decades.”

Abbott estimated that it will take about 6 weeks for Similac products to ship to stores. Production has restarted, which will be followed by “enhanced” testing before and after the formula is made.

In February, Abbott voluntarily recalled batches of three formulas after the Food and Drug Administration received consumer complaints about infants becoming sick. Four babies who consumed formulas from the Michigan plant got bacterial infections, and at least two babies died.

The illnesses were linked to Cronobacter sakazakii – bacteria that can lead to life-threatening infections and inflammation of the brain and spine.

After investigations at the plant, Abbott said there is no conclusive evidence to link the formula to the illnesses. No samples of the recalled product tested positive for the bacteria, and in all four cases, unopened containers of formula in the infants’ homes tested negative for the bacteria.

At the same time, FDA officials said in May that the Michigan plant had a leaking roof, water pooling on the floor, and cracks in production equipment that could allow bacteria to grow, according to The New York Times.

Abbott agreed with the federal government to create new safeguards, such as hiring a qualified expert to oversee improvements at the plant and notify the FDA if any issues were identified, the newspaper reported.

On July 1, the company restarted production of EleCare, a specialty formula, and later resumed production of some metabolic formulas. These products will begin to ship in coming weeks, the company said.

Since July, C. sakazakii has been found in a couple of batches of formula.

“In those cases, we found the issue, addressed it and no affected product has been or will be distributed,” Abbott said in the statement. “This confirms our quality systems work.”

In August, Abbott will supply the United States with more than 8 million pounds of infant formula, which is higher than the levels in August 2021, the company said. To ensure that people in the federal Special Supplemental Nutrition Program for Women, Infants and Children have access to formula, the company is extending rebates until the end of October.

“Restarting a large manufacturing facility after a several-month shutdown is a complex process, and it takes time to ensure that equipment, processes and production are functioning smoothly and sustainably,” the company said in the statement. “There have been – and likely will be – stops and starts from time to time. We’ve experienced events like severe weather, we’ve had to make mechanical adjustments, and we’ve had to discard some early production batches that didn’t meet our standards.”

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

Abbott Nutrition is resuming production of Similac, its leading baby formula, at a Michigan plant that was shut down earlier in 2022 because of contamination concerns.

The company closed the plant in February, which triggered a national shortage of baby formula amid pandemic-related supply chain issues that created a lack of formula ingredients.

“We know that the nationwide infant formula shortage has been difficult for the families we serve, and while restarting Similac production in Michigan is an important milestone, we won’t rest until this product is back on shelves,” Robert Ford, chairman and CEO of Abbott, said in a statement on Aug. 26.

“Making infant formula is a responsibility we take very seriously, and parents can feel confident in the quality and safety of Similac and other Abbott formulas,” he said. “We are committed to re-earning the trust parents and health care providers have placed in us for decades.”

Abbott estimated that it will take about 6 weeks for Similac products to ship to stores. Production has restarted, which will be followed by “enhanced” testing before and after the formula is made.

In February, Abbott voluntarily recalled batches of three formulas after the Food and Drug Administration received consumer complaints about infants becoming sick. Four babies who consumed formulas from the Michigan plant got bacterial infections, and at least two babies died.

The illnesses were linked to Cronobacter sakazakii – bacteria that can lead to life-threatening infections and inflammation of the brain and spine.

After investigations at the plant, Abbott said there is no conclusive evidence to link the formula to the illnesses. No samples of the recalled product tested positive for the bacteria, and in all four cases, unopened containers of formula in the infants’ homes tested negative for the bacteria.

At the same time, FDA officials said in May that the Michigan plant had a leaking roof, water pooling on the floor, and cracks in production equipment that could allow bacteria to grow, according to The New York Times.

Abbott agreed with the federal government to create new safeguards, such as hiring a qualified expert to oversee improvements at the plant and notify the FDA if any issues were identified, the newspaper reported.

On July 1, the company restarted production of EleCare, a specialty formula, and later resumed production of some metabolic formulas. These products will begin to ship in coming weeks, the company said.

Since July, C. sakazakii has been found in a couple of batches of formula.

“In those cases, we found the issue, addressed it and no affected product has been or will be distributed,” Abbott said in the statement. “This confirms our quality systems work.”

In August, Abbott will supply the United States with more than 8 million pounds of infant formula, which is higher than the levels in August 2021, the company said. To ensure that people in the federal Special Supplemental Nutrition Program for Women, Infants and Children have access to formula, the company is extending rebates until the end of October.

“Restarting a large manufacturing facility after a several-month shutdown is a complex process, and it takes time to ensure that equipment, processes and production are functioning smoothly and sustainably,” the company said in the statement. “There have been – and likely will be – stops and starts from time to time. We’ve experienced events like severe weather, we’ve had to make mechanical adjustments, and we’ve had to discard some early production batches that didn’t meet our standards.”

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

Abbott Nutrition is resuming production of Similac, its leading baby formula, at a Michigan plant that was shut down earlier in 2022 because of contamination concerns.

The company closed the plant in February, which triggered a national shortage of baby formula amid pandemic-related supply chain issues that created a lack of formula ingredients.

“We know that the nationwide infant formula shortage has been difficult for the families we serve, and while restarting Similac production in Michigan is an important milestone, we won’t rest until this product is back on shelves,” Robert Ford, chairman and CEO of Abbott, said in a statement on Aug. 26.

“Making infant formula is a responsibility we take very seriously, and parents can feel confident in the quality and safety of Similac and other Abbott formulas,” he said. “We are committed to re-earning the trust parents and health care providers have placed in us for decades.”

Abbott estimated that it will take about 6 weeks for Similac products to ship to stores. Production has restarted, which will be followed by “enhanced” testing before and after the formula is made.

In February, Abbott voluntarily recalled batches of three formulas after the Food and Drug Administration received consumer complaints about infants becoming sick. Four babies who consumed formulas from the Michigan plant got bacterial infections, and at least two babies died.

The illnesses were linked to Cronobacter sakazakii – bacteria that can lead to life-threatening infections and inflammation of the brain and spine.

After investigations at the plant, Abbott said there is no conclusive evidence to link the formula to the illnesses. No samples of the recalled product tested positive for the bacteria, and in all four cases, unopened containers of formula in the infants’ homes tested negative for the bacteria.

At the same time, FDA officials said in May that the Michigan plant had a leaking roof, water pooling on the floor, and cracks in production equipment that could allow bacteria to grow, according to The New York Times.

Abbott agreed with the federal government to create new safeguards, such as hiring a qualified expert to oversee improvements at the plant and notify the FDA if any issues were identified, the newspaper reported.

On July 1, the company restarted production of EleCare, a specialty formula, and later resumed production of some metabolic formulas. These products will begin to ship in coming weeks, the company said.

Since July, C. sakazakii has been found in a couple of batches of formula.

“In those cases, we found the issue, addressed it and no affected product has been or will be distributed,” Abbott said in the statement. “This confirms our quality systems work.”

In August, Abbott will supply the United States with more than 8 million pounds of infant formula, which is higher than the levels in August 2021, the company said. To ensure that people in the federal Special Supplemental Nutrition Program for Women, Infants and Children have access to formula, the company is extending rebates until the end of October.

“Restarting a large manufacturing facility after a several-month shutdown is a complex process, and it takes time to ensure that equipment, processes and production are functioning smoothly and sustainably,” the company said in the statement. “There have been – and likely will be – stops and starts from time to time. We’ve experienced events like severe weather, we’ve had to make mechanical adjustments, and we’ve had to discard some early production batches that didn’t meet our standards.”

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

A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.

In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.

A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.

In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.

A systematic review of immune checkpoint inhibitor (ICI) combinations suggests that they have a significant survival benefit over the tyrosine kinase inhibitor (TKI) sunitinib and should be made generally available to patients with advanced renal cell carcinoma (RCC).

Until recently, first-line therapy for RCC has primarily been TKIs that target vascular endothelial growth factor (VEGF) and other receptors, including sunitinib and pazopanib. Explorations of novel therapeutic regimens focused on the use of multiple TKIs in combination with monoclonal antibodies that directly inhibit VEGF and inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus.

Some ICIs have already become the preferred first-line treatment for RCC. VEGF and VEGF receptors inhibitors are believed to have immunomodulatory effects, including boosting immune cell infiltration as a result of their effect on tumor vasculature. That idea has spurred recent clinical trials that have examined ICIs in combination with VEGF-directed therapies.

In a study published online in Therapeutic Advances in Medical Oncology, researchers examined six phase 3 clinical trials. Each compared ICI combinations versus sunitinib as first-line therapy for advanced or metastatic RCC. Four of the studies tested TKI/ICI combinations, and one each tested an ICI/anti-VEGF antibody and dual ICIs.

After median follow-ups of 20-30 months, there was no benefit to PD-L1 inhibitor combinations (atezolizumab plus bevacizumab or avelumab plus axitinib) compared with sunitinib. Final survival analyses from one of the trials have not been reported yet.

PD-1 inhibitor combinations fared better. Nivolumab plus ipilimumab led to a 32% reduced risk of death in intermediate/poor-risk patients, compared with sunitinib, but the combination led to more frequent discontinuation because of toxicity (21.8% versus 12.3%). Nivolumab plus cabozantinib produced a 34% reduction in risk of death (P = .003) and a 48% reduction in risk of progression (P < .0001). Rates of discontinuation because of toxicity were similar to sunitinib.

Pembrolizumab combined with TKIs led to a 32% reduced risk of death (P = .003) and a 29% reduced risk of progression (P < .001). Pembrolizumab plus lenvatinib reduced risk of death by 28% (P value not reported) and the risk of progression by 61% (P < .001). Both combinations had a higher frequency of discontinuation because of toxicity (25.9% versus 10.1% and 37.2% versus 14.4%, respectively).

Given that there are no head-to-head comparisons between dual ICI or PD-1/TKI combinations, the researchers suggested that response outcomes may assist in selection between the two approaches. Overall, PD-1/TKI combinations had better overall response rates. The highest was seen in pembrolizumab plus lenvatinib, where frequency of progressive disease ranged from 5.4% to 11.3%. Complete response rate ranged from 8% to 10%.

The authors suggest that upfront treatment with a PD-1 inhibitor and a TKI could be appropriate for patients with a high tumor burden or aggressive disease, in whom stopping tumor growth is urgent and progression could be particularly worrisome.

Safety concerns associated with dual-ICI combination therapy was similar to that seen in RCC and other cancers. Dose delays, rapid diagnostic workups, appropriate timing, and the use of glucocorticoids were among strategies used to manage treatment-related adverse events.

The authors note that five combinations are approved by either the Food and Drug Administration or the European Medicines Agency for first-line treatment of metastatic RCC. Factors to consider for treatment selection include patient and disease characteristics, IMDC risk status, treatment history during earlier disease stage, and eligibility for immunotherapy. Nivolumab plus ipilimumab may be a good choice for patients with an intermediate or poor IMDC risk since it provides a strong and durable overall survival benefit. Pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib all have good overall response rates and can prolong life, though extended TKI use can lead to chronic toxicity. Nivolumab plus ipilimumab is not approved for those with a favorable IMDC risk in many regions.

Four of the authors reported receiving honoraria, research funding, or consulting for a variety of pharmaceutical companies, including AbbVie, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera.

A new online tool can quickly and accurately identify individuals who may benefit from genetic testing because they likely carry pathogenic germline variants (PGVs) in a diverse spectrum of cancer susceptibility genes.

The PREMMplus online tool was developed and validated by researchers at the Dana-Farber Cancer Institute, Boston using three cohorts involving more than 30,000 individuals who had undergone multigene hereditary cancer risk testing.

The study was published online  in the Journal of Clinical Oncology.

“Our findings show that PREMMplus has the potential to change the model by which patients and family members are referred for genetic testing and counseling,” senior author Sapna Syngal, MD, MPH, with Dana-Farber/Brigham and Women’s Hospital, Boston, said in an institution news release.

Traditionally, when there is concern about a family cancer history, the individual is referred to a genetics clinic, where a counselor takes a complete family history.

“At a time when there’s a shortage of genetic counselors, PREMMplus can help streamline risk assessment and ensure that their time can be focused on where they’re most needed – helping people understand the results of genetic testing and the options available when a cancer-susceptibility gene is found,” Dr. Syngal says.
 

Online tool

The tool uses clinical data (age, sex, ethnicity, and personal/family history of 18 cancers) to determine an individual’s likelihood of harboring a PGV in 19 cancer susceptibility genes.

A PREMMplus score of 2.5% or greater had a 89%-94% sensitivity and > 97% negative predictive value (NPV) for identifying individuals with PGVs in 11 well-defined “category A” high-penetrance cancer risk genes: APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53.

These PGVs “represent diverse types of inherited cancer risk for which there are established risk-reduction guidelines,” the study team says. Cancers associated with these PGVs include breast, ovarian, colorectal, pancreatic, and prostate cancer, as well as those that make up Lynch syndrome.

The ability of PREMMplus to identify individuals with PGVs in “moderate-penetrance” cancer risk genes (such as CHEK2 and ATM) was somewhat reduced but was still “quite strong” (84%-90% sensitivity and > 93% NPV), the study team reports.

In an interview, Dr. Syngal said her ultimate vision of this online tool is that it will be adapted into the electronic medical record (EMR).

“Through the EMR, it might somehow get pushed out to people before an oncology or primary care appointment or before a mammography or colonoscopy. Then by the time they come in, the doctor or nurse practitioner has the information and can refer them for genetic testing if appropriate,” Dr. Syngal explained.

The tool is not currently available for routine clinical use. The goal is to make it available online in a couple of months.

Dr. Syngal said two versions will be available. One will be a user-friendly version that can be filled out directly by patients and that will tell whether someone passes the threshold of needing genetic testing. The patient would then take that information to their primary care doctor.

With the second version, the doctor and patient would fill out the information together during an office visit.

PREMMplus would be free for the individual patient or provider.

“What we hope is that hospital systems will use it and that insurance companies will also use it as a way to say who needs testing and who to approve for testing,” Dr. Syngal told this news organization.

“For a hospital system or a genetic testing company, for example, that wants to integrate it into their direct-to-consumer platform, they would have to take out a license from Dana-Farber, and cost would be negotiated with each entity based on how they’re going to use it,” Dr. Syngal said.

Funding for the research was provided by the National Institutes of Health. A complete list of author disclosures is available with the original article.

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

A new online tool can quickly and accurately identify individuals who may benefit from genetic testing because they likely carry pathogenic germline variants (PGVs) in a diverse spectrum of cancer susceptibility genes.

The PREMMplus online tool was developed and validated by researchers at the Dana-Farber Cancer Institute, Boston using three cohorts involving more than 30,000 individuals who had undergone multigene hereditary cancer risk testing.

The study was published online  in the Journal of Clinical Oncology.

“Our findings show that PREMMplus has the potential to change the model by which patients and family members are referred for genetic testing and counseling,” senior author Sapna Syngal, MD, MPH, with Dana-Farber/Brigham and Women’s Hospital, Boston, said in an institution news release.

Traditionally, when there is concern about a family cancer history, the individual is referred to a genetics clinic, where a counselor takes a complete family history.

“At a time when there’s a shortage of genetic counselors, PREMMplus can help streamline risk assessment and ensure that their time can be focused on where they’re most needed – helping people understand the results of genetic testing and the options available when a cancer-susceptibility gene is found,” Dr. Syngal says.
 

Online tool

The tool uses clinical data (age, sex, ethnicity, and personal/family history of 18 cancers) to determine an individual’s likelihood of harboring a PGV in 19 cancer susceptibility genes.

A PREMMplus score of 2.5% or greater had a 89%-94% sensitivity and > 97% negative predictive value (NPV) for identifying individuals with PGVs in 11 well-defined “category A” high-penetrance cancer risk genes: APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53.

These PGVs “represent diverse types of inherited cancer risk for which there are established risk-reduction guidelines,” the study team says. Cancers associated with these PGVs include breast, ovarian, colorectal, pancreatic, and prostate cancer, as well as those that make up Lynch syndrome.

The ability of PREMMplus to identify individuals with PGVs in “moderate-penetrance” cancer risk genes (such as CHEK2 and ATM) was somewhat reduced but was still “quite strong” (84%-90% sensitivity and > 93% NPV), the study team reports.

In an interview, Dr. Syngal said her ultimate vision of this online tool is that it will be adapted into the electronic medical record (EMR).

“Through the EMR, it might somehow get pushed out to people before an oncology or primary care appointment or before a mammography or colonoscopy. Then by the time they come in, the doctor or nurse practitioner has the information and can refer them for genetic testing if appropriate,” Dr. Syngal explained.

The tool is not currently available for routine clinical use. The goal is to make it available online in a couple of months.

Dr. Syngal said two versions will be available. One will be a user-friendly version that can be filled out directly by patients and that will tell whether someone passes the threshold of needing genetic testing. The patient would then take that information to their primary care doctor.

With the second version, the doctor and patient would fill out the information together during an office visit.

PREMMplus would be free for the individual patient or provider.

“What we hope is that hospital systems will use it and that insurance companies will also use it as a way to say who needs testing and who to approve for testing,” Dr. Syngal told this news organization.

“For a hospital system or a genetic testing company, for example, that wants to integrate it into their direct-to-consumer platform, they would have to take out a license from Dana-Farber, and cost would be negotiated with each entity based on how they’re going to use it,” Dr. Syngal said.

Funding for the research was provided by the National Institutes of Health. A complete list of author disclosures is available with the original article.

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

A new online tool can quickly and accurately identify individuals who may benefit from genetic testing because they likely carry pathogenic germline variants (PGVs) in a diverse spectrum of cancer susceptibility genes.

The PREMMplus online tool was developed and validated by researchers at the Dana-Farber Cancer Institute, Boston using three cohorts involving more than 30,000 individuals who had undergone multigene hereditary cancer risk testing.

The study was published online  in the Journal of Clinical Oncology.

“Our findings show that PREMMplus has the potential to change the model by which patients and family members are referred for genetic testing and counseling,” senior author Sapna Syngal, MD, MPH, with Dana-Farber/Brigham and Women’s Hospital, Boston, said in an institution news release.

Traditionally, when there is concern about a family cancer history, the individual is referred to a genetics clinic, where a counselor takes a complete family history.

“At a time when there’s a shortage of genetic counselors, PREMMplus can help streamline risk assessment and ensure that their time can be focused on where they’re most needed – helping people understand the results of genetic testing and the options available when a cancer-susceptibility gene is found,” Dr. Syngal says.
 

Online tool

The tool uses clinical data (age, sex, ethnicity, and personal/family history of 18 cancers) to determine an individual’s likelihood of harboring a PGV in 19 cancer susceptibility genes.

A PREMMplus score of 2.5% or greater had a 89%-94% sensitivity and > 97% negative predictive value (NPV) for identifying individuals with PGVs in 11 well-defined “category A” high-penetrance cancer risk genes: APC, BRCA1, BRCA2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53.

These PGVs “represent diverse types of inherited cancer risk for which there are established risk-reduction guidelines,” the study team says. Cancers associated with these PGVs include breast, ovarian, colorectal, pancreatic, and prostate cancer, as well as those that make up Lynch syndrome.

The ability of PREMMplus to identify individuals with PGVs in “moderate-penetrance” cancer risk genes (such as CHEK2 and ATM) was somewhat reduced but was still “quite strong” (84%-90% sensitivity and > 93% NPV), the study team reports.

In an interview, Dr. Syngal said her ultimate vision of this online tool is that it will be adapted into the electronic medical record (EMR).

“Through the EMR, it might somehow get pushed out to people before an oncology or primary care appointment or before a mammography or colonoscopy. Then by the time they come in, the doctor or nurse practitioner has the information and can refer them for genetic testing if appropriate,” Dr. Syngal explained.

The tool is not currently available for routine clinical use. The goal is to make it available online in a couple of months.

Dr. Syngal said two versions will be available. One will be a user-friendly version that can be filled out directly by patients and that will tell whether someone passes the threshold of needing genetic testing. The patient would then take that information to their primary care doctor.

With the second version, the doctor and patient would fill out the information together during an office visit.

PREMMplus would be free for the individual patient or provider.

“What we hope is that hospital systems will use it and that insurance companies will also use it as a way to say who needs testing and who to approve for testing,” Dr. Syngal told this news organization.

“For a hospital system or a genetic testing company, for example, that wants to integrate it into their direct-to-consumer platform, they would have to take out a license from Dana-Farber, and cost would be negotiated with each entity based on how they’re going to use it,” Dr. Syngal said.

Funding for the research was provided by the National Institutes of Health. A complete list of author disclosures is available with the original article.

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