Mixed Topics

New research suggests there may be better times during the day for eating and fasting. 

Eating earlier in the day may help you lose weight, and eating meals within a 10-hour window could improve blood sugar and cholesterol levels, according to two new studies published in Cell Metabolism.

“You have this internal biological clock that makes you better at doing different things at different times of the day,” Courtney Peterson, PhD, an associate professor of nutrition sciences at the University of Alabama at Birmingham, told NBC News. Dr. Peterson wasn’t involved with the studies.

“It seems like the best time for your metabolism, in most people, is the mid to late morning,” she said.

In one study, researchers found that eating later in the day made people hungrier during a 24-hour period, as compared with eating the same meals earlier in the day. Late eating also burned calories at a slower rate and led to fat tissue that stored more calories. Combined, the changes may increase the risk for obesity, the study authors found.

In another study, among firefighters as shift workers, researchers found that eating meals within a 10-hour window decreased the size of bad cholesterol particles, which could reduce risk factors for heart disease. The 10-hour eating window also improved blood pressure and blood sugar levels among those with health conditions such as diabetes, high blood pressure, and high cholesterol.

The two new studies confirm findings from previous studies that indicate humans may have an ideal eating window based on the body’s circadian rhythms, which regulate sleep and wake cycles and can affect appetite, metabolism, and blood sugar levels.

In the firefighter study, for instance, the 10-hour window appears to be a “sweet spot” for the body, the authors found. More severe restrictions, as found with many intermittent fasting diets, could be difficult for the body to maintain.

“When we think about 6 or 8 hours, you might see a benefit, but people might not stick to it for a long time,” Satchidananda Panda, PhD, one of the study authors and a professor at the Salk Institute, La Jolla, Calif., told NBC News.

The new studies had small sample sizes, though they offer insight for future research. In the first study, 16 people who were overweight or obese tried two eating plans for 24-hour periods. Some of them began eating an hour after their natural wake-up time, and others waited to begin eating until about 5 hours after waking up. They ate the same meals with the same calories and nutrients.

The researchers measured their hormone levels and found that eating later decreased the levels of leptin, which helps people to feel full. Eating later also doubled the odds that people felt hungry throughout the day. Those in the study who ate later in the day also had more cravings for starchy or salty foods, as well as meat and dairy, which are energy-dense foods.

The research team also found changes in fat tissue, which could lead to a higher chance of building up new fat cells and a lower chance of burning fat. Late eaters burned about 60 fewer calories than early eaters during the day.

“Your body processes calories differently when you eat late in the day. It tips the scale in favor of weight gain and fat gain,” Dr. Peterson said. “From this study, we can get pretty clear recommendations that people shouldn’t skip breakfast.”

The second study followed 137 firefighters in San Diego who ate a Mediterranean diet with fish, vegetables, fruit, and olive oil for 12 weeks. Among those, 70 firefighters ate during a 10-hour window, and the rest ate during a longer window, generally about 13 hours. They logged their meals in an app and wore devices to track blood sugar levels.

In the 10-hour group, most firefighters ate between 8 a.m. or 9 a.m. and 6 p.m. or 7 p.m. The time-restricted eating appeared to be linked with health benefits, such as less harmful cholesterol buildup and reduced heart disease. 

Among firefighters with risk factors for heart disease, such as high blood pressure and high blood sugar, the time-restricted eating decreased their blood pressure and blood sugar levels. 

The restricted window appears to allow the body to break down toxins and get rid of sodium and other things that can drive up blood pressure and blood sugar, the authors wrote.

During periods of fasting, “organs get some rest from digesting food so they can divert their energy toward repairing cells,” Dr. Panda said.

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

New research suggests there may be better times during the day for eating and fasting. 

Eating earlier in the day may help you lose weight, and eating meals within a 10-hour window could improve blood sugar and cholesterol levels, according to two new studies published in Cell Metabolism.

“You have this internal biological clock that makes you better at doing different things at different times of the day,” Courtney Peterson, PhD, an associate professor of nutrition sciences at the University of Alabama at Birmingham, told NBC News. Dr. Peterson wasn’t involved with the studies.

“It seems like the best time for your metabolism, in most people, is the mid to late morning,” she said.

In one study, researchers found that eating later in the day made people hungrier during a 24-hour period, as compared with eating the same meals earlier in the day. Late eating also burned calories at a slower rate and led to fat tissue that stored more calories. Combined, the changes may increase the risk for obesity, the study authors found.

In another study, among firefighters as shift workers, researchers found that eating meals within a 10-hour window decreased the size of bad cholesterol particles, which could reduce risk factors for heart disease. The 10-hour eating window also improved blood pressure and blood sugar levels among those with health conditions such as diabetes, high blood pressure, and high cholesterol.

The two new studies confirm findings from previous studies that indicate humans may have an ideal eating window based on the body’s circadian rhythms, which regulate sleep and wake cycles and can affect appetite, metabolism, and blood sugar levels.

In the firefighter study, for instance, the 10-hour window appears to be a “sweet spot” for the body, the authors found. More severe restrictions, as found with many intermittent fasting diets, could be difficult for the body to maintain.

“When we think about 6 or 8 hours, you might see a benefit, but people might not stick to it for a long time,” Satchidananda Panda, PhD, one of the study authors and a professor at the Salk Institute, La Jolla, Calif., told NBC News.

The new studies had small sample sizes, though they offer insight for future research. In the first study, 16 people who were overweight or obese tried two eating plans for 24-hour periods. Some of them began eating an hour after their natural wake-up time, and others waited to begin eating until about 5 hours after waking up. They ate the same meals with the same calories and nutrients.

The researchers measured their hormone levels and found that eating later decreased the levels of leptin, which helps people to feel full. Eating later also doubled the odds that people felt hungry throughout the day. Those in the study who ate later in the day also had more cravings for starchy or salty foods, as well as meat and dairy, which are energy-dense foods.

The research team also found changes in fat tissue, which could lead to a higher chance of building up new fat cells and a lower chance of burning fat. Late eaters burned about 60 fewer calories than early eaters during the day.

“Your body processes calories differently when you eat late in the day. It tips the scale in favor of weight gain and fat gain,” Dr. Peterson said. “From this study, we can get pretty clear recommendations that people shouldn’t skip breakfast.”

The second study followed 137 firefighters in San Diego who ate a Mediterranean diet with fish, vegetables, fruit, and olive oil for 12 weeks. Among those, 70 firefighters ate during a 10-hour window, and the rest ate during a longer window, generally about 13 hours. They logged their meals in an app and wore devices to track blood sugar levels.

In the 10-hour group, most firefighters ate between 8 a.m. or 9 a.m. and 6 p.m. or 7 p.m. The time-restricted eating appeared to be linked with health benefits, such as less harmful cholesterol buildup and reduced heart disease. 

Among firefighters with risk factors for heart disease, such as high blood pressure and high blood sugar, the time-restricted eating decreased their blood pressure and blood sugar levels. 

The restricted window appears to allow the body to break down toxins and get rid of sodium and other things that can drive up blood pressure and blood sugar, the authors wrote.

During periods of fasting, “organs get some rest from digesting food so they can divert their energy toward repairing cells,” Dr. Panda said.

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

New research suggests there may be better times during the day for eating and fasting. 

Eating earlier in the day may help you lose weight, and eating meals within a 10-hour window could improve blood sugar and cholesterol levels, according to two new studies published in Cell Metabolism.

“You have this internal biological clock that makes you better at doing different things at different times of the day,” Courtney Peterson, PhD, an associate professor of nutrition sciences at the University of Alabama at Birmingham, told NBC News. Dr. Peterson wasn’t involved with the studies.

“It seems like the best time for your metabolism, in most people, is the mid to late morning,” she said.

In one study, researchers found that eating later in the day made people hungrier during a 24-hour period, as compared with eating the same meals earlier in the day. Late eating also burned calories at a slower rate and led to fat tissue that stored more calories. Combined, the changes may increase the risk for obesity, the study authors found.

In another study, among firefighters as shift workers, researchers found that eating meals within a 10-hour window decreased the size of bad cholesterol particles, which could reduce risk factors for heart disease. The 10-hour eating window also improved blood pressure and blood sugar levels among those with health conditions such as diabetes, high blood pressure, and high cholesterol.

The two new studies confirm findings from previous studies that indicate humans may have an ideal eating window based on the body’s circadian rhythms, which regulate sleep and wake cycles and can affect appetite, metabolism, and blood sugar levels.

In the firefighter study, for instance, the 10-hour window appears to be a “sweet spot” for the body, the authors found. More severe restrictions, as found with many intermittent fasting diets, could be difficult for the body to maintain.

“When we think about 6 or 8 hours, you might see a benefit, but people might not stick to it for a long time,” Satchidananda Panda, PhD, one of the study authors and a professor at the Salk Institute, La Jolla, Calif., told NBC News.

The new studies had small sample sizes, though they offer insight for future research. In the first study, 16 people who were overweight or obese tried two eating plans for 24-hour periods. Some of them began eating an hour after their natural wake-up time, and others waited to begin eating until about 5 hours after waking up. They ate the same meals with the same calories and nutrients.

The researchers measured their hormone levels and found that eating later decreased the levels of leptin, which helps people to feel full. Eating later also doubled the odds that people felt hungry throughout the day. Those in the study who ate later in the day also had more cravings for starchy or salty foods, as well as meat and dairy, which are energy-dense foods.

The research team also found changes in fat tissue, which could lead to a higher chance of building up new fat cells and a lower chance of burning fat. Late eaters burned about 60 fewer calories than early eaters during the day.

“Your body processes calories differently when you eat late in the day. It tips the scale in favor of weight gain and fat gain,” Dr. Peterson said. “From this study, we can get pretty clear recommendations that people shouldn’t skip breakfast.”

The second study followed 137 firefighters in San Diego who ate a Mediterranean diet with fish, vegetables, fruit, and olive oil for 12 weeks. Among those, 70 firefighters ate during a 10-hour window, and the rest ate during a longer window, generally about 13 hours. They logged their meals in an app and wore devices to track blood sugar levels.

In the 10-hour group, most firefighters ate between 8 a.m. or 9 a.m. and 6 p.m. or 7 p.m. The time-restricted eating appeared to be linked with health benefits, such as less harmful cholesterol buildup and reduced heart disease. 

Among firefighters with risk factors for heart disease, such as high blood pressure and high blood sugar, the time-restricted eating decreased their blood pressure and blood sugar levels. 

The restricted window appears to allow the body to break down toxins and get rid of sodium and other things that can drive up blood pressure and blood sugar, the authors wrote.

During periods of fasting, “organs get some rest from digesting food so they can divert their energy toward repairing cells,” Dr. Panda said.

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

A “plethora of new agents” has transformed the treatment landscape for relapsed/refractory mantle cell lymphoma (R/RMCL) in recent years, according to an updated literature review that also included a proposed new treatment algorithm and identified areas for further investigation.

Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.

The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.

“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.

Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.

“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.

Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”

Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.

These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.

Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.

Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.

For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).

Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:

“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”

For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.

“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”

Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.

“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.

For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.

A “plethora of new agents” has transformed the treatment landscape for relapsed/refractory mantle cell lymphoma (R/RMCL) in recent years, according to an updated literature review that also included a proposed new treatment algorithm and identified areas for further investigation.

Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.

The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.

“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.

Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.

“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.

Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”

Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.

These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.

Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.

Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.

For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).

Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:

“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”

For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.

“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”

Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.

“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.

For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.

A “plethora of new agents” has transformed the treatment landscape for relapsed/refractory mantle cell lymphoma (R/RMCL) in recent years, according to an updated literature review that also included a proposed new treatment algorithm and identified areas for further investigation.

Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.

The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.

“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.

Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.

“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.

Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”

Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.

These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.

Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.

Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.

For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).

Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:

“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”

For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.

“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”

Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.

“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.

For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.

Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.

gaetan stoffel/gettyimages

The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.

“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”

The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.

“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”

The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.

Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).

One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.

“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
 

Encouraging findings, lingering concerns

Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.

“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”

Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.

John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.

“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”

Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.

“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.

Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.

While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.

“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.

This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.

Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.

Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.

gaetan stoffel/gettyimages

The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.

“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”

The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.

“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”

The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.

Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).

One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.

“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
 

Encouraging findings, lingering concerns

Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.

“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”

Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.

John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.

“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”

Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.

“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.

Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.

While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.

“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.

This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.

Fecal microbiota transplantation (FMT) is safe and highly effective as first-line therapy for patients with first or second Clostridioides difficile infection, according to the first randomized, double-blind, placebo-controlled trial of its kind.

Study enrollment was halted after an interim analysis revealed significantly better outcomes among patients who received vancomycin plus FMT versus vancomycin alone, reported lead author Simon Mark Dahl Baunwall, MD, of Aarhus (Denmark) University Hospital and colleagues in The Lancet Gastroenterology & Hepatology.

gaetan stoffel/gettyimages

The investigators noted that the participants represented a real-world patient population, so the data support FMT “as a necessary, effective first-line option” in routine management of C. difficile infection.

“Previous studies have demonstrated clinical cure rates [with FMT] of up to 92%,” Dr. Baunwall and colleagues wrote. “Early use of FMT for first or second C. difficile infection has therapeutic potential, but no formal randomized trials to support use of the approach as a first-line therapy have been done.”

The present trial, conducted at a university hospital in Denmark, involved 42 adult patients with first or second C. difficile infection. Patients were randomized in a 1:1 ratio to receive either vancomycin alone or vancomycin plus FMT. All patients received 125 mg oral vancomycin four times daily for a minimum of 10 days after diagnosis. On day 1 after completion of vancomycin therapy and again between day 3 and 7, patients received either oral FMT or matching placebo, depending on their group. After completing the protocol, patients were followed for 8 weeks or C. difficile recurrence to evaluate resolution of C. difficile–associated diarrhea.

“In this trial, patients were treated with two sequential FMT procedures on separate days,” the investigators noted. “This practice might have overtreated some patients and differs from previous trials. It remains unknown whether optimal effect is achieved by one or two treatments.”

The trial design called for 84 patients, but enrollment was halted after an interim analysis of the above cohort of 42 patients because of significantly lower rate resolution in the placebo group. At the 2-month mark, 90% (95% confidence interval, 70%-99%) of patients in the FMT group had resolution, compared with only 33% (95% CI, 15%-57%) of patients in the placebo group (P = .0003), constituting a 57% (95% CI, 33%-81%) absolute risk reduction.

Most patients experienced adverse events, including 20 in the FMT group and all 21 in the placebo group, although most were transient and nonserious. The most common adverse events were diarrhea, which occurred more frequently in the FMT group (23 vs. 14 events), followed by abdominal pain(14 vs. 11 events) and nausea (12 vs. 5 events).

One limitation of the study was its single-center design with regional uptake; the authors noted that, despite having high statistical power for the clinical effect, the study’s premature termination and low patient number prevent inferences regarding mortality, time to effect, and cost.

“The results of this trial highlight how the use of fecal microbiota transplantation as a first-line treatment can effectively prevent C. difficile recurrence and suggests that microbiota restoration might be necessary to obtain sustained resolution,” the investigators wrote. “At present, only 10% of patients with multiple, recurrent C. difficile infection and indication for FMT receive it. International initiatives address the unmet need, but logistic and regulatory obstacles remain unsolved.”
 

Encouraging findings, lingering concerns

Nicholas Turner, MD, assistant professor in the division of infectious diseases at Duke University, Durham, N.C., praised the study for “pushing the boundaries for FMT,” and noted that the methodology appeared sound. Results in the placebo group, however, cast doubt on the generalizability of the findings, he said.

“If you look at the group that received vancomycin plus placebo, their failure rate was really astoundingly high,” Dr. Turner said in an interview, referring to the 67% failure rate in the control group; he noted previous studies had reported failure rates closer to 10%. “I think that just calls into question just a little bit what happened with that control group.”

Dr. Turner said his confidence would go “way, way up” if the findings were reproduced in a larger study. Ideally, these future trials would use fidaxomicin, he added, which is becoming the preferred option over vancomycin for treating C. difficile.

John Y. Kao, MD, professor of medicine and codirector of the FMT program at University of Michigan Medicine, Ann Arbor, offered a different perspective, suggesting that the control group findings shouldn’t overshadow the efficacy of FMT.

“I agree that historical data would tell us that the placebo population should see a much higher response,” Dr. Kao said in an interview. “In my mind though, the success rate of FMT over placebo is what I would expect. The message of the study should be upheld: that FMT is an effective therapy whether it’s given early or, as the way we give it now, as a sort of rescue therapy.”

Despite this confidence in FMT as an efficacious first-line option, Dr. Kao said it is unlikely to be routinely used in this way anytime soon, even if a larger trial echoes the present results.

“We don’t know the long-term risks of FMT therapy, although we’ve been doing this now probably close to 20 years,” Dr. Kao said.

Specifically, Dr. Kao was most concerned about the long-term risk of colon cancer, as mouse models suggest that microbiome characteristics may affect risk level, and risk may vary based on host-microbiome relationships. In other words, an organism may pose no risk in the gut of the donor, but the same may not be true for the recipient.

While increased rates of colon cancer or other serious illnesses have not been detected in humans who have undergone FMT over the past 2 decades, Dr. Kao said that these findings cannot be extrapolated over a patient’s entire lifetime, especially for younger individuals.

“In a patient that’s 80, you would say, yeah, let’s go ahead and treat you [with FMT] as first-line therapy, whereas someone who’s 20, and has maybe another 50 or 60 years longevity, you may not want to give FMT as first-line therapy,” Dr. Kao said.

This study was supported by Innovation Fund Denmark. The investigators disclosed no competing interests. Dr. Turner previously performed statistical analyses for a Merck study comparing vancomycin, fidaxomicin, and metronidazole for C. difficile infection. Dr. Kao disclosed no relevant conflicts of interest.

Don’t like needles? Have we got a vaccine for you

Here’s a quick question: How do you turn the most annoying thing ever into something positive?

No, we’re not talking about politicians this time. No, not Elon Musk, either. Infomercials? Guess again. Humidity? Nope, even more annoying than that.

Give up? The most annoying thing ever is mosquitoes. This time, however, NPR reports that mosquitoes have been used to deliver a vaccine for the very disease they’ve been transmitting to their human food sources all these years.

Courtesy Jim Gathany/CDC

In a recent proof-of-concept trial, investigators used CRISPR technology to genetically modify malaria-causing Plasmodium falciparum sporozoites, which just happen to live in the salivary glands of Anopheles mosquitoes. And since the Plasmodium parasites are already in the mosquitoes, it made sense to use the buzzy little critters as the delivery device for the vaccine.

More sense than a syringe, you ask? Have you ever tried to poke a syringe into the salivary gland of a mosquito? No, we thought not. Well, we can tell you from experience that it’s really, really hard. Never mind how we know. We just do.

The 14 study volunteers – who were paid $4,100 for their participation – were first exposed to hundreds of mosquitoes carrying the altered Plasmodium parasites. Then, to test the vaccine, they were exposed to mosquitoes that had actual, malaria-carrying Plasmodium. Half of the subjects got malaria, so the vaccine was only 50% effective, meaning there’s still work to do.

Meanwhile, the scientists here at LOTMEco are all over this mosquito-delivery business, working on a vaccine to prevent Elon Musk. Plan B involves some sort of really big swatter.
 

Climate change: Sleeping your life away

It’s no secret that climate change is raising the temperature on everything. You may think you’re getting relief when the sun goes down, but in some places it’s still hot. A new survey conducted in central Japan shows how bad it can be and how higher nighttime temperatures can have a serious impact on people’s health.

Public Domain Vectors

That online survey, the Sleep Quality Index for Daily Sleep, enabled the investigators to correlate sleep quality with daily temperature for 1,284 adults in 2011 and 2012 who completed the survey over 10 days.

Not only was there a significant difference in sleep disturbance among younger men (higher) versus older men, but the prevalence of sleep disturbance went up when the daytime temperature was above 24.8° C. They also found that disability-adjusted life-years (DALYs), which measure time lost through premature death and time lived in certain conditions that put one’s health at risk, were 81.8 years for the city of Nagoya (population, 2.2 million) in 2012.

The damage to health from sleep disorders caused by daily temperatures higher than 25° C “is comparable to that of heatstroke and must be addressed,” lead author Tomohiko Ihara of the University of Tokyo said in a written statement.

The researchers hope that this information will help sway legislators to consider the impact of higher nighttime temperatures and that it can be used to provide guidance for better sleep. The solution for now? Sleep with the air conditioner on. Your energy bill might increase, but just think about those DALYs. If using the AC lowers DALYs and increases time lived, then we say it’s worth it.
 

Maybe it would have been a dragon WITH cancer

If you ask a random person on the street to tell you all they know about the country of Wales, they’ll probably mention two things: One, the contorted collection of jumbled-up letters that is the Welsh language (looking at you, Llanfairpwllgwyngyll­gogery­chwyrn­drobwll­llan­tysilio­gogo­goch) and, two, the association with dragons. The Welsh flag even has a dragon on it.

evakocsan/Pixnio

With that in mind, take a guess as to what sort of statue art dealer Simon Wingett wanted to build in the Welsh town of Wrexham. No, not a monument to the second-longest place name in the world. Try again. His dragon would not be some piddly little thing either; he wanted a virtual kaiju overlooking the town, with the whole statue to stand about 60 meters high. That’s taller than the original 1954 Godzilla.

Artistic masterpieces may sell for frankly insane prices, but art dealers themselves are not the wealthiest of individuals, so Mr. Wingett needed money to fund his dragon-based dream. Lucky for him, he also happened to be the manager of a cancer charity – initially set up by Mr. Wingett’s father, who had throat cancer – which nominally aimed to provide equipment and resources to cancer patients in the Wrexham area.

Yes, this is going precisely where you think it’s going. From 2011 to 2018, when the charity closed, Mr. Wingett used the charity’s donations to fund his dragon statue – which never actually got built, by the way – to the tune of over 400,000 pounds. Of course, Mr. Wingett came under scrutiny when people started to notice that his cancer charity hadn’t actually done anything charitable since 2011, and he was recently banned by the Welsh High Court from serving as trustee of any charity for 10 years. Oh no, tragedy and horror! Truly a punishment worse than death itself.

Okay fine, he also has to pay back 117,000 pounds to actual legitimate cancer charities. The astute mathematicians out there may notice that 117,000 is a lot less than 400,000. But it’s just as the old saying goes: One-quarter of crime doesn’t pay. You can keep three-quarters of it, though, that’s completely fine.

Don’t like needles? Have we got a vaccine for you

Here’s a quick question: How do you turn the most annoying thing ever into something positive?

No, we’re not talking about politicians this time. No, not Elon Musk, either. Infomercials? Guess again. Humidity? Nope, even more annoying than that.

Give up? The most annoying thing ever is mosquitoes. This time, however, NPR reports that mosquitoes have been used to deliver a vaccine for the very disease they’ve been transmitting to their human food sources all these years.

Courtesy Jim Gathany/CDC

In a recent proof-of-concept trial, investigators used CRISPR technology to genetically modify malaria-causing Plasmodium falciparum sporozoites, which just happen to live in the salivary glands of Anopheles mosquitoes. And since the Plasmodium parasites are already in the mosquitoes, it made sense to use the buzzy little critters as the delivery device for the vaccine.

More sense than a syringe, you ask? Have you ever tried to poke a syringe into the salivary gland of a mosquito? No, we thought not. Well, we can tell you from experience that it’s really, really hard. Never mind how we know. We just do.

The 14 study volunteers – who were paid $4,100 for their participation – were first exposed to hundreds of mosquitoes carrying the altered Plasmodium parasites. Then, to test the vaccine, they were exposed to mosquitoes that had actual, malaria-carrying Plasmodium. Half of the subjects got malaria, so the vaccine was only 50% effective, meaning there’s still work to do.

Meanwhile, the scientists here at LOTMEco are all over this mosquito-delivery business, working on a vaccine to prevent Elon Musk. Plan B involves some sort of really big swatter.
 

Climate change: Sleeping your life away

It’s no secret that climate change is raising the temperature on everything. You may think you’re getting relief when the sun goes down, but in some places it’s still hot. A new survey conducted in central Japan shows how bad it can be and how higher nighttime temperatures can have a serious impact on people’s health.

Public Domain Vectors

That online survey, the Sleep Quality Index for Daily Sleep, enabled the investigators to correlate sleep quality with daily temperature for 1,284 adults in 2011 and 2012 who completed the survey over 10 days.

Not only was there a significant difference in sleep disturbance among younger men (higher) versus older men, but the prevalence of sleep disturbance went up when the daytime temperature was above 24.8° C. They also found that disability-adjusted life-years (DALYs), which measure time lost through premature death and time lived in certain conditions that put one’s health at risk, were 81.8 years for the city of Nagoya (population, 2.2 million) in 2012.

The damage to health from sleep disorders caused by daily temperatures higher than 25° C “is comparable to that of heatstroke and must be addressed,” lead author Tomohiko Ihara of the University of Tokyo said in a written statement.

The researchers hope that this information will help sway legislators to consider the impact of higher nighttime temperatures and that it can be used to provide guidance for better sleep. The solution for now? Sleep with the air conditioner on. Your energy bill might increase, but just think about those DALYs. If using the AC lowers DALYs and increases time lived, then we say it’s worth it.
 

Maybe it would have been a dragon WITH cancer

If you ask a random person on the street to tell you all they know about the country of Wales, they’ll probably mention two things: One, the contorted collection of jumbled-up letters that is the Welsh language (looking at you, Llanfairpwllgwyngyll­gogery­chwyrn­drobwll­llan­tysilio­gogo­goch) and, two, the association with dragons. The Welsh flag even has a dragon on it.

evakocsan/Pixnio

With that in mind, take a guess as to what sort of statue art dealer Simon Wingett wanted to build in the Welsh town of Wrexham. No, not a monument to the second-longest place name in the world. Try again. His dragon would not be some piddly little thing either; he wanted a virtual kaiju overlooking the town, with the whole statue to stand about 60 meters high. That’s taller than the original 1954 Godzilla.

Artistic masterpieces may sell for frankly insane prices, but art dealers themselves are not the wealthiest of individuals, so Mr. Wingett needed money to fund his dragon-based dream. Lucky for him, he also happened to be the manager of a cancer charity – initially set up by Mr. Wingett’s father, who had throat cancer – which nominally aimed to provide equipment and resources to cancer patients in the Wrexham area.

Yes, this is going precisely where you think it’s going. From 2011 to 2018, when the charity closed, Mr. Wingett used the charity’s donations to fund his dragon statue – which never actually got built, by the way – to the tune of over 400,000 pounds. Of course, Mr. Wingett came under scrutiny when people started to notice that his cancer charity hadn’t actually done anything charitable since 2011, and he was recently banned by the Welsh High Court from serving as trustee of any charity for 10 years. Oh no, tragedy and horror! Truly a punishment worse than death itself.

Okay fine, he also has to pay back 117,000 pounds to actual legitimate cancer charities. The astute mathematicians out there may notice that 117,000 is a lot less than 400,000. But it’s just as the old saying goes: One-quarter of crime doesn’t pay. You can keep three-quarters of it, though, that’s completely fine.

Don’t like needles? Have we got a vaccine for you

Here’s a quick question: How do you turn the most annoying thing ever into something positive?

No, we’re not talking about politicians this time. No, not Elon Musk, either. Infomercials? Guess again. Humidity? Nope, even more annoying than that.

Give up? The most annoying thing ever is mosquitoes. This time, however, NPR reports that mosquitoes have been used to deliver a vaccine for the very disease they’ve been transmitting to their human food sources all these years.

Courtesy Jim Gathany/CDC

In a recent proof-of-concept trial, investigators used CRISPR technology to genetically modify malaria-causing Plasmodium falciparum sporozoites, which just happen to live in the salivary glands of Anopheles mosquitoes. And since the Plasmodium parasites are already in the mosquitoes, it made sense to use the buzzy little critters as the delivery device for the vaccine.

More sense than a syringe, you ask? Have you ever tried to poke a syringe into the salivary gland of a mosquito? No, we thought not. Well, we can tell you from experience that it’s really, really hard. Never mind how we know. We just do.

The 14 study volunteers – who were paid $4,100 for their participation – were first exposed to hundreds of mosquitoes carrying the altered Plasmodium parasites. Then, to test the vaccine, they were exposed to mosquitoes that had actual, malaria-carrying Plasmodium. Half of the subjects got malaria, so the vaccine was only 50% effective, meaning there’s still work to do.

Meanwhile, the scientists here at LOTMEco are all over this mosquito-delivery business, working on a vaccine to prevent Elon Musk. Plan B involves some sort of really big swatter.
 

Climate change: Sleeping your life away

It’s no secret that climate change is raising the temperature on everything. You may think you’re getting relief when the sun goes down, but in some places it’s still hot. A new survey conducted in central Japan shows how bad it can be and how higher nighttime temperatures can have a serious impact on people’s health.

Public Domain Vectors

That online survey, the Sleep Quality Index for Daily Sleep, enabled the investigators to correlate sleep quality with daily temperature for 1,284 adults in 2011 and 2012 who completed the survey over 10 days.

Not only was there a significant difference in sleep disturbance among younger men (higher) versus older men, but the prevalence of sleep disturbance went up when the daytime temperature was above 24.8° C. They also found that disability-adjusted life-years (DALYs), which measure time lost through premature death and time lived in certain conditions that put one’s health at risk, were 81.8 years for the city of Nagoya (population, 2.2 million) in 2012.

The damage to health from sleep disorders caused by daily temperatures higher than 25° C “is comparable to that of heatstroke and must be addressed,” lead author Tomohiko Ihara of the University of Tokyo said in a written statement.

The researchers hope that this information will help sway legislators to consider the impact of higher nighttime temperatures and that it can be used to provide guidance for better sleep. The solution for now? Sleep with the air conditioner on. Your energy bill might increase, but just think about those DALYs. If using the AC lowers DALYs and increases time lived, then we say it’s worth it.
 

Maybe it would have been a dragon WITH cancer

If you ask a random person on the street to tell you all they know about the country of Wales, they’ll probably mention two things: One, the contorted collection of jumbled-up letters that is the Welsh language (looking at you, Llanfairpwllgwyngyll­gogery­chwyrn­drobwll­llan­tysilio­gogo­goch) and, two, the association with dragons. The Welsh flag even has a dragon on it.

evakocsan/Pixnio

With that in mind, take a guess as to what sort of statue art dealer Simon Wingett wanted to build in the Welsh town of Wrexham. No, not a monument to the second-longest place name in the world. Try again. His dragon would not be some piddly little thing either; he wanted a virtual kaiju overlooking the town, with the whole statue to stand about 60 meters high. That’s taller than the original 1954 Godzilla.

Artistic masterpieces may sell for frankly insane prices, but art dealers themselves are not the wealthiest of individuals, so Mr. Wingett needed money to fund his dragon-based dream. Lucky for him, he also happened to be the manager of a cancer charity – initially set up by Mr. Wingett’s father, who had throat cancer – which nominally aimed to provide equipment and resources to cancer patients in the Wrexham area.

Yes, this is going precisely where you think it’s going. From 2011 to 2018, when the charity closed, Mr. Wingett used the charity’s donations to fund his dragon statue – which never actually got built, by the way – to the tune of over 400,000 pounds. Of course, Mr. Wingett came under scrutiny when people started to notice that his cancer charity hadn’t actually done anything charitable since 2011, and he was recently banned by the Welsh High Court from serving as trustee of any charity for 10 years. Oh no, tragedy and horror! Truly a punishment worse than death itself.

Okay fine, he also has to pay back 117,000 pounds to actual legitimate cancer charities. The astute mathematicians out there may notice that 117,000 is a lot less than 400,000. But it’s just as the old saying goes: One-quarter of crime doesn’t pay. You can keep three-quarters of it, though, that’s completely fine.

Glucocorticoids (GCs) are among the most widely prescribed medications in dermatologic practice. Although GCs are highly effective anti-inflammatory agents, long-term systemic therapy can result in dangerous adverse effects, including GC-induced osteoporosis (GIO), a bone disease associated with a heightened risk for fragility fractures.^1,2 In the United States, an estimated 10.2 million adults have osteoporosis—defined as a T-score lower than −2.5 measured via a bone densitometry scan—and 43.4 million adults have low bone mineral density (BMD).^3,4 The prevalence of osteoporosis is increasing, and the diagnosis is more common in females and adults 55 years and older.² More than 2 million individuals have osteoporosis-related fractures annually, and the mortality risk is increased at 5 and 10 years following low-energy osteoporosis-related fractures.^3-5

Glucocorticoid therapy is the leading iatrogenic cause of secondary osteoporosis. As many as 30% of all patients treated with systemic GCs for more than 6 months develop GIO.^1,6,7 Glucocorticoid-induced BMD loss occurs at a rate of 6% to 12% of total BMD during the first year, slowing to approximately 3% per year during subsequent therapy.¹ The risk for insufficiency fractures increases by as much as 75% from baseline in adults with rheumatic, pulmonary, and skin disorders within the first 3 months of therapy and peaks at approximately 12 months.^1,2

Despite the risks, many long-term GC users never receive therapy to prevent bone loss; others are only started on therapy once they have sustained an insufficiency fracture. A 5-year international observational study including more than 40,000 postmenopausal women found that only 51% of patients who were on continuous GC therapy were undergoing BMD testing and appropriate medical management.⁸ This review highlights the existing evidence on the risks of osteoporosis and osteoporotic (OP) fractures in the setting of topical, intralesional, intramuscular, and systemic GC treatment, as well as recommendations for nutritional supplementation to reduce these risks.

Pathophysiology

The pathophysiology of GIO is multifactorial and occurs in both early and late phases.^9,10 The early phase is characterized by rapid BMD reduction due to excessive bone resorption. The late phase is characterized by slower and more progressive BMD reduction due to impaired bone formation.⁹ At the osteocyte level, GCs decrease cell viability and induce apoptosis.¹¹ At the osteoblast level, GCs impair cell replication and differentiation and have proapoptotic effects, resulting in decreased cell numbers and subsequent bone formation.¹⁰ At the osteoclast level, GCs increase expression of pro-osteoclastic cytokines and decrease mature osteoclast apoptosis, resulting in an expanded osteoclastic life span and prolonged bone resorption.^12,13 Indirectly, GCs alter calcium metabolism by decreasing gastrointestinal calcium absorption and impairing renal absorption.^14,15

GCs and Osteoporosis

Oral GCs—Glucocorticoid-induced osteoporosis and fracture risk are dose and duration dependent.⁶ A study of 244,235 patients taking GCs and 244,235 controls found the relative risk of vertebral fracture was 1.55 (range, 1.20–2.01) for daily prednisone use at less than 2.5 mg, 2.59 (range, 2.16–3.10) for daily prednisone use from 2.5 to 7.4 mg, and 5.18 (range, 4.25–6.31) for daily doses of 7.5 mg or higher; the relative risk for hip fractures was 0.99 (range, 0.82–1.20), 1.77 (range, 1.55–2.02), and 2.27 (range, 1.94–2.66), respectively.¹⁶ Another large retrospective cohort study found that continuous treatment with prednisone 10 mg/d for more than 90 days compared to no GC exposure increased the risk for hip fractures 7-fold and 17-fold for vertebral fractures.¹⁷ Although the minimum cumulative dose of GCs known to cause osteoporosis is not clearly established, the American College of Rheumatology has proposed an algorithm as a basic approach to anticipate, prevent, and treat GIO (Figure).^18,19 Fracture risk should be assessed in all patients who are prescribed prednisone 2.5 mg/d for 3 months or longer or an anticipated cumulative dose of more than 1 g per year. Patients 40 years and older with anticipated GC use of 3 months or longer should have both a bone densitometry scan and a Fracture Risk Assessment (FRAX) score. The FRAX tool estimates the 10-year probability of fracture in patients aged 40 to 80 years, and those patients can be further risk stratified as low (FRAX <10%), moderate (FRAX 10%–19%), or high (FRAX ≥20%) risk. In patients with moderate to high risk of fracture (FRAX >10%), initiation of pharmacologic treatment or referral to a metabolic bone specialist should be considered.^18,19 First-line therapy is an oral bisphosphonate, and second-line therapies include intravenous bisphosphonates, teriparatide, denosumab, or raloxifene for patients at high risk for GIO.¹⁹ Adults younger than 40 years with a history of OP fracture or considerable risk factors for OP fractures should have a bone densitometry scan, and, if results are abnormal, the patient should be referred to a metabolic bone specialist. Those with low fracture risk based on bone densitometry and FRAX and those with no risk factors should be assessed annually for bone health (additional risk factors, GC dose and duration, bone densitometry/FRAX if indicated).¹⁸ In addition to GC dose and duration, additional risk factors for GIO, which are factored into the FRAX tool, include advanced age, low body mass index, history of bone fracture, smoking, excessive alcohol use (≥3 drinks/d), history of falls, low BMD, family history of bone fracture, and hypovitaminosis D.⁶

Topical GCs—Although there is strong evidence and clear guidelines regarding oral GIO, there is a dearth of data surrounding OP risk due to treatment with topical GCs. A recent retrospective nationwide Danish study evaluating the risk of osteoporosis and major OP fracture in 723,251 adults treated with potent or very potent topical steroids sought to evaluate these risks.²⁰ Patients were included if they had filled prescriptions of at least 500 g of topical mometasone or an equivalent alternative. The investigators reported a 3% increase in relative risk of osteoporosis and major OP fracture with doubling of the cumulative topical GC dose (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for major OP fracture. Notably, at least 10,000 g of mometasone was required for 1 additional patient to have a major OP fracture.²⁰ In a commentary based on this study, Jackson²¹ noted that the number of patient-years of topical GC use needed for 1 fracture was 4-fold higher than that for high-dose oral GCs (40 mg/d prednisolone for ≥30 days). Another study assessed the effects of topical GCs on BMD in adults with moderate to severe atopic dermatitis over a 2-year period.²² No significant difference in BMD assessed via bone densitometry of either the lumbar spine or total hip at baseline or at 2-year follow-up was reported for either group treated with corticosteroids (<75 g per month or ≥75 g per month). Of note, the authors did not account for steroid potency, which ranged from class 1 through class 4.²² Although limited data exist, these studies suggest topical GCs used at conventional doses with appropriate breaks in therapy will not substantially increase risk for GIO or OP fracture; however, in the small subset of patients requiring chronic use of superpotent topical corticosteroids with other OP risk factors, transitioning to non–GC-based therapy or initiating bone health therapy may be advised to improve patient outcomes. Risk assessment, as in cases of chronic topical GC use, may be beneficial.

Intralesional GCs—Intralesional GCs are indicated for numerous inflammatory conditions including alopecia areata, discoid lupus erythematosus, keloids, and granuloma annulare. It generally is accepted that doses of triamcinolone acetonide should not exceed 20 mg per session spaced at least 3 weeks apart or up to 40 mg per month.¹⁸ One study demonstrated that doses of triamcinolone diacetate of 25 mg or less were unlikely to produce systemic effects and were determined to be a safe dose for intralesional injections.²³ A retrospective cross-sectional case series including 18 patients with alopecia areata reported decreased BMD in 9 patients receiving intralesional triamcinolone acetonide 10 mg/mL at 4- to 8-week intervals for at least 20 months, with cumulative doses greater than 500 mg. This was particularly notable in postmenopausal women and men older than 50 years; participants with a body mass index less than 18.5 kg/m², history of a stress fracture, family history of osteopenia or osteoporosis, and history of smoking; and those who did not regularly engage in weight-bearing exercises.²⁴ Patients receiving long-term (ie, >1 year) intralesional steroids should be evaluated for osteoporosis risk and preventative strategies should be considered (ie, regular weight-bearing exercises, calcium and vitamin D supplementation, bisphosphate therapy). As with topical GCs, there are no clear guidelines for risk assessment or treatment recommendations for GIO.

Intramuscular GCs—The data regarding intramuscular (IM) GCs and dermatologic disease is severely limited, and to the best of our knowledge, no studies specifically assess the risk for GIO or fracture secondary to intramuscular GCs; however, a retrospective study of 27 patients (4 female, 23 male; mean age, 33 years [range, 12–61 years]) with refractory alopecia areata receiving IM triamcinolone acetonide (40 mg every 4 weeks for 3–6 months) reported 1 patient (a 56-year-old woman) with notably decreased bone densitometry from baseline requiring treatment discontinuation.²⁵ No other patients at risk for osteoporosis had decreased BMD from treatment with IM triamcinolone; however, it was noted that 1 month following treatment, 10 of 11 assessed patients demonstrated decreased levels of morning serum cortisol and plasma adrenocorticotropic hormone—despite baseline levels within reference range—that resolved 3 months after treatment completion,²⁵ which suggests a prolonged release of IM triamcinolone and sustained systemic effect. One systematic review of 342 patients with dermatologic diseases treated with IM corticosteroids found the primary side effects included dysmenorrhea, injection-site lipoatrophy, and adrenocortical suppression, with only a single reported case of low BMD.²⁶ Given the paucity of evidence, additional studies are required to assess the effect of IM triamcinolone on BMD and risk for major OP fractures with regard to dosing and frequency. As there are no clear guidelines for osteoporosis evaluation in the setting of intramuscular GCs, it may be prudent to follow the algorithmic model recommended for oral steroids when anticipating at least 3 months of intramuscular GCs.

Diet and Prevention of Bone Loss

Given the profound impact that systemic GCs have on osteoporosis and fracture risk and the sparse data regarding risk from topical, intralesional, or intramuscular GCs, diet and nutrition represent a simple, safe, and potentially preventative method of slowing BMD loss and minimizing fracture risk. In higher-risk patients, nutritional assessment in combination with medical therapy also is likely warranted.

Calcium and Vitamin D₃—Patients treated with any GC dose longer than 3 months should undergo calcium and vitamin D optimization.¹⁹ Exceptions for supplementation include certain patients with sarcoidosis, which can be associated with high vitamin D levels; patients with a history of hypercalcemia or hypercalciuria; and patients with chronic kidney disease.⁶ In a meta-analysis including 30,970 patients in 8 randomized controlled trials, calcium (500–1200 mg/d) and vitamin D (400–800 IU/d) supplementation reduced the risk of total fractures by 15% (summary relative risk estimate, 0.85 [95% CI, 0.73-0.98]) and hip fractures by 30% (summary relative risk estimate, 0.70 [95% CI, 0.56-0.87]).⁴ One double-blind, placebo-controlled clinical trial conducted by the Women’s Health Initiative that included 36,282 postmenopausal women who were taking 1000 mg of calcium and 400 IU of vitamin D₃ daily for more than 5 years reported an HR of 0.62 (95% CI, 0.38-1.00) for hip fracture for supplementation vs placebo.²⁷ Lastly, a 2016 Cochrane Review including 12 randomized trials and 1343 participants reported a 43% lower risk of new vertebral fractures following supplementation with calcium, vitamin D, or both compared with controls.²⁸

Specific recommendations for calcium and vitamin D₃ supplementation vary based on age and sex. The US Preventive Services Task Force concluded that insufficient evidence exists to support calcium and vitamin D₃ supplementation in asymptomatic men and premenopausal women.²⁹ The National Osteoporosis Foundation (NOF) supports the use of calcium supplementation for fracture risk reduction in middle-aged and older adults.⁴ Furthermore, the NOF supports the Institute of Medicine recommendations³¹ that men aged 50 to 70 years consume 1000 mg/d of calcium and that women 51 years and older as well as men 71 years and older consume 1200 mg/d of calcium.³⁰ The NOF recommends 800 to 1000 IU/d of vitamin D in adults 50 years and older, while the Institute of Medicine recommends 600 IU/d in adults 70 years and younger and 800 IU/d in adults 71 years and older.³¹ These recommendations are similar to both the Endocrine Society and the American Geriatric Society.^32,33 Total calcium should not exceed 2000 mg/d due to risk of adverse effects.

Dietary sources of vitamin D include fatty fish, mushrooms, and fortified dairy products, though recommended doses rarely can be achieved through diet alone.³⁴ Dairy products are the primary source of dietary calcium. Other high-calcium foods include green leafy vegetables, nuts and seeds, soft-boned fish, and fortified beverages and cereals.³⁵

Probiotics—A growing body of evidence suggests that probiotics may be beneficial in promoting bone health by improving calcium homeostasis, reducing risk for hyperparathyroidism secondary to GC therapy, and decreasing age-related bone resorption.³⁶ An animal study demonstrated that probiotics can regulate bone resorption and formation as well as reduce bone loss secondary to GC therapy.³⁷ A randomized, double-blind, placebo-controlled, multicenter trial randomly assigned 249 healthy, early postmenopausal women to receive probiotic treatment containing 3 lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and L plantarum DSM 15313) or placebo once daily for 12 months.³⁸ Bone mineral density was measured at baseline and at 12 months. Of the 234 participants who completed the study, lactobacillus treatment reduced lumbosacral BMD loss compared to the placebo group (mean difference, 0.71% [95% CI, 0.06-1.35]). They also reported significant lumbosacral BMD loss in the placebo group (−0.72% [95% CI, −1.22 to −0.22]) compared to no BMD loss in the group treated with lactobacillus (−0.01% [95% CI, −0.50 to 0.48]).³⁸ Although the data may be encouraging, more studies are needed to determine if probiotics should be regarded as an adjuvant treatment to calcium, vitamin D, and pharmacologic therapy for long-term prevention of bone loss in the setting of GIO.³⁹ Because existing studies on probiotics include varying compositions and doses, larger studies with consistent supplementation are required. Encouraging probiotic intake through fermented dairy products may represent a simple low-risk intervention to support bone health.

Anti-inflammatory Diet—The traditional Mediterranean diet is rich in fruits, vegetables, fish, nuts, whole grains, legumes, and monounsaturated fats and low in meat and dairy products. The Mediterranean diet has been shown to be modestly protective against osteoporosis and fracture risk. A large US observational study including 93,676 women showed that those with the highest quintile of the alternate Mediterranean diet score had a lower risk for hip fracture (HR, 0.80 [95% CI, 0.66-0.97]), with an absolute risk reduction of 0.29% and number needed to treat at 342.⁴⁰ A multicenter study involving adults from 8 European countries found that increased adherence to the Mediterranean diet was associated with a 7% reduction in hip fracture incidence (HR per 1 unit increase in Mediterranean diet, 0.93 [95% CI, 0.89-0.98]). High vegetable and fruit intake was associated with decreased hip fracture incidence (HR, 0.86 and 0.89 [95% CI, 0.79-0.94 and 0.82-0.97, respectively]), and high meat and excessive ethanol consumption were associated with increased fracture incidence (HR, 1.18 and 1.74 [95% CI, 1.06-1.31 and 1.32-2.31, respectively]).⁴¹ Similarly, a large observational study in Sweden that included 37,903 men and 33,403 women reported similar findings, noting a 6% lower hip fracture rate per one unit increase in alternate Mediterranean diet score (adjusted HR, 0.94 [95% CI, 0.92-0.96]).⁴² This is thought to be due in part to higher levels of dietary vitamin D present in many foods traditionally included in the Mediterranean diet.⁴³ Additionally, olive oil, a staple in the Mediterranean diet, appears to reduce bone loss by promoting osteoblast proliferation and maturation, inhibiting bone resorption, suppressing oxidative stress and inflammation, and increasing calcium deposition in the extracellular matrix.^44,45 Fruits, vegetables, legumes, and nuts also are rich in minerals including potassium and magnesium, which are important in bone health to promote osteoblast proliferation and vitamin D activation.^36,46-48

Final Thoughts

Osteoporosis-related fractures are common and are associated with high morbidity and health care costs. Dermatologists using and prescribing corticosteroids must be aware of the risk for GIO, particularly in patients with a pre-existing diagnosis of osteopenia or osteoporosis. There likely is no oral corticosteroid dose that does not increase a patient’s risk for osteoporosis; therefore, oral GCs should be used at the lowest effective daily dose for the shortest duration possible. Patients with an anticipated duration of at least 3 months—regardless of dose—should be assessed for their risk for GIO. Patients using topical and intralesional corticosteroids are unlikely to develop GIO; however, those with risk factors and a considerable cumulative dose may warrant further evaluation. In all cases, we advocate for supplementing with calcium and vitamin D as well as promoting probiotic intake and the Mediterranean diet. Those at moderate to high risk for fracture may require additional medical therapy. Dermatologists are uniquely positioned to identify this at-risk population, and because osteoporosis is a chronic illness, primary care providers should be notified of prolonged GC therapy to help with risk assessment, initiation of vitamin and mineral supplementation, and follow-up with metabolic bone health specialists. Through a multidisciplinary approach and patient education, GIO and the potential risk for fracture can be successfully mitigated in most patients.

Glucocorticoids (GCs) are among the most widely prescribed medications in dermatologic practice. Although GCs are highly effective anti-inflammatory agents, long-term systemic therapy can result in dangerous adverse effects, including GC-induced osteoporosis (GIO), a bone disease associated with a heightened risk for fragility fractures.^1,2 In the United States, an estimated 10.2 million adults have osteoporosis—defined as a T-score lower than −2.5 measured via a bone densitometry scan—and 43.4 million adults have low bone mineral density (BMD).^3,4 The prevalence of osteoporosis is increasing, and the diagnosis is more common in females and adults 55 years and older.² More than 2 million individuals have osteoporosis-related fractures annually, and the mortality risk is increased at 5 and 10 years following low-energy osteoporosis-related fractures.^3-5

Glucocorticoid therapy is the leading iatrogenic cause of secondary osteoporosis. As many as 30% of all patients treated with systemic GCs for more than 6 months develop GIO.^1,6,7 Glucocorticoid-induced BMD loss occurs at a rate of 6% to 12% of total BMD during the first year, slowing to approximately 3% per year during subsequent therapy.¹ The risk for insufficiency fractures increases by as much as 75% from baseline in adults with rheumatic, pulmonary, and skin disorders within the first 3 months of therapy and peaks at approximately 12 months.^1,2

Despite the risks, many long-term GC users never receive therapy to prevent bone loss; others are only started on therapy once they have sustained an insufficiency fracture. A 5-year international observational study including more than 40,000 postmenopausal women found that only 51% of patients who were on continuous GC therapy were undergoing BMD testing and appropriate medical management.⁸ This review highlights the existing evidence on the risks of osteoporosis and osteoporotic (OP) fractures in the setting of topical, intralesional, intramuscular, and systemic GC treatment, as well as recommendations for nutritional supplementation to reduce these risks.

Pathophysiology

The pathophysiology of GIO is multifactorial and occurs in both early and late phases.^9,10 The early phase is characterized by rapid BMD reduction due to excessive bone resorption. The late phase is characterized by slower and more progressive BMD reduction due to impaired bone formation.⁹ At the osteocyte level, GCs decrease cell viability and induce apoptosis.¹¹ At the osteoblast level, GCs impair cell replication and differentiation and have proapoptotic effects, resulting in decreased cell numbers and subsequent bone formation.¹⁰ At the osteoclast level, GCs increase expression of pro-osteoclastic cytokines and decrease mature osteoclast apoptosis, resulting in an expanded osteoclastic life span and prolonged bone resorption.^12,13 Indirectly, GCs alter calcium metabolism by decreasing gastrointestinal calcium absorption and impairing renal absorption.^14,15

GCs and Osteoporosis

Oral GCs—Glucocorticoid-induced osteoporosis and fracture risk are dose and duration dependent.⁶ A study of 244,235 patients taking GCs and 244,235 controls found the relative risk of vertebral fracture was 1.55 (range, 1.20–2.01) for daily prednisone use at less than 2.5 mg, 2.59 (range, 2.16–3.10) for daily prednisone use from 2.5 to 7.4 mg, and 5.18 (range, 4.25–6.31) for daily doses of 7.5 mg or higher; the relative risk for hip fractures was 0.99 (range, 0.82–1.20), 1.77 (range, 1.55–2.02), and 2.27 (range, 1.94–2.66), respectively.¹⁶ Another large retrospective cohort study found that continuous treatment with prednisone 10 mg/d for more than 90 days compared to no GC exposure increased the risk for hip fractures 7-fold and 17-fold for vertebral fractures.¹⁷ Although the minimum cumulative dose of GCs known to cause osteoporosis is not clearly established, the American College of Rheumatology has proposed an algorithm as a basic approach to anticipate, prevent, and treat GIO (Figure).^18,19 Fracture risk should be assessed in all patients who are prescribed prednisone 2.5 mg/d for 3 months or longer or an anticipated cumulative dose of more than 1 g per year. Patients 40 years and older with anticipated GC use of 3 months or longer should have both a bone densitometry scan and a Fracture Risk Assessment (FRAX) score. The FRAX tool estimates the 10-year probability of fracture in patients aged 40 to 80 years, and those patients can be further risk stratified as low (FRAX <10%), moderate (FRAX 10%–19%), or high (FRAX ≥20%) risk. In patients with moderate to high risk of fracture (FRAX >10%), initiation of pharmacologic treatment or referral to a metabolic bone specialist should be considered.^18,19 First-line therapy is an oral bisphosphonate, and second-line therapies include intravenous bisphosphonates, teriparatide, denosumab, or raloxifene for patients at high risk for GIO.¹⁹ Adults younger than 40 years with a history of OP fracture or considerable risk factors for OP fractures should have a bone densitometry scan, and, if results are abnormal, the patient should be referred to a metabolic bone specialist. Those with low fracture risk based on bone densitometry and FRAX and those with no risk factors should be assessed annually for bone health (additional risk factors, GC dose and duration, bone densitometry/FRAX if indicated).¹⁸ In addition to GC dose and duration, additional risk factors for GIO, which are factored into the FRAX tool, include advanced age, low body mass index, history of bone fracture, smoking, excessive alcohol use (≥3 drinks/d), history of falls, low BMD, family history of bone fracture, and hypovitaminosis D.⁶

Topical GCs—Although there is strong evidence and clear guidelines regarding oral GIO, there is a dearth of data surrounding OP risk due to treatment with topical GCs. A recent retrospective nationwide Danish study evaluating the risk of osteoporosis and major OP fracture in 723,251 adults treated with potent or very potent topical steroids sought to evaluate these risks.²⁰ Patients were included if they had filled prescriptions of at least 500 g of topical mometasone or an equivalent alternative. The investigators reported a 3% increase in relative risk of osteoporosis and major OP fracture with doubling of the cumulative topical GC dose (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for major OP fracture. Notably, at least 10,000 g of mometasone was required for 1 additional patient to have a major OP fracture.²⁰ In a commentary based on this study, Jackson²¹ noted that the number of patient-years of topical GC use needed for 1 fracture was 4-fold higher than that for high-dose oral GCs (40 mg/d prednisolone for ≥30 days). Another study assessed the effects of topical GCs on BMD in adults with moderate to severe atopic dermatitis over a 2-year period.²² No significant difference in BMD assessed via bone densitometry of either the lumbar spine or total hip at baseline or at 2-year follow-up was reported for either group treated with corticosteroids (<75 g per month or ≥75 g per month). Of note, the authors did not account for steroid potency, which ranged from class 1 through class 4.²² Although limited data exist, these studies suggest topical GCs used at conventional doses with appropriate breaks in therapy will not substantially increase risk for GIO or OP fracture; however, in the small subset of patients requiring chronic use of superpotent topical corticosteroids with other OP risk factors, transitioning to non–GC-based therapy or initiating bone health therapy may be advised to improve patient outcomes. Risk assessment, as in cases of chronic topical GC use, may be beneficial.

Intralesional GCs—Intralesional GCs are indicated for numerous inflammatory conditions including alopecia areata, discoid lupus erythematosus, keloids, and granuloma annulare. It generally is accepted that doses of triamcinolone acetonide should not exceed 20 mg per session spaced at least 3 weeks apart or up to 40 mg per month.¹⁸ One study demonstrated that doses of triamcinolone diacetate of 25 mg or less were unlikely to produce systemic effects and were determined to be a safe dose for intralesional injections.²³ A retrospective cross-sectional case series including 18 patients with alopecia areata reported decreased BMD in 9 patients receiving intralesional triamcinolone acetonide 10 mg/mL at 4- to 8-week intervals for at least 20 months, with cumulative doses greater than 500 mg. This was particularly notable in postmenopausal women and men older than 50 years; participants with a body mass index less than 18.5 kg/m², history of a stress fracture, family history of osteopenia or osteoporosis, and history of smoking; and those who did not regularly engage in weight-bearing exercises.²⁴ Patients receiving long-term (ie, >1 year) intralesional steroids should be evaluated for osteoporosis risk and preventative strategies should be considered (ie, regular weight-bearing exercises, calcium and vitamin D supplementation, bisphosphate therapy). As with topical GCs, there are no clear guidelines for risk assessment or treatment recommendations for GIO.

Intramuscular GCs—The data regarding intramuscular (IM) GCs and dermatologic disease is severely limited, and to the best of our knowledge, no studies specifically assess the risk for GIO or fracture secondary to intramuscular GCs; however, a retrospective study of 27 patients (4 female, 23 male; mean age, 33 years [range, 12–61 years]) with refractory alopecia areata receiving IM triamcinolone acetonide (40 mg every 4 weeks for 3–6 months) reported 1 patient (a 56-year-old woman) with notably decreased bone densitometry from baseline requiring treatment discontinuation.²⁵ No other patients at risk for osteoporosis had decreased BMD from treatment with IM triamcinolone; however, it was noted that 1 month following treatment, 10 of 11 assessed patients demonstrated decreased levels of morning serum cortisol and plasma adrenocorticotropic hormone—despite baseline levels within reference range—that resolved 3 months after treatment completion,²⁵ which suggests a prolonged release of IM triamcinolone and sustained systemic effect. One systematic review of 342 patients with dermatologic diseases treated with IM corticosteroids found the primary side effects included dysmenorrhea, injection-site lipoatrophy, and adrenocortical suppression, with only a single reported case of low BMD.²⁶ Given the paucity of evidence, additional studies are required to assess the effect of IM triamcinolone on BMD and risk for major OP fractures with regard to dosing and frequency. As there are no clear guidelines for osteoporosis evaluation in the setting of intramuscular GCs, it may be prudent to follow the algorithmic model recommended for oral steroids when anticipating at least 3 months of intramuscular GCs.

Diet and Prevention of Bone Loss

Given the profound impact that systemic GCs have on osteoporosis and fracture risk and the sparse data regarding risk from topical, intralesional, or intramuscular GCs, diet and nutrition represent a simple, safe, and potentially preventative method of slowing BMD loss and minimizing fracture risk. In higher-risk patients, nutritional assessment in combination with medical therapy also is likely warranted.

Calcium and Vitamin D₃—Patients treated with any GC dose longer than 3 months should undergo calcium and vitamin D optimization.¹⁹ Exceptions for supplementation include certain patients with sarcoidosis, which can be associated with high vitamin D levels; patients with a history of hypercalcemia or hypercalciuria; and patients with chronic kidney disease.⁶ In a meta-analysis including 30,970 patients in 8 randomized controlled trials, calcium (500–1200 mg/d) and vitamin D (400–800 IU/d) supplementation reduced the risk of total fractures by 15% (summary relative risk estimate, 0.85 [95% CI, 0.73-0.98]) and hip fractures by 30% (summary relative risk estimate, 0.70 [95% CI, 0.56-0.87]).⁴ One double-blind, placebo-controlled clinical trial conducted by the Women’s Health Initiative that included 36,282 postmenopausal women who were taking 1000 mg of calcium and 400 IU of vitamin D₃ daily for more than 5 years reported an HR of 0.62 (95% CI, 0.38-1.00) for hip fracture for supplementation vs placebo.²⁷ Lastly, a 2016 Cochrane Review including 12 randomized trials and 1343 participants reported a 43% lower risk of new vertebral fractures following supplementation with calcium, vitamin D, or both compared with controls.²⁸

Specific recommendations for calcium and vitamin D₃ supplementation vary based on age and sex. The US Preventive Services Task Force concluded that insufficient evidence exists to support calcium and vitamin D₃ supplementation in asymptomatic men and premenopausal women.²⁹ The National Osteoporosis Foundation (NOF) supports the use of calcium supplementation for fracture risk reduction in middle-aged and older adults.⁴ Furthermore, the NOF supports the Institute of Medicine recommendations³¹ that men aged 50 to 70 years consume 1000 mg/d of calcium and that women 51 years and older as well as men 71 years and older consume 1200 mg/d of calcium.³⁰ The NOF recommends 800 to 1000 IU/d of vitamin D in adults 50 years and older, while the Institute of Medicine recommends 600 IU/d in adults 70 years and younger and 800 IU/d in adults 71 years and older.³¹ These recommendations are similar to both the Endocrine Society and the American Geriatric Society.^32,33 Total calcium should not exceed 2000 mg/d due to risk of adverse effects.

Dietary sources of vitamin D include fatty fish, mushrooms, and fortified dairy products, though recommended doses rarely can be achieved through diet alone.³⁴ Dairy products are the primary source of dietary calcium. Other high-calcium foods include green leafy vegetables, nuts and seeds, soft-boned fish, and fortified beverages and cereals.³⁵

Probiotics—A growing body of evidence suggests that probiotics may be beneficial in promoting bone health by improving calcium homeostasis, reducing risk for hyperparathyroidism secondary to GC therapy, and decreasing age-related bone resorption.³⁶ An animal study demonstrated that probiotics can regulate bone resorption and formation as well as reduce bone loss secondary to GC therapy.³⁷ A randomized, double-blind, placebo-controlled, multicenter trial randomly assigned 249 healthy, early postmenopausal women to receive probiotic treatment containing 3 lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and L plantarum DSM 15313) or placebo once daily for 12 months.³⁸ Bone mineral density was measured at baseline and at 12 months. Of the 234 participants who completed the study, lactobacillus treatment reduced lumbosacral BMD loss compared to the placebo group (mean difference, 0.71% [95% CI, 0.06-1.35]). They also reported significant lumbosacral BMD loss in the placebo group (−0.72% [95% CI, −1.22 to −0.22]) compared to no BMD loss in the group treated with lactobacillus (−0.01% [95% CI, −0.50 to 0.48]).³⁸ Although the data may be encouraging, more studies are needed to determine if probiotics should be regarded as an adjuvant treatment to calcium, vitamin D, and pharmacologic therapy for long-term prevention of bone loss in the setting of GIO.³⁹ Because existing studies on probiotics include varying compositions and doses, larger studies with consistent supplementation are required. Encouraging probiotic intake through fermented dairy products may represent a simple low-risk intervention to support bone health.

Anti-inflammatory Diet—The traditional Mediterranean diet is rich in fruits, vegetables, fish, nuts, whole grains, legumes, and monounsaturated fats and low in meat and dairy products. The Mediterranean diet has been shown to be modestly protective against osteoporosis and fracture risk. A large US observational study including 93,676 women showed that those with the highest quintile of the alternate Mediterranean diet score had a lower risk for hip fracture (HR, 0.80 [95% CI, 0.66-0.97]), with an absolute risk reduction of 0.29% and number needed to treat at 342.⁴⁰ A multicenter study involving adults from 8 European countries found that increased adherence to the Mediterranean diet was associated with a 7% reduction in hip fracture incidence (HR per 1 unit increase in Mediterranean diet, 0.93 [95% CI, 0.89-0.98]). High vegetable and fruit intake was associated with decreased hip fracture incidence (HR, 0.86 and 0.89 [95% CI, 0.79-0.94 and 0.82-0.97, respectively]), and high meat and excessive ethanol consumption were associated with increased fracture incidence (HR, 1.18 and 1.74 [95% CI, 1.06-1.31 and 1.32-2.31, respectively]).⁴¹ Similarly, a large observational study in Sweden that included 37,903 men and 33,403 women reported similar findings, noting a 6% lower hip fracture rate per one unit increase in alternate Mediterranean diet score (adjusted HR, 0.94 [95% CI, 0.92-0.96]).⁴² This is thought to be due in part to higher levels of dietary vitamin D present in many foods traditionally included in the Mediterranean diet.⁴³ Additionally, olive oil, a staple in the Mediterranean diet, appears to reduce bone loss by promoting osteoblast proliferation and maturation, inhibiting bone resorption, suppressing oxidative stress and inflammation, and increasing calcium deposition in the extracellular matrix.^44,45 Fruits, vegetables, legumes, and nuts also are rich in minerals including potassium and magnesium, which are important in bone health to promote osteoblast proliferation and vitamin D activation.^36,46-48

Final Thoughts

Osteoporosis-related fractures are common and are associated with high morbidity and health care costs. Dermatologists using and prescribing corticosteroids must be aware of the risk for GIO, particularly in patients with a pre-existing diagnosis of osteopenia or osteoporosis. There likely is no oral corticosteroid dose that does not increase a patient’s risk for osteoporosis; therefore, oral GCs should be used at the lowest effective daily dose for the shortest duration possible. Patients with an anticipated duration of at least 3 months—regardless of dose—should be assessed for their risk for GIO. Patients using topical and intralesional corticosteroids are unlikely to develop GIO; however, those with risk factors and a considerable cumulative dose may warrant further evaluation. In all cases, we advocate for supplementing with calcium and vitamin D as well as promoting probiotic intake and the Mediterranean diet. Those at moderate to high risk for fracture may require additional medical therapy. Dermatologists are uniquely positioned to identify this at-risk population, and because osteoporosis is a chronic illness, primary care providers should be notified of prolonged GC therapy to help with risk assessment, initiation of vitamin and mineral supplementation, and follow-up with metabolic bone health specialists. Through a multidisciplinary approach and patient education, GIO and the potential risk for fracture can be successfully mitigated in most patients.

Glucocorticoids (GCs) are among the most widely prescribed medications in dermatologic practice. Although GCs are highly effective anti-inflammatory agents, long-term systemic therapy can result in dangerous adverse effects, including GC-induced osteoporosis (GIO), a bone disease associated with a heightened risk for fragility fractures.^1,2 In the United States, an estimated 10.2 million adults have osteoporosis—defined as a T-score lower than −2.5 measured via a bone densitometry scan—and 43.4 million adults have low bone mineral density (BMD).^3,4 The prevalence of osteoporosis is increasing, and the diagnosis is more common in females and adults 55 years and older.² More than 2 million individuals have osteoporosis-related fractures annually, and the mortality risk is increased at 5 and 10 years following low-energy osteoporosis-related fractures.^3-5

Glucocorticoid therapy is the leading iatrogenic cause of secondary osteoporosis. As many as 30% of all patients treated with systemic GCs for more than 6 months develop GIO.^1,6,7 Glucocorticoid-induced BMD loss occurs at a rate of 6% to 12% of total BMD during the first year, slowing to approximately 3% per year during subsequent therapy.¹ The risk for insufficiency fractures increases by as much as 75% from baseline in adults with rheumatic, pulmonary, and skin disorders within the first 3 months of therapy and peaks at approximately 12 months.^1,2

Despite the risks, many long-term GC users never receive therapy to prevent bone loss; others are only started on therapy once they have sustained an insufficiency fracture. A 5-year international observational study including more than 40,000 postmenopausal women found that only 51% of patients who were on continuous GC therapy were undergoing BMD testing and appropriate medical management.⁸ This review highlights the existing evidence on the risks of osteoporosis and osteoporotic (OP) fractures in the setting of topical, intralesional, intramuscular, and systemic GC treatment, as well as recommendations for nutritional supplementation to reduce these risks.

Pathophysiology

The pathophysiology of GIO is multifactorial and occurs in both early and late phases.^9,10 The early phase is characterized by rapid BMD reduction due to excessive bone resorption. The late phase is characterized by slower and more progressive BMD reduction due to impaired bone formation.⁹ At the osteocyte level, GCs decrease cell viability and induce apoptosis.¹¹ At the osteoblast level, GCs impair cell replication and differentiation and have proapoptotic effects, resulting in decreased cell numbers and subsequent bone formation.¹⁰ At the osteoclast level, GCs increase expression of pro-osteoclastic cytokines and decrease mature osteoclast apoptosis, resulting in an expanded osteoclastic life span and prolonged bone resorption.^12,13 Indirectly, GCs alter calcium metabolism by decreasing gastrointestinal calcium absorption and impairing renal absorption.^14,15

GCs and Osteoporosis

Oral GCs—Glucocorticoid-induced osteoporosis and fracture risk are dose and duration dependent.⁶ A study of 244,235 patients taking GCs and 244,235 controls found the relative risk of vertebral fracture was 1.55 (range, 1.20–2.01) for daily prednisone use at less than 2.5 mg, 2.59 (range, 2.16–3.10) for daily prednisone use from 2.5 to 7.4 mg, and 5.18 (range, 4.25–6.31) for daily doses of 7.5 mg or higher; the relative risk for hip fractures was 0.99 (range, 0.82–1.20), 1.77 (range, 1.55–2.02), and 2.27 (range, 1.94–2.66), respectively.¹⁶ Another large retrospective cohort study found that continuous treatment with prednisone 10 mg/d for more than 90 days compared to no GC exposure increased the risk for hip fractures 7-fold and 17-fold for vertebral fractures.¹⁷ Although the minimum cumulative dose of GCs known to cause osteoporosis is not clearly established, the American College of Rheumatology has proposed an algorithm as a basic approach to anticipate, prevent, and treat GIO (Figure).^18,19 Fracture risk should be assessed in all patients who are prescribed prednisone 2.5 mg/d for 3 months or longer or an anticipated cumulative dose of more than 1 g per year. Patients 40 years and older with anticipated GC use of 3 months or longer should have both a bone densitometry scan and a Fracture Risk Assessment (FRAX) score. The FRAX tool estimates the 10-year probability of fracture in patients aged 40 to 80 years, and those patients can be further risk stratified as low (FRAX <10%), moderate (FRAX 10%–19%), or high (FRAX ≥20%) risk. In patients with moderate to high risk of fracture (FRAX >10%), initiation of pharmacologic treatment or referral to a metabolic bone specialist should be considered.^18,19 First-line therapy is an oral bisphosphonate, and second-line therapies include intravenous bisphosphonates, teriparatide, denosumab, or raloxifene for patients at high risk for GIO.¹⁹ Adults younger than 40 years with a history of OP fracture or considerable risk factors for OP fractures should have a bone densitometry scan, and, if results are abnormal, the patient should be referred to a metabolic bone specialist. Those with low fracture risk based on bone densitometry and FRAX and those with no risk factors should be assessed annually for bone health (additional risk factors, GC dose and duration, bone densitometry/FRAX if indicated).¹⁸ In addition to GC dose and duration, additional risk factors for GIO, which are factored into the FRAX tool, include advanced age, low body mass index, history of bone fracture, smoking, excessive alcohol use (≥3 drinks/d), history of falls, low BMD, family history of bone fracture, and hypovitaminosis D.⁶

Topical GCs—Although there is strong evidence and clear guidelines regarding oral GIO, there is a dearth of data surrounding OP risk due to treatment with topical GCs. A recent retrospective nationwide Danish study evaluating the risk of osteoporosis and major OP fracture in 723,251 adults treated with potent or very potent topical steroids sought to evaluate these risks.²⁰ Patients were included if they had filled prescriptions of at least 500 g of topical mometasone or an equivalent alternative. The investigators reported a 3% increase in relative risk of osteoporosis and major OP fracture with doubling of the cumulative topical GC dose (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for major OP fracture. Notably, at least 10,000 g of mometasone was required for 1 additional patient to have a major OP fracture.²⁰ In a commentary based on this study, Jackson²¹ noted that the number of patient-years of topical GC use needed for 1 fracture was 4-fold higher than that for high-dose oral GCs (40 mg/d prednisolone for ≥30 days). Another study assessed the effects of topical GCs on BMD in adults with moderate to severe atopic dermatitis over a 2-year period.²² No significant difference in BMD assessed via bone densitometry of either the lumbar spine or total hip at baseline or at 2-year follow-up was reported for either group treated with corticosteroids (<75 g per month or ≥75 g per month). Of note, the authors did not account for steroid potency, which ranged from class 1 through class 4.²² Although limited data exist, these studies suggest topical GCs used at conventional doses with appropriate breaks in therapy will not substantially increase risk for GIO or OP fracture; however, in the small subset of patients requiring chronic use of superpotent topical corticosteroids with other OP risk factors, transitioning to non–GC-based therapy or initiating bone health therapy may be advised to improve patient outcomes. Risk assessment, as in cases of chronic topical GC use, may be beneficial.

Intralesional GCs—Intralesional GCs are indicated for numerous inflammatory conditions including alopecia areata, discoid lupus erythematosus, keloids, and granuloma annulare. It generally is accepted that doses of triamcinolone acetonide should not exceed 20 mg per session spaced at least 3 weeks apart or up to 40 mg per month.¹⁸ One study demonstrated that doses of triamcinolone diacetate of 25 mg or less were unlikely to produce systemic effects and were determined to be a safe dose for intralesional injections.²³ A retrospective cross-sectional case series including 18 patients with alopecia areata reported decreased BMD in 9 patients receiving intralesional triamcinolone acetonide 10 mg/mL at 4- to 8-week intervals for at least 20 months, with cumulative doses greater than 500 mg. This was particularly notable in postmenopausal women and men older than 50 years; participants with a body mass index less than 18.5 kg/m², history of a stress fracture, family history of osteopenia or osteoporosis, and history of smoking; and those who did not regularly engage in weight-bearing exercises.²⁴ Patients receiving long-term (ie, >1 year) intralesional steroids should be evaluated for osteoporosis risk and preventative strategies should be considered (ie, regular weight-bearing exercises, calcium and vitamin D supplementation, bisphosphate therapy). As with topical GCs, there are no clear guidelines for risk assessment or treatment recommendations for GIO.

Intramuscular GCs—The data regarding intramuscular (IM) GCs and dermatologic disease is severely limited, and to the best of our knowledge, no studies specifically assess the risk for GIO or fracture secondary to intramuscular GCs; however, a retrospective study of 27 patients (4 female, 23 male; mean age, 33 years [range, 12–61 years]) with refractory alopecia areata receiving IM triamcinolone acetonide (40 mg every 4 weeks for 3–6 months) reported 1 patient (a 56-year-old woman) with notably decreased bone densitometry from baseline requiring treatment discontinuation.²⁵ No other patients at risk for osteoporosis had decreased BMD from treatment with IM triamcinolone; however, it was noted that 1 month following treatment, 10 of 11 assessed patients demonstrated decreased levels of morning serum cortisol and plasma adrenocorticotropic hormone—despite baseline levels within reference range—that resolved 3 months after treatment completion,²⁵ which suggests a prolonged release of IM triamcinolone and sustained systemic effect. One systematic review of 342 patients with dermatologic diseases treated with IM corticosteroids found the primary side effects included dysmenorrhea, injection-site lipoatrophy, and adrenocortical suppression, with only a single reported case of low BMD.²⁶ Given the paucity of evidence, additional studies are required to assess the effect of IM triamcinolone on BMD and risk for major OP fractures with regard to dosing and frequency. As there are no clear guidelines for osteoporosis evaluation in the setting of intramuscular GCs, it may be prudent to follow the algorithmic model recommended for oral steroids when anticipating at least 3 months of intramuscular GCs.

Diet and Prevention of Bone Loss

Given the profound impact that systemic GCs have on osteoporosis and fracture risk and the sparse data regarding risk from topical, intralesional, or intramuscular GCs, diet and nutrition represent a simple, safe, and potentially preventative method of slowing BMD loss and minimizing fracture risk. In higher-risk patients, nutritional assessment in combination with medical therapy also is likely warranted.

Calcium and Vitamin D₃—Patients treated with any GC dose longer than 3 months should undergo calcium and vitamin D optimization.¹⁹ Exceptions for supplementation include certain patients with sarcoidosis, which can be associated with high vitamin D levels; patients with a history of hypercalcemia or hypercalciuria; and patients with chronic kidney disease.⁶ In a meta-analysis including 30,970 patients in 8 randomized controlled trials, calcium (500–1200 mg/d) and vitamin D (400–800 IU/d) supplementation reduced the risk of total fractures by 15% (summary relative risk estimate, 0.85 [95% CI, 0.73-0.98]) and hip fractures by 30% (summary relative risk estimate, 0.70 [95% CI, 0.56-0.87]).⁴ One double-blind, placebo-controlled clinical trial conducted by the Women’s Health Initiative that included 36,282 postmenopausal women who were taking 1000 mg of calcium and 400 IU of vitamin D₃ daily for more than 5 years reported an HR of 0.62 (95% CI, 0.38-1.00) for hip fracture for supplementation vs placebo.²⁷ Lastly, a 2016 Cochrane Review including 12 randomized trials and 1343 participants reported a 43% lower risk of new vertebral fractures following supplementation with calcium, vitamin D, or both compared with controls.²⁸

Specific recommendations for calcium and vitamin D₃ supplementation vary based on age and sex. The US Preventive Services Task Force concluded that insufficient evidence exists to support calcium and vitamin D₃ supplementation in asymptomatic men and premenopausal women.²⁹ The National Osteoporosis Foundation (NOF) supports the use of calcium supplementation for fracture risk reduction in middle-aged and older adults.⁴ Furthermore, the NOF supports the Institute of Medicine recommendations³¹ that men aged 50 to 70 years consume 1000 mg/d of calcium and that women 51 years and older as well as men 71 years and older consume 1200 mg/d of calcium.³⁰ The NOF recommends 800 to 1000 IU/d of vitamin D in adults 50 years and older, while the Institute of Medicine recommends 600 IU/d in adults 70 years and younger and 800 IU/d in adults 71 years and older.³¹ These recommendations are similar to both the Endocrine Society and the American Geriatric Society.^32,33 Total calcium should not exceed 2000 mg/d due to risk of adverse effects.

Dietary sources of vitamin D include fatty fish, mushrooms, and fortified dairy products, though recommended doses rarely can be achieved through diet alone.³⁴ Dairy products are the primary source of dietary calcium. Other high-calcium foods include green leafy vegetables, nuts and seeds, soft-boned fish, and fortified beverages and cereals.³⁵

Probiotics—A growing body of evidence suggests that probiotics may be beneficial in promoting bone health by improving calcium homeostasis, reducing risk for hyperparathyroidism secondary to GC therapy, and decreasing age-related bone resorption.³⁶ An animal study demonstrated that probiotics can regulate bone resorption and formation as well as reduce bone loss secondary to GC therapy.³⁷ A randomized, double-blind, placebo-controlled, multicenter trial randomly assigned 249 healthy, early postmenopausal women to receive probiotic treatment containing 3 lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312, and L plantarum DSM 15313) or placebo once daily for 12 months.³⁸ Bone mineral density was measured at baseline and at 12 months. Of the 234 participants who completed the study, lactobacillus treatment reduced lumbosacral BMD loss compared to the placebo group (mean difference, 0.71% [95% CI, 0.06-1.35]). They also reported significant lumbosacral BMD loss in the placebo group (−0.72% [95% CI, −1.22 to −0.22]) compared to no BMD loss in the group treated with lactobacillus (−0.01% [95% CI, −0.50 to 0.48]).³⁸ Although the data may be encouraging, more studies are needed to determine if probiotics should be regarded as an adjuvant treatment to calcium, vitamin D, and pharmacologic therapy for long-term prevention of bone loss in the setting of GIO.³⁹ Because existing studies on probiotics include varying compositions and doses, larger studies with consistent supplementation are required. Encouraging probiotic intake through fermented dairy products may represent a simple low-risk intervention to support bone health.

Anti-inflammatory Diet—The traditional Mediterranean diet is rich in fruits, vegetables, fish, nuts, whole grains, legumes, and monounsaturated fats and low in meat and dairy products. The Mediterranean diet has been shown to be modestly protective against osteoporosis and fracture risk. A large US observational study including 93,676 women showed that those with the highest quintile of the alternate Mediterranean diet score had a lower risk for hip fracture (HR, 0.80 [95% CI, 0.66-0.97]), with an absolute risk reduction of 0.29% and number needed to treat at 342.⁴⁰ A multicenter study involving adults from 8 European countries found that increased adherence to the Mediterranean diet was associated with a 7% reduction in hip fracture incidence (HR per 1 unit increase in Mediterranean diet, 0.93 [95% CI, 0.89-0.98]). High vegetable and fruit intake was associated with decreased hip fracture incidence (HR, 0.86 and 0.89 [95% CI, 0.79-0.94 and 0.82-0.97, respectively]), and high meat and excessive ethanol consumption were associated with increased fracture incidence (HR, 1.18 and 1.74 [95% CI, 1.06-1.31 and 1.32-2.31, respectively]).⁴¹ Similarly, a large observational study in Sweden that included 37,903 men and 33,403 women reported similar findings, noting a 6% lower hip fracture rate per one unit increase in alternate Mediterranean diet score (adjusted HR, 0.94 [95% CI, 0.92-0.96]).⁴² This is thought to be due in part to higher levels of dietary vitamin D present in many foods traditionally included in the Mediterranean diet.⁴³ Additionally, olive oil, a staple in the Mediterranean diet, appears to reduce bone loss by promoting osteoblast proliferation and maturation, inhibiting bone resorption, suppressing oxidative stress and inflammation, and increasing calcium deposition in the extracellular matrix.^44,45 Fruits, vegetables, legumes, and nuts also are rich in minerals including potassium and magnesium, which are important in bone health to promote osteoblast proliferation and vitamin D activation.^36,46-48

Final Thoughts

Osteoporosis-related fractures are common and are associated with high morbidity and health care costs. Dermatologists using and prescribing corticosteroids must be aware of the risk for GIO, particularly in patients with a pre-existing diagnosis of osteopenia or osteoporosis. There likely is no oral corticosteroid dose that does not increase a patient’s risk for osteoporosis; therefore, oral GCs should be used at the lowest effective daily dose for the shortest duration possible. Patients with an anticipated duration of at least 3 months—regardless of dose—should be assessed for their risk for GIO. Patients using topical and intralesional corticosteroids are unlikely to develop GIO; however, those with risk factors and a considerable cumulative dose may warrant further evaluation. In all cases, we advocate for supplementing with calcium and vitamin D as well as promoting probiotic intake and the Mediterranean diet. Those at moderate to high risk for fracture may require additional medical therapy. Dermatologists are uniquely positioned to identify this at-risk population, and because osteoporosis is a chronic illness, primary care providers should be notified of prolonged GC therapy to help with risk assessment, initiation of vitamin and mineral supplementation, and follow-up with metabolic bone health specialists. Through a multidisciplinary approach and patient education, GIO and the potential risk for fracture can be successfully mitigated in most patients.

This transcript has been edited for clarity.

John Whyte, MD: Welcome, everyone. I’m Dr John Whyte. I’m the chief medical officer at WebMD, and I’m joined today by Fabrice André. He is the chair of the scientific committee at the European Society for Medical Oncology, where we are today in Paris, France. Bonjour, Fabrice.

So, remind our viewers: What is ESMO? What does it do? And why is it so important?

Fabrice André, MD, PhD: First ESMO, is a scientific society – a member-based organization with around 25,000 members.

Dr. Whyte: Equivalent to ASCO (American Society of Clinical Oncology) in the United States, correct?

Dr. André: It has members worldwide, from all over the world. And it aims at disseminating science, educating. The name is European, so it has some roots in Europe; but it is really a global organization for education, dissemination, and also more and more to generate frameworks for the standards of treatment and the common terminology for healthcare professionals to better care for patients.

Dr. Whyte: What are you most excited by at this conference in terms of the innovations that are being discussed?

Dr. André: Today we are at ESMO 2022 in Paris, with 28,000 people registered and the vast majority on site, and what has been the editorial line – the tagline – for the scientific committee is “understand the disease to better treat the patient.” This is extremely important; all of the educational program is built on this tagline, meaning that we need to understand what are the mechanisms of cancer progression? What are the determinants of outcomes if we want to integrate all the wealth of innovation that is coming?

So, then, what are the new things? In the Presidential Symposium, where we usually have the very new things, we will have very important presentations on the role of pollution on cancer and the biological mechanism that induces cancer. Why is it important? First, it has impact on public health. But also, it’s important because, for us, it’s raising the signal that the oncology community must start to invest in this field of prevention.

Dr. Whyte: I was at your booth, by the way, the ESMO booth here, and you have two bicycles, which impressed me. Nobody was on them, I might point out, but the focus was on prevention. But let’s also address how historically, the academic community, the scientific community hasn’t really been focused on prevention. It’s about treatment. So it’s fascinating that you’re talking about prevention, because usually we talk about precision medicine, right? We talk about checkpoint inhibitors; we talk about immunomodulators. And here you’re saying, “Hey, John, we need to understand how we prevent cancer,” which is really a misnomer in a way, because there are many different diseases. Would you agree with that?

Dr. André: I fully agree with you. But what is the premise we are trying to address here? The premise is that prevention has always been very low in the agenda of international conferences. And we think we want to give the signal that it’s really time now that clinical infrastructure, hospitals, invest in this field, create teams dedicated to prevention, new structures for prevention. Why? Because we are discovering step by step that it could be that some drugs we use for patients with cancer could also be developed in the field of prevention. And for this, we need the oncologists. So, more and more, our conviction is that it is the oncology community that will transform the field of prevention, and we need to invest now. Having said that, we have two very important abstracts on this question. The other one is about early cancer detection. But of course, we have our traditional session on immunotherapeutics, precision medicine, and all the wealth of randomized trials. And so in this field, for patients with cancer, what is the new information?

Dr. Whyte: We have this whole continuum. So you talk about prevention – how much cancer is preventable? Eighty percent? Seventy percent? What do you estimate?

Dr. André: You know, I’m also a scientist. So as a scientist, I will say that there is no limit for this question. No, the only limit is the knowledge.

Dr. Whyte: Well, there is some inherited mutation, so we do know that.

Dr. André: We can just go to the current status – what we know now – but I don’t see why we would put some limit on how much we can prevent cancer. But indeed, so far, what are the risk factors? Genetics, hereditary cancer, all habits, and we know them. It’s about tobacco, alcohol, sun, some sexual behavior, etc., that indeed account. In France, we say that around 40% of cancer could be preventable.

Dr. Whyte: More and more, we learn about the issues of gout, other inflammatory diseases; it can have an association, but then we have early screening as well. So, if we’re on this continuum, how excited are you by what’s happening with liquid biopsies, with other testing? Because if we can get a cancer instead of at 500,000 cells at the time of imaging, at 10 or 50 cells, while there are fragments, that’s revolutionary, isn’t it?

Dr. André: I fully agree with you. We will have an important trial presented during ESMO that is the first prospective trial testing the device called Galleri, a tool for early cancer detection based on ctDNA (circulating tumor DNA) analysis by methylation pattern.

Dr. Whyte: General screening of the population or a more tailored population with certain indications? Because right now, most of those have focused on a limited population or are used for patients who already have a cancer, and testing that way – you think it’s going to be broader?

Dr. André: What this trial is investigating is in participants who do not have cancer, 6,000 participants ...

Dr. Whyte: Pas de tout? No cancer at all?

Dr. André: No cancer.

Dr. Whyte: No family history?

Dr. André: They can have family history, but no detectable cancer – can ctDNA analysis detect cancer? And the answer is, indeed, there is around 1% positivity, and around 40% of them, indeed, had cancer. So why is it important? Because it’s really a landmark prospective trial that is telling us that a device based on ctDNA can detect cancer at early stage. Then, how many cancers? What percentage?

Dr. Whyte: Which type of cancer?

Dr. André: And is it going to have an impact on outcome? And for all the questions, we don’t have the answer here. But the answer we have here today is that with this device, done prospectively, you can detect some cancer that would not be detectable without symptoms.

Dr. Whyte: It’s only going to get better, too.

Dr. André: Yeah. So then the next step is improving technology, integrating this technology with other ones we already have, in order to increase the percentage of patients in which we detect cancer at an earlier stage.

Dr. Whyte: What about pancreatic cancer, cancers we can’t detect through screening? People forget that most cancers cannot be detected through screening, so we need better tools. We do know that there are inherited mutations. Those really aren’t preventable in many ways; the goal is to get them early. So then we move to treatments, and you talked about precision medicine. What excites you about what’s going on these days at ESMO right now.

Dr. André: We have many trials on precision medicine. We will have two randomized trials that investigate two new targets; one is gamma secretase inhibitor. So, it’s a first-in-class, first time we even hear about this target at a clinical conference. And the second highly expected trial is a clinical trial in patients with metastatic lung cancer, KRAS mutated, testing sotorasib, which is a KRAS inhibitor, and showing the magnitude of improvement associated with sotorasib. The trial is positive, and it improved PFS [progression-free survival] in these patients. So these are two new targets that are validated at this conference.

Then, if we go on another topic of genomics, there is a question that is extremely important: Can we define patients who present an outlier sensitivity to immunotherapeutics? There will be one trial presented in the Presidential Symposium of immunotherapeutics in patients with colon cancer and microsatellite instability (MSI), showing that a few weeks of immunotherapeutics followed by surgery can cure patients. Why is it important? It’s important because we are all facing a shortage in the healthcare workforce. We have fewer nurses, fewer doctors, and we all have issues of sustainability. So, really now is the time to think about precision medicine, how precision medicine, by identifying outlier responders, can decrease the amount of resources we need to cure a patient. And this trial on immunotherapeutics, guided by genomics, is exactly this point: 8 weeks of treatment to cure a patient.

Dr. Whyte: Do you think there’s going to be a cure for cancer 10 years from now?

Dr. André: What I’m convinced of is that, in the 10 years that are coming, we are going step by step; we’re going to continue to increase the life expectancy of patients with cancer.

Dr. Whyte: And quality of life too, right?

Dr. André: Quality of life is a major issue. We had today a keynote on digital medicine and how ePRO (electronic patient-reported outcomes) can help the patient to really decrease the burden of symptoms. Quality of life is, of course, extremely important because of the very high number of patients who are cured of cancer; we need to decrease the burden of symptom in patients.

Dr. Whyte: And even though cancer rates are going down in most areas of the world, we still globally have millions of deaths from cancer every year. And sometimes people forget that, because they hear about some of the innovations. But I want to end with this: Are we investing enough in cancer care? Because let’s be honest – there are other diseases that we also need to spend time on. Cardiovascular disease is a global burden; infectious disease is a global burden. Are governments, are industries spending enough on cancer research and development?

Dr. André: Well, we can always claim for more, no? This is how everyone is trying to be, I think. But the reality is that we are living in a world where we have limited resources. I think what is more important for me is to be sure that any euro or dollar invested in cancer research is well used and generates an impact for patients. That is the most important, I think.

Dr. Whyte: And that’s why outcomes are so important in this research.

Dr. André: My conviction is that we have the tools, meaning the knowledge, the biotechnology, to really go the next step in terms of improving outcomes for patients. And for this, we now need clinical trials and translational research, but the tools, meaning basic science, basic knowledge, biotechnology – the basement for progress is here. We need now to transform this into direct impact for the patient. But I would not like to finish by saying we need more money in the field; what we need are people who can transform one euro, one dollar into concrete and measurable advances.

Dr. Whyte: We’re going to need more time on another day because I want to ask you about diversity in clinical trials, how important that is. I want to ask you about pediatric cancers; there are a whole bunch of things that I want to talk to you about. So hopefully we’ll find more time when we’re not at a big international conference such as ESMO. So, Dr Fabrice André, I want to thank you for taking time today.

Dr. André: Thank you and have a nice day.

Dr. Whyte: Stay tuned for a future discussion with Dr André on more about where we’re going in terms of cancer research and development. Thanks for watching, everyone.

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

This transcript has been edited for clarity.

John Whyte, MD: Welcome, everyone. I’m Dr John Whyte. I’m the chief medical officer at WebMD, and I’m joined today by Fabrice André. He is the chair of the scientific committee at the European Society for Medical Oncology, where we are today in Paris, France. Bonjour, Fabrice.

So, remind our viewers: What is ESMO? What does it do? And why is it so important?

Fabrice André, MD, PhD: First ESMO, is a scientific society – a member-based organization with around 25,000 members.

Dr. Whyte: Equivalent to ASCO (American Society of Clinical Oncology) in the United States, correct?

Dr. André: It has members worldwide, from all over the world. And it aims at disseminating science, educating. The name is European, so it has some roots in Europe; but it is really a global organization for education, dissemination, and also more and more to generate frameworks for the standards of treatment and the common terminology for healthcare professionals to better care for patients.

Dr. Whyte: What are you most excited by at this conference in terms of the innovations that are being discussed?

Dr. André: Today we are at ESMO 2022 in Paris, with 28,000 people registered and the vast majority on site, and what has been the editorial line – the tagline – for the scientific committee is “understand the disease to better treat the patient.” This is extremely important; all of the educational program is built on this tagline, meaning that we need to understand what are the mechanisms of cancer progression? What are the determinants of outcomes if we want to integrate all the wealth of innovation that is coming?

So, then, what are the new things? In the Presidential Symposium, where we usually have the very new things, we will have very important presentations on the role of pollution on cancer and the biological mechanism that induces cancer. Why is it important? First, it has impact on public health. But also, it’s important because, for us, it’s raising the signal that the oncology community must start to invest in this field of prevention.

Dr. Whyte: I was at your booth, by the way, the ESMO booth here, and you have two bicycles, which impressed me. Nobody was on them, I might point out, but the focus was on prevention. But let’s also address how historically, the academic community, the scientific community hasn’t really been focused on prevention. It’s about treatment. So it’s fascinating that you’re talking about prevention, because usually we talk about precision medicine, right? We talk about checkpoint inhibitors; we talk about immunomodulators. And here you’re saying, “Hey, John, we need to understand how we prevent cancer,” which is really a misnomer in a way, because there are many different diseases. Would you agree with that?

Dr. André: I fully agree with you. But what is the premise we are trying to address here? The premise is that prevention has always been very low in the agenda of international conferences. And we think we want to give the signal that it’s really time now that clinical infrastructure, hospitals, invest in this field, create teams dedicated to prevention, new structures for prevention. Why? Because we are discovering step by step that it could be that some drugs we use for patients with cancer could also be developed in the field of prevention. And for this, we need the oncologists. So, more and more, our conviction is that it is the oncology community that will transform the field of prevention, and we need to invest now. Having said that, we have two very important abstracts on this question. The other one is about early cancer detection. But of course, we have our traditional session on immunotherapeutics, precision medicine, and all the wealth of randomized trials. And so in this field, for patients with cancer, what is the new information?

Dr. Whyte: We have this whole continuum. So you talk about prevention – how much cancer is preventable? Eighty percent? Seventy percent? What do you estimate?

Dr. André: You know, I’m also a scientist. So as a scientist, I will say that there is no limit for this question. No, the only limit is the knowledge.

Dr. Whyte: Well, there is some inherited mutation, so we do know that.

Dr. André: We can just go to the current status – what we know now – but I don’t see why we would put some limit on how much we can prevent cancer. But indeed, so far, what are the risk factors? Genetics, hereditary cancer, all habits, and we know them. It’s about tobacco, alcohol, sun, some sexual behavior, etc., that indeed account. In France, we say that around 40% of cancer could be preventable.

Dr. Whyte: More and more, we learn about the issues of gout, other inflammatory diseases; it can have an association, but then we have early screening as well. So, if we’re on this continuum, how excited are you by what’s happening with liquid biopsies, with other testing? Because if we can get a cancer instead of at 500,000 cells at the time of imaging, at 10 or 50 cells, while there are fragments, that’s revolutionary, isn’t it?

Dr. André: I fully agree with you. We will have an important trial presented during ESMO that is the first prospective trial testing the device called Galleri, a tool for early cancer detection based on ctDNA (circulating tumor DNA) analysis by methylation pattern.

Dr. Whyte: General screening of the population or a more tailored population with certain indications? Because right now, most of those have focused on a limited population or are used for patients who already have a cancer, and testing that way – you think it’s going to be broader?

Dr. André: What this trial is investigating is in participants who do not have cancer, 6,000 participants ...

Dr. Whyte: Pas de tout? No cancer at all?

Dr. André: No cancer.

Dr. Whyte: No family history?

Dr. André: They can have family history, but no detectable cancer – can ctDNA analysis detect cancer? And the answer is, indeed, there is around 1% positivity, and around 40% of them, indeed, had cancer. So why is it important? Because it’s really a landmark prospective trial that is telling us that a device based on ctDNA can detect cancer at early stage. Then, how many cancers? What percentage?

Dr. Whyte: Which type of cancer?

Dr. André: And is it going to have an impact on outcome? And for all the questions, we don’t have the answer here. But the answer we have here today is that with this device, done prospectively, you can detect some cancer that would not be detectable without symptoms.

Dr. Whyte: It’s only going to get better, too.

Dr. André: Yeah. So then the next step is improving technology, integrating this technology with other ones we already have, in order to increase the percentage of patients in which we detect cancer at an earlier stage.

Dr. Whyte: What about pancreatic cancer, cancers we can’t detect through screening? People forget that most cancers cannot be detected through screening, so we need better tools. We do know that there are inherited mutations. Those really aren’t preventable in many ways; the goal is to get them early. So then we move to treatments, and you talked about precision medicine. What excites you about what’s going on these days at ESMO right now.

Dr. André: We have many trials on precision medicine. We will have two randomized trials that investigate two new targets; one is gamma secretase inhibitor. So, it’s a first-in-class, first time we even hear about this target at a clinical conference. And the second highly expected trial is a clinical trial in patients with metastatic lung cancer, KRAS mutated, testing sotorasib, which is a KRAS inhibitor, and showing the magnitude of improvement associated with sotorasib. The trial is positive, and it improved PFS [progression-free survival] in these patients. So these are two new targets that are validated at this conference.

Then, if we go on another topic of genomics, there is a question that is extremely important: Can we define patients who present an outlier sensitivity to immunotherapeutics? There will be one trial presented in the Presidential Symposium of immunotherapeutics in patients with colon cancer and microsatellite instability (MSI), showing that a few weeks of immunotherapeutics followed by surgery can cure patients. Why is it important? It’s important because we are all facing a shortage in the healthcare workforce. We have fewer nurses, fewer doctors, and we all have issues of sustainability. So, really now is the time to think about precision medicine, how precision medicine, by identifying outlier responders, can decrease the amount of resources we need to cure a patient. And this trial on immunotherapeutics, guided by genomics, is exactly this point: 8 weeks of treatment to cure a patient.

Dr. Whyte: Do you think there’s going to be a cure for cancer 10 years from now?

Dr. André: What I’m convinced of is that, in the 10 years that are coming, we are going step by step; we’re going to continue to increase the life expectancy of patients with cancer.

Dr. Whyte: And quality of life too, right?

Dr. André: Quality of life is a major issue. We had today a keynote on digital medicine and how ePRO (electronic patient-reported outcomes) can help the patient to really decrease the burden of symptoms. Quality of life is, of course, extremely important because of the very high number of patients who are cured of cancer; we need to decrease the burden of symptom in patients.

Dr. Whyte: And even though cancer rates are going down in most areas of the world, we still globally have millions of deaths from cancer every year. And sometimes people forget that, because they hear about some of the innovations. But I want to end with this: Are we investing enough in cancer care? Because let’s be honest – there are other diseases that we also need to spend time on. Cardiovascular disease is a global burden; infectious disease is a global burden. Are governments, are industries spending enough on cancer research and development?

Dr. André: Well, we can always claim for more, no? This is how everyone is trying to be, I think. But the reality is that we are living in a world where we have limited resources. I think what is more important for me is to be sure that any euro or dollar invested in cancer research is well used and generates an impact for patients. That is the most important, I think.

Dr. Whyte: And that’s why outcomes are so important in this research.

Dr. André: My conviction is that we have the tools, meaning the knowledge, the biotechnology, to really go the next step in terms of improving outcomes for patients. And for this, we now need clinical trials and translational research, but the tools, meaning basic science, basic knowledge, biotechnology – the basement for progress is here. We need now to transform this into direct impact for the patient. But I would not like to finish by saying we need more money in the field; what we need are people who can transform one euro, one dollar into concrete and measurable advances.

Dr. Whyte: We’re going to need more time on another day because I want to ask you about diversity in clinical trials, how important that is. I want to ask you about pediatric cancers; there are a whole bunch of things that I want to talk to you about. So hopefully we’ll find more time when we’re not at a big international conference such as ESMO. So, Dr Fabrice André, I want to thank you for taking time today.

Dr. André: Thank you and have a nice day.

Dr. Whyte: Stay tuned for a future discussion with Dr André on more about where we’re going in terms of cancer research and development. Thanks for watching, everyone.

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

This transcript has been edited for clarity.

John Whyte, MD: Welcome, everyone. I’m Dr John Whyte. I’m the chief medical officer at WebMD, and I’m joined today by Fabrice André. He is the chair of the scientific committee at the European Society for Medical Oncology, where we are today in Paris, France. Bonjour, Fabrice.

So, remind our viewers: What is ESMO? What does it do? And why is it so important?

Fabrice André, MD, PhD: First ESMO, is a scientific society – a member-based organization with around 25,000 members.

Dr. Whyte: Equivalent to ASCO (American Society of Clinical Oncology) in the United States, correct?

Dr. André: It has members worldwide, from all over the world. And it aims at disseminating science, educating. The name is European, so it has some roots in Europe; but it is really a global organization for education, dissemination, and also more and more to generate frameworks for the standards of treatment and the common terminology for healthcare professionals to better care for patients.

Dr. Whyte: What are you most excited by at this conference in terms of the innovations that are being discussed?

Dr. André: Today we are at ESMO 2022 in Paris, with 28,000 people registered and the vast majority on site, and what has been the editorial line – the tagline – for the scientific committee is “understand the disease to better treat the patient.” This is extremely important; all of the educational program is built on this tagline, meaning that we need to understand what are the mechanisms of cancer progression? What are the determinants of outcomes if we want to integrate all the wealth of innovation that is coming?

So, then, what are the new things? In the Presidential Symposium, where we usually have the very new things, we will have very important presentations on the role of pollution on cancer and the biological mechanism that induces cancer. Why is it important? First, it has impact on public health. But also, it’s important because, for us, it’s raising the signal that the oncology community must start to invest in this field of prevention.

Dr. Whyte: I was at your booth, by the way, the ESMO booth here, and you have two bicycles, which impressed me. Nobody was on them, I might point out, but the focus was on prevention. But let’s also address how historically, the academic community, the scientific community hasn’t really been focused on prevention. It’s about treatment. So it’s fascinating that you’re talking about prevention, because usually we talk about precision medicine, right? We talk about checkpoint inhibitors; we talk about immunomodulators. And here you’re saying, “Hey, John, we need to understand how we prevent cancer,” which is really a misnomer in a way, because there are many different diseases. Would you agree with that?

Dr. André: I fully agree with you. But what is the premise we are trying to address here? The premise is that prevention has always been very low in the agenda of international conferences. And we think we want to give the signal that it’s really time now that clinical infrastructure, hospitals, invest in this field, create teams dedicated to prevention, new structures for prevention. Why? Because we are discovering step by step that it could be that some drugs we use for patients with cancer could also be developed in the field of prevention. And for this, we need the oncologists. So, more and more, our conviction is that it is the oncology community that will transform the field of prevention, and we need to invest now. Having said that, we have two very important abstracts on this question. The other one is about early cancer detection. But of course, we have our traditional session on immunotherapeutics, precision medicine, and all the wealth of randomized trials. And so in this field, for patients with cancer, what is the new information?

Dr. Whyte: We have this whole continuum. So you talk about prevention – how much cancer is preventable? Eighty percent? Seventy percent? What do you estimate?

Dr. André: You know, I’m also a scientist. So as a scientist, I will say that there is no limit for this question. No, the only limit is the knowledge.

Dr. Whyte: Well, there is some inherited mutation, so we do know that.

Dr. André: We can just go to the current status – what we know now – but I don’t see why we would put some limit on how much we can prevent cancer. But indeed, so far, what are the risk factors? Genetics, hereditary cancer, all habits, and we know them. It’s about tobacco, alcohol, sun, some sexual behavior, etc., that indeed account. In France, we say that around 40% of cancer could be preventable.

Dr. Whyte: More and more, we learn about the issues of gout, other inflammatory diseases; it can have an association, but then we have early screening as well. So, if we’re on this continuum, how excited are you by what’s happening with liquid biopsies, with other testing? Because if we can get a cancer instead of at 500,000 cells at the time of imaging, at 10 or 50 cells, while there are fragments, that’s revolutionary, isn’t it?

Dr. André: I fully agree with you. We will have an important trial presented during ESMO that is the first prospective trial testing the device called Galleri, a tool for early cancer detection based on ctDNA (circulating tumor DNA) analysis by methylation pattern.

Dr. Whyte: General screening of the population or a more tailored population with certain indications? Because right now, most of those have focused on a limited population or are used for patients who already have a cancer, and testing that way – you think it’s going to be broader?

Dr. André: What this trial is investigating is in participants who do not have cancer, 6,000 participants ...

Dr. Whyte: Pas de tout? No cancer at all?

Dr. André: No cancer.

Dr. Whyte: No family history?

Dr. André: They can have family history, but no detectable cancer – can ctDNA analysis detect cancer? And the answer is, indeed, there is around 1% positivity, and around 40% of them, indeed, had cancer. So why is it important? Because it’s really a landmark prospective trial that is telling us that a device based on ctDNA can detect cancer at early stage. Then, how many cancers? What percentage?

Dr. Whyte: Which type of cancer?

Dr. André: And is it going to have an impact on outcome? And for all the questions, we don’t have the answer here. But the answer we have here today is that with this device, done prospectively, you can detect some cancer that would not be detectable without symptoms.

Dr. Whyte: It’s only going to get better, too.

Dr. André: Yeah. So then the next step is improving technology, integrating this technology with other ones we already have, in order to increase the percentage of patients in which we detect cancer at an earlier stage.

Dr. Whyte: What about pancreatic cancer, cancers we can’t detect through screening? People forget that most cancers cannot be detected through screening, so we need better tools. We do know that there are inherited mutations. Those really aren’t preventable in many ways; the goal is to get them early. So then we move to treatments, and you talked about precision medicine. What excites you about what’s going on these days at ESMO right now.

Dr. André: We have many trials on precision medicine. We will have two randomized trials that investigate two new targets; one is gamma secretase inhibitor. So, it’s a first-in-class, first time we even hear about this target at a clinical conference. And the second highly expected trial is a clinical trial in patients with metastatic lung cancer, KRAS mutated, testing sotorasib, which is a KRAS inhibitor, and showing the magnitude of improvement associated with sotorasib. The trial is positive, and it improved PFS [progression-free survival] in these patients. So these are two new targets that are validated at this conference.

Then, if we go on another topic of genomics, there is a question that is extremely important: Can we define patients who present an outlier sensitivity to immunotherapeutics? There will be one trial presented in the Presidential Symposium of immunotherapeutics in patients with colon cancer and microsatellite instability (MSI), showing that a few weeks of immunotherapeutics followed by surgery can cure patients. Why is it important? It’s important because we are all facing a shortage in the healthcare workforce. We have fewer nurses, fewer doctors, and we all have issues of sustainability. So, really now is the time to think about precision medicine, how precision medicine, by identifying outlier responders, can decrease the amount of resources we need to cure a patient. And this trial on immunotherapeutics, guided by genomics, is exactly this point: 8 weeks of treatment to cure a patient.

Dr. Whyte: Do you think there’s going to be a cure for cancer 10 years from now?

Dr. André: What I’m convinced of is that, in the 10 years that are coming, we are going step by step; we’re going to continue to increase the life expectancy of patients with cancer.

Dr. Whyte: And quality of life too, right?

Dr. André: Quality of life is a major issue. We had today a keynote on digital medicine and how ePRO (electronic patient-reported outcomes) can help the patient to really decrease the burden of symptoms. Quality of life is, of course, extremely important because of the very high number of patients who are cured of cancer; we need to decrease the burden of symptom in patients.

Dr. Whyte: And even though cancer rates are going down in most areas of the world, we still globally have millions of deaths from cancer every year. And sometimes people forget that, because they hear about some of the innovations. But I want to end with this: Are we investing enough in cancer care? Because let’s be honest – there are other diseases that we also need to spend time on. Cardiovascular disease is a global burden; infectious disease is a global burden. Are governments, are industries spending enough on cancer research and development?

Dr. André: Well, we can always claim for more, no? This is how everyone is trying to be, I think. But the reality is that we are living in a world where we have limited resources. I think what is more important for me is to be sure that any euro or dollar invested in cancer research is well used and generates an impact for patients. That is the most important, I think.

Dr. Whyte: And that’s why outcomes are so important in this research.

Dr. André: My conviction is that we have the tools, meaning the knowledge, the biotechnology, to really go the next step in terms of improving outcomes for patients. And for this, we now need clinical trials and translational research, but the tools, meaning basic science, basic knowledge, biotechnology – the basement for progress is here. We need now to transform this into direct impact for the patient. But I would not like to finish by saying we need more money in the field; what we need are people who can transform one euro, one dollar into concrete and measurable advances.

Dr. Whyte: We’re going to need more time on another day because I want to ask you about diversity in clinical trials, how important that is. I want to ask you about pediatric cancers; there are a whole bunch of things that I want to talk to you about. So hopefully we’ll find more time when we’re not at a big international conference such as ESMO. So, Dr Fabrice André, I want to thank you for taking time today.

Dr. André: Thank you and have a nice day.

Dr. Whyte: Stay tuned for a future discussion with Dr André on more about where we’re going in terms of cancer research and development. Thanks for watching, everyone.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

Prescription folic acid, a synthetic form of vitamin B₉, may provide a safe and effective approach for decreasing suicidal ideation, new research suggests.

After adjusting for multiple factors, results from a large pharmaco-epidemiological study showed taking folic acid was associated with a 44% reduction in suicide events.

“These results are really putting folic acid squarely on the map as a potential for large-scale, population-level prevention,” lead author Robert D. Gibbons, PhD, professor of biostatistics, Center for Health Statistics, University of Chicago, said in an interview.

University of Chicago

“Folic acid is safe, inexpensive, and generally available, and if future randomized controlled trials show this association is beyond a shadow of a doubt causal, we have a new tool in the arsenal,” Dr. Gibbons said.

Having such a tool would be extremely important given that suicide is such a significant public health crisis worldwide, he added.

The findings were published online in JAMA Psychiatry.
 

Previous research ‘fairly thin’

Folate, the naturally occurring form of B₉, is essential for neurogenesis, nucleotide synthesis, and methylation of homocysteine. Past research has suggested that taking folate can prevent neural tube and heart defects in the fetus during pregnancy – and may prevent strokes and reduce age-related hearing loss in adults.

In psychiatry, the role of folate has been recognized for more than a decade. It may enhance the effects of antidepressants; and folate deficiency can predict poorer response to SSRIs.

This has led to recommendations for folate augmentation in patients with low or normal levels at the start of depression treatment.

Although previous research has shown a link between folic acid and suicidality, the findings have been “fairly thin,” with studies being “generally small, and many are case series,” Dr. Gibbons said.

The current study follows an earlier analysis that used a novel statistical methodology for generating drug safety signals that was developed by Dr. Gibbons and colleagues. That study compared rates of suicide attempts before and after initiation of 922 drugs with at least 3,000 prescriptions.

Its results showed 10 drugs were associated with increased risk after exposure, with the strongest associations for alprazolam, butalbital, hydrocodone, and combination codeine/promethazine. In addition, 44 drugs were associated with decreased risk, many of which were antidepressants and antipsychotics.

“One of the most interesting findings in terms of the decreased risk was for folic acid,” said Dr. Gibbons.

He and his colleagues initially thought this was because of women taking folic acid during pregnancy. But when restricting the analysis to men, they found the same effect.

Their next step was to carry out the current large-scale pharmaco-epidemiological study.
 

Prescriptions for pain

The researchers used a health claims database that included 164 million enrollees. The study cohort was comprised of 866,586 adults with private health insurance (81.3% women; 10.4% aged 60 years and older) who filled a folic acid prescription between 2012 and 2017.

More than half of the folic acid prescriptions were associated with pain disorders. About 48% were for a single agent at a dosage of 1 mg/d, which is the upper tolerable limit for adults – including in pregnancy and lactation.

Other single-agent daily dosages ranging from 0.4 mg to 5 mg accounted for 0.11% of prescriptions. The remainder were multivitamins.

The participants were followed for 24 months. The within-person analysis compared suicide attempts or self-harm events resulting in an outpatient visit or inpatient admission during periods of folic acid treatment versus during periods without treatment.

During the study period, the overall suicidal event rate was 133 per 100,000 population, which is one-fourth the national rate reported by the National Institutes of Health of 600 per 100,000.

After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated hazard ratio for suicide events when taking folic acid was 0.56 (95% confidence interal, 0.48-0.65) – which indicates a 44% reduction in suicide events.

“This is a very large decrease and is extremely significant and exciting,” Dr. Gibbons said.

He noted the decrease in suicidal events may have been even greater considering the study captured only prescription folic acid, and participants may also have also taken over-the-counter products.

“The 44% reduction in suicide attempts may actually be an underestimate,” said Dr. Gibbons.

Age and sex did not moderate the association between folic acid and suicide attempts, and a similar association was found in women of childbearing age.
 

Provocative results?

The investigators also assessed a negative control group of 236,610 individuals using cyanocobalamin during the study period. Cyanocobalamin is a form of vitamin B₁₂ that is essential for metabolism, blood cell synthesis, and the nervous system. It does not contain folic acid and is commonly used to treat anemia.

Results showed no association between cyanocobalamin and suicidal events in the adjusted analysis (HR, 1.01; 95% CI, 0.80-1.27) or unadjusted analysis (HR, 1.02; 95% CI, 0.80-1.28).

Dr. Gibbons noted this result boosts the argument that the association between folic acid and reduced suicidal attempts “isn’t just about health-seeking behavior like taking vitamin supplements.”

Another sensitivity analysis showed every additional month of treatment was associated with a 5% reduction in the suicidal event rate.

“This means the longer you take folic acid, the greater the benefit, which is what you would expect to see if there was a real association between a treatment and an outcome,” said Dr. Gibbons.

The new results “are so provocative that they really mandate the need for a well-controlled randomized controlled trial of folic acid and suicide events,” possibly in a high-risk population such as veterans, he noted.

Such a study could use longitudinal assessments of suicidal events, such as the validated Computerized Adaptive Test Suicide Scale, he added. This continuous scale of suicidality ranges from subclinical, signifying helplessness, hopelessness, and loss of pleasure, to suicide attempts and completion.

As for study limitations, the investigators noted that this study was observational, so there could be selection effects. And using claims data likely underrepresented the number of suicidal events because of incomplete reporting. As the researchers pointed out, the rate of suicidal events in this study was much lower than the national rate.

Other limitations cited were that the association between folic acid and suicidal events may be explained by healthy user bias; and although the investigators conducted a sensitivity analysis in women of childbearing age, they did not have data on women actively planning for a pregnancy.
 

‘Impressive, encouraging’

In a comment, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, described the new findings as “quite impressive” and “extremely encouraging.”

However, she noted “it’s too premature” to suggest widespread use of folic acid in patients with depressive symptoms.

Dr. Yen, who has researched suicide risks previously, was not involved with the current study.

She did agree with the investigators that the results call for “more robustly controlled studies. These could include double-blind, randomized, controlled trials that could “more formally assess” all folic acid usage as opposed to prescriptions only, Dr. Yen said.

The study was funded by the NIH, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention. Dr. Gibbons reported serving as an expert witness in cases for the Department of Justice; receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Dr. Yen reported no relevant financial relationships.

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

Prescription folic acid, a synthetic form of vitamin B₉, may provide a safe and effective approach for decreasing suicidal ideation, new research suggests.

After adjusting for multiple factors, results from a large pharmaco-epidemiological study showed taking folic acid was associated with a 44% reduction in suicide events.

“These results are really putting folic acid squarely on the map as a potential for large-scale, population-level prevention,” lead author Robert D. Gibbons, PhD, professor of biostatistics, Center for Health Statistics, University of Chicago, said in an interview.

University of Chicago

“Folic acid is safe, inexpensive, and generally available, and if future randomized controlled trials show this association is beyond a shadow of a doubt causal, we have a new tool in the arsenal,” Dr. Gibbons said.

Having such a tool would be extremely important given that suicide is such a significant public health crisis worldwide, he added.

The findings were published online in JAMA Psychiatry.
 

Previous research ‘fairly thin’

Folate, the naturally occurring form of B₉, is essential for neurogenesis, nucleotide synthesis, and methylation of homocysteine. Past research has suggested that taking folate can prevent neural tube and heart defects in the fetus during pregnancy – and may prevent strokes and reduce age-related hearing loss in adults.

In psychiatry, the role of folate has been recognized for more than a decade. It may enhance the effects of antidepressants; and folate deficiency can predict poorer response to SSRIs.

This has led to recommendations for folate augmentation in patients with low or normal levels at the start of depression treatment.

Although previous research has shown a link between folic acid and suicidality, the findings have been “fairly thin,” with studies being “generally small, and many are case series,” Dr. Gibbons said.

The current study follows an earlier analysis that used a novel statistical methodology for generating drug safety signals that was developed by Dr. Gibbons and colleagues. That study compared rates of suicide attempts before and after initiation of 922 drugs with at least 3,000 prescriptions.

Its results showed 10 drugs were associated with increased risk after exposure, with the strongest associations for alprazolam, butalbital, hydrocodone, and combination codeine/promethazine. In addition, 44 drugs were associated with decreased risk, many of which were antidepressants and antipsychotics.

“One of the most interesting findings in terms of the decreased risk was for folic acid,” said Dr. Gibbons.

He and his colleagues initially thought this was because of women taking folic acid during pregnancy. But when restricting the analysis to men, they found the same effect.

Their next step was to carry out the current large-scale pharmaco-epidemiological study.
 

Prescriptions for pain

The researchers used a health claims database that included 164 million enrollees. The study cohort was comprised of 866,586 adults with private health insurance (81.3% women; 10.4% aged 60 years and older) who filled a folic acid prescription between 2012 and 2017.

More than half of the folic acid prescriptions were associated with pain disorders. About 48% were for a single agent at a dosage of 1 mg/d, which is the upper tolerable limit for adults – including in pregnancy and lactation.

Other single-agent daily dosages ranging from 0.4 mg to 5 mg accounted for 0.11% of prescriptions. The remainder were multivitamins.

The participants were followed for 24 months. The within-person analysis compared suicide attempts or self-harm events resulting in an outpatient visit or inpatient admission during periods of folic acid treatment versus during periods without treatment.

During the study period, the overall suicidal event rate was 133 per 100,000 population, which is one-fourth the national rate reported by the National Institutes of Health of 600 per 100,000.

After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated hazard ratio for suicide events when taking folic acid was 0.56 (95% confidence interal, 0.48-0.65) – which indicates a 44% reduction in suicide events.

“This is a very large decrease and is extremely significant and exciting,” Dr. Gibbons said.

He noted the decrease in suicidal events may have been even greater considering the study captured only prescription folic acid, and participants may also have also taken over-the-counter products.

“The 44% reduction in suicide attempts may actually be an underestimate,” said Dr. Gibbons.

Age and sex did not moderate the association between folic acid and suicide attempts, and a similar association was found in women of childbearing age.
 

Provocative results?

The investigators also assessed a negative control group of 236,610 individuals using cyanocobalamin during the study period. Cyanocobalamin is a form of vitamin B₁₂ that is essential for metabolism, blood cell synthesis, and the nervous system. It does not contain folic acid and is commonly used to treat anemia.

Results showed no association between cyanocobalamin and suicidal events in the adjusted analysis (HR, 1.01; 95% CI, 0.80-1.27) or unadjusted analysis (HR, 1.02; 95% CI, 0.80-1.28).

Dr. Gibbons noted this result boosts the argument that the association between folic acid and reduced suicidal attempts “isn’t just about health-seeking behavior like taking vitamin supplements.”

Another sensitivity analysis showed every additional month of treatment was associated with a 5% reduction in the suicidal event rate.

“This means the longer you take folic acid, the greater the benefit, which is what you would expect to see if there was a real association between a treatment and an outcome,” said Dr. Gibbons.

The new results “are so provocative that they really mandate the need for a well-controlled randomized controlled trial of folic acid and suicide events,” possibly in a high-risk population such as veterans, he noted.

Such a study could use longitudinal assessments of suicidal events, such as the validated Computerized Adaptive Test Suicide Scale, he added. This continuous scale of suicidality ranges from subclinical, signifying helplessness, hopelessness, and loss of pleasure, to suicide attempts and completion.

As for study limitations, the investigators noted that this study was observational, so there could be selection effects. And using claims data likely underrepresented the number of suicidal events because of incomplete reporting. As the researchers pointed out, the rate of suicidal events in this study was much lower than the national rate.

Other limitations cited were that the association between folic acid and suicidal events may be explained by healthy user bias; and although the investigators conducted a sensitivity analysis in women of childbearing age, they did not have data on women actively planning for a pregnancy.
 

‘Impressive, encouraging’

In a comment, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, described the new findings as “quite impressive” and “extremely encouraging.”

However, she noted “it’s too premature” to suggest widespread use of folic acid in patients with depressive symptoms.

Dr. Yen, who has researched suicide risks previously, was not involved with the current study.

She did agree with the investigators that the results call for “more robustly controlled studies. These could include double-blind, randomized, controlled trials that could “more formally assess” all folic acid usage as opposed to prescriptions only, Dr. Yen said.

The study was funded by the NIH, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention. Dr. Gibbons reported serving as an expert witness in cases for the Department of Justice; receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Dr. Yen reported no relevant financial relationships.

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

Prescription folic acid, a synthetic form of vitamin B₉, may provide a safe and effective approach for decreasing suicidal ideation, new research suggests.

After adjusting for multiple factors, results from a large pharmaco-epidemiological study showed taking folic acid was associated with a 44% reduction in suicide events.

“These results are really putting folic acid squarely on the map as a potential for large-scale, population-level prevention,” lead author Robert D. Gibbons, PhD, professor of biostatistics, Center for Health Statistics, University of Chicago, said in an interview.

University of Chicago

“Folic acid is safe, inexpensive, and generally available, and if future randomized controlled trials show this association is beyond a shadow of a doubt causal, we have a new tool in the arsenal,” Dr. Gibbons said.

Having such a tool would be extremely important given that suicide is such a significant public health crisis worldwide, he added.

The findings were published online in JAMA Psychiatry.
 

Previous research ‘fairly thin’

Folate, the naturally occurring form of B₉, is essential for neurogenesis, nucleotide synthesis, and methylation of homocysteine. Past research has suggested that taking folate can prevent neural tube and heart defects in the fetus during pregnancy – and may prevent strokes and reduce age-related hearing loss in adults.

In psychiatry, the role of folate has been recognized for more than a decade. It may enhance the effects of antidepressants; and folate deficiency can predict poorer response to SSRIs.

This has led to recommendations for folate augmentation in patients with low or normal levels at the start of depression treatment.

Although previous research has shown a link between folic acid and suicidality, the findings have been “fairly thin,” with studies being “generally small, and many are case series,” Dr. Gibbons said.

The current study follows an earlier analysis that used a novel statistical methodology for generating drug safety signals that was developed by Dr. Gibbons and colleagues. That study compared rates of suicide attempts before and after initiation of 922 drugs with at least 3,000 prescriptions.

Its results showed 10 drugs were associated with increased risk after exposure, with the strongest associations for alprazolam, butalbital, hydrocodone, and combination codeine/promethazine. In addition, 44 drugs were associated with decreased risk, many of which were antidepressants and antipsychotics.

“One of the most interesting findings in terms of the decreased risk was for folic acid,” said Dr. Gibbons.

He and his colleagues initially thought this was because of women taking folic acid during pregnancy. But when restricting the analysis to men, they found the same effect.

Their next step was to carry out the current large-scale pharmaco-epidemiological study.
 

Prescriptions for pain

The researchers used a health claims database that included 164 million enrollees. The study cohort was comprised of 866,586 adults with private health insurance (81.3% women; 10.4% aged 60 years and older) who filled a folic acid prescription between 2012 and 2017.

More than half of the folic acid prescriptions were associated with pain disorders. About 48% were for a single agent at a dosage of 1 mg/d, which is the upper tolerable limit for adults – including in pregnancy and lactation.

Other single-agent daily dosages ranging from 0.4 mg to 5 mg accounted for 0.11% of prescriptions. The remainder were multivitamins.

The participants were followed for 24 months. The within-person analysis compared suicide attempts or self-harm events resulting in an outpatient visit or inpatient admission during periods of folic acid treatment versus during periods without treatment.

During the study period, the overall suicidal event rate was 133 per 100,000 population, which is one-fourth the national rate reported by the National Institutes of Health of 600 per 100,000.

After adjusting for age, sex, diagnoses related to suicidal behavior and folic acid deficiency, history of folate-reducing medications, and history of suicidal events, the estimated hazard ratio for suicide events when taking folic acid was 0.56 (95% confidence interal, 0.48-0.65) – which indicates a 44% reduction in suicide events.

“This is a very large decrease and is extremely significant and exciting,” Dr. Gibbons said.

He noted the decrease in suicidal events may have been even greater considering the study captured only prescription folic acid, and participants may also have also taken over-the-counter products.

“The 44% reduction in suicide attempts may actually be an underestimate,” said Dr. Gibbons.

Age and sex did not moderate the association between folic acid and suicide attempts, and a similar association was found in women of childbearing age.
 

Provocative results?

The investigators also assessed a negative control group of 236,610 individuals using cyanocobalamin during the study period. Cyanocobalamin is a form of vitamin B₁₂ that is essential for metabolism, blood cell synthesis, and the nervous system. It does not contain folic acid and is commonly used to treat anemia.

Results showed no association between cyanocobalamin and suicidal events in the adjusted analysis (HR, 1.01; 95% CI, 0.80-1.27) or unadjusted analysis (HR, 1.02; 95% CI, 0.80-1.28).

Dr. Gibbons noted this result boosts the argument that the association between folic acid and reduced suicidal attempts “isn’t just about health-seeking behavior like taking vitamin supplements.”

Another sensitivity analysis showed every additional month of treatment was associated with a 5% reduction in the suicidal event rate.

“This means the longer you take folic acid, the greater the benefit, which is what you would expect to see if there was a real association between a treatment and an outcome,” said Dr. Gibbons.

The new results “are so provocative that they really mandate the need for a well-controlled randomized controlled trial of folic acid and suicide events,” possibly in a high-risk population such as veterans, he noted.

Such a study could use longitudinal assessments of suicidal events, such as the validated Computerized Adaptive Test Suicide Scale, he added. This continuous scale of suicidality ranges from subclinical, signifying helplessness, hopelessness, and loss of pleasure, to suicide attempts and completion.

As for study limitations, the investigators noted that this study was observational, so there could be selection effects. And using claims data likely underrepresented the number of suicidal events because of incomplete reporting. As the researchers pointed out, the rate of suicidal events in this study was much lower than the national rate.

Other limitations cited were that the association between folic acid and suicidal events may be explained by healthy user bias; and although the investigators conducted a sensitivity analysis in women of childbearing age, they did not have data on women actively planning for a pregnancy.
 

‘Impressive, encouraging’

In a comment, Shirley Yen, PhD, associate professor of psychology, Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, described the new findings as “quite impressive” and “extremely encouraging.”

However, she noted “it’s too premature” to suggest widespread use of folic acid in patients with depressive symptoms.

Dr. Yen, who has researched suicide risks previously, was not involved with the current study.

She did agree with the investigators that the results call for “more robustly controlled studies. These could include double-blind, randomized, controlled trials that could “more formally assess” all folic acid usage as opposed to prescriptions only, Dr. Yen said.

The study was funded by the NIH, the Agency for Healthcare Research and Quality, and the Center of Excellence for Suicide Prevention. Dr. Gibbons reported serving as an expert witness in cases for the Department of Justice; receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and having founded Adaptive Testing Technologies, which distributes the Computerized Adaptive Test Suicide Scale. Dr. Yen reported no relevant financial relationships.

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

The Nobel Committee announced Oct. 3 it was awarding Svante Pääbo, PhD, the Nobel Prize in Physiology or Medicine for 2022 for his “pioneering research” into ancient DNA.

It all started with a 40,000-year-old bone. That Neanderthal bone contained enough DNA that Dr. Pääbo could start decades of research showing us modern humans, Homo sapiens, are genetically distinct from other now-extinct hominins such as Neanderthals and Denisovans.

The connection to physiology and medicine comes from the genes some modern humans carry from these ancient relatives. For example, Neanderthal genes transferred to Homo sapiens can explain how our immune systems react to different infections. Dr. Pääbo also discovered that a copy of a gene from another extinct relative, the Denisovans, gives modern-day Tibetans a survival advantage for living at high altitudes.

“Svante Pääbo accomplished something seemingly impossible: sequencing the genome of the Neanderthal, an extinct relative of present-day humans. He also made the sensational discovery of a previously unknown hominin, Denisova,” the Nobel Committee stated in a news release announcing the award. “Importantly, [Dr.] Pääbo also found that gene transfer had occurred from these now extinct hominins to Homo sapiens following the migration out of Africa around 70,000 years ago.”

Dr. Pääbo’s scientific discoveries only happened by pairing ancient DNA evidence with modern technology. An initial discovery occurred when Dr. Pääbo worked at the University of Munich (Germany), where he sequenced mitochondrial DNA from the 40,000-year-old Neanderthal bone. The sequencing of the human genome in the 1990s coupled with genomic DNA recovered from ancient bones allowed Dr. Pääbo to compare our DNA with that of Neanderthals and Denisovans. A lot of this work happened at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, which Dr. Pääbo founded in 1999 and where he still works today.

In 2008, a different 40,000-year-old fragment from a finger bone was discovered in a Denisova cave in the southern part of Siberia. Fortunately for Dr. Pääbo and his team, the DNA was well preserved and could be sequenced.

“The results caused a sensation: the DNA sequence was unique when compared to all known sequences from Neanderthals and present-day humans,” the Nobel Committee said.

In a big picture sense, Dr. Pääbo’s research helps answer where modern-day humans come from and how we interacted with our hominin relatives tens of thousands of years ago. His research is so pioneering that it created a new field of science called paleogenomics, the Nobel Committee noted.

“On behalf of The Physiological Society, I am delighted to congratulate Svante Pääbo for being awarded the Nobel Prize. His pioneering research shines a light on the physiology that makes humans unique from their ancestors,” David Paterson, DPhil, president of The Physiological Society, said in a statement.

“This is an important science discovery in evolutionary biology,” Dr. Paterson added. “Ascribing physiological function to highly conserved mitochondrial genes has been important in our understanding in high-altitude acclimatization as populations move and adapt to new environments, and how genetic variants affect us on a day-to-day basis in health and disease.”

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

The Nobel Committee announced Oct. 3 it was awarding Svante Pääbo, PhD, the Nobel Prize in Physiology or Medicine for 2022 for his “pioneering research” into ancient DNA.

It all started with a 40,000-year-old bone. That Neanderthal bone contained enough DNA that Dr. Pääbo could start decades of research showing us modern humans, Homo sapiens, are genetically distinct from other now-extinct hominins such as Neanderthals and Denisovans.

The connection to physiology and medicine comes from the genes some modern humans carry from these ancient relatives. For example, Neanderthal genes transferred to Homo sapiens can explain how our immune systems react to different infections. Dr. Pääbo also discovered that a copy of a gene from another extinct relative, the Denisovans, gives modern-day Tibetans a survival advantage for living at high altitudes.

“Svante Pääbo accomplished something seemingly impossible: sequencing the genome of the Neanderthal, an extinct relative of present-day humans. He also made the sensational discovery of a previously unknown hominin, Denisova,” the Nobel Committee stated in a news release announcing the award. “Importantly, [Dr.] Pääbo also found that gene transfer had occurred from these now extinct hominins to Homo sapiens following the migration out of Africa around 70,000 years ago.”

Dr. Pääbo’s scientific discoveries only happened by pairing ancient DNA evidence with modern technology. An initial discovery occurred when Dr. Pääbo worked at the University of Munich (Germany), where he sequenced mitochondrial DNA from the 40,000-year-old Neanderthal bone. The sequencing of the human genome in the 1990s coupled with genomic DNA recovered from ancient bones allowed Dr. Pääbo to compare our DNA with that of Neanderthals and Denisovans. A lot of this work happened at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, which Dr. Pääbo founded in 1999 and where he still works today.

In 2008, a different 40,000-year-old fragment from a finger bone was discovered in a Denisova cave in the southern part of Siberia. Fortunately for Dr. Pääbo and his team, the DNA was well preserved and could be sequenced.

“The results caused a sensation: the DNA sequence was unique when compared to all known sequences from Neanderthals and present-day humans,” the Nobel Committee said.

In a big picture sense, Dr. Pääbo’s research helps answer where modern-day humans come from and how we interacted with our hominin relatives tens of thousands of years ago. His research is so pioneering that it created a new field of science called paleogenomics, the Nobel Committee noted.

“On behalf of The Physiological Society, I am delighted to congratulate Svante Pääbo for being awarded the Nobel Prize. His pioneering research shines a light on the physiology that makes humans unique from their ancestors,” David Paterson, DPhil, president of The Physiological Society, said in a statement.

“This is an important science discovery in evolutionary biology,” Dr. Paterson added. “Ascribing physiological function to highly conserved mitochondrial genes has been important in our understanding in high-altitude acclimatization as populations move and adapt to new environments, and how genetic variants affect us on a day-to-day basis in health and disease.”

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

The Nobel Committee announced Oct. 3 it was awarding Svante Pääbo, PhD, the Nobel Prize in Physiology or Medicine for 2022 for his “pioneering research” into ancient DNA.

It all started with a 40,000-year-old bone. That Neanderthal bone contained enough DNA that Dr. Pääbo could start decades of research showing us modern humans, Homo sapiens, are genetically distinct from other now-extinct hominins such as Neanderthals and Denisovans.

The connection to physiology and medicine comes from the genes some modern humans carry from these ancient relatives. For example, Neanderthal genes transferred to Homo sapiens can explain how our immune systems react to different infections. Dr. Pääbo also discovered that a copy of a gene from another extinct relative, the Denisovans, gives modern-day Tibetans a survival advantage for living at high altitudes.

“Svante Pääbo accomplished something seemingly impossible: sequencing the genome of the Neanderthal, an extinct relative of present-day humans. He also made the sensational discovery of a previously unknown hominin, Denisova,” the Nobel Committee stated in a news release announcing the award. “Importantly, [Dr.] Pääbo also found that gene transfer had occurred from these now extinct hominins to Homo sapiens following the migration out of Africa around 70,000 years ago.”

Dr. Pääbo’s scientific discoveries only happened by pairing ancient DNA evidence with modern technology. An initial discovery occurred when Dr. Pääbo worked at the University of Munich (Germany), where he sequenced mitochondrial DNA from the 40,000-year-old Neanderthal bone. The sequencing of the human genome in the 1990s coupled with genomic DNA recovered from ancient bones allowed Dr. Pääbo to compare our DNA with that of Neanderthals and Denisovans. A lot of this work happened at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, which Dr. Pääbo founded in 1999 and where he still works today.

In 2008, a different 40,000-year-old fragment from a finger bone was discovered in a Denisova cave in the southern part of Siberia. Fortunately for Dr. Pääbo and his team, the DNA was well preserved and could be sequenced.

“The results caused a sensation: the DNA sequence was unique when compared to all known sequences from Neanderthals and present-day humans,” the Nobel Committee said.

In a big picture sense, Dr. Pääbo’s research helps answer where modern-day humans come from and how we interacted with our hominin relatives tens of thousands of years ago. His research is so pioneering that it created a new field of science called paleogenomics, the Nobel Committee noted.

“On behalf of The Physiological Society, I am delighted to congratulate Svante Pääbo for being awarded the Nobel Prize. His pioneering research shines a light on the physiology that makes humans unique from their ancestors,” David Paterson, DPhil, president of The Physiological Society, said in a statement.

“This is an important science discovery in evolutionary biology,” Dr. Paterson added. “Ascribing physiological function to highly conserved mitochondrial genes has been important in our understanding in high-altitude acclimatization as populations move and adapt to new environments, and how genetic variants affect us on a day-to-day basis in health and disease.”

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