CASE Alice D is 20 years old and has type 1 diabetes, as well as retinopathy, hypertension, bipolar I disorder, and hyperlipidemia. She is a new patient at your clinic and reports that she is ­“occasionally homeless” and has difficulty affording food.

You renew Ms. D’s prescriptions during the visit, discuss nutrition with her, and order lab testing, including a test of hemoglobin A1C, a lipid panel, and a basic metabolic panel. You ask her to follow up in 1 week to discuss the test results and next steps in her care.

© Masterfile

According to a 2016 report from the US Department of Agriculture (USDA) Economic Research Service, an estimated 12.3% of households in the United States are “food insecure.”¹ To ascertain what food security and insecurity are, the USDA measured numerous variables, including household structure, race and ethnicity, geography, and income. The report of the Economic Research Service stands as one of the largest domestic sources of information about food insecurity.

Food insecurity is defined as “food intake of household members [that is] reduced and normal eating patterns that are disrupted.”¹ It is often measured “per household,” but those data must be interpreted carefully because food insecurity affects household members differently. Some members, such as children, might be affected only mildly; adults, on the other hand, might be more severely affected. (Adults may, for instance, disrupt or skip their meals to maintain normal diets and meal patterns for their children.) In some households, food insecurity affects only a single member—such as an older adult—because of conditions unique to the people living in the home.

Adults may disrupt or skip their meals to maintain normal diets and meal patterns for their children.

In this article, we review variables that can give rise to food insecurity in children, adults, and the elderly, and offer ­strategies to the family physician for identifying and alleviating the burden of food insecurity in these populations.

Food insecurity threatens children’s health, development

In 2016, households with children faced a higher level of food insecurity (16.5%) than the national average (12.3%).¹ In a study of more than 280,000 households, food ­insecurity was sometimes so severe that children skipped meals or did not eat for the whole day.¹ Although income strongly correlates with food insecurity, evidence shows that families above and below the poverty line suffer from food insecurity.^2,3

According to the USDA, the rate of food insecurity is higher than the national average of 12.3% in several subgroups of ­children¹:

• households with children < 6 years of age (16.6%)
• households with children headed by a single woman (31.6%) or single man (21.7%)
• households headed by a black non-Hispanic (22.5%) or Hispanic (18.5%) person
• low-income households in which the annual income is < 185% of the poverty threshold (31.6%).

Continue to: Evidence suggests that...

Evidence suggests that children in food-insecure homes experience poor diet, impaired cognitive development, an increased risk of chronic illness in adulthood, and emotional and behavioral problems.^4-7 For caregivers in food-insecure homes, purchase price is the most influential factor when making food purchasing decisions. Thus, caregivers often purchase cheaper, more calorie-dense foods, rather than more expensive, nutrient-rich foods—leading to childhood obesity.⁸

Food insecurity affects 12% of households in the United States.

Relief eludes many. Federal programs, such as the National School Lunch Program, School Breakfast Program, the Summer Food Service Program, and the Child and Adult Care Food Program, provide free or reduced-price meals for school-age children. Although these programs reduce food insecurity in households that participate, program policy has established that participation is based on household income.⁹ This is problematic: According to the literature,² the income of 50% of households that are food-insecure is above the federal poverty level.

It would be more effective to have these programs target families based on geography, not income, because programs would then benefit those who are food-insecure but who live above the poverty line. Location is a significant factor in identifying food-insecure populations: Households outside metropolitan areas are disproportionately affected.¹ If these programs were to privilege geography over income, they would include (for example): families in school districts with a low number of grocery stores; families with poor access to public transportation; and families that live in a “food desert”—ie, where fresh, low-cost food options are overshadowed by fast food.

One such program closely applied the model of privilege based on geography: In 2010, the Healthy, Hunger-Free Kids Act was passed, with a Community Eligibility Provision (CEP) that funded school districts in which ≥ 40% of students lived below the poverty line, so that students in those districts received a free school lunch.¹⁰ Although eligibility for CEP is still based on income, benefits go to all students who live in the district, including food-insecure students who live in a household above the poverty line. If eligibility criteria were expanded with CEP so that more school districts could participate, it might solve many obstacles faced by other existing programs.

Programs that provide nutrition for households with an infant or young child—eg, the Women, Infants and Children Special Supplemental Nutrition Program (WIC) and the Supplemental Nutrition Assistance Program (SNAP)—reduce food insecurity in households by 20%. However, several unstudied factors can affect food insecurity in families beyond these programs¹¹; some assumptions about food insecurity, for example, strongly point to the influence of maternal mental health.¹²

Continue to: Data from the...

Data from the Early Childhood Longitudinal Study, Birth Cohort showed that mothers (with an infant) who were suffering from depression had a significantly increased risk of food insecurity.¹³ To better identify infants at risk of food insecurity, it would be beneficial to identify women suffering from depression during pregnancy or postpartum.¹³ These patients could then be referred to WIC and for SNAP benefits.

What you can do. The American Academy of Pediatrics recommends that physicians identify families that are food-insecure by conducting a validated¹⁴ 2-question survey about food insecurity at every health-­maintenance visit, as long as the child is a patient in the practice (TABLE 1).¹⁵ Physicians can then refer families that screen positively to local WIC and SNAP centers.

Ideally, physicians should be prepared to facilitate more active engagement by providing patients with the contact information of staff members working in such local programs. Staffing the practice with a patient-care manager can be an efficient way to navigate this process.

CASE Over the 6 weeks following Ms. D’s visit with you, she is admitted 5 times to the hospital in diabetic ketoacidosis, always with a significantly elevated blood glucose level. At each admission, she admits to “sometimes forgetting” to take insulin. Hospital staff members do not ask about her food intake. During each hospitalization, Ms. D is treated with insulin and intravenous fluids and discharged to home on her prior insulin regimen.

During a follow-up appointment with you and the clinic’s nurse–care manager, she talks about missing doses of insulin. She tells you that she has been getting food from the local food pantry, where available stocks are typically carbohydrate-based, including bread, rice, and cereal. She admits that she cannot afford other kinds of food—specifically, those that contain protein and monosaturated and polyunsaturated fats.

Continue to: Adults...

 

 

Adults: Poor financial health correlates with insecurity

The correlation between food insecurity and income is strong—evidenced by the spike in the number of adults who reported food insecurity during the 2008-2011 recession in the United States, to a high of 14.9%.¹ As noted, households with children are more likely to report food insecurity. In addition, studies show that limited resources, race and ethnicity, underemployment or unemployment, and high housing costs are also strongly associated with food insecurity.¹⁶ Even subtle economic fluctuations—for example, an increase in the price of gasoline, natural gas, or electricity—contribute to food insecurity.¹⁷ Debt and coping mechanisms influence whether a household living below the poverty line is food-secure or food-insecure. Additional factors contributing to food insecurity include participation in SNAP, education, and severe depression.

To identify families that are food-insecure, conduct the 2-question AAP survey on food insecurity at every healthmaintenance visit.

Food insecurity in adults reduces the quality of food and nutritional intake, and is associated with chronic morbidity, such as type 2 diabetes, hypertension, and obesity.^5-7 Adults in food-insecure homes are more likely to purchase cheap, calorie-dense, nutritionally poor foods (or refrain from purchasing food altogether, to pay other debts).^17,18 The literature further suggests that food insecurity is associated with diseases that limit function and lead to disability, such as arthritis, stroke, and coronary artery disease, in adults and older adults (> 65 years of age; see the next section).^5,6,19 These studies are weak, however, in their ability to show directionality: Does food insecurity cause disability or does disability cause food insecurity?

Patchwork of programs. Programs such as WIC are available for women who are pregnant or have children < 5 years of age. Federal programs for adults who do not have children are scarce, however, and the burden of food insecurity for this population is typically addressed by local programs, such as food banks and food kitchens. Evidence shows that (1) combining the efforts of federal and local food programs is the most effective method of stymieing food insecurity in adults and (2) it would benefit food-insecure adults to have access to such programs. Regrettably, many food programs are underutilized because of barriers that include poor outreach, ineffectual application, and ineligibility.

What you can do. Although it might not be an official, professional society guideline to include questions about food security in a patient wellness survey, physicians should consider creating one for their practice that they (or the office staff) can administer. Furthermore, physicians (or, again, the office staff) should familiarize themselves with programs in the community, such as SNAP or a food bank, to which they can refer patients, as needed.

CASE You ask the nurse–care manager to consult with staff of the food bank and request that, based on your evaluation and recommendation, Ms. D be given more protein-based foods, including peanut butter and beans, when she visits the food bank. The nurse–care manager also makes arrangements to procure an insulin pump for Ms. D.

Continue to: In a short time...

In a short time, Ms. D’s blood glucose level normalizes. She has no further admissions for diabetic ketoacidosis.

Older adults: Interplay of risk factors takes a toll

The USDA Economic Research Report on food insecurity¹ states that older adults (≥ 65 years of age) report a lower rate of food insecurity—ie, 7.8% of households with an older adult and 8.9% of households in which the older adult lives alone—compared with the national average.¹ The report is limited, however, in its ability to extrapolate data from older adults on food insecurity because its focus is on factors specific to adults and children.

Factors that contribute to food insecurity in the elderly include race and ethnicity, education, income, being a SNAP recipient, and severe depression.^1,2,17,20,21 Older adult subgroups more likely to be food-insecure are Hispanic and black non-Hispanic—both significantly associated with being food-­insecure, with Hispanic populations reporting the highest rates of food insecurity.^20,21 This is a particularly interesting observation: Many traditional Hispanic homes are multigenerational and maintain a culture in which older adults are cared for by their children; that value system might be an indication of why many Hispanic households are disproportionately affected by food insecurity.

Adults in food-insecure homes are more likely to purchase cheap, calorie-dense food that lacks nutrition.

Other problems directly caused or exacerbated by food insecurity in the older population include a higher risk of malnutrition from periodontal disease, more frequent hospital admissions with longer length of stay, and an increased rate of falls and fractures. Polypharmacy, which can cause food–drug interactions that inhibit uptake of vitamins or create a higher demand for certain vitamins, is a noteworthy problem associated with food insecurity.

Problems with functionality might prevent older adults from performing physical tasks, such as shopping and preparing foods.^21,22 Older adults who reported functional impairment in performing activities of daily living are more likely to report food insecurity.^21,22 Last,older adults who live alone are more likely to have diminished nutritional intake than those who live with a spouse or partner.^2,22,23

Continue to: Legislation enacted in 2010...

Legislation enacted in 2010 under the existing Older Americans Act provided home-delivered meals, nutritional screening, and education counseling to Americans > 60 years of age. That provision was not based on an income test, however, and served only 18% of the older population.²³ (Other programs, such as SNAP, are utilized to a greater degree: 30% of eligible older adults participate, 75% of whom live alone.²³) Possible reasons for underutilization include restricted funding, lower education level, lack of outreach, a confusing application process, and the impression that the process is intrusive.^24-26

What you can do. To improve the nutritional intake of older adults, reconcile the patient’s medications at each visit to ensure that polypharmacy does not play a role in causing or exacerbating underlying conditions that can lead to poor nutritional intake. AARP (formerly the American Association of Retired Persons) recommends devising and conducting a survey of food insecurity with older adults that includes the 2-question American Academy of Pediatrics survey described earlier²⁷ (TABLE 2^15,27).Such a survey, which can be administered by office staff, should also include a screen for depression, financial stability, ability to perform activities of daily living (eg, shopping and driving), and changes in diet that are a result of periodontal disease. The survey should also inquire about the effects of current or chronic disability on day-to-day life.

For all patients: Refer to community resources

The problems of food insecurity presented here only broadly address what each of these 3 groups face. Although the overall trend in food insecurity has been downward since 2011, deeper issues of food insecurity need to be studied more within each population. This is particularly true among the geriatric population, whose numbers are increasing, and among ethnic minorities, including black non-Hispanics, and Hispanics, who face additional daily stressors because of implicit biases in society.

Ask older adults about any decline in performing activities of daily living, which can lead to food insecurity and poor nutritional intake.

More study is needed to decrease the rate of food insecurity across all populations in the United States. In the interim, family physicians should take advantage of their role in the care of families, children, and older people to address the problem of food insecurity in their patient population by applying the interventions we’ve outlined, with an emphasis on referral to resources in the community.

CORRESPONDENCE
Lillian Amèzquita, BS, The Warren Alpert Medical School, Brown University, Box G-9999, 222 Richmond Street, Providence, RI; lillian_amezquita@brown.edu.

CASE Alice D is 20 years old and has type 1 diabetes, as well as retinopathy, hypertension, bipolar I disorder, and hyperlipidemia. She is a new patient at your clinic and reports that she is ­“occasionally homeless” and has difficulty affording food.

You renew Ms. D’s prescriptions during the visit, discuss nutrition with her, and order lab testing, including a test of hemoglobin A1C, a lipid panel, and a basic metabolic panel. You ask her to follow up in 1 week to discuss the test results and next steps in her care.

© Masterfile

According to a 2016 report from the US Department of Agriculture (USDA) Economic Research Service, an estimated 12.3% of households in the United States are “food insecure.”¹ To ascertain what food security and insecurity are, the USDA measured numerous variables, including household structure, race and ethnicity, geography, and income. The report of the Economic Research Service stands as one of the largest domestic sources of information about food insecurity.

Food insecurity is defined as “food intake of household members [that is] reduced and normal eating patterns that are disrupted.”¹ It is often measured “per household,” but those data must be interpreted carefully because food insecurity affects household members differently. Some members, such as children, might be affected only mildly; adults, on the other hand, might be more severely affected. (Adults may, for instance, disrupt or skip their meals to maintain normal diets and meal patterns for their children.) In some households, food insecurity affects only a single member—such as an older adult—because of conditions unique to the people living in the home.

Adults may disrupt or skip their meals to maintain normal diets and meal patterns for their children.

In this article, we review variables that can give rise to food insecurity in children, adults, and the elderly, and offer ­strategies to the family physician for identifying and alleviating the burden of food insecurity in these populations.

Food insecurity threatens children’s health, development

In 2016, households with children faced a higher level of food insecurity (16.5%) than the national average (12.3%).¹ In a study of more than 280,000 households, food ­insecurity was sometimes so severe that children skipped meals or did not eat for the whole day.¹ Although income strongly correlates with food insecurity, evidence shows that families above and below the poverty line suffer from food insecurity.^2,3

According to the USDA, the rate of food insecurity is higher than the national average of 12.3% in several subgroups of ­children¹:

• households with children < 6 years of age (16.6%)
• households with children headed by a single woman (31.6%) or single man (21.7%)
• households headed by a black non-Hispanic (22.5%) or Hispanic (18.5%) person
• low-income households in which the annual income is < 185% of the poverty threshold (31.6%).

Continue to: Evidence suggests that...

Evidence suggests that children in food-insecure homes experience poor diet, impaired cognitive development, an increased risk of chronic illness in adulthood, and emotional and behavioral problems.^4-7 For caregivers in food-insecure homes, purchase price is the most influential factor when making food purchasing decisions. Thus, caregivers often purchase cheaper, more calorie-dense foods, rather than more expensive, nutrient-rich foods—leading to childhood obesity.⁸

Food insecurity affects 12% of households in the United States.

Relief eludes many. Federal programs, such as the National School Lunch Program, School Breakfast Program, the Summer Food Service Program, and the Child and Adult Care Food Program, provide free or reduced-price meals for school-age children. Although these programs reduce food insecurity in households that participate, program policy has established that participation is based on household income.⁹ This is problematic: According to the literature,² the income of 50% of households that are food-insecure is above the federal poverty level.

It would be more effective to have these programs target families based on geography, not income, because programs would then benefit those who are food-insecure but who live above the poverty line. Location is a significant factor in identifying food-insecure populations: Households outside metropolitan areas are disproportionately affected.¹ If these programs were to privilege geography over income, they would include (for example): families in school districts with a low number of grocery stores; families with poor access to public transportation; and families that live in a “food desert”—ie, where fresh, low-cost food options are overshadowed by fast food.

One such program closely applied the model of privilege based on geography: In 2010, the Healthy, Hunger-Free Kids Act was passed, with a Community Eligibility Provision (CEP) that funded school districts in which ≥ 40% of students lived below the poverty line, so that students in those districts received a free school lunch.¹⁰ Although eligibility for CEP is still based on income, benefits go to all students who live in the district, including food-insecure students who live in a household above the poverty line. If eligibility criteria were expanded with CEP so that more school districts could participate, it might solve many obstacles faced by other existing programs.

Programs that provide nutrition for households with an infant or young child—eg, the Women, Infants and Children Special Supplemental Nutrition Program (WIC) and the Supplemental Nutrition Assistance Program (SNAP)—reduce food insecurity in households by 20%. However, several unstudied factors can affect food insecurity in families beyond these programs¹¹; some assumptions about food insecurity, for example, strongly point to the influence of maternal mental health.¹²

Continue to: Data from the...

Data from the Early Childhood Longitudinal Study, Birth Cohort showed that mothers (with an infant) who were suffering from depression had a significantly increased risk of food insecurity.¹³ To better identify infants at risk of food insecurity, it would be beneficial to identify women suffering from depression during pregnancy or postpartum.¹³ These patients could then be referred to WIC and for SNAP benefits.

What you can do. The American Academy of Pediatrics recommends that physicians identify families that are food-insecure by conducting a validated¹⁴ 2-question survey about food insecurity at every health-­maintenance visit, as long as the child is a patient in the practice (TABLE 1).¹⁵ Physicians can then refer families that screen positively to local WIC and SNAP centers.

Ideally, physicians should be prepared to facilitate more active engagement by providing patients with the contact information of staff members working in such local programs. Staffing the practice with a patient-care manager can be an efficient way to navigate this process.

CASE Over the 6 weeks following Ms. D’s visit with you, she is admitted 5 times to the hospital in diabetic ketoacidosis, always with a significantly elevated blood glucose level. At each admission, she admits to “sometimes forgetting” to take insulin. Hospital staff members do not ask about her food intake. During each hospitalization, Ms. D is treated with insulin and intravenous fluids and discharged to home on her prior insulin regimen.

During a follow-up appointment with you and the clinic’s nurse–care manager, she talks about missing doses of insulin. She tells you that she has been getting food from the local food pantry, where available stocks are typically carbohydrate-based, including bread, rice, and cereal. She admits that she cannot afford other kinds of food—specifically, those that contain protein and monosaturated and polyunsaturated fats.

Continue to: Adults...

 

 

Adults: Poor financial health correlates with insecurity

The correlation between food insecurity and income is strong—evidenced by the spike in the number of adults who reported food insecurity during the 2008-2011 recession in the United States, to a high of 14.9%.¹ As noted, households with children are more likely to report food insecurity. In addition, studies show that limited resources, race and ethnicity, underemployment or unemployment, and high housing costs are also strongly associated with food insecurity.¹⁶ Even subtle economic fluctuations—for example, an increase in the price of gasoline, natural gas, or electricity—contribute to food insecurity.¹⁷ Debt and coping mechanisms influence whether a household living below the poverty line is food-secure or food-insecure. Additional factors contributing to food insecurity include participation in SNAP, education, and severe depression.

To identify families that are food-insecure, conduct the 2-question AAP survey on food insecurity at every healthmaintenance visit.

Food insecurity in adults reduces the quality of food and nutritional intake, and is associated with chronic morbidity, such as type 2 diabetes, hypertension, and obesity.^5-7 Adults in food-insecure homes are more likely to purchase cheap, calorie-dense, nutritionally poor foods (or refrain from purchasing food altogether, to pay other debts).^17,18 The literature further suggests that food insecurity is associated with diseases that limit function and lead to disability, such as arthritis, stroke, and coronary artery disease, in adults and older adults (> 65 years of age; see the next section).^5,6,19 These studies are weak, however, in their ability to show directionality: Does food insecurity cause disability or does disability cause food insecurity?

Patchwork of programs. Programs such as WIC are available for women who are pregnant or have children < 5 years of age. Federal programs for adults who do not have children are scarce, however, and the burden of food insecurity for this population is typically addressed by local programs, such as food banks and food kitchens. Evidence shows that (1) combining the efforts of federal and local food programs is the most effective method of stymieing food insecurity in adults and (2) it would benefit food-insecure adults to have access to such programs. Regrettably, many food programs are underutilized because of barriers that include poor outreach, ineffectual application, and ineligibility.

What you can do. Although it might not be an official, professional society guideline to include questions about food security in a patient wellness survey, physicians should consider creating one for their practice that they (or the office staff) can administer. Furthermore, physicians (or, again, the office staff) should familiarize themselves with programs in the community, such as SNAP or a food bank, to which they can refer patients, as needed.

CASE You ask the nurse–care manager to consult with staff of the food bank and request that, based on your evaluation and recommendation, Ms. D be given more protein-based foods, including peanut butter and beans, when she visits the food bank. The nurse–care manager also makes arrangements to procure an insulin pump for Ms. D.

Continue to: In a short time...

In a short time, Ms. D’s blood glucose level normalizes. She has no further admissions for diabetic ketoacidosis.

Older adults: Interplay of risk factors takes a toll

The USDA Economic Research Report on food insecurity¹ states that older adults (≥ 65 years of age) report a lower rate of food insecurity—ie, 7.8% of households with an older adult and 8.9% of households in which the older adult lives alone—compared with the national average.¹ The report is limited, however, in its ability to extrapolate data from older adults on food insecurity because its focus is on factors specific to adults and children.

Factors that contribute to food insecurity in the elderly include race and ethnicity, education, income, being a SNAP recipient, and severe depression.^1,2,17,20,21 Older adult subgroups more likely to be food-insecure are Hispanic and black non-Hispanic—both significantly associated with being food-­insecure, with Hispanic populations reporting the highest rates of food insecurity.^20,21 This is a particularly interesting observation: Many traditional Hispanic homes are multigenerational and maintain a culture in which older adults are cared for by their children; that value system might be an indication of why many Hispanic households are disproportionately affected by food insecurity.

Adults in food-insecure homes are more likely to purchase cheap, calorie-dense food that lacks nutrition.

Other problems directly caused or exacerbated by food insecurity in the older population include a higher risk of malnutrition from periodontal disease, more frequent hospital admissions with longer length of stay, and an increased rate of falls and fractures. Polypharmacy, which can cause food–drug interactions that inhibit uptake of vitamins or create a higher demand for certain vitamins, is a noteworthy problem associated with food insecurity.

Problems with functionality might prevent older adults from performing physical tasks, such as shopping and preparing foods.^21,22 Older adults who reported functional impairment in performing activities of daily living are more likely to report food insecurity.^21,22 Last,older adults who live alone are more likely to have diminished nutritional intake than those who live with a spouse or partner.^2,22,23

Continue to: Legislation enacted in 2010...

Legislation enacted in 2010 under the existing Older Americans Act provided home-delivered meals, nutritional screening, and education counseling to Americans > 60 years of age. That provision was not based on an income test, however, and served only 18% of the older population.²³ (Other programs, such as SNAP, are utilized to a greater degree: 30% of eligible older adults participate, 75% of whom live alone.²³) Possible reasons for underutilization include restricted funding, lower education level, lack of outreach, a confusing application process, and the impression that the process is intrusive.^24-26

What you can do. To improve the nutritional intake of older adults, reconcile the patient’s medications at each visit to ensure that polypharmacy does not play a role in causing or exacerbating underlying conditions that can lead to poor nutritional intake. AARP (formerly the American Association of Retired Persons) recommends devising and conducting a survey of food insecurity with older adults that includes the 2-question American Academy of Pediatrics survey described earlier²⁷ (TABLE 2^15,27).Such a survey, which can be administered by office staff, should also include a screen for depression, financial stability, ability to perform activities of daily living (eg, shopping and driving), and changes in diet that are a result of periodontal disease. The survey should also inquire about the effects of current or chronic disability on day-to-day life.

For all patients: Refer to community resources

The problems of food insecurity presented here only broadly address what each of these 3 groups face. Although the overall trend in food insecurity has been downward since 2011, deeper issues of food insecurity need to be studied more within each population. This is particularly true among the geriatric population, whose numbers are increasing, and among ethnic minorities, including black non-Hispanics, and Hispanics, who face additional daily stressors because of implicit biases in society.

Ask older adults about any decline in performing activities of daily living, which can lead to food insecurity and poor nutritional intake.

More study is needed to decrease the rate of food insecurity across all populations in the United States. In the interim, family physicians should take advantage of their role in the care of families, children, and older people to address the problem of food insecurity in their patient population by applying the interventions we’ve outlined, with an emphasis on referral to resources in the community.

CORRESPONDENCE
Lillian Amèzquita, BS, The Warren Alpert Medical School, Brown University, Box G-9999, 222 Richmond Street, Providence, RI; lillian_amezquita@brown.edu.

CASE Alice D is 20 years old and has type 1 diabetes, as well as retinopathy, hypertension, bipolar I disorder, and hyperlipidemia. She is a new patient at your clinic and reports that she is ­“occasionally homeless” and has difficulty affording food.

You renew Ms. D’s prescriptions during the visit, discuss nutrition with her, and order lab testing, including a test of hemoglobin A1C, a lipid panel, and a basic metabolic panel. You ask her to follow up in 1 week to discuss the test results and next steps in her care.

© Masterfile

According to a 2016 report from the US Department of Agriculture (USDA) Economic Research Service, an estimated 12.3% of households in the United States are “food insecure.”¹ To ascertain what food security and insecurity are, the USDA measured numerous variables, including household structure, race and ethnicity, geography, and income. The report of the Economic Research Service stands as one of the largest domestic sources of information about food insecurity.

Food insecurity is defined as “food intake of household members [that is] reduced and normal eating patterns that are disrupted.”¹ It is often measured “per household,” but those data must be interpreted carefully because food insecurity affects household members differently. Some members, such as children, might be affected only mildly; adults, on the other hand, might be more severely affected. (Adults may, for instance, disrupt or skip their meals to maintain normal diets and meal patterns for their children.) In some households, food insecurity affects only a single member—such as an older adult—because of conditions unique to the people living in the home.

Adults may disrupt or skip their meals to maintain normal diets and meal patterns for their children.

In this article, we review variables that can give rise to food insecurity in children, adults, and the elderly, and offer ­strategies to the family physician for identifying and alleviating the burden of food insecurity in these populations.

Food insecurity threatens children’s health, development

In 2016, households with children faced a higher level of food insecurity (16.5%) than the national average (12.3%).¹ In a study of more than 280,000 households, food ­insecurity was sometimes so severe that children skipped meals or did not eat for the whole day.¹ Although income strongly correlates with food insecurity, evidence shows that families above and below the poverty line suffer from food insecurity.^2,3

According to the USDA, the rate of food insecurity is higher than the national average of 12.3% in several subgroups of ­children¹:

• households with children < 6 years of age (16.6%)
• households with children headed by a single woman (31.6%) or single man (21.7%)
• households headed by a black non-Hispanic (22.5%) or Hispanic (18.5%) person
• low-income households in which the annual income is < 185% of the poverty threshold (31.6%).

Continue to: Evidence suggests that...

Evidence suggests that children in food-insecure homes experience poor diet, impaired cognitive development, an increased risk of chronic illness in adulthood, and emotional and behavioral problems.^4-7 For caregivers in food-insecure homes, purchase price is the most influential factor when making food purchasing decisions. Thus, caregivers often purchase cheaper, more calorie-dense foods, rather than more expensive, nutrient-rich foods—leading to childhood obesity.⁸

Food insecurity affects 12% of households in the United States.

Relief eludes many. Federal programs, such as the National School Lunch Program, School Breakfast Program, the Summer Food Service Program, and the Child and Adult Care Food Program, provide free or reduced-price meals for school-age children. Although these programs reduce food insecurity in households that participate, program policy has established that participation is based on household income.⁹ This is problematic: According to the literature,² the income of 50% of households that are food-insecure is above the federal poverty level.

It would be more effective to have these programs target families based on geography, not income, because programs would then benefit those who are food-insecure but who live above the poverty line. Location is a significant factor in identifying food-insecure populations: Households outside metropolitan areas are disproportionately affected.¹ If these programs were to privilege geography over income, they would include (for example): families in school districts with a low number of grocery stores; families with poor access to public transportation; and families that live in a “food desert”—ie, where fresh, low-cost food options are overshadowed by fast food.

One such program closely applied the model of privilege based on geography: In 2010, the Healthy, Hunger-Free Kids Act was passed, with a Community Eligibility Provision (CEP) that funded school districts in which ≥ 40% of students lived below the poverty line, so that students in those districts received a free school lunch.¹⁰ Although eligibility for CEP is still based on income, benefits go to all students who live in the district, including food-insecure students who live in a household above the poverty line. If eligibility criteria were expanded with CEP so that more school districts could participate, it might solve many obstacles faced by other existing programs.

Programs that provide nutrition for households with an infant or young child—eg, the Women, Infants and Children Special Supplemental Nutrition Program (WIC) and the Supplemental Nutrition Assistance Program (SNAP)—reduce food insecurity in households by 20%. However, several unstudied factors can affect food insecurity in families beyond these programs¹¹; some assumptions about food insecurity, for example, strongly point to the influence of maternal mental health.¹²

Continue to: Data from the...

Data from the Early Childhood Longitudinal Study, Birth Cohort showed that mothers (with an infant) who were suffering from depression had a significantly increased risk of food insecurity.¹³ To better identify infants at risk of food insecurity, it would be beneficial to identify women suffering from depression during pregnancy or postpartum.¹³ These patients could then be referred to WIC and for SNAP benefits.

What you can do. The American Academy of Pediatrics recommends that physicians identify families that are food-insecure by conducting a validated¹⁴ 2-question survey about food insecurity at every health-­maintenance visit, as long as the child is a patient in the practice (TABLE 1).¹⁵ Physicians can then refer families that screen positively to local WIC and SNAP centers.

Ideally, physicians should be prepared to facilitate more active engagement by providing patients with the contact information of staff members working in such local programs. Staffing the practice with a patient-care manager can be an efficient way to navigate this process.

CASE Over the 6 weeks following Ms. D’s visit with you, she is admitted 5 times to the hospital in diabetic ketoacidosis, always with a significantly elevated blood glucose level. At each admission, she admits to “sometimes forgetting” to take insulin. Hospital staff members do not ask about her food intake. During each hospitalization, Ms. D is treated with insulin and intravenous fluids and discharged to home on her prior insulin regimen.

During a follow-up appointment with you and the clinic’s nurse–care manager, she talks about missing doses of insulin. She tells you that she has been getting food from the local food pantry, where available stocks are typically carbohydrate-based, including bread, rice, and cereal. She admits that she cannot afford other kinds of food—specifically, those that contain protein and monosaturated and polyunsaturated fats.

Continue to: Adults...

 

 

Adults: Poor financial health correlates with insecurity

The correlation between food insecurity and income is strong—evidenced by the spike in the number of adults who reported food insecurity during the 2008-2011 recession in the United States, to a high of 14.9%.¹ As noted, households with children are more likely to report food insecurity. In addition, studies show that limited resources, race and ethnicity, underemployment or unemployment, and high housing costs are also strongly associated with food insecurity.¹⁶ Even subtle economic fluctuations—for example, an increase in the price of gasoline, natural gas, or electricity—contribute to food insecurity.¹⁷ Debt and coping mechanisms influence whether a household living below the poverty line is food-secure or food-insecure. Additional factors contributing to food insecurity include participation in SNAP, education, and severe depression.

To identify families that are food-insecure, conduct the 2-question AAP survey on food insecurity at every healthmaintenance visit.

Food insecurity in adults reduces the quality of food and nutritional intake, and is associated with chronic morbidity, such as type 2 diabetes, hypertension, and obesity.^5-7 Adults in food-insecure homes are more likely to purchase cheap, calorie-dense, nutritionally poor foods (or refrain from purchasing food altogether, to pay other debts).^17,18 The literature further suggests that food insecurity is associated with diseases that limit function and lead to disability, such as arthritis, stroke, and coronary artery disease, in adults and older adults (> 65 years of age; see the next section).^5,6,19 These studies are weak, however, in their ability to show directionality: Does food insecurity cause disability or does disability cause food insecurity?

Patchwork of programs. Programs such as WIC are available for women who are pregnant or have children < 5 years of age. Federal programs for adults who do not have children are scarce, however, and the burden of food insecurity for this population is typically addressed by local programs, such as food banks and food kitchens. Evidence shows that (1) combining the efforts of federal and local food programs is the most effective method of stymieing food insecurity in adults and (2) it would benefit food-insecure adults to have access to such programs. Regrettably, many food programs are underutilized because of barriers that include poor outreach, ineffectual application, and ineligibility.

What you can do. Although it might not be an official, professional society guideline to include questions about food security in a patient wellness survey, physicians should consider creating one for their practice that they (or the office staff) can administer. Furthermore, physicians (or, again, the office staff) should familiarize themselves with programs in the community, such as SNAP or a food bank, to which they can refer patients, as needed.

CASE You ask the nurse–care manager to consult with staff of the food bank and request that, based on your evaluation and recommendation, Ms. D be given more protein-based foods, including peanut butter and beans, when she visits the food bank. The nurse–care manager also makes arrangements to procure an insulin pump for Ms. D.

Continue to: In a short time...

In a short time, Ms. D’s blood glucose level normalizes. She has no further admissions for diabetic ketoacidosis.

Older adults: Interplay of risk factors takes a toll

The USDA Economic Research Report on food insecurity¹ states that older adults (≥ 65 years of age) report a lower rate of food insecurity—ie, 7.8% of households with an older adult and 8.9% of households in which the older adult lives alone—compared with the national average.¹ The report is limited, however, in its ability to extrapolate data from older adults on food insecurity because its focus is on factors specific to adults and children.

Factors that contribute to food insecurity in the elderly include race and ethnicity, education, income, being a SNAP recipient, and severe depression.^1,2,17,20,21 Older adult subgroups more likely to be food-insecure are Hispanic and black non-Hispanic—both significantly associated with being food-­insecure, with Hispanic populations reporting the highest rates of food insecurity.^20,21 This is a particularly interesting observation: Many traditional Hispanic homes are multigenerational and maintain a culture in which older adults are cared for by their children; that value system might be an indication of why many Hispanic households are disproportionately affected by food insecurity.

Adults in food-insecure homes are more likely to purchase cheap, calorie-dense food that lacks nutrition.

Other problems directly caused or exacerbated by food insecurity in the older population include a higher risk of malnutrition from periodontal disease, more frequent hospital admissions with longer length of stay, and an increased rate of falls and fractures. Polypharmacy, which can cause food–drug interactions that inhibit uptake of vitamins or create a higher demand for certain vitamins, is a noteworthy problem associated with food insecurity.

Problems with functionality might prevent older adults from performing physical tasks, such as shopping and preparing foods.^21,22 Older adults who reported functional impairment in performing activities of daily living are more likely to report food insecurity.^21,22 Last,older adults who live alone are more likely to have diminished nutritional intake than those who live with a spouse or partner.^2,22,23

Continue to: Legislation enacted in 2010...

Legislation enacted in 2010 under the existing Older Americans Act provided home-delivered meals, nutritional screening, and education counseling to Americans > 60 years of age. That provision was not based on an income test, however, and served only 18% of the older population.²³ (Other programs, such as SNAP, are utilized to a greater degree: 30% of eligible older adults participate, 75% of whom live alone.²³) Possible reasons for underutilization include restricted funding, lower education level, lack of outreach, a confusing application process, and the impression that the process is intrusive.^24-26

What you can do. To improve the nutritional intake of older adults, reconcile the patient’s medications at each visit to ensure that polypharmacy does not play a role in causing or exacerbating underlying conditions that can lead to poor nutritional intake. AARP (formerly the American Association of Retired Persons) recommends devising and conducting a survey of food insecurity with older adults that includes the 2-question American Academy of Pediatrics survey described earlier²⁷ (TABLE 2^15,27).Such a survey, which can be administered by office staff, should also include a screen for depression, financial stability, ability to perform activities of daily living (eg, shopping and driving), and changes in diet that are a result of periodontal disease. The survey should also inquire about the effects of current or chronic disability on day-to-day life.

For all patients: Refer to community resources

The problems of food insecurity presented here only broadly address what each of these 3 groups face. Although the overall trend in food insecurity has been downward since 2011, deeper issues of food insecurity need to be studied more within each population. This is particularly true among the geriatric population, whose numbers are increasing, and among ethnic minorities, including black non-Hispanics, and Hispanics, who face additional daily stressors because of implicit biases in society.

Ask older adults about any decline in performing activities of daily living, which can lead to food insecurity and poor nutritional intake.

More study is needed to decrease the rate of food insecurity across all populations in the United States. In the interim, family physicians should take advantage of their role in the care of families, children, and older people to address the problem of food insecurity in their patient population by applying the interventions we’ve outlined, with an emphasis on referral to resources in the community.

CORRESPONDENCE
Lillian Amèzquita, BS, The Warren Alpert Medical School, Brown University, Box G-9999, 222 Richmond Street, Providence, RI; lillian_amezquita@brown.edu.

MAUI, HAWAII – A variant in the human leukocyte antigen gene – DQA1*05 – almost doubled the risk of antibodies forming against tumor necrosis factor (TNF) inhibitors in Crohn’s disease patients, irrespective of concomitant immunomodulator use, according to a report in Gastroenterology.

“Pretreatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF and the need for combination therapy,” concluded investigators led by Aleksejs Sazonovs, of the Wellcome Sanger Institute in Hinxton, England.

The same variant increases the risk of celiac disease, and it is included in commercial celiac genotyping assays. The allele is carried by about 40% of Europeans.

“This is turning into a hot topic; people are talking about it, [and it’s] blowing up on Twitter,” said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. “It turns out this is really a significant predictor of immunogenicity. Whatever your risk of developing antibodies, it’s going to double if you have this HLA marker, and it’s common.

M. Alexander Otto/MDedge News

“I think we are going to start [stratifying] our decision on combination [or] monotherapy based on this,” added Dr. Loftus, speaking at the Gastroenterology Updates, IBD, Liver Disease Conference. “I would argue that, if your patient has this marker, it would be criminal to give that patient infliximab monotherapy.”

The finding also begs the question of whether to bypass anti-TNFs altogether if a patient has the marker, Dr. Loftus noted, and just use ustekinumab, vedolizumab, or another agent.

Checking for celiac disease in inflammatory bowel disease isn’t unusual and involves the same gene variant, he added, so payer coverage shouldn’t be much of a problem.

The investigators ran a genome-wide association study on 1,418 biologic-naive Crohn’s patients starting infliximab or adalimumab therapy. Patients were in their 30s, on average, with a disease duration of about 3 years; there were about equal numbers of men and women.

A total of 44% of patients developed antidrug antibodies within a year. Overall, the rate of immunogenicity – defined as an antidrug antibody titer of at least 10 AU/mL – was nearly doubled in HLA-DQA1*05 carriers (hazard ratio, 1.90; 95% confidence interval, 1.60-2.25).

The association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33) and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator, usually azathioprine (HR, 2.01; 95% CI, 1.57-2.58).

The highest rates of immunogenicity, 92% at 1 year, were in HLA-DQA1*05 carriers on infliximab monotherapy. The lowest rates, 10% at 1 year, were in adalimumab patients on combination therapy who didn’t carry the variant. HLA-DQA1*05 was also associated with lower drug persistence rates.

The specific alleles HLA-DQA1*05:01 and HLA-DQA1*05:05 mediated most of the risk.

The study authors advised that “all patients treated with an anti-TNF should be prescribed an immunomodulator to lower the risk of immunogenicity.” Among HLA-DQA1*05 carriers “in whom immunomodulators are contraindicated or not tolerated, clinicians might advise against the use of anti-TNF drugs, particularly infliximab.”

In contrast, “patients who do not carry HLA-DQA1*05 might be given the choice between adalimumab or infliximab combination therapy,” the investigators said. “Patients without the risk allele and a history of adverse drug reactions to thiopurines and/or methotrexate, or who are at high risk of opportunistic infections, might be spared the additional risks of combination therapy and treated with adalimumab monotherapy.”

The mechanism for the association is unknown, the authors said.

The work was funded by the British Society of Gastroenterology, AbbVie, Merck, Pfizer, and others. The authors disclosed numerous ties to those or other pharmaceutical companies. Two authors were employees of AbbVie, marketer of the branded adalimumab Humira.
 

aotto@mdedge.com

SOURCE: Sazonovs A et al. Gastroenterology. 2020 Jan;158(1):189-99.

MAUI, HAWAII – A variant in the human leukocyte antigen gene – DQA1*05 – almost doubled the risk of antibodies forming against tumor necrosis factor (TNF) inhibitors in Crohn’s disease patients, irrespective of concomitant immunomodulator use, according to a report in Gastroenterology.

“Pretreatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF and the need for combination therapy,” concluded investigators led by Aleksejs Sazonovs, of the Wellcome Sanger Institute in Hinxton, England.

The same variant increases the risk of celiac disease, and it is included in commercial celiac genotyping assays. The allele is carried by about 40% of Europeans.

“This is turning into a hot topic; people are talking about it, [and it’s] blowing up on Twitter,” said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. “It turns out this is really a significant predictor of immunogenicity. Whatever your risk of developing antibodies, it’s going to double if you have this HLA marker, and it’s common.

M. Alexander Otto/MDedge News

“I think we are going to start [stratifying] our decision on combination [or] monotherapy based on this,” added Dr. Loftus, speaking at the Gastroenterology Updates, IBD, Liver Disease Conference. “I would argue that, if your patient has this marker, it would be criminal to give that patient infliximab monotherapy.”

The finding also begs the question of whether to bypass anti-TNFs altogether if a patient has the marker, Dr. Loftus noted, and just use ustekinumab, vedolizumab, or another agent.

Checking for celiac disease in inflammatory bowel disease isn’t unusual and involves the same gene variant, he added, so payer coverage shouldn’t be much of a problem.

The investigators ran a genome-wide association study on 1,418 biologic-naive Crohn’s patients starting infliximab or adalimumab therapy. Patients were in their 30s, on average, with a disease duration of about 3 years; there were about equal numbers of men and women.

A total of 44% of patients developed antidrug antibodies within a year. Overall, the rate of immunogenicity – defined as an antidrug antibody titer of at least 10 AU/mL – was nearly doubled in HLA-DQA1*05 carriers (hazard ratio, 1.90; 95% confidence interval, 1.60-2.25).

The association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33) and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator, usually azathioprine (HR, 2.01; 95% CI, 1.57-2.58).

The highest rates of immunogenicity, 92% at 1 year, were in HLA-DQA1*05 carriers on infliximab monotherapy. The lowest rates, 10% at 1 year, were in adalimumab patients on combination therapy who didn’t carry the variant. HLA-DQA1*05 was also associated with lower drug persistence rates.

The specific alleles HLA-DQA1*05:01 and HLA-DQA1*05:05 mediated most of the risk.

The study authors advised that “all patients treated with an anti-TNF should be prescribed an immunomodulator to lower the risk of immunogenicity.” Among HLA-DQA1*05 carriers “in whom immunomodulators are contraindicated or not tolerated, clinicians might advise against the use of anti-TNF drugs, particularly infliximab.”

In contrast, “patients who do not carry HLA-DQA1*05 might be given the choice between adalimumab or infliximab combination therapy,” the investigators said. “Patients without the risk allele and a history of adverse drug reactions to thiopurines and/or methotrexate, or who are at high risk of opportunistic infections, might be spared the additional risks of combination therapy and treated with adalimumab monotherapy.”

The mechanism for the association is unknown, the authors said.

The work was funded by the British Society of Gastroenterology, AbbVie, Merck, Pfizer, and others. The authors disclosed numerous ties to those or other pharmaceutical companies. Two authors were employees of AbbVie, marketer of the branded adalimumab Humira.
 

aotto@mdedge.com

SOURCE: Sazonovs A et al. Gastroenterology. 2020 Jan;158(1):189-99.

MAUI, HAWAII – A variant in the human leukocyte antigen gene – DQA1*05 – almost doubled the risk of antibodies forming against tumor necrosis factor (TNF) inhibitors in Crohn’s disease patients, irrespective of concomitant immunomodulator use, according to a report in Gastroenterology.

“Pretreatment genetic testing for HLA-DQA1*05 may help personalize the choice of anti-TNF and the need for combination therapy,” concluded investigators led by Aleksejs Sazonovs, of the Wellcome Sanger Institute in Hinxton, England.

The same variant increases the risk of celiac disease, and it is included in commercial celiac genotyping assays. The allele is carried by about 40% of Europeans.

“This is turning into a hot topic; people are talking about it, [and it’s] blowing up on Twitter,” said Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn. “It turns out this is really a significant predictor of immunogenicity. Whatever your risk of developing antibodies, it’s going to double if you have this HLA marker, and it’s common.

M. Alexander Otto/MDedge News

“I think we are going to start [stratifying] our decision on combination [or] monotherapy based on this,” added Dr. Loftus, speaking at the Gastroenterology Updates, IBD, Liver Disease Conference. “I would argue that, if your patient has this marker, it would be criminal to give that patient infliximab monotherapy.”

The finding also begs the question of whether to bypass anti-TNFs altogether if a patient has the marker, Dr. Loftus noted, and just use ustekinumab, vedolizumab, or another agent.

Checking for celiac disease in inflammatory bowel disease isn’t unusual and involves the same gene variant, he added, so payer coverage shouldn’t be much of a problem.

The investigators ran a genome-wide association study on 1,418 biologic-naive Crohn’s patients starting infliximab or adalimumab therapy. Patients were in their 30s, on average, with a disease duration of about 3 years; there were about equal numbers of men and women.

A total of 44% of patients developed antidrug antibodies within a year. Overall, the rate of immunogenicity – defined as an antidrug antibody titer of at least 10 AU/mL – was nearly doubled in HLA-DQA1*05 carriers (hazard ratio, 1.90; 95% confidence interval, 1.60-2.25).

The association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33) and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator, usually azathioprine (HR, 2.01; 95% CI, 1.57-2.58).

The highest rates of immunogenicity, 92% at 1 year, were in HLA-DQA1*05 carriers on infliximab monotherapy. The lowest rates, 10% at 1 year, were in adalimumab patients on combination therapy who didn’t carry the variant. HLA-DQA1*05 was also associated with lower drug persistence rates.

The specific alleles HLA-DQA1*05:01 and HLA-DQA1*05:05 mediated most of the risk.

The study authors advised that “all patients treated with an anti-TNF should be prescribed an immunomodulator to lower the risk of immunogenicity.” Among HLA-DQA1*05 carriers “in whom immunomodulators are contraindicated or not tolerated, clinicians might advise against the use of anti-TNF drugs, particularly infliximab.”

In contrast, “patients who do not carry HLA-DQA1*05 might be given the choice between adalimumab or infliximab combination therapy,” the investigators said. “Patients without the risk allele and a history of adverse drug reactions to thiopurines and/or methotrexate, or who are at high risk of opportunistic infections, might be spared the additional risks of combination therapy and treated with adalimumab monotherapy.”

The mechanism for the association is unknown, the authors said.

The work was funded by the British Society of Gastroenterology, AbbVie, Merck, Pfizer, and others. The authors disclosed numerous ties to those or other pharmaceutical companies. Two authors were employees of AbbVie, marketer of the branded adalimumab Humira.
 

aotto@mdedge.com

SOURCE: Sazonovs A et al. Gastroenterology. 2020 Jan;158(1):189-99.

Adults aged 18-79 years should be screened for hepatitis C virus infection, according to an updated grade B recommendation from the U.S. Preventive Services Task Force.

Cases of acute hepatitis C virus (HCV) infection have spiked in the last decade, in part because of increased use of injection drugs and in part because of better surveillance, Douglas K. Owens, MD, of Stanford (Calif.) University, and colleagues wrote in the recommendation statement published in JAMA.

The recommendation applies to all asymptomatic adults aged 18-79 years without known liver disease, and expands on the 2013 recommendation to screen adults born between 1945 and 1965. The grade B designation means that the task force concluded with moderate certainty that HCV screening for adults aged 18-79 years had “substantial net benefit.”

The recommendations are based on an evidence report including 8 randomized, controlled trials, 48 other treatment studies, and 33 cohort studies published through February 2019 for a total of 179,230 individuals.

The screening is a one-time procedure for most adults, according to the task force, but clinicians should periodically screen individuals at increased risk, such as those with a past or current history of injection drug use. In addition, clinicians should consider screening individuals at increased risk who are above or below the recommended age range.

Although the task force identified no direct evidence on the benefit of screening for HCV infection in asymptomatic adults, a notable finding was that the newer direct-acting antiviral (DAA) regimens are sufficiently effective to support the expanded screening recommendation, they said. However, clinicians should inform patients that screening is voluntary and conducted only with the patient’s knowledge. Clinicians should educate patients about hepatitis C and give them an opportunity to ask questions and to make a decision about screening, according to the task force.

In the evidence report, a total of 49 studies including 10,181 individuals showed DAA treatment associated with pooled sustained virologic response rates greater than 95% across all virus genotypes, and a short-term serious adverse event rate of 1.9%. In addition, sustained virologic response following an antiviral therapy was associated with a reduction in risk of all-cause mortality (pooled hazard ratio 0.40) and of hepatocellular carcinoma (pooled HR 0.29) compared with cases of no sustained virologic response.

The evidence report findings were limited by several factors, including the relatively small number of randomized trials involving current DAA treatments, limited data on baseline symptoms, limited data on adolescents, and limited evidence on potential long-term harms of DAA therapy, noted Richard Chou, MD, of Oregon Health & Science University, Portland, and colleagues. However, new pooled evidence “indicates that SVR rates with currently recommended all-oral DAA regimens are substantially higher (more than 95%) than with interferon-based therapies evaluated in the prior review (68%-78%),” they said.

Several editorials were published concurrently with the recommendation.

In an editorial published in JAMA, Camilla S. Graham, MD, of Harvard Medical School, Boston, and Stacey Trooskin, MD, of the University of Pennsylvania, Philadelphia, wrote that the new recommendation reflects changes in hepatitis C virus management.

“With the approvals of sofosbuvir and simeprevir in 2013, patients with hepatitis C, a chronic viral illness associated with the deaths of more U.S. patients than the next 60 reportable infectious diseases combined, including HIV and tuberculosis, could expect a greater than 90% rate of achieving sustained virologic response (SVR, defined as undetectable HCV levels 12 weeks or longer after treatment completion, which is consistent with virologic cure of HCV infection) following 12 weeks of treatment,” they said.

These medications are effective but expensive; however, the combination of the availability of generic medications and the ongoing opioid epidemic in the United States are important contributors to the expanded recommendations, which “are welcome,” and may help meeting WHO 2030 targets for reducing new HCV infections, they said.

Dr. Graham disclosed personal fees from UpToDate. Dr. Trooskin disclosed grants from Gilead Sciences and personal fees from Merck, AbbVie, and Gilead Sciences.

In an editorial published in JAMA Internal Medicine, Jennifer C. Price, MD, and Danielle Brandman, MD, both of the University of California, San Francisco, wrote that “the advancements in HCV diagnosis and treatment have been extraordinary,” but that the new recommendation does not go far enough. “Implementation of HCV screening and linkage to treatment requires large-scale coordinated efforts, innovation, and resources. For example, point-of-care HCV RNA testing would enable scale-up of HCV screening and confirmatory testing among individuals at greatest risk of HCV infection,” they said. “Additionally, barriers remain between diagnosis and treatment, such as access to a health care provider who can treat HCV and authorization to receive affordable DAAs,” they noted. “Although the USPSTF HCV screening recommendation is a step forward for controlling HCV infection in the U.S., it will take a coordinated and funded effort to ensure that the anticipated benefits are realized,” they concluded.

Dr. Price disclosed research funding from Gilead Sciences and Merck. Dr. Brandman disclosed research funding from Gilead Sciences, Pfizer, Conatus, Allergan, and Grifols, as well as personal fees from Alnylam.

In an editorial published in JAMA Network Open, Eli S. Rosenberg, PhD, of the University at Albany (N.Y.) School of Public Health, and Joshua A. Barocas, MD, of Boston University, emphasized the need to change the stigma surrounding HCV infection in the United States.

“Given the changing epidemiology of HCV infection, new public health priorities, advancements in treatment, and unmet diagnostic needs, it is wise to periodically reevaluate screening recommendations to ensure that they are maximally addressing these areas and patients’ individual needs,” they said. “The Affordable Care Act requires private insurers and Medicaid to cover preventive services recommended by the USPSTF with a grade of A or B with no cost sharing (i.e., no deductible or copayment),” they noted. Although the new recommendation for one-time screening will likely identify more cases, improve outcomes, and reduce deaths, the editorialists cautioned that “one-time screening should not be interpreted like catch-up vaccinations, whereby we immunize someone at any age for hepatitis B virus, for example, and they are then immunized for the remainder of their life,” and that reassessments are needed, especially for younger adults.

In addition, they emphasized the need to reduce the stigma surrounding HCV and allow for recommendations based on risk, rather than age. “We have forced the USPSTF to adopt age-based screening recommendations because we, as a society, have created a culture in which we have stigmatized these behaviors and we, as practitioners, have proven to be inadequate at eliciting HCV risk behaviors,” they said. “Our responsibility as a society and practice community is to address structural and individual factors that limit our ability to most precisely address the needs of our patients and truly move toward HCV elimination,” they concluded.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The task force researchers had no financial conflicts to disclose.

SOURCES: Owens DK et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2020.1123; Chou R et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.20788; Graham CS, Trooskin S. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.22313; Price JC and Brandman D. JAMA Intern Med. 2020 Mar 2. doi: 10.1001/jamainternmed.2019.7334; Rosenberg ES, Barocas JA. JAMA Network Open. 2020 Mar 2. doi: 10.1001/jamanetworkopen.2020.0538.

Adults aged 18-79 years should be screened for hepatitis C virus infection, according to an updated grade B recommendation from the U.S. Preventive Services Task Force.

Cases of acute hepatitis C virus (HCV) infection have spiked in the last decade, in part because of increased use of injection drugs and in part because of better surveillance, Douglas K. Owens, MD, of Stanford (Calif.) University, and colleagues wrote in the recommendation statement published in JAMA.

The recommendation applies to all asymptomatic adults aged 18-79 years without known liver disease, and expands on the 2013 recommendation to screen adults born between 1945 and 1965. The grade B designation means that the task force concluded with moderate certainty that HCV screening for adults aged 18-79 years had “substantial net benefit.”

The recommendations are based on an evidence report including 8 randomized, controlled trials, 48 other treatment studies, and 33 cohort studies published through February 2019 for a total of 179,230 individuals.

The screening is a one-time procedure for most adults, according to the task force, but clinicians should periodically screen individuals at increased risk, such as those with a past or current history of injection drug use. In addition, clinicians should consider screening individuals at increased risk who are above or below the recommended age range.

Although the task force identified no direct evidence on the benefit of screening for HCV infection in asymptomatic adults, a notable finding was that the newer direct-acting antiviral (DAA) regimens are sufficiently effective to support the expanded screening recommendation, they said. However, clinicians should inform patients that screening is voluntary and conducted only with the patient’s knowledge. Clinicians should educate patients about hepatitis C and give them an opportunity to ask questions and to make a decision about screening, according to the task force.

In the evidence report, a total of 49 studies including 10,181 individuals showed DAA treatment associated with pooled sustained virologic response rates greater than 95% across all virus genotypes, and a short-term serious adverse event rate of 1.9%. In addition, sustained virologic response following an antiviral therapy was associated with a reduction in risk of all-cause mortality (pooled hazard ratio 0.40) and of hepatocellular carcinoma (pooled HR 0.29) compared with cases of no sustained virologic response.

The evidence report findings were limited by several factors, including the relatively small number of randomized trials involving current DAA treatments, limited data on baseline symptoms, limited data on adolescents, and limited evidence on potential long-term harms of DAA therapy, noted Richard Chou, MD, of Oregon Health & Science University, Portland, and colleagues. However, new pooled evidence “indicates that SVR rates with currently recommended all-oral DAA regimens are substantially higher (more than 95%) than with interferon-based therapies evaluated in the prior review (68%-78%),” they said.

Several editorials were published concurrently with the recommendation.

In an editorial published in JAMA, Camilla S. Graham, MD, of Harvard Medical School, Boston, and Stacey Trooskin, MD, of the University of Pennsylvania, Philadelphia, wrote that the new recommendation reflects changes in hepatitis C virus management.

“With the approvals of sofosbuvir and simeprevir in 2013, patients with hepatitis C, a chronic viral illness associated with the deaths of more U.S. patients than the next 60 reportable infectious diseases combined, including HIV and tuberculosis, could expect a greater than 90% rate of achieving sustained virologic response (SVR, defined as undetectable HCV levels 12 weeks or longer after treatment completion, which is consistent with virologic cure of HCV infection) following 12 weeks of treatment,” they said.

These medications are effective but expensive; however, the combination of the availability of generic medications and the ongoing opioid epidemic in the United States are important contributors to the expanded recommendations, which “are welcome,” and may help meeting WHO 2030 targets for reducing new HCV infections, they said.

Dr. Graham disclosed personal fees from UpToDate. Dr. Trooskin disclosed grants from Gilead Sciences and personal fees from Merck, AbbVie, and Gilead Sciences.

In an editorial published in JAMA Internal Medicine, Jennifer C. Price, MD, and Danielle Brandman, MD, both of the University of California, San Francisco, wrote that “the advancements in HCV diagnosis and treatment have been extraordinary,” but that the new recommendation does not go far enough. “Implementation of HCV screening and linkage to treatment requires large-scale coordinated efforts, innovation, and resources. For example, point-of-care HCV RNA testing would enable scale-up of HCV screening and confirmatory testing among individuals at greatest risk of HCV infection,” they said. “Additionally, barriers remain between diagnosis and treatment, such as access to a health care provider who can treat HCV and authorization to receive affordable DAAs,” they noted. “Although the USPSTF HCV screening recommendation is a step forward for controlling HCV infection in the U.S., it will take a coordinated and funded effort to ensure that the anticipated benefits are realized,” they concluded.

Dr. Price disclosed research funding from Gilead Sciences and Merck. Dr. Brandman disclosed research funding from Gilead Sciences, Pfizer, Conatus, Allergan, and Grifols, as well as personal fees from Alnylam.

In an editorial published in JAMA Network Open, Eli S. Rosenberg, PhD, of the University at Albany (N.Y.) School of Public Health, and Joshua A. Barocas, MD, of Boston University, emphasized the need to change the stigma surrounding HCV infection in the United States.

“Given the changing epidemiology of HCV infection, new public health priorities, advancements in treatment, and unmet diagnostic needs, it is wise to periodically reevaluate screening recommendations to ensure that they are maximally addressing these areas and patients’ individual needs,” they said. “The Affordable Care Act requires private insurers and Medicaid to cover preventive services recommended by the USPSTF with a grade of A or B with no cost sharing (i.e., no deductible or copayment),” they noted. Although the new recommendation for one-time screening will likely identify more cases, improve outcomes, and reduce deaths, the editorialists cautioned that “one-time screening should not be interpreted like catch-up vaccinations, whereby we immunize someone at any age for hepatitis B virus, for example, and they are then immunized for the remainder of their life,” and that reassessments are needed, especially for younger adults.

In addition, they emphasized the need to reduce the stigma surrounding HCV and allow for recommendations based on risk, rather than age. “We have forced the USPSTF to adopt age-based screening recommendations because we, as a society, have created a culture in which we have stigmatized these behaviors and we, as practitioners, have proven to be inadequate at eliciting HCV risk behaviors,” they said. “Our responsibility as a society and practice community is to address structural and individual factors that limit our ability to most precisely address the needs of our patients and truly move toward HCV elimination,” they concluded.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The task force researchers had no financial conflicts to disclose.

SOURCES: Owens DK et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2020.1123; Chou R et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.20788; Graham CS, Trooskin S. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.22313; Price JC and Brandman D. JAMA Intern Med. 2020 Mar 2. doi: 10.1001/jamainternmed.2019.7334; Rosenberg ES, Barocas JA. JAMA Network Open. 2020 Mar 2. doi: 10.1001/jamanetworkopen.2020.0538.

Adults aged 18-79 years should be screened for hepatitis C virus infection, according to an updated grade B recommendation from the U.S. Preventive Services Task Force.

Cases of acute hepatitis C virus (HCV) infection have spiked in the last decade, in part because of increased use of injection drugs and in part because of better surveillance, Douglas K. Owens, MD, of Stanford (Calif.) University, and colleagues wrote in the recommendation statement published in JAMA.

The recommendation applies to all asymptomatic adults aged 18-79 years without known liver disease, and expands on the 2013 recommendation to screen adults born between 1945 and 1965. The grade B designation means that the task force concluded with moderate certainty that HCV screening for adults aged 18-79 years had “substantial net benefit.”

The recommendations are based on an evidence report including 8 randomized, controlled trials, 48 other treatment studies, and 33 cohort studies published through February 2019 for a total of 179,230 individuals.

The screening is a one-time procedure for most adults, according to the task force, but clinicians should periodically screen individuals at increased risk, such as those with a past or current history of injection drug use. In addition, clinicians should consider screening individuals at increased risk who are above or below the recommended age range.

Although the task force identified no direct evidence on the benefit of screening for HCV infection in asymptomatic adults, a notable finding was that the newer direct-acting antiviral (DAA) regimens are sufficiently effective to support the expanded screening recommendation, they said. However, clinicians should inform patients that screening is voluntary and conducted only with the patient’s knowledge. Clinicians should educate patients about hepatitis C and give them an opportunity to ask questions and to make a decision about screening, according to the task force.

In the evidence report, a total of 49 studies including 10,181 individuals showed DAA treatment associated with pooled sustained virologic response rates greater than 95% across all virus genotypes, and a short-term serious adverse event rate of 1.9%. In addition, sustained virologic response following an antiviral therapy was associated with a reduction in risk of all-cause mortality (pooled hazard ratio 0.40) and of hepatocellular carcinoma (pooled HR 0.29) compared with cases of no sustained virologic response.

The evidence report findings were limited by several factors, including the relatively small number of randomized trials involving current DAA treatments, limited data on baseline symptoms, limited data on adolescents, and limited evidence on potential long-term harms of DAA therapy, noted Richard Chou, MD, of Oregon Health & Science University, Portland, and colleagues. However, new pooled evidence “indicates that SVR rates with currently recommended all-oral DAA regimens are substantially higher (more than 95%) than with interferon-based therapies evaluated in the prior review (68%-78%),” they said.

Several editorials were published concurrently with the recommendation.

In an editorial published in JAMA, Camilla S. Graham, MD, of Harvard Medical School, Boston, and Stacey Trooskin, MD, of the University of Pennsylvania, Philadelphia, wrote that the new recommendation reflects changes in hepatitis C virus management.

“With the approvals of sofosbuvir and simeprevir in 2013, patients with hepatitis C, a chronic viral illness associated with the deaths of more U.S. patients than the next 60 reportable infectious diseases combined, including HIV and tuberculosis, could expect a greater than 90% rate of achieving sustained virologic response (SVR, defined as undetectable HCV levels 12 weeks or longer after treatment completion, which is consistent with virologic cure of HCV infection) following 12 weeks of treatment,” they said.

These medications are effective but expensive; however, the combination of the availability of generic medications and the ongoing opioid epidemic in the United States are important contributors to the expanded recommendations, which “are welcome,” and may help meeting WHO 2030 targets for reducing new HCV infections, they said.

Dr. Graham disclosed personal fees from UpToDate. Dr. Trooskin disclosed grants from Gilead Sciences and personal fees from Merck, AbbVie, and Gilead Sciences.

In an editorial published in JAMA Internal Medicine, Jennifer C. Price, MD, and Danielle Brandman, MD, both of the University of California, San Francisco, wrote that “the advancements in HCV diagnosis and treatment have been extraordinary,” but that the new recommendation does not go far enough. “Implementation of HCV screening and linkage to treatment requires large-scale coordinated efforts, innovation, and resources. For example, point-of-care HCV RNA testing would enable scale-up of HCV screening and confirmatory testing among individuals at greatest risk of HCV infection,” they said. “Additionally, barriers remain between diagnosis and treatment, such as access to a health care provider who can treat HCV and authorization to receive affordable DAAs,” they noted. “Although the USPSTF HCV screening recommendation is a step forward for controlling HCV infection in the U.S., it will take a coordinated and funded effort to ensure that the anticipated benefits are realized,” they concluded.

Dr. Price disclosed research funding from Gilead Sciences and Merck. Dr. Brandman disclosed research funding from Gilead Sciences, Pfizer, Conatus, Allergan, and Grifols, as well as personal fees from Alnylam.

In an editorial published in JAMA Network Open, Eli S. Rosenberg, PhD, of the University at Albany (N.Y.) School of Public Health, and Joshua A. Barocas, MD, of Boston University, emphasized the need to change the stigma surrounding HCV infection in the United States.

“Given the changing epidemiology of HCV infection, new public health priorities, advancements in treatment, and unmet diagnostic needs, it is wise to periodically reevaluate screening recommendations to ensure that they are maximally addressing these areas and patients’ individual needs,” they said. “The Affordable Care Act requires private insurers and Medicaid to cover preventive services recommended by the USPSTF with a grade of A or B with no cost sharing (i.e., no deductible or copayment),” they noted. Although the new recommendation for one-time screening will likely identify more cases, improve outcomes, and reduce deaths, the editorialists cautioned that “one-time screening should not be interpreted like catch-up vaccinations, whereby we immunize someone at any age for hepatitis B virus, for example, and they are then immunized for the remainder of their life,” and that reassessments are needed, especially for younger adults.

In addition, they emphasized the need to reduce the stigma surrounding HCV and allow for recommendations based on risk, rather than age. “We have forced the USPSTF to adopt age-based screening recommendations because we, as a society, have created a culture in which we have stigmatized these behaviors and we, as practitioners, have proven to be inadequate at eliciting HCV risk behaviors,” they said. “Our responsibility as a society and practice community is to address structural and individual factors that limit our ability to most precisely address the needs of our patients and truly move toward HCV elimination,” they concluded.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The task force researchers had no financial conflicts to disclose.

SOURCES: Owens DK et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2020.1123; Chou R et al. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.20788; Graham CS, Trooskin S. JAMA. 2020 Mar 2. doi: 10.1001/jama.2019.22313; Price JC and Brandman D. JAMA Intern Med. 2020 Mar 2. doi: 10.1001/jamainternmed.2019.7334; Rosenberg ES, Barocas JA. JAMA Network Open. 2020 Mar 2. doi: 10.1001/jamanetworkopen.2020.0538.

A variety of toys and other play products can cause contact dermatitis in children because of the nature of their ingredients, according to the results of a review of 25 published articles.

Motortion/Getty Images

“In recent years the products have become a reflection of the compounds used frequently in manufacturing, including metals and plastic compounds,” wrote Justine Fenner, MD, and coauthors, from the departments of dermatology and pediatrics at the Icahn School of Medicine at Mount Sinai, New York,

In a study published in Contact Dermatitis, the researchers identified 25 articles describing dermatitis, rash, or eczema associated with a range of toy and play product terms including Nintendo, PlayStation, putty, glue, doll, game, car, bicycle, slime, iPad, and iPhone.

Overall, nickel was the most common allergen. Cases of nickel dermatitis were associated with laptops, videogame controllers, iPads, and cell phones. Cell phones were the most common electronics associated with contact dermatitis, which was observed on the cheek, periauricular area, and hand, as well as the breast in one case of a patient who kept her phone in her bra.

Other sources of metal allergens were identified in toy cars and costume jewelry, the researchers noted.

In addition, temporary tattoos have been associated with contact dermatitis in children, as have homemade “slime” products, which often contain not only borax or other household detergents, but also glue, shaving cream, or coloring.

However, identification of true allergic contact dermatitis from toys “requires both identification of the chemical contents of toys, which are proprietary in nature, and then epicutaneous allergy testing of these ingredients,” the researchers said.

The study findings were limited by several factors including the consideration only of English-language articles and of cases in children, which thus eliminates other potential cases, the researchers noted. However, the results suggest that dermatologists consider toys as a source of contact dermatitis in children, especially if the time to diagnosis is months to years, they said. “Additionally, it may be useful, as it was in several of the above cases, to have the patient bring in his or her favorite toys for the dermatologist to examine and help further understand the etiology of patient’s rash,” they noted. Moreover, “there is an unmet need for corporations to reveal the chemical ingredients of their toys when allergic contact dermatitis is suspected in order to properly evaluate the patient,” they added.

“Contact dermatitis has been underreported in children and constitutes an ongoing concern,” senior author Nanette Silverberg, MD, chief of pediatric dermatology for the Mount Sinai Health System, said in an interview.

“In particular, toy-related allergy is concerning due to the rise in allergen inclusion in common play items,” she commented. The current analysis identified many case reports of allergens that pediatric dermatologists are frequently seeing in their offices, notably metals such as nickel, she pointed out. “The allergen that always stands out ahead of others is nickel,” Dr. Silverberg said. “Nickel allergy affects about 25% of Americans, often starting in early childhood,” she said. “In the European Union, legislation has been passed to reduce nickel release from metals, which has resulted in less sensitization to nickel. We lack such legislation in the United States,” she added. 

Other trending allergens include methylchloroisothiazolinone/methylisothiazolinone, which may be components of glue or other ingredients in some “slime” products, Dr. Silverberg said.

She advised clinicians to consider patch testing when addressing localized or persistent dermatitis in children. “Furthermore, consider toys as potential relevant allergens that should be modified in order to achieve skin improvement,” she said.

“Greater reporting of pediatric allergic contact dermatitis is needed,” Dr. Silverberg emphasized. “Additionally, surveillance and monitoring for trends in allergen exposures in toys and personal care items is required to analyze this ongoing concern of childhood,” she said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Fenner J et al. Contact Dermatitis. 2020 Feb 22. doi: 10.1111/cod.13500.

A variety of toys and other play products can cause contact dermatitis in children because of the nature of their ingredients, according to the results of a review of 25 published articles.

Motortion/Getty Images

“In recent years the products have become a reflection of the compounds used frequently in manufacturing, including metals and plastic compounds,” wrote Justine Fenner, MD, and coauthors, from the departments of dermatology and pediatrics at the Icahn School of Medicine at Mount Sinai, New York,

In a study published in Contact Dermatitis, the researchers identified 25 articles describing dermatitis, rash, or eczema associated with a range of toy and play product terms including Nintendo, PlayStation, putty, glue, doll, game, car, bicycle, slime, iPad, and iPhone.

Overall, nickel was the most common allergen. Cases of nickel dermatitis were associated with laptops, videogame controllers, iPads, and cell phones. Cell phones were the most common electronics associated with contact dermatitis, which was observed on the cheek, periauricular area, and hand, as well as the breast in one case of a patient who kept her phone in her bra.

Other sources of metal allergens were identified in toy cars and costume jewelry, the researchers noted.

In addition, temporary tattoos have been associated with contact dermatitis in children, as have homemade “slime” products, which often contain not only borax or other household detergents, but also glue, shaving cream, or coloring.

However, identification of true allergic contact dermatitis from toys “requires both identification of the chemical contents of toys, which are proprietary in nature, and then epicutaneous allergy testing of these ingredients,” the researchers said.

The study findings were limited by several factors including the consideration only of English-language articles and of cases in children, which thus eliminates other potential cases, the researchers noted. However, the results suggest that dermatologists consider toys as a source of contact dermatitis in children, especially if the time to diagnosis is months to years, they said. “Additionally, it may be useful, as it was in several of the above cases, to have the patient bring in his or her favorite toys for the dermatologist to examine and help further understand the etiology of patient’s rash,” they noted. Moreover, “there is an unmet need for corporations to reveal the chemical ingredients of their toys when allergic contact dermatitis is suspected in order to properly evaluate the patient,” they added.

“Contact dermatitis has been underreported in children and constitutes an ongoing concern,” senior author Nanette Silverberg, MD, chief of pediatric dermatology for the Mount Sinai Health System, said in an interview.

“In particular, toy-related allergy is concerning due to the rise in allergen inclusion in common play items,” she commented. The current analysis identified many case reports of allergens that pediatric dermatologists are frequently seeing in their offices, notably metals such as nickel, she pointed out. “The allergen that always stands out ahead of others is nickel,” Dr. Silverberg said. “Nickel allergy affects about 25% of Americans, often starting in early childhood,” she said. “In the European Union, legislation has been passed to reduce nickel release from metals, which has resulted in less sensitization to nickel. We lack such legislation in the United States,” she added. 

Other trending allergens include methylchloroisothiazolinone/methylisothiazolinone, which may be components of glue or other ingredients in some “slime” products, Dr. Silverberg said.

She advised clinicians to consider patch testing when addressing localized or persistent dermatitis in children. “Furthermore, consider toys as potential relevant allergens that should be modified in order to achieve skin improvement,” she said.

“Greater reporting of pediatric allergic contact dermatitis is needed,” Dr. Silverberg emphasized. “Additionally, surveillance and monitoring for trends in allergen exposures in toys and personal care items is required to analyze this ongoing concern of childhood,” she said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Fenner J et al. Contact Dermatitis. 2020 Feb 22. doi: 10.1111/cod.13500.

A variety of toys and other play products can cause contact dermatitis in children because of the nature of their ingredients, according to the results of a review of 25 published articles.

Motortion/Getty Images

“In recent years the products have become a reflection of the compounds used frequently in manufacturing, including metals and plastic compounds,” wrote Justine Fenner, MD, and coauthors, from the departments of dermatology and pediatrics at the Icahn School of Medicine at Mount Sinai, New York,

In a study published in Contact Dermatitis, the researchers identified 25 articles describing dermatitis, rash, or eczema associated with a range of toy and play product terms including Nintendo, PlayStation, putty, glue, doll, game, car, bicycle, slime, iPad, and iPhone.

Overall, nickel was the most common allergen. Cases of nickel dermatitis were associated with laptops, videogame controllers, iPads, and cell phones. Cell phones were the most common electronics associated with contact dermatitis, which was observed on the cheek, periauricular area, and hand, as well as the breast in one case of a patient who kept her phone in her bra.

Other sources of metal allergens were identified in toy cars and costume jewelry, the researchers noted.

In addition, temporary tattoos have been associated with contact dermatitis in children, as have homemade “slime” products, which often contain not only borax or other household detergents, but also glue, shaving cream, or coloring.

However, identification of true allergic contact dermatitis from toys “requires both identification of the chemical contents of toys, which are proprietary in nature, and then epicutaneous allergy testing of these ingredients,” the researchers said.

The study findings were limited by several factors including the consideration only of English-language articles and of cases in children, which thus eliminates other potential cases, the researchers noted. However, the results suggest that dermatologists consider toys as a source of contact dermatitis in children, especially if the time to diagnosis is months to years, they said. “Additionally, it may be useful, as it was in several of the above cases, to have the patient bring in his or her favorite toys for the dermatologist to examine and help further understand the etiology of patient’s rash,” they noted. Moreover, “there is an unmet need for corporations to reveal the chemical ingredients of their toys when allergic contact dermatitis is suspected in order to properly evaluate the patient,” they added.

“Contact dermatitis has been underreported in children and constitutes an ongoing concern,” senior author Nanette Silverberg, MD, chief of pediatric dermatology for the Mount Sinai Health System, said in an interview.

“In particular, toy-related allergy is concerning due to the rise in allergen inclusion in common play items,” she commented. The current analysis identified many case reports of allergens that pediatric dermatologists are frequently seeing in their offices, notably metals such as nickel, she pointed out. “The allergen that always stands out ahead of others is nickel,” Dr. Silverberg said. “Nickel allergy affects about 25% of Americans, often starting in early childhood,” she said. “In the European Union, legislation has been passed to reduce nickel release from metals, which has resulted in less sensitization to nickel. We lack such legislation in the United States,” she added. 

Other trending allergens include methylchloroisothiazolinone/methylisothiazolinone, which may be components of glue or other ingredients in some “slime” products, Dr. Silverberg said.

She advised clinicians to consider patch testing when addressing localized or persistent dermatitis in children. “Furthermore, consider toys as potential relevant allergens that should be modified in order to achieve skin improvement,” she said.

“Greater reporting of pediatric allergic contact dermatitis is needed,” Dr. Silverberg emphasized. “Additionally, surveillance and monitoring for trends in allergen exposures in toys and personal care items is required to analyze this ongoing concern of childhood,” she said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

SOURCE: Fenner J et al. Contact Dermatitis. 2020 Feb 22. doi: 10.1111/cod.13500.

Less than one-third of first authors on rheumatology guidelines or recommendations are women, according to a research letter published in Annals of the Rheumatic Diseases.

Giovanni Adami, MD, from the department of medicine at the University of Verona (Italy), and coauthors examined 366 English-language guidelines and recommendations published between 2004 and 2019 around the world.

They found that only 32% featured a female first author. However, they did observe a significant trend toward increasing female first authorship over the study period, with parity first being achieved for guidelines and recommendations published in 2017.

Male-dominated first authorship was seen almost across the disease subject matter. For RA, only 18.8% of the 96 guidelines or recommendations examined had a female first author, and of the 12 documents on polymyalgia rheumatica and giant cell arteritis, none featured a female first author.

Among the 73 guidelines and recommendations relating to psoriatic arthritis and spondyloarthritis, only 23.3% featured a female first author. However, three of the six documents on polymyositis and dermatomyositis had a female lead author, the only area where parity was achieved.

The authors noted the recent establishment of the EULAR Task Force on Gender Equity in Academic Rheumatology, which they said was an important first step toward gender equity in rheumatology guidelines authorship.

“Indeed, in the last 15 years we have witnessed an increase in female representativeness,” they wrote. “Notwithstanding, efforts should be made to improve the representation of female authors nationally and internationally.”

Commenting on the findings, rheumatologist Jean Liew, MD, said an interesting thing is that, in the United States at least, rheumatology is not a male-dominated field.

“Even though the practicing clinicians in rheumatology, most of them are women ... at the top of things it’s not as equitable as what it should be,” said Dr. Liew, acting instructor and senior fellow in the division of rheumatology at the University of Washington, Seattle.

Dr. Liew, who coauthored another study showing a significant gender gap in speakers at American College of Rheumatology meetings, said there was evidence suggesting men were more likely to be promoted, get grants, and get positive reviews, which made it harder for women to advance to senior research and leadership positions.

She noted that the ACR has been making a concerted effort to improve gender balance in the choice of speakers for meetings, but said that the problem of gender inequity in rheumatology required more widespread initiatives to address.

“It really takes people being aware of the problem and being good sponsors and promoting women who are qualified,” she said in an interview. “There should be more mentorship and sponsorship for women, otherwise this will never change.”

She also commented that pursuing research careers in rheumatology was difficult enough without the additional pressures of family life. “It’s years and years of sacrifice, it’s hard to get funding, which already makes it harder, especially for women with families who feel like they have to also be there at home.”

The study had no outside funding, and the authors declared no competing interests.

SOURCE: Adami G et al. Ann Rheum Dis. 2020 Feb 26. doi: 10.1136/annrheumdis-2020-217119.

Less than one-third of first authors on rheumatology guidelines or recommendations are women, according to a research letter published in Annals of the Rheumatic Diseases.

Giovanni Adami, MD, from the department of medicine at the University of Verona (Italy), and coauthors examined 366 English-language guidelines and recommendations published between 2004 and 2019 around the world.

They found that only 32% featured a female first author. However, they did observe a significant trend toward increasing female first authorship over the study period, with parity first being achieved for guidelines and recommendations published in 2017.

Male-dominated first authorship was seen almost across the disease subject matter. For RA, only 18.8% of the 96 guidelines or recommendations examined had a female first author, and of the 12 documents on polymyalgia rheumatica and giant cell arteritis, none featured a female first author.

Among the 73 guidelines and recommendations relating to psoriatic arthritis and spondyloarthritis, only 23.3% featured a female first author. However, three of the six documents on polymyositis and dermatomyositis had a female lead author, the only area where parity was achieved.

The authors noted the recent establishment of the EULAR Task Force on Gender Equity in Academic Rheumatology, which they said was an important first step toward gender equity in rheumatology guidelines authorship.

“Indeed, in the last 15 years we have witnessed an increase in female representativeness,” they wrote. “Notwithstanding, efforts should be made to improve the representation of female authors nationally and internationally.”

Commenting on the findings, rheumatologist Jean Liew, MD, said an interesting thing is that, in the United States at least, rheumatology is not a male-dominated field.

“Even though the practicing clinicians in rheumatology, most of them are women ... at the top of things it’s not as equitable as what it should be,” said Dr. Liew, acting instructor and senior fellow in the division of rheumatology at the University of Washington, Seattle.

Dr. Liew, who coauthored another study showing a significant gender gap in speakers at American College of Rheumatology meetings, said there was evidence suggesting men were more likely to be promoted, get grants, and get positive reviews, which made it harder for women to advance to senior research and leadership positions.

She noted that the ACR has been making a concerted effort to improve gender balance in the choice of speakers for meetings, but said that the problem of gender inequity in rheumatology required more widespread initiatives to address.

“It really takes people being aware of the problem and being good sponsors and promoting women who are qualified,” she said in an interview. “There should be more mentorship and sponsorship for women, otherwise this will never change.”

She also commented that pursuing research careers in rheumatology was difficult enough without the additional pressures of family life. “It’s years and years of sacrifice, it’s hard to get funding, which already makes it harder, especially for women with families who feel like they have to also be there at home.”

The study had no outside funding, and the authors declared no competing interests.

SOURCE: Adami G et al. Ann Rheum Dis. 2020 Feb 26. doi: 10.1136/annrheumdis-2020-217119.

Less than one-third of first authors on rheumatology guidelines or recommendations are women, according to a research letter published in Annals of the Rheumatic Diseases.

Giovanni Adami, MD, from the department of medicine at the University of Verona (Italy), and coauthors examined 366 English-language guidelines and recommendations published between 2004 and 2019 around the world.

They found that only 32% featured a female first author. However, they did observe a significant trend toward increasing female first authorship over the study period, with parity first being achieved for guidelines and recommendations published in 2017.

Male-dominated first authorship was seen almost across the disease subject matter. For RA, only 18.8% of the 96 guidelines or recommendations examined had a female first author, and of the 12 documents on polymyalgia rheumatica and giant cell arteritis, none featured a female first author.

Among the 73 guidelines and recommendations relating to psoriatic arthritis and spondyloarthritis, only 23.3% featured a female first author. However, three of the six documents on polymyositis and dermatomyositis had a female lead author, the only area where parity was achieved.

The authors noted the recent establishment of the EULAR Task Force on Gender Equity in Academic Rheumatology, which they said was an important first step toward gender equity in rheumatology guidelines authorship.

“Indeed, in the last 15 years we have witnessed an increase in female representativeness,” they wrote. “Notwithstanding, efforts should be made to improve the representation of female authors nationally and internationally.”

Commenting on the findings, rheumatologist Jean Liew, MD, said an interesting thing is that, in the United States at least, rheumatology is not a male-dominated field.

“Even though the practicing clinicians in rheumatology, most of them are women ... at the top of things it’s not as equitable as what it should be,” said Dr. Liew, acting instructor and senior fellow in the division of rheumatology at the University of Washington, Seattle.

Dr. Liew, who coauthored another study showing a significant gender gap in speakers at American College of Rheumatology meetings, said there was evidence suggesting men were more likely to be promoted, get grants, and get positive reviews, which made it harder for women to advance to senior research and leadership positions.

She noted that the ACR has been making a concerted effort to improve gender balance in the choice of speakers for meetings, but said that the problem of gender inequity in rheumatology required more widespread initiatives to address.

“It really takes people being aware of the problem and being good sponsors and promoting women who are qualified,” she said in an interview. “There should be more mentorship and sponsorship for women, otherwise this will never change.”

She also commented that pursuing research careers in rheumatology was difficult enough without the additional pressures of family life. “It’s years and years of sacrifice, it’s hard to get funding, which already makes it harder, especially for women with families who feel like they have to also be there at home.”

The study had no outside funding, and the authors declared no competing interests.

SOURCE: Adami G et al. Ann Rheum Dis. 2020 Feb 26. doi: 10.1136/annrheumdis-2020-217119.

Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.

Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.

The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.

The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.

“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.

Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”

Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.

The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).

“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”

The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.

The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.

SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.

Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.

Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.

The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.

The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.

“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.

Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”

Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.

The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).

“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”

The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.

The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.

SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.

Glucocorticoid use is associated with greater mortality and cardiovascular risk in RA patients, and the associated risk is greater still in patients with RA and comorbid diabetes. The findings come from a new retrospective analysis derived from U.K. primary care records.

Although patients with diabetes actually had a lower relative risk for mortality than the nondiabetes cohort, they had a greater mortality difference because of a greater baseline risk. Ultimately, glucocorticoid (GC) use was associated with an additional 44.9 deaths per 1,000 person-years in the diabetes group, compared with 34.4 per 1,000 person-years in the RA-only group.

The study, led by Ruth Costello and William Dixon, MBBS, PhD of the University of Manchester (England), was published in BMC Rheumatology.

The findings aren’t particularly surprising, given that steroid use and diabetes have associated cardiovascular risks, and physicians generally try to reduce or eliminate their use. “There’s a group [of physicians] saying that we don’t need to use steroids at all in rheumatoid arthritis, except maybe for [a] short time at diagnosis to bridge to other therapies, or during flares,” Gordon Starkebaum, MD, professor emeritus of rheumatology at the University of Washington, Seattle, said in an interview. He recounted a session at last year’s annual meeting of the American College of Rheumatology that advocated for only injectable steroid use during flare-ups. “That was provocative,” Dr. Starkebaum said.

“It’s a retrospective study, so it has some limitations, but it provides good insight, and some substantiation to what we already think,” added Brett Smith, DO, a rheumatologist practicing in Knoxville, Tenn.

Dr. Smith suggested that the study further underscores the need to follow treat-to-target protocols in RA. He emphasized that lifetime exposure to steroids is likely the greatest concern, and that steady accumulating doses are a sign of trouble. “If you need that much steroids, you need to go up on your medication – your methotrexate, or sulfasalazine, or your biologic,” said Dr. Smith. “At least 50% of people will need a biologic to [achieve] disease control, and if you get them on it, they’re going to have better disease control, compliance is typically better, and they’re going to have less steroid exposure.”

Dr. Smith also noted that comorbid diabetes shouldn’t affect treat-to-target strategies. In fact, in such patients “you should probably be following it more tightly to reduce the cardiovascular outcomes,” he said.

The retrospective analysis included 9,085 patients with RA and with or without type 2 diabetes, with a mean follow-up of 5.2 years. They were recruited to the study between 1998 and 2011. Among patients with comorbid diabetes, those exposed to GC had a mortality of 67.4 per 1,000 person-years, compared with 22.5 among those not exposed to GC. Among those with RA alone, mortality was 44.6 versus 10.2 with and without GC exposure, respectively. Those with diabetes had a lower risk ratio for mortality (2.99 vs. 4.37), but a higher mortality difference (44.9 vs. 34.4 per 1,000 person-years).

“The increased absolute hazard for all-cause mortality indicates the greater public health impact of people with RA using GCs if they have [diabetes],” the researchers wrote. “Rheumatologists should consider [diabetes] status when prescribing GCs to patients with RA given this potential impact of GC therapy on glucose control and mortality.”

The study was limited by a lack of information on GC dose and cumulative exposure. Given its retrospective nature, the study could have been affected by confounding by indication, as well as unknown confounders.

The study was funded by the Centre for Epidemiology Versus Arthritis and the National Institute for Health Research Biomedical Research Centre. Dr. Starkebaum has no relevant financial disclosures. Dr. Smith is on the speaker’s bureau for AbbVie and serves on the company’s advisory board. He is also on the advisory boards of Regeneron and Sanofi Genzyme.

SOURCE: Costello R et al. BMC Rheumatol. 2020 Feb 19. doi: 10.1186/s41927-019-0105-4.

A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).

Bruce Jancin/MDedge News

“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.

To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.

In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”

Mitchel L. Zoler/Frontline Medical News

“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.

“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
 

Contraception

In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.

For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
 

Assisted reproductive technology

In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.

For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
 

Fertility preservation

In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.

Hormone therapy

In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.

Pregnancy assessment and management

Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.

For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”

Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily

For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.

For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.

Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.

Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.

The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.

The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.

The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.

SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.

A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).

Bruce Jancin/MDedge News

“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.

To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.

In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”

Mitchel L. Zoler/Frontline Medical News

“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.

“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
 

Contraception

In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.

For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
 

Assisted reproductive technology

In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.

For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
 

Fertility preservation

In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.

Hormone therapy

In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.

Pregnancy assessment and management

Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.

For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”

Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily

For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.

For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.

Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.

Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.

The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.

The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.

The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.

SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.

A new guideline from the American College of Rheumatology offers the organization’s first clinical recommendations on how to manage reproductive health issues in patients with rheumatic and musculoskeletal diseases (RMDs).

Bruce Jancin/MDedge News

“With the development of this guideline, the ACR recognizes the key role of clinical rheumatologists not only in managing disease activity but also in understanding the interactions of RMDs and their therapies in the context of reproductive health,” wrote Lisa R. Sammaritano, MD, of Weill Cornell Medicine and the Hospital for Special Surgery in New York, and coauthors. The guideline was published in Arthritis & Rheumatology.

To develop an evidence-based guideline on reproductive health in RMD patients, the researchers embarked on a systematic review of studies in areas like contraception, pregnancy and lactation, assisted reproductive technology (ART), fertility preservation, and hormone therapy. The guideline contains 12 ungraded good practice statements and 131 graded recommendations, all developed through the Grading of Recommendations Assessment, Development, and Evaluation methodology.

In counseling patients about these areas of care, the guideline says that rheumatologists and other clinicians “must collaborate with specialists in the fields of obstetrics-gynecology, maternal-fetal medicine, and reproductive endocrinology and infertility.”

Mitchel L. Zoler/Frontline Medical News

“One thing this guideline does well is highlight the importance of involving maternal-fetal medicine colleagues,” Alison Cahill, MD, a professor in the department of women’s health at the University of Texas at Austin and a maternal-fetal medicine specialist within UT Health Austin’s Women’s Health Institute, said when asked for comment on the guideline. “We’re always very happy to see patients ahead of time who are planning pregnancy to be able to discuss what the care plan would look like. And specifically, to address medications, if required, for their rheumatologic care.

“As we learn more and more,” she added, “we’ve come to understand that most treatments and medications are actually safe or relatively safe to take in pregnancy. Certainly, the benefit of taking them outweighs any small or theoretic risks. On the flip side, the guideline does a nice job of highlighting the importance of good disease control, both at the time of conception and during pregnancy.”
 

Contraception

In regard to contraception, the guideline strongly recommends the use of effective contraceptives – with a conditional recommendation of IUDs or a subdermal progestin implant – in fertile women with a RMD who have neither systemic lupus erythematosus (SLE) nor positive antiphospholipid antibody (aPL). They also strongly recommend discussing the use of emergency contraception with all RMD patients.

For SLE patients, the guideline strongly recommends the use of effective contraceptives in those with stable or low disease activity who are not positive for aPL. They also strongly recommend progestin‐only or IUD contraceptives over combined estrogen‐progestin contraception. For aPL-positive patients, the guideline strongly recommends against combined estrogen‐progestin contraceptives and for levonorgestrel or copper IUDs or the progestin‐only pill.
 

Assisted reproductive technology

In regard to ART, the guideline strongly recommends proceeding as needed in aPL-negative women with uncomplicated, stable RMD who are on pregnancy‐compatible medications. They also strongly recommend deferring ART in any RMD patients with moderately or severely active disease.

For aPL-positive patients undergoing ART procedures, they strongly recommend prophylactic anticoagulation with heparin or low-molecular-weight heparin (LMWH) in women with obstetric antiphospholipid syndrome (APS) and therapeutic anticoagulation in women with thrombotic APS. In patients undergoing embryo and oocyte cryopreservation, they strongly recommend continuing immunosuppressive and biologic therapies – the exception being cyclophosphamide (CYC) – for anyone in stable condition.
 

Fertility preservation

In regard to fertility preservation in patients taking CYC, the guideline strongly suggests sperm cryopreservation as good practice prior to treatment. They also conditionally recommend monthly gonadotropin‐releasing hormone agonist cotherapy in premenopausal women with RMD.

Hormone therapy

In regard to menopause and hormone therapy, the guideline strongly suggests hormone therapy as good practice in postmenopausal women with RMD, without SLE or positive aPL, and who have severe vasomotor symptoms. Hormone therapy is conditionally recommended in patients with SLE, without positive aPL, and with no contraindications. For aPL-positive patients, they strongly recommend against hormone therapy in women with obstetric and/or thrombotic APS.

Pregnancy assessment and management

Among the many recommendations regarding pregnancy assessment and management, the guideline strongly suggests counseling women with RMD who are considering pregnancy to take into account the improved outcomes for pregnant women with low disease activity. They strongly recommend that women considering pregnancy should switch to pregnancy‐compatible medication and pause to assess its efficacy and tolerability before moving forward, along with strongly recommending that pregnant women with active disease initiate or continue a pregnancy‐compatible steroid‐sparing medication. They also recommend testing for anti‐Ro/SS-A and anti‐La/SS-B in women with SLE, Sjögren’s syndrome, systemic sclerosis, or rheumatoid arthritis, but only once and only before or early in the pregnancy.

For women with systemic sclerosis who develop scleroderma renal crisis during pregnancy, the authors strongly advise using ACE inhibitors or angiotensin receptor blockers “because the risk of maternal or fetal death with untreated disease is higher than the risk associated with use of these medications during pregnancy.”

Among women with SLE, the recommendations strongly call for testing either before or early in pregnancy for anticardiolipin antibody, anti–beta2-glycoprotein I, or positive lupus anticoagulant, as well as initiating or continuing hydroxychloroquine (HCQ) if possible. Starting in the first trimester, the authors also conditionally recommend that SLE patients take low-dose aspirin daily

For pregnant women who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the guideline conditionally recommends prophylactic treatment with low-dose aspirin daily to protect against preeclampsia. When obstetric APS criteria are met, the guideline strongly advises combined treatment with daily low-dose aspirin and prophylactic-dose heparin (or LMWH), as well as prophylactic-dose anticoagulation for 6-12 weeks post partum. When patients have thrombotic APS, this combination treatment should contain heparin dose at a therapeutic level throughout pregnancy and postpartum. However, the authors conditionally recommend against giving low-dose aspirin plus prophylactic-dose heparin to women without obstetric APS. For refractory obstetric APS, the guideline also contains recommendations that are conditionally against treatment with intravenous immunoglobulin or an increased LMWH dose and strongly against adding prednisone to prophylactic-dose heparin or LMWH and low-dose aspirin. In pregnant patients with primary APS, the authors conditionally advise adding HCQ to prophylactic-dose heparin or LMWH and low-dose aspirin therapy. However, women with aPL who do not meet APS criteria or have another indication for HCQ are conditionally advised against prophylactic treatment with the antimalarial.

For women with Anti-Ro/SS-A and/or anti-La/SS-B antibodies in pregnancy, there is conditional advice to use HCQ. When there is no history of an infant with complete heart block or neonatal lupus erythematosus among women with these antibodies, the guideline conditionally advises serial fetal echocardiography (less often than weekly) starting between 16 and 18 weeks and continuing through 26 weeks, but this should be weekly when there is a prior history. Treatment with oral dexamethasone 4 mg daily is conditionally advised when there is echocardiographic evidence of fetal first- or second-degree heart block, but dexamethasone is not recommended when complete heart block is present.

Finally, in regard to medication use, the authors strongly recommend that men who are planning to be fathers continue on HCQ, azathioprine, 6‐mercaptopurine, colchicine, or tumor necrosis factor inhibitors. Conditional treatment recommendations for men planning for pregnancy include methotrexate, mycophenolate mofetil/mycophenolic acid (MMF), leflunomide, sulfasalazine, calcineurin inhibitors, and NSAIDs. They also strongly recommend that this group of men discontinue CYC and thalidomide.

Pregnant women are strongly recommended to discontinue methotrexate, leflunomide (with cholestyramine washout if there are detectable serum levels of its metabolite prior to pregnancy or as soon as it is confirmed), MMF, CYC, and thalidomide within 3 months prior to conception, and they strongly recommend HCQ (in women with SLE), azathioprine/6‐mercaptopurine, colchicine, or sulfasalazine for use throughout pregnancy. They strongly recommend a combination of low‐dose aspirin and prophylactic‐dose heparin for pregnant women with obstetric APS, along with low‐dose aspirin and therapeutic‐dose heparin for women with thrombotic APS throughout pregnancy and postpartum. However, for women with SLE and those who test positive for aPL but do not meet criteria for obstetric or thrombotic APS, the authors conditionally recommend low-dose aspirin starting in the first trimester.

The guideline suggests that women with RMD should be encouraged to breastfeed if they are willing and able; they also suggest that disease control be maintained through lactation‐compatible medications and that the risks and benefits be reviewed on a patient-by-patient basis. Treatment with HCQ, colchicine, sulfasalazine, rituximab, and all tumor necrosis factor inhibitors are strongly recommended as being compatible with breastfeeding, and they strongly recommend against using CYC, leflunomide, MMF, and thalidomide while breastfeeding.

The authors acknowledged the limitations of their guideline, including the literature review being conducted on studies involving adults and an “inability to include recommendations for uncommon but important clinical situations,” including those involving transgender patients and hormonal therapies.

The authors reported numerous potential conflicts of interest, including receiving research support, consulting fees, speaking fees, and honoraria from various pharmaceutical companies.

SOURCE: Sammaritano LR et al. Arthritis Rheumatol. 2020 Feb 23. doi: 10.1002/art.41191.

Individuals exposed to pks+ Escherichia coli may have an increased risk of colorectal cancer (CRC), which suggests that treating this genotoxic strain could potentially reduce risk of CRC, according to investigators.

While previous studies have demonstrated associations between various intestinal bacteria and CRC, this is the first study to show a direct link between exposure to a particular strain of bacteria and a unique mutational signature, reported lead author Cayetano Pleguezuelos-Manzano, of the Hubrecht Institute in Utrecht, Netherlands.

Recent studies showed that colibactin, a toxin produced by pks+ E. coli, causes a specific type of DNA damage, although the outcome of this damage remained unclear, the investigators wrote in Nature.

To look for a possible mutational signature resulting from this damage, the investigators used human intestinal organoids, which were established from primary crypt stem cells. A pks+ E. coli strain was microinjected into one group of organoids, while another E. coli strain (pks∆clbQ), which does not produce colibactin, was injected into a second group.

Immunofluorescence showed that the organoids exposed to the pks+ E. coli strain developed characteristic DNA damage, whereas the control group did not.

Next, the investigators repeatedly injected organoids with either pks+ E. coli, pks∆clbQ, or dye only. This experiment was conducted for 5 months to achieve long-term exposure. Whole genome sequencing showed that the pks+ E. coli group developed two unique mutational signatures: a single-base substitution (SBS-pks) and a small indel signature (ID-pks). Neither of the other two groups developed these signatures, which suggests that they were a direct consequence of exposure to pks+ E. coli.

To determine the prevalence of such mutational signatures in human patients, the investigators looked for the SBS-pks and ID-pks signatures in 5,876 human cancer genomes. One analysis involving 496 CRC metastases showed strong enrichment of both signatures, compared with other cancer types (P less than .0001). Another analysis involving 2,208 CRC tumors found that 5.0% and 4.4% of patients had SBS-pks and ID-pks enrichment, respectively.

“This study implies that detection and removal of pks+ E. coli, as well as re-evaluation of probiotic strains harboring the pks island, could decrease the risk of cancer in a large group of individuals,” the investigators concluded.

The study was funded by the Ministry of Education, Culture and Science of the government of the Netherlands. The investigators reported additional relationships with OrigiMed, Bayer, Janssen, and others.

SOURCE: Pleguezuelos-Manzano C et al. Nature. 2020 Feb 27. doi: 10.1038/s41586-020-2080-8.

Individuals exposed to pks+ Escherichia coli may have an increased risk of colorectal cancer (CRC), which suggests that treating this genotoxic strain could potentially reduce risk of CRC, according to investigators.

While previous studies have demonstrated associations between various intestinal bacteria and CRC, this is the first study to show a direct link between exposure to a particular strain of bacteria and a unique mutational signature, reported lead author Cayetano Pleguezuelos-Manzano, of the Hubrecht Institute in Utrecht, Netherlands.

Recent studies showed that colibactin, a toxin produced by pks+ E. coli, causes a specific type of DNA damage, although the outcome of this damage remained unclear, the investigators wrote in Nature.

To look for a possible mutational signature resulting from this damage, the investigators used human intestinal organoids, which were established from primary crypt stem cells. A pks+ E. coli strain was microinjected into one group of organoids, while another E. coli strain (pks∆clbQ), which does not produce colibactin, was injected into a second group.

Immunofluorescence showed that the organoids exposed to the pks+ E. coli strain developed characteristic DNA damage, whereas the control group did not.

Next, the investigators repeatedly injected organoids with either pks+ E. coli, pks∆clbQ, or dye only. This experiment was conducted for 5 months to achieve long-term exposure. Whole genome sequencing showed that the pks+ E. coli group developed two unique mutational signatures: a single-base substitution (SBS-pks) and a small indel signature (ID-pks). Neither of the other two groups developed these signatures, which suggests that they were a direct consequence of exposure to pks+ E. coli.

To determine the prevalence of such mutational signatures in human patients, the investigators looked for the SBS-pks and ID-pks signatures in 5,876 human cancer genomes. One analysis involving 496 CRC metastases showed strong enrichment of both signatures, compared with other cancer types (P less than .0001). Another analysis involving 2,208 CRC tumors found that 5.0% and 4.4% of patients had SBS-pks and ID-pks enrichment, respectively.

“This study implies that detection and removal of pks+ E. coli, as well as re-evaluation of probiotic strains harboring the pks island, could decrease the risk of cancer in a large group of individuals,” the investigators concluded.

The study was funded by the Ministry of Education, Culture and Science of the government of the Netherlands. The investigators reported additional relationships with OrigiMed, Bayer, Janssen, and others.

SOURCE: Pleguezuelos-Manzano C et al. Nature. 2020 Feb 27. doi: 10.1038/s41586-020-2080-8.

Individuals exposed to pks+ Escherichia coli may have an increased risk of colorectal cancer (CRC), which suggests that treating this genotoxic strain could potentially reduce risk of CRC, according to investigators.

While previous studies have demonstrated associations between various intestinal bacteria and CRC, this is the first study to show a direct link between exposure to a particular strain of bacteria and a unique mutational signature, reported lead author Cayetano Pleguezuelos-Manzano, of the Hubrecht Institute in Utrecht, Netherlands.

Recent studies showed that colibactin, a toxin produced by pks+ E. coli, causes a specific type of DNA damage, although the outcome of this damage remained unclear, the investigators wrote in Nature.

To look for a possible mutational signature resulting from this damage, the investigators used human intestinal organoids, which were established from primary crypt stem cells. A pks+ E. coli strain was microinjected into one group of organoids, while another E. coli strain (pks∆clbQ), which does not produce colibactin, was injected into a second group.

Immunofluorescence showed that the organoids exposed to the pks+ E. coli strain developed characteristic DNA damage, whereas the control group did not.

Next, the investigators repeatedly injected organoids with either pks+ E. coli, pks∆clbQ, or dye only. This experiment was conducted for 5 months to achieve long-term exposure. Whole genome sequencing showed that the pks+ E. coli group developed two unique mutational signatures: a single-base substitution (SBS-pks) and a small indel signature (ID-pks). Neither of the other two groups developed these signatures, which suggests that they were a direct consequence of exposure to pks+ E. coli.

To determine the prevalence of such mutational signatures in human patients, the investigators looked for the SBS-pks and ID-pks signatures in 5,876 human cancer genomes. One analysis involving 496 CRC metastases showed strong enrichment of both signatures, compared with other cancer types (P less than .0001). Another analysis involving 2,208 CRC tumors found that 5.0% and 4.4% of patients had SBS-pks and ID-pks enrichment, respectively.

“This study implies that detection and removal of pks+ E. coli, as well as re-evaluation of probiotic strains harboring the pks island, could decrease the risk of cancer in a large group of individuals,” the investigators concluded.

The study was funded by the Ministry of Education, Culture and Science of the government of the Netherlands. The investigators reported additional relationships with OrigiMed, Bayer, Janssen, and others.

SOURCE: Pleguezuelos-Manzano C et al. Nature. 2020 Feb 27. doi: 10.1038/s41586-020-2080-8.

There are currently 7 FDA-approved second-generation long-acting injectable antipsychotics (LAIAs).^1-7 These LAIAs provide a unique dosage form that allows patients to receive an antipsychotic without taking oral medications every day, or multiple times per day. This may be an appealing option for patients and clinicians, but because there are several types of LAIAs available, it may be difficult to determine which LAIA characteristics are best for a given patient.

Since the FDA approved the first second-generation LAIA, risperidone long-acting injectable (LAI),¹ in 2003, 6 additional second-generation LAIAs have been approved:

• aripiprazole LAI
• aripiprazole lauroxil LAI
• olanzapine pamoate LAI
• paliperidone palmitate monthly injection
• paliperidone palmitate 3-month LAI
• risperidone LAI for subcutaneous (SQ) injection.

When discussing medication options with patients, clinicians need to consider factors that are unique to each LAIA. In this article, I describe the similarities and differences among the second-generation LAIAs, and address common questions about these medications.

A major potential benefit: Increased adherence

One potential benefit of all LAIAs is increased medication adherence compared with oral antipsychotics. One meta-analysis of 21 randomized controlled trials (RCTs) that compared LAIAs with oral antipsychotics and included 5,176 patients found that LAIAs had a similar efficacy to oral antipsychotics in preventing relapse.⁸ However, a meta-analysis of 25 mirror-image studies comparing LAIAs with oral antipsychotics that included 5,940 patients found that LAIAs were superior in preventing hospitalization.⁹ In these mirror-image studies, participants received oral antipsychotics first and then switched to LAIAs, and the 2 study periods were compared. Because mirror-image studies are observational, participants do not engage with research teams to the extent that they do in RCTs.⁹ Although mirror-image studies have limitations, participants in these studies may be a better representation of patients encountered in clinical practice due to the extensive monitoring and follow-up RCT participants typically receive.⁹

Differences in FDA-approved indications

The 7 currently available LAIAs vary in terms of FDA-approved indications, dose options, frequency, need for oral antipsychotic overlap, route of administration, and other factors. Table 1^1-7 summarizes some of these differences. Although all second-generation LAIAs are approved for schizophrenia,^1-7 risperidone LAI and aripiprazole LAI are also approved for bipolar I disorder.^1,4 Paliperidone palmitate monthly injection is the only LAIA approved for treating patients with schizoaffective disorder.²

Starting doses

For most LAIAs, the starting dose is the same as the maintenance dose (Table 1^1-7). One exception is paliperidone palmitate monthly injection, which requires a 234-mg dose on Day 1 followed by a 156-mg dose on Day 8 for all patients, regardless of the maintenance dose required.² The 156-mg dose may be given 4 days before or after Day 8.² The first maintenance dose of paliperidone palmitate monthly injection should be administered 5 weeks after the 234-mg dose on Day 1.² Before starting paliperidone palmitate 3-month injection, patients should be stable on paliperidone palmitate monthly injection for 4 months, and the 2 most recent doses of paliperidone palmitate monthly injection should be the same.³

Maintenance doses

Dosing frequency may be an important factor for some patients when deciding to receive a LAIA. The frequency of the maintenance doses for all second-generation LAIAs varies from every 2 weeks to 12 weeks (Table 1^1-7). Paliperidone palmitate 3-month LAI is the only LAIA that is administered every 12 weeks.³ Some dosages of aripiprazole lauroxil LAI are administered every 6 or 8 weeks.⁶ All other second-generation LAIAs are given every 2 to 4 weeks.

Continue to: Start with an oral antipsychotic

 

 

Start with an oral antipsychotic

Before starting any LAIA, patients should receive the oral formulation of that antipsychotic to establish tolerability.^1-7 Four of the 7 available LAIAs have an oral-to-LAI dose equivalency recommendation in their prescribing information (Table 2^2,5-7). This can help clinicians estimate the LAIA maintenance dose required to control a patient’s symptoms. If a dose adjustment is needed once a patient starts an LAIA, the dose adjustment can be made when the next injection is due.²

There are 2 important considerations when prescribing olanzapine pamoate LAI. First, the recommended dose for olanzapine pamoate LAI based on oral olanzapine doses differs during the first 8 weeks of treatment compared with after 8 weeks of treatment (Table 2^2,5-7). Additionally, because there are both short-acting and long-acting injections of olanzapine, it is essential to choose the correct formulation when prescribing this medication.⁵

Overlap with an oral antipsychotic might be necessary

Administration of several of the LAIAs may require overlap with an oral antipsychotic (Table 3^1,2,4-7). Patients who refuse to take oral medications may benefit from one of the LAIAs that does not require oral overlap—paliperidone palmitate monthly injection, olanzapine pamoate LAI, and risperidone LAI for SQ.^2,5,7 Risperidone LAI requires overlap with oral risperidone for 3 weeks.¹

Aripiprazole is available in 2 LAI formulations: aripiprazole LAI and aripiprazole lauroxil LAI. Aripiprazole lauroxil is a prodrug of aripiprazole, and these 2 LAI medications differ in available dose options and dosing frequency.^4,6 Aripiprazole LAI requires an oral overlap for 2 weeks after the first injection, whereas aripiprazole lauroxil LAI requires 3 weeks of oral overlap unless aripiprazole lauroxil 675-mg LAI is administered (Figure⁶).^4,6,10

Aripiprazole lauroxil 675-mg LAI is formulated with drug particles that are smaller than those in aripiprazole lauroxil LAI.¹¹ The smaller particle size results in faster dissolution and a more rapid increase in plasma aripiprazole levels. Aripiprazole lauroxil 675-mg LAI is a single injection that should be given with one 30-mg dose of oral aripiprazole.¹⁰ This combination results in aripiprazole concentrations that are comparable to aripiprazole lauroxil LAI and oral aripiprazole overlap for 3 weeks after the first injection.¹⁰

Continue to: The starting dose of aripiprazole lauroxil LAI...

The starting dose of aripiprazole lauroxil LAI may be administered on the same day as aripiprazole lauroxil 675-mg LAI and the 30-mg oral aripiprazole dose, or it may be administered up to 10 days after.¹⁰ Aripiprazole lauroxil LAI and aripiprazole lauroxil 675-mg LAI are not interchangeable due to differing pharmacokinetic profiles.^6,10 Aripiprazole lauroxil 675-mg LAI may be used to re-initiate treatment in a patient who missed doses of aripiprazole lauroxil LAI.¹⁰ Aripiprazole lauroxil LAI and aripiprazole lauroxil 675 mg should not be injected together into the same deltoid or gluteal muscle.

Be mindful of differences in dosing windows

Each LAIA has a specific frequency recommendation, but due to scheduling or other factors, it may not be possible for patients to receive their injection on the specified day. The prescribing information for some LAIAs provides a dosing window (Table 4^1-7). The prescribing information for risperidone LAI, olanzapine pamoate LAI, and risperidone LAI for SQ does not specify how many days the injection can be administered before or after the due date; however, the prescribing information for risperidone LAI for SQ indicates that if the injection is not given on the due date, it should be administered as soon as possible after that.^1,5,7

Paliperidone palmitate monthly injection and paliperidone palmitate 3-month LAI have the clearest recommendations for a dosing window. Paliperidone palmitate monthly injection may be administered 7 days before or after the 4-week due date, and paliperidone palmitate 3-month LAI can be administered 14 days before or after the 12-week due date.^2,3

Aripiprazole LAI should not be administered sooner than 26 days after the previous injection, which means that it can be administered up to 2 days before the 4-week due date.⁴ If administered after the due date, it should be given as soon as possible, although oral overlap is not needed until ≥7 days past the due date.⁴

Aripiprazole lauroxil LAI has similar recommendations to aripiprazole LAI in that it should not be administered sooner than 14 days after the previous injection.⁶ If it is given after the due date, it should be administered as soon as possible; oral overlap/starting dose is needed if it has been ≥2 to 4 weeks since the due date, depending on which dose and frequency the patient is receiving.⁶

Continue to: Recommendations for missed doses

 

 

Recommendations for missed doses

Each LAIA has specific recommendations for missed dosing. Carpenter and Wong¹² reviewed the recommendations for managing missed LAIA doses in Current Psychiatry July 2018. This article is available at mdedge.com/psychiatry/article/168776/schizophrenia-other-psychotic-disorders/long-acting-injectable.¹²

Consider patient preference

Patient preference for the type and location of the injection may factor into a clinician’s choice of LAIA (Table 5^1-7,10). Risperidone LAI for SQ is the only LAIA that is administered as an SQ abdominal injection.⁷ All other LAIAs are IM injections in the deltoid or gluteal muscle.^1-6 All doses of risperidone LAI, paliperidone palmitate 3-month LAI, aripiprazole LAI, and aripiprazole lauroxil 675-mg LAI can be administered in the deltoid or gluteal muscle.^1,3,4,10 Deltoid administration is required for the 2 starting doses of paliperidone palmitate monthly injection, but maintenance doses can be administered in the deltoid or gluteal muscle. Because administration into the deltoid results in a higher concentration of the drug compared with gluteal administration, administering the 2 starting doses of paliperidone palmitate monthly injection into the deltoid helps to rapidly attain therapeutic concentrations.² Olanzapine pamoate LAI should be administered only in the gluteal muscle.⁵ The 441-mg dose of aripiprazole lauroxil LAI may be administered in the deltoid or gluteal muscle, but all other doses of aripiprazole lauroxil LAI should be administered only in the gluteal muscle.⁶

Storage

Most LAIAs can be stored at room temperature^2-6; however, risperidone LAI and risperidone LAI for SQ need to be stored in the refrigerator. Both risperidone LAI and risperidone LAI for SQ may be kept at room temperature for up to 7 days. If they are not used within 7 days at room temperature, they should be discarded.^1,7

Clinical pearls for specific LAIAs

Aripiprazole LAI. The recommended starting and maintenance dose for aripiprazole LAI is 400 mg monthly, unless the patient has drug interactions or other factors that require dose adjustment. If patients experience adverse reactions to the 400-mg dose, a reduction to 300 mg monthly could be considered.⁴

Olanzapine pamoate LAI has a Risk Evaluation and Mitigation Strategy (REMS) due to the potential for post-injection delirium/sedation syndrome (PDSS). Prescribing clinicians, dispensing pharmacies, and administering health care facilities must all be certified to prescribe, dispense, or administer olanzapine pamoate LAI. The patient must also be enrolled in the REMS program.¹³ Patients must be observed by health care staff for 3 hours after receiving a dose of olanzapine pamoate LAI to monitor for signs and symptoms of PDSS.⁵

Continue to: Risperidone LAI

Risperidone LAI. When increasing the dose of risperidone LAI, do not expect to see the clinical effects of the new dose earlier than 3 weeks after initiating the higher dose, because the main release of the medication starts at 3 weeks after the injection.¹

Risperidone LAI for SQ has specific recommendations for the LAI dose based on whether the patient was stable when receiving 3 or 4 mg/d of oral risperidone. If patients are stable on <3 or >4 mg/d, they may not be candidates for risperidone LAI for SQ.⁷

Table 6^1-7,10 lists additional factors to consider when prescribing a specific LAIA.

Bottom Line

Second-generation long-acting injectable antipsychotics (LAIAs) have the potential to increase medication adherence. There are important differences among the 7 currently available LAIAs. For effective prescribing, clinicians need to understand each medication’s unique aspects, including dosing options, frequency, need for oral antipsychotic overlap, and route of administration.

Related Resources

• Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24.
• Peters L, Krogmann A, von Hardenberg L, et al. Long-acting injections in schizophrenia: a 3-year update on randomized controlled trials published January 2016-March 2019. Curr Psychiatry Rep. 2019;21(12):124.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole long-acting injectable • Abilify Maintena
Aripiprazole lauroxil extended-release injectable suspension • Aristada
Aripiprazole lauroxil 675 mg • Aristada Initio
Olanzapine pamoate long-acting injection • Zyprexa Relprevv
Paliperidone palmitate monthly long-acting injection • Invega Sustenna
Paliperidone palmitate 3-month injection • Invega Trinza
Risperidone • Risperdal
Risperidone long-acting injection • Risperdal Consta
Risperidone long-acting injection for SQ • Perseris

There are currently 7 FDA-approved second-generation long-acting injectable antipsychotics (LAIAs).^1-7 These LAIAs provide a unique dosage form that allows patients to receive an antipsychotic without taking oral medications every day, or multiple times per day. This may be an appealing option for patients and clinicians, but because there are several types of LAIAs available, it may be difficult to determine which LAIA characteristics are best for a given patient.

Since the FDA approved the first second-generation LAIA, risperidone long-acting injectable (LAI),¹ in 2003, 6 additional second-generation LAIAs have been approved:

• aripiprazole LAI
• aripiprazole lauroxil LAI
• olanzapine pamoate LAI
• paliperidone palmitate monthly injection
• paliperidone palmitate 3-month LAI
• risperidone LAI for subcutaneous (SQ) injection.

When discussing medication options with patients, clinicians need to consider factors that are unique to each LAIA. In this article, I describe the similarities and differences among the second-generation LAIAs, and address common questions about these medications.

A major potential benefit: Increased adherence

One potential benefit of all LAIAs is increased medication adherence compared with oral antipsychotics. One meta-analysis of 21 randomized controlled trials (RCTs) that compared LAIAs with oral antipsychotics and included 5,176 patients found that LAIAs had a similar efficacy to oral antipsychotics in preventing relapse.⁸ However, a meta-analysis of 25 mirror-image studies comparing LAIAs with oral antipsychotics that included 5,940 patients found that LAIAs were superior in preventing hospitalization.⁹ In these mirror-image studies, participants received oral antipsychotics first and then switched to LAIAs, and the 2 study periods were compared. Because mirror-image studies are observational, participants do not engage with research teams to the extent that they do in RCTs.⁹ Although mirror-image studies have limitations, participants in these studies may be a better representation of patients encountered in clinical practice due to the extensive monitoring and follow-up RCT participants typically receive.⁹

Differences in FDA-approved indications

The 7 currently available LAIAs vary in terms of FDA-approved indications, dose options, frequency, need for oral antipsychotic overlap, route of administration, and other factors. Table 1^1-7 summarizes some of these differences. Although all second-generation LAIAs are approved for schizophrenia,^1-7 risperidone LAI and aripiprazole LAI are also approved for bipolar I disorder.^1,4 Paliperidone palmitate monthly injection is the only LAIA approved for treating patients with schizoaffective disorder.²

Starting doses

For most LAIAs, the starting dose is the same as the maintenance dose (Table 1^1-7). One exception is paliperidone palmitate monthly injection, which requires a 234-mg dose on Day 1 followed by a 156-mg dose on Day 8 for all patients, regardless of the maintenance dose required.² The 156-mg dose may be given 4 days before or after Day 8.² The first maintenance dose of paliperidone palmitate monthly injection should be administered 5 weeks after the 234-mg dose on Day 1.² Before starting paliperidone palmitate 3-month injection, patients should be stable on paliperidone palmitate monthly injection for 4 months, and the 2 most recent doses of paliperidone palmitate monthly injection should be the same.³

Maintenance doses

Dosing frequency may be an important factor for some patients when deciding to receive a LAIA. The frequency of the maintenance doses for all second-generation LAIAs varies from every 2 weeks to 12 weeks (Table 1^1-7). Paliperidone palmitate 3-month LAI is the only LAIA that is administered every 12 weeks.³ Some dosages of aripiprazole lauroxil LAI are administered every 6 or 8 weeks.⁶ All other second-generation LAIAs are given every 2 to 4 weeks.

Continue to: Start with an oral antipsychotic

 

 

Start with an oral antipsychotic

Before starting any LAIA, patients should receive the oral formulation of that antipsychotic to establish tolerability.^1-7 Four of the 7 available LAIAs have an oral-to-LAI dose equivalency recommendation in their prescribing information (Table 2^2,5-7). This can help clinicians estimate the LAIA maintenance dose required to control a patient’s symptoms. If a dose adjustment is needed once a patient starts an LAIA, the dose adjustment can be made when the next injection is due.²

There are 2 important considerations when prescribing olanzapine pamoate LAI. First, the recommended dose for olanzapine pamoate LAI based on oral olanzapine doses differs during the first 8 weeks of treatment compared with after 8 weeks of treatment (Table 2^2,5-7). Additionally, because there are both short-acting and long-acting injections of olanzapine, it is essential to choose the correct formulation when prescribing this medication.⁵

Overlap with an oral antipsychotic might be necessary

Administration of several of the LAIAs may require overlap with an oral antipsychotic (Table 3^1,2,4-7). Patients who refuse to take oral medications may benefit from one of the LAIAs that does not require oral overlap—paliperidone palmitate monthly injection, olanzapine pamoate LAI, and risperidone LAI for SQ.^2,5,7 Risperidone LAI requires overlap with oral risperidone for 3 weeks.¹

Aripiprazole is available in 2 LAI formulations: aripiprazole LAI and aripiprazole lauroxil LAI. Aripiprazole lauroxil is a prodrug of aripiprazole, and these 2 LAI medications differ in available dose options and dosing frequency.^4,6 Aripiprazole LAI requires an oral overlap for 2 weeks after the first injection, whereas aripiprazole lauroxil LAI requires 3 weeks of oral overlap unless aripiprazole lauroxil 675-mg LAI is administered (Figure⁶).^4,6,10

Aripiprazole lauroxil 675-mg LAI is formulated with drug particles that are smaller than those in aripiprazole lauroxil LAI.¹¹ The smaller particle size results in faster dissolution and a more rapid increase in plasma aripiprazole levels. Aripiprazole lauroxil 675-mg LAI is a single injection that should be given with one 30-mg dose of oral aripiprazole.¹⁰ This combination results in aripiprazole concentrations that are comparable to aripiprazole lauroxil LAI and oral aripiprazole overlap for 3 weeks after the first injection.¹⁰

Continue to: The starting dose of aripiprazole lauroxil LAI...

The starting dose of aripiprazole lauroxil LAI may be administered on the same day as aripiprazole lauroxil 675-mg LAI and the 30-mg oral aripiprazole dose, or it may be administered up to 10 days after.¹⁰ Aripiprazole lauroxil LAI and aripiprazole lauroxil 675-mg LAI are not interchangeable due to differing pharmacokinetic profiles.^6,10 Aripiprazole lauroxil 675-mg LAI may be used to re-initiate treatment in a patient who missed doses of aripiprazole lauroxil LAI.¹⁰ Aripiprazole lauroxil LAI and aripiprazole lauroxil 675 mg should not be injected together into the same deltoid or gluteal muscle.

Be mindful of differences in dosing windows

Each LAIA has a specific frequency recommendation, but due to scheduling or other factors, it may not be possible for patients to receive their injection on the specified day. The prescribing information for some LAIAs provides a dosing window (Table 4^1-7). The prescribing information for risperidone LAI, olanzapine pamoate LAI, and risperidone LAI for SQ does not specify how many days the injection can be administered before or after the due date; however, the prescribing information for risperidone LAI for SQ indicates that if the injection is not given on the due date, it should be administered as soon as possible after that.^1,5,7

Paliperidone palmitate monthly injection and paliperidone palmitate 3-month LAI have the clearest recommendations for a dosing window. Paliperidone palmitate monthly injection may be administered 7 days before or after the 4-week due date, and paliperidone palmitate 3-month LAI can be administered 14 days before or after the 12-week due date.^2,3

Aripiprazole LAI should not be administered sooner than 26 days after the previous injection, which means that it can be administered up to 2 days before the 4-week due date.⁴ If administered after the due date, it should be given as soon as possible, although oral overlap is not needed until ≥7 days past the due date.⁴

Aripiprazole lauroxil LAI has similar recommendations to aripiprazole LAI in that it should not be administered sooner than 14 days after the previous injection.⁶ If it is given after the due date, it should be administered as soon as possible; oral overlap/starting dose is needed if it has been ≥2 to 4 weeks since the due date, depending on which dose and frequency the patient is receiving.⁶

Continue to: Recommendations for missed doses

 

 

Recommendations for missed doses

Each LAIA has specific recommendations for missed dosing. Carpenter and Wong¹² reviewed the recommendations for managing missed LAIA doses in Current Psychiatry July 2018. This article is available at mdedge.com/psychiatry/article/168776/schizophrenia-other-psychotic-disorders/long-acting-injectable.¹²

Consider patient preference

Patient preference for the type and location of the injection may factor into a clinician’s choice of LAIA (Table 5^1-7,10). Risperidone LAI for SQ is the only LAIA that is administered as an SQ abdominal injection.⁷ All other LAIAs are IM injections in the deltoid or gluteal muscle.^1-6 All doses of risperidone LAI, paliperidone palmitate 3-month LAI, aripiprazole LAI, and aripiprazole lauroxil 675-mg LAI can be administered in the deltoid or gluteal muscle.^1,3,4,10 Deltoid administration is required for the 2 starting doses of paliperidone palmitate monthly injection, but maintenance doses can be administered in the deltoid or gluteal muscle. Because administration into the deltoid results in a higher concentration of the drug compared with gluteal administration, administering the 2 starting doses of paliperidone palmitate monthly injection into the deltoid helps to rapidly attain therapeutic concentrations.² Olanzapine pamoate LAI should be administered only in the gluteal muscle.⁵ The 441-mg dose of aripiprazole lauroxil LAI may be administered in the deltoid or gluteal muscle, but all other doses of aripiprazole lauroxil LAI should be administered only in the gluteal muscle.⁶

Storage

Most LAIAs can be stored at room temperature^2-6; however, risperidone LAI and risperidone LAI for SQ need to be stored in the refrigerator. Both risperidone LAI and risperidone LAI for SQ may be kept at room temperature for up to 7 days. If they are not used within 7 days at room temperature, they should be discarded.^1,7

Clinical pearls for specific LAIAs

Aripiprazole LAI. The recommended starting and maintenance dose for aripiprazole LAI is 400 mg monthly, unless the patient has drug interactions or other factors that require dose adjustment. If patients experience adverse reactions to the 400-mg dose, a reduction to 300 mg monthly could be considered.⁴

Olanzapine pamoate LAI has a Risk Evaluation and Mitigation Strategy (REMS) due to the potential for post-injection delirium/sedation syndrome (PDSS). Prescribing clinicians, dispensing pharmacies, and administering health care facilities must all be certified to prescribe, dispense, or administer olanzapine pamoate LAI. The patient must also be enrolled in the REMS program.¹³ Patients must be observed by health care staff for 3 hours after receiving a dose of olanzapine pamoate LAI to monitor for signs and symptoms of PDSS.⁵

Continue to: Risperidone LAI

Risperidone LAI. When increasing the dose of risperidone LAI, do not expect to see the clinical effects of the new dose earlier than 3 weeks after initiating the higher dose, because the main release of the medication starts at 3 weeks after the injection.¹

Risperidone LAI for SQ has specific recommendations for the LAI dose based on whether the patient was stable when receiving 3 or 4 mg/d of oral risperidone. If patients are stable on <3 or >4 mg/d, they may not be candidates for risperidone LAI for SQ.⁷

Table 6^1-7,10 lists additional factors to consider when prescribing a specific LAIA.

Bottom Line

Second-generation long-acting injectable antipsychotics (LAIAs) have the potential to increase medication adherence. There are important differences among the 7 currently available LAIAs. For effective prescribing, clinicians need to understand each medication’s unique aspects, including dosing options, frequency, need for oral antipsychotic overlap, and route of administration.

Related Resources

• Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24.
• Peters L, Krogmann A, von Hardenberg L, et al. Long-acting injections in schizophrenia: a 3-year update on randomized controlled trials published January 2016-March 2019. Curr Psychiatry Rep. 2019;21(12):124.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole long-acting injectable • Abilify Maintena
Aripiprazole lauroxil extended-release injectable suspension • Aristada
Aripiprazole lauroxil 675 mg • Aristada Initio
Olanzapine pamoate long-acting injection • Zyprexa Relprevv
Paliperidone palmitate monthly long-acting injection • Invega Sustenna
Paliperidone palmitate 3-month injection • Invega Trinza
Risperidone • Risperdal
Risperidone long-acting injection • Risperdal Consta
Risperidone long-acting injection for SQ • Perseris

There are currently 7 FDA-approved second-generation long-acting injectable antipsychotics (LAIAs).^1-7 These LAIAs provide a unique dosage form that allows patients to receive an antipsychotic without taking oral medications every day, or multiple times per day. This may be an appealing option for patients and clinicians, but because there are several types of LAIAs available, it may be difficult to determine which LAIA characteristics are best for a given patient.

Since the FDA approved the first second-generation LAIA, risperidone long-acting injectable (LAI),¹ in 2003, 6 additional second-generation LAIAs have been approved:

• aripiprazole LAI
• aripiprazole lauroxil LAI
• olanzapine pamoate LAI
• paliperidone palmitate monthly injection
• paliperidone palmitate 3-month LAI
• risperidone LAI for subcutaneous (SQ) injection.

When discussing medication options with patients, clinicians need to consider factors that are unique to each LAIA. In this article, I describe the similarities and differences among the second-generation LAIAs, and address common questions about these medications.

A major potential benefit: Increased adherence

One potential benefit of all LAIAs is increased medication adherence compared with oral antipsychotics. One meta-analysis of 21 randomized controlled trials (RCTs) that compared LAIAs with oral antipsychotics and included 5,176 patients found that LAIAs had a similar efficacy to oral antipsychotics in preventing relapse.⁸ However, a meta-analysis of 25 mirror-image studies comparing LAIAs with oral antipsychotics that included 5,940 patients found that LAIAs were superior in preventing hospitalization.⁹ In these mirror-image studies, participants received oral antipsychotics first and then switched to LAIAs, and the 2 study periods were compared. Because mirror-image studies are observational, participants do not engage with research teams to the extent that they do in RCTs.⁹ Although mirror-image studies have limitations, participants in these studies may be a better representation of patients encountered in clinical practice due to the extensive monitoring and follow-up RCT participants typically receive.⁹

Differences in FDA-approved indications

The 7 currently available LAIAs vary in terms of FDA-approved indications, dose options, frequency, need for oral antipsychotic overlap, route of administration, and other factors. Table 1^1-7 summarizes some of these differences. Although all second-generation LAIAs are approved for schizophrenia,^1-7 risperidone LAI and aripiprazole LAI are also approved for bipolar I disorder.^1,4 Paliperidone palmitate monthly injection is the only LAIA approved for treating patients with schizoaffective disorder.²

Starting doses

For most LAIAs, the starting dose is the same as the maintenance dose (Table 1^1-7). One exception is paliperidone palmitate monthly injection, which requires a 234-mg dose on Day 1 followed by a 156-mg dose on Day 8 for all patients, regardless of the maintenance dose required.² The 156-mg dose may be given 4 days before or after Day 8.² The first maintenance dose of paliperidone palmitate monthly injection should be administered 5 weeks after the 234-mg dose on Day 1.² Before starting paliperidone palmitate 3-month injection, patients should be stable on paliperidone palmitate monthly injection for 4 months, and the 2 most recent doses of paliperidone palmitate monthly injection should be the same.³

Maintenance doses

Dosing frequency may be an important factor for some patients when deciding to receive a LAIA. The frequency of the maintenance doses for all second-generation LAIAs varies from every 2 weeks to 12 weeks (Table 1^1-7). Paliperidone palmitate 3-month LAI is the only LAIA that is administered every 12 weeks.³ Some dosages of aripiprazole lauroxil LAI are administered every 6 or 8 weeks.⁶ All other second-generation LAIAs are given every 2 to 4 weeks.

Continue to: Start with an oral antipsychotic

 

 

Start with an oral antipsychotic

Before starting any LAIA, patients should receive the oral formulation of that antipsychotic to establish tolerability.^1-7 Four of the 7 available LAIAs have an oral-to-LAI dose equivalency recommendation in their prescribing information (Table 2^2,5-7). This can help clinicians estimate the LAIA maintenance dose required to control a patient’s symptoms. If a dose adjustment is needed once a patient starts an LAIA, the dose adjustment can be made when the next injection is due.²

There are 2 important considerations when prescribing olanzapine pamoate LAI. First, the recommended dose for olanzapine pamoate LAI based on oral olanzapine doses differs during the first 8 weeks of treatment compared with after 8 weeks of treatment (Table 2^2,5-7). Additionally, because there are both short-acting and long-acting injections of olanzapine, it is essential to choose the correct formulation when prescribing this medication.⁵

Overlap with an oral antipsychotic might be necessary

Administration of several of the LAIAs may require overlap with an oral antipsychotic (Table 3^1,2,4-7). Patients who refuse to take oral medications may benefit from one of the LAIAs that does not require oral overlap—paliperidone palmitate monthly injection, olanzapine pamoate LAI, and risperidone LAI for SQ.^2,5,7 Risperidone LAI requires overlap with oral risperidone for 3 weeks.¹

Aripiprazole is available in 2 LAI formulations: aripiprazole LAI and aripiprazole lauroxil LAI. Aripiprazole lauroxil is a prodrug of aripiprazole, and these 2 LAI medications differ in available dose options and dosing frequency.^4,6 Aripiprazole LAI requires an oral overlap for 2 weeks after the first injection, whereas aripiprazole lauroxil LAI requires 3 weeks of oral overlap unless aripiprazole lauroxil 675-mg LAI is administered (Figure⁶).^4,6,10

Aripiprazole lauroxil 675-mg LAI is formulated with drug particles that are smaller than those in aripiprazole lauroxil LAI.¹¹ The smaller particle size results in faster dissolution and a more rapid increase in plasma aripiprazole levels. Aripiprazole lauroxil 675-mg LAI is a single injection that should be given with one 30-mg dose of oral aripiprazole.¹⁰ This combination results in aripiprazole concentrations that are comparable to aripiprazole lauroxil LAI and oral aripiprazole overlap for 3 weeks after the first injection.¹⁰

Continue to: The starting dose of aripiprazole lauroxil LAI...

The starting dose of aripiprazole lauroxil LAI may be administered on the same day as aripiprazole lauroxil 675-mg LAI and the 30-mg oral aripiprazole dose, or it may be administered up to 10 days after.¹⁰ Aripiprazole lauroxil LAI and aripiprazole lauroxil 675-mg LAI are not interchangeable due to differing pharmacokinetic profiles.^6,10 Aripiprazole lauroxil 675-mg LAI may be used to re-initiate treatment in a patient who missed doses of aripiprazole lauroxil LAI.¹⁰ Aripiprazole lauroxil LAI and aripiprazole lauroxil 675 mg should not be injected together into the same deltoid or gluteal muscle.

Be mindful of differences in dosing windows

Each LAIA has a specific frequency recommendation, but due to scheduling or other factors, it may not be possible for patients to receive their injection on the specified day. The prescribing information for some LAIAs provides a dosing window (Table 4^1-7). The prescribing information for risperidone LAI, olanzapine pamoate LAI, and risperidone LAI for SQ does not specify how many days the injection can be administered before or after the due date; however, the prescribing information for risperidone LAI for SQ indicates that if the injection is not given on the due date, it should be administered as soon as possible after that.^1,5,7

Paliperidone palmitate monthly injection and paliperidone palmitate 3-month LAI have the clearest recommendations for a dosing window. Paliperidone palmitate monthly injection may be administered 7 days before or after the 4-week due date, and paliperidone palmitate 3-month LAI can be administered 14 days before or after the 12-week due date.^2,3

Aripiprazole LAI should not be administered sooner than 26 days after the previous injection, which means that it can be administered up to 2 days before the 4-week due date.⁴ If administered after the due date, it should be given as soon as possible, although oral overlap is not needed until ≥7 days past the due date.⁴

Aripiprazole lauroxil LAI has similar recommendations to aripiprazole LAI in that it should not be administered sooner than 14 days after the previous injection.⁶ If it is given after the due date, it should be administered as soon as possible; oral overlap/starting dose is needed if it has been ≥2 to 4 weeks since the due date, depending on which dose and frequency the patient is receiving.⁶

Continue to: Recommendations for missed doses

 

 

Recommendations for missed doses

Each LAIA has specific recommendations for missed dosing. Carpenter and Wong¹² reviewed the recommendations for managing missed LAIA doses in Current Psychiatry July 2018. This article is available at mdedge.com/psychiatry/article/168776/schizophrenia-other-psychotic-disorders/long-acting-injectable.¹²

Consider patient preference

Patient preference for the type and location of the injection may factor into a clinician’s choice of LAIA (Table 5^1-7,10). Risperidone LAI for SQ is the only LAIA that is administered as an SQ abdominal injection.⁷ All other LAIAs are IM injections in the deltoid or gluteal muscle.^1-6 All doses of risperidone LAI, paliperidone palmitate 3-month LAI, aripiprazole LAI, and aripiprazole lauroxil 675-mg LAI can be administered in the deltoid or gluteal muscle.^1,3,4,10 Deltoid administration is required for the 2 starting doses of paliperidone palmitate monthly injection, but maintenance doses can be administered in the deltoid or gluteal muscle. Because administration into the deltoid results in a higher concentration of the drug compared with gluteal administration, administering the 2 starting doses of paliperidone palmitate monthly injection into the deltoid helps to rapidly attain therapeutic concentrations.² Olanzapine pamoate LAI should be administered only in the gluteal muscle.⁵ The 441-mg dose of aripiprazole lauroxil LAI may be administered in the deltoid or gluteal muscle, but all other doses of aripiprazole lauroxil LAI should be administered only in the gluteal muscle.⁶

Storage

Most LAIAs can be stored at room temperature^2-6; however, risperidone LAI and risperidone LAI for SQ need to be stored in the refrigerator. Both risperidone LAI and risperidone LAI for SQ may be kept at room temperature for up to 7 days. If they are not used within 7 days at room temperature, they should be discarded.^1,7

Clinical pearls for specific LAIAs

Aripiprazole LAI. The recommended starting and maintenance dose for aripiprazole LAI is 400 mg monthly, unless the patient has drug interactions or other factors that require dose adjustment. If patients experience adverse reactions to the 400-mg dose, a reduction to 300 mg monthly could be considered.⁴

Olanzapine pamoate LAI has a Risk Evaluation and Mitigation Strategy (REMS) due to the potential for post-injection delirium/sedation syndrome (PDSS). Prescribing clinicians, dispensing pharmacies, and administering health care facilities must all be certified to prescribe, dispense, or administer olanzapine pamoate LAI. The patient must also be enrolled in the REMS program.¹³ Patients must be observed by health care staff for 3 hours after receiving a dose of olanzapine pamoate LAI to monitor for signs and symptoms of PDSS.⁵

Continue to: Risperidone LAI

Risperidone LAI. When increasing the dose of risperidone LAI, do not expect to see the clinical effects of the new dose earlier than 3 weeks after initiating the higher dose, because the main release of the medication starts at 3 weeks after the injection.¹

Risperidone LAI for SQ has specific recommendations for the LAI dose based on whether the patient was stable when receiving 3 or 4 mg/d of oral risperidone. If patients are stable on <3 or >4 mg/d, they may not be candidates for risperidone LAI for SQ.⁷

Table 6^1-7,10 lists additional factors to consider when prescribing a specific LAIA.

Bottom Line

Second-generation long-acting injectable antipsychotics (LAIAs) have the potential to increase medication adherence. There are important differences among the 7 currently available LAIAs. For effective prescribing, clinicians need to understand each medication’s unique aspects, including dosing options, frequency, need for oral antipsychotic overlap, and route of administration.

Related Resources

• Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24.
• Peters L, Krogmann A, von Hardenberg L, et al. Long-acting injections in schizophrenia: a 3-year update on randomized controlled trials published January 2016-March 2019. Curr Psychiatry Rep. 2019;21(12):124.

Drug Brand Names

Aripiprazole • Abilify
Aripiprazole long-acting injectable • Abilify Maintena
Aripiprazole lauroxil extended-release injectable suspension • Aristada
Aripiprazole lauroxil 675 mg • Aristada Initio
Olanzapine pamoate long-acting injection • Zyprexa Relprevv
Paliperidone palmitate monthly long-acting injection • Invega Sustenna
Paliperidone palmitate 3-month injection • Invega Trinza
Risperidone • Risperdal
Risperidone long-acting injection • Risperdal Consta
Risperidone long-acting injection for SQ • Perseris

Mitragyna speciosa, better known as kratom, is a tropical evergreen tree that is native to Southeast Asia. Botanically, it is a member of the Rubiaceae family, as is the coffee plant, and physical laborers among indigenous populations have historically chewed the leaves or brewed them as a tea to improve endurance and reduce fatigue.¹ Kratom is psychoactive; small amounts (up to 5 g of plant material) possess stimulant properties, while larger doses (>5 g) produce opioid-like, sedative, euphoric, and antinociceptive effects.²

In recent years, kratom has gained popularity in Western parts of the world due to its unique properties and perceived safety as a botanical product. Individuals may use kratom to boost their energy, relieve pain, or treat a wide range of physical or mood problems. Increasingly, kratom is being used by people who abuse opioids to self-manage opioid withdrawal, or for its euphoric effects. But kratom carries several important risks, including addiction, serious adverse effects, and possibly death. In this article, we review the epidemiology and pharmacology of kratom, and provide some guidance for educating patients about this substance.

Widely used but not FDA approved

Although kratom is not regulated or approved by the FDA, 3 to 5 million Americans use it regularly.³ According to an internet survey, kratom users are mostly college-educated, employed white men, age 31 to 50, who take the substance to manage pain or to treat general anxiety and mood disorders.⁴ Some individuals use kratom as an opioid substitute to reduce symptoms of opioid withdrawal.⁴

Kratom is available from a wide range of manufacturers in various formulations, including powders, tablets, liquids, and gum. It is sometimes sold in combination with other agents as a single product. Low-cost, over-the-counter kratom products are available as “dietary supplements” in retail stores or online. Although the product packaging sometimes recommends a specific dose, the amount of active ingredients (as well as other agents) is unknown. Kratom is illegal in several states (Box⁵).

Box

The 2 alkaloids of interest

More than 40 alkaloids have been isolated from kratom leaves. The proportions of these alkaloids vary significantly depending on the environment in which the plant is grown, the breeding and harvesting techniques, and the age of the plant.⁶ Two alkaloids of significant interest are mitragynine (Figure 1) and 7-hydroxymitragynine (Figure 2), both of which are unique to M. speciosa and have opioid-like properties. Administering these alkaloids to morphine-dependent rats resulted in cross-tolerance and precipitated withdrawal when the rats were given naloxone.⁷ The potency of kratom at the mu opioid receptor has been found to exceed that of morphine.

Competitive binding studies that examined the affinity of mitragynine and 7-hydroxymitragynine at the various opioid receptor subtypes found a preference for the kappa receptors (antagonism), followed by mu (partial agonism), and lastly delta. This profile of mitragynine is very similar to that of buprenorphine.⁸ The affinity of 7-hydroxymitragynine for the mu receptor (agonism) is significantly greater than that of mitragynine.⁹ Mitragynine also interacts with noradrenergic and serotonergic pathways by stimulating postsynaptic alpha-2 adrenergic receptors and inhibiting 5-HT2A receptors.⁹ These properties are responsible for kratom’s ability to manage opioid withdrawal symptoms, which are generally attributed to a hyperactive noradrenergic system. There also is evidence that the hepatic metabolite 7-hydroxymitragynine is important in mediating the analgesic component of mitragynine.¹⁰

The initial effects of kratom typically begin within 10 to 20 minutes of consumption, and the full effects are experienced in 30 to 60 minutes.¹ The half-life of mitragynine in humans has not yet been determined, but is believed to be relatively short.¹¹ In rats, the half-life of mitragynine is 2 to 3 hours.¹² Individuals who use kratom to prevent opioid withdrawal have reported taking it as often as every 6 to 12 hours.¹³

Continue to: Metabolism of mitragynine...

Metabolism of mitragynine is predominantly carried out through cytochrome P450 (CYP) 3A4, with minor contributions by 2D6 and 2C9. A total of 13 metabolites are produced, including 7-hydroxymitragynine.¹⁴ Kratom’s constituents also interact with the CYP system, inhibiting 2C9, 2D6, and 3A4 isoenzymes, and to some extent, 1A2.

Adverse effects can be fatal

An animal study revealed that when administered intravenously, mitragynine and 7-hydroxymitragynine have a similar toxicity profile to heroin.¹⁵ When these alkaloids were administered in ascending doses, increases in blood pressure and elevations in liver function tests and creatinine levels from baseline were observed.

Chronic kratom use can result in weight loss, insomnia, constipation, dehydration, skin hyperpigmentation, and extreme fatigue.¹⁶ There have also been reports of seizures, delusions, hallucinations, respiratory depression, hepatotoxicity, coma, and death.^17,18 An emerging concern is the potential development of fatty liver infiltrates leading to cholestatic liver damage.^19-25 One case report described a young man who developed a serum aspartate aminotransferase level of 1,300 IU/L (reference range: 5 to 45 IU/L) and a serum alanine aminotransaminase level of 3,700 IU/L (reference range: 5 to 60 IU/L) after he ingested a kratom product.²⁶ Histologically, the pattern of liver injury mimics primary biliary cholangitis.²⁷

In recent years, calls to poison control centers in the United States related to kratom exposure have risen. Between 2011 and 2017, the number of calls increased from 1 a month to 2 each day.²⁸ The US National Poison Data System has also noted an increase in the number of calls in reference to kratom. It received 2,312 calls from January 2011 through July 2018, with 18 calls occurring in 2011, and 357 within the first 7 months of 2018.²⁹

As of February 2018, the FDA had received reports of 44 deaths associated with kratom.³⁰ There have been reports of fatal overdoses involving kratom, particularly when kratom is co-ingested or used with adulterated and/or combination agents, including one case that involved quetiapine.^31-33 There have been reports of deaths believed to be attributed to the use of kratom alone; in one such case, a 35-year-old man experienced a fatal cardiac arrest due to kratom use with no other coingestants.³⁴ Among the reports of deaths in which kratom was the only substance consumed, the mitragynine blood levels of the deceased individuals were found to be higher than the levels associated with individuals who had consumed traditional kratom teas.²⁹

Continue to: There is a lack of quality control...

There is a lack of quality control of commercially available kratom preparations. The FDA has found kratom products that exceeded the level of safe exposure to nickel and lead.³⁵ There have also been reports of Salmonella outbreaks associated with kratom products.³⁶

Detecting kratom use

Mitragynine is a lipophilic alkaloid that is poorly soluble in water³⁷ and eliminated primarily in urine.¹² Based on data from treatment center admissions, kratom can be detected in urine samples for 5 to 6 days after use.^24,38,39 However, kratom is not detectable by a standard urine toxicology screen; therefore, a high degree of suspicion and special confirmatory testing are necessary. The breakdown products of mitragynine can be detected through gas chromatography coupled with mass spectrometry (GC/MS), liquid chromatography with linear ion trap mass spectrometry, or electrospray tandem mass spectrometry.^40-42

A familiar withdrawal syndrome

Abrupt discontinuation of high-dose, long-term kratom use can produce withdrawal symptoms.¹³ Symptoms of kratom withdrawal resemble those of opioid withdrawal. These include physiological symptoms (mydriasis, nausea, sweating and chills, muscle and body aches, tremors and twitches, diarrhea, rhinorrhea, and lacrimation) and psychological symptoms (insomnia, restlessness, irritability/hostility, fatigue, anxiety, mood disturbances, and hallucinations).¹³ Symptoms are first noted starting 12 hours after the last use of kratom, and can last up to 7 days.⁴³ Withdrawal intensity has been positively correlated with the daily amount of kratom consumed, as well as the duration and frequency of use.^13,16

In 2 case reports, the newborns of women who used kratom during pregnancy experienced neonatal abstinence syndrome.^44,45 In these 2 reports, symptoms such as jitteriness, irritability, feeding intolerance, and vomiting emerged on postpartum Day 2. The newborns were admitted to a neonatal ICU and started on a standard opioid protocol with IV morphine and subsequently tapered with an oral formulation over 5 days.^44,45

Helping patients who use kratom

The best approach to treating a patient who is experiencing kratom withdrawal is symptomatic management, as would be appropriate for a patient experiencing opioid withdrawal.¹³ However, the use of agents such as methadone or buprenorphine for patients undergoing kratom withdrawal has not been thoroughly evaluated; very few reports have been published.^46,47

Continue to: Similarly, while the standard of care...

Similarly, while the standard of care for treating a patient with opioid use disorder is medication-assisted treatment in combination with counseling and behavioral therapies, there is little evidence on the efficacy of such treatments for patients who use kratom. There are no specific guidelines, and the risk of relapsing to kratom use is high.^48,49 Nonetheless, some clinicians have used the same protocol for patients with opioid use disorder to treat patients using kratom, and several published case reports describe this approach.^50,51 Because administering buprenorphine/naltrexone to a patient who is dependent on kratom can precipitate withdrawal, clinicians should follow a similar initiation protocol as for opioid dependence when starting a patient on these agents (ie, a washout period with a challenge test would be prudent prior to starting naltrexone).

In cases of kratom overdose, naloxone has been shown to reverse the analgesic effects of mitragynine in rats. However, in a case report of an individual who accidently overdosed on a kratom product, naloxone had a modest effect.⁵²

Bottom Line

Kratom is a botanical substance that acts like a stimulant at low doses and an opioid at higher doses. Patients might use it to treat mood-related symptoms, relieve pain, or manage opioid withdrawal. Kratom use has been associated with the development of addiction as well as a multitude of serious adverse effects, including hepatotoxicity and overdose. Long-term management may be required for a patient who uses kratom.

Related Resources

• White CM. Pharmacologic and clinical assessment of kratom: an update. Am J Health Syst Pharm. 2019;76(23):1915-1925.
• Smith KE, Lawson T. Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend. 2017;180:340-348.

Drug Brand Names

Buprenorphine • Subutex, Sublocade
Buprenorphine/naltrexone • Suboxone
Methadone • Methadose
Naltrexone • Revia
Naloxone • Narcan
Quetiapine • Seroquel

Mitragyna speciosa, better known as kratom, is a tropical evergreen tree that is native to Southeast Asia. Botanically, it is a member of the Rubiaceae family, as is the coffee plant, and physical laborers among indigenous populations have historically chewed the leaves or brewed them as a tea to improve endurance and reduce fatigue.¹ Kratom is psychoactive; small amounts (up to 5 g of plant material) possess stimulant properties, while larger doses (>5 g) produce opioid-like, sedative, euphoric, and antinociceptive effects.²

In recent years, kratom has gained popularity in Western parts of the world due to its unique properties and perceived safety as a botanical product. Individuals may use kratom to boost their energy, relieve pain, or treat a wide range of physical or mood problems. Increasingly, kratom is being used by people who abuse opioids to self-manage opioid withdrawal, or for its euphoric effects. But kratom carries several important risks, including addiction, serious adverse effects, and possibly death. In this article, we review the epidemiology and pharmacology of kratom, and provide some guidance for educating patients about this substance.

Widely used but not FDA approved

Although kratom is not regulated or approved by the FDA, 3 to 5 million Americans use it regularly.³ According to an internet survey, kratom users are mostly college-educated, employed white men, age 31 to 50, who take the substance to manage pain or to treat general anxiety and mood disorders.⁴ Some individuals use kratom as an opioid substitute to reduce symptoms of opioid withdrawal.⁴

Kratom is available from a wide range of manufacturers in various formulations, including powders, tablets, liquids, and gum. It is sometimes sold in combination with other agents as a single product. Low-cost, over-the-counter kratom products are available as “dietary supplements” in retail stores or online. Although the product packaging sometimes recommends a specific dose, the amount of active ingredients (as well as other agents) is unknown. Kratom is illegal in several states (Box⁵).

Box

The 2 alkaloids of interest

More than 40 alkaloids have been isolated from kratom leaves. The proportions of these alkaloids vary significantly depending on the environment in which the plant is grown, the breeding and harvesting techniques, and the age of the plant.⁶ Two alkaloids of significant interest are mitragynine (Figure 1) and 7-hydroxymitragynine (Figure 2), both of which are unique to M. speciosa and have opioid-like properties. Administering these alkaloids to morphine-dependent rats resulted in cross-tolerance and precipitated withdrawal when the rats were given naloxone.⁷ The potency of kratom at the mu opioid receptor has been found to exceed that of morphine.

Competitive binding studies that examined the affinity of mitragynine and 7-hydroxymitragynine at the various opioid receptor subtypes found a preference for the kappa receptors (antagonism), followed by mu (partial agonism), and lastly delta. This profile of mitragynine is very similar to that of buprenorphine.⁸ The affinity of 7-hydroxymitragynine for the mu receptor (agonism) is significantly greater than that of mitragynine.⁹ Mitragynine also interacts with noradrenergic and serotonergic pathways by stimulating postsynaptic alpha-2 adrenergic receptors and inhibiting 5-HT2A receptors.⁹ These properties are responsible for kratom’s ability to manage opioid withdrawal symptoms, which are generally attributed to a hyperactive noradrenergic system. There also is evidence that the hepatic metabolite 7-hydroxymitragynine is important in mediating the analgesic component of mitragynine.¹⁰

The initial effects of kratom typically begin within 10 to 20 minutes of consumption, and the full effects are experienced in 30 to 60 minutes.¹ The half-life of mitragynine in humans has not yet been determined, but is believed to be relatively short.¹¹ In rats, the half-life of mitragynine is 2 to 3 hours.¹² Individuals who use kratom to prevent opioid withdrawal have reported taking it as often as every 6 to 12 hours.¹³

Continue to: Metabolism of mitragynine...

Metabolism of mitragynine is predominantly carried out through cytochrome P450 (CYP) 3A4, with minor contributions by 2D6 and 2C9. A total of 13 metabolites are produced, including 7-hydroxymitragynine.¹⁴ Kratom’s constituents also interact with the CYP system, inhibiting 2C9, 2D6, and 3A4 isoenzymes, and to some extent, 1A2.

Adverse effects can be fatal

An animal study revealed that when administered intravenously, mitragynine and 7-hydroxymitragynine have a similar toxicity profile to heroin.¹⁵ When these alkaloids were administered in ascending doses, increases in blood pressure and elevations in liver function tests and creatinine levels from baseline were observed.

Chronic kratom use can result in weight loss, insomnia, constipation, dehydration, skin hyperpigmentation, and extreme fatigue.¹⁶ There have also been reports of seizures, delusions, hallucinations, respiratory depression, hepatotoxicity, coma, and death.^17,18 An emerging concern is the potential development of fatty liver infiltrates leading to cholestatic liver damage.^19-25 One case report described a young man who developed a serum aspartate aminotransferase level of 1,300 IU/L (reference range: 5 to 45 IU/L) and a serum alanine aminotransaminase level of 3,700 IU/L (reference range: 5 to 60 IU/L) after he ingested a kratom product.²⁶ Histologically, the pattern of liver injury mimics primary biliary cholangitis.²⁷

In recent years, calls to poison control centers in the United States related to kratom exposure have risen. Between 2011 and 2017, the number of calls increased from 1 a month to 2 each day.²⁸ The US National Poison Data System has also noted an increase in the number of calls in reference to kratom. It received 2,312 calls from January 2011 through July 2018, with 18 calls occurring in 2011, and 357 within the first 7 months of 2018.²⁹

As of February 2018, the FDA had received reports of 44 deaths associated with kratom.³⁰ There have been reports of fatal overdoses involving kratom, particularly when kratom is co-ingested or used with adulterated and/or combination agents, including one case that involved quetiapine.^31-33 There have been reports of deaths believed to be attributed to the use of kratom alone; in one such case, a 35-year-old man experienced a fatal cardiac arrest due to kratom use with no other coingestants.³⁴ Among the reports of deaths in which kratom was the only substance consumed, the mitragynine blood levels of the deceased individuals were found to be higher than the levels associated with individuals who had consumed traditional kratom teas.²⁹

Continue to: There is a lack of quality control...

There is a lack of quality control of commercially available kratom preparations. The FDA has found kratom products that exceeded the level of safe exposure to nickel and lead.³⁵ There have also been reports of Salmonella outbreaks associated with kratom products.³⁶

Detecting kratom use

Mitragynine is a lipophilic alkaloid that is poorly soluble in water³⁷ and eliminated primarily in urine.¹² Based on data from treatment center admissions, kratom can be detected in urine samples for 5 to 6 days after use.^24,38,39 However, kratom is not detectable by a standard urine toxicology screen; therefore, a high degree of suspicion and special confirmatory testing are necessary. The breakdown products of mitragynine can be detected through gas chromatography coupled with mass spectrometry (GC/MS), liquid chromatography with linear ion trap mass spectrometry, or electrospray tandem mass spectrometry.^40-42

A familiar withdrawal syndrome

Abrupt discontinuation of high-dose, long-term kratom use can produce withdrawal symptoms.¹³ Symptoms of kratom withdrawal resemble those of opioid withdrawal. These include physiological symptoms (mydriasis, nausea, sweating and chills, muscle and body aches, tremors and twitches, diarrhea, rhinorrhea, and lacrimation) and psychological symptoms (insomnia, restlessness, irritability/hostility, fatigue, anxiety, mood disturbances, and hallucinations).¹³ Symptoms are first noted starting 12 hours after the last use of kratom, and can last up to 7 days.⁴³ Withdrawal intensity has been positively correlated with the daily amount of kratom consumed, as well as the duration and frequency of use.^13,16

In 2 case reports, the newborns of women who used kratom during pregnancy experienced neonatal abstinence syndrome.^44,45 In these 2 reports, symptoms such as jitteriness, irritability, feeding intolerance, and vomiting emerged on postpartum Day 2. The newborns were admitted to a neonatal ICU and started on a standard opioid protocol with IV morphine and subsequently tapered with an oral formulation over 5 days.^44,45

Helping patients who use kratom

The best approach to treating a patient who is experiencing kratom withdrawal is symptomatic management, as would be appropriate for a patient experiencing opioid withdrawal.¹³ However, the use of agents such as methadone or buprenorphine for patients undergoing kratom withdrawal has not been thoroughly evaluated; very few reports have been published.^46,47

Continue to: Similarly, while the standard of care...

Similarly, while the standard of care for treating a patient with opioid use disorder is medication-assisted treatment in combination with counseling and behavioral therapies, there is little evidence on the efficacy of such treatments for patients who use kratom. There are no specific guidelines, and the risk of relapsing to kratom use is high.^48,49 Nonetheless, some clinicians have used the same protocol for patients with opioid use disorder to treat patients using kratom, and several published case reports describe this approach.^50,51 Because administering buprenorphine/naltrexone to a patient who is dependent on kratom can precipitate withdrawal, clinicians should follow a similar initiation protocol as for opioid dependence when starting a patient on these agents (ie, a washout period with a challenge test would be prudent prior to starting naltrexone).

In cases of kratom overdose, naloxone has been shown to reverse the analgesic effects of mitragynine in rats. However, in a case report of an individual who accidently overdosed on a kratom product, naloxone had a modest effect.⁵²

Bottom Line

Kratom is a botanical substance that acts like a stimulant at low doses and an opioid at higher doses. Patients might use it to treat mood-related symptoms, relieve pain, or manage opioid withdrawal. Kratom use has been associated with the development of addiction as well as a multitude of serious adverse effects, including hepatotoxicity and overdose. Long-term management may be required for a patient who uses kratom.

Related Resources

• White CM. Pharmacologic and clinical assessment of kratom: an update. Am J Health Syst Pharm. 2019;76(23):1915-1925.
• Smith KE, Lawson T. Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend. 2017;180:340-348.

Drug Brand Names

Buprenorphine • Subutex, Sublocade
Buprenorphine/naltrexone • Suboxone
Methadone • Methadose
Naltrexone • Revia
Naloxone • Narcan
Quetiapine • Seroquel

Mitragyna speciosa, better known as kratom, is a tropical evergreen tree that is native to Southeast Asia. Botanically, it is a member of the Rubiaceae family, as is the coffee plant, and physical laborers among indigenous populations have historically chewed the leaves or brewed them as a tea to improve endurance and reduce fatigue.¹ Kratom is psychoactive; small amounts (up to 5 g of plant material) possess stimulant properties, while larger doses (>5 g) produce opioid-like, sedative, euphoric, and antinociceptive effects.²

In recent years, kratom has gained popularity in Western parts of the world due to its unique properties and perceived safety as a botanical product. Individuals may use kratom to boost their energy, relieve pain, or treat a wide range of physical or mood problems. Increasingly, kratom is being used by people who abuse opioids to self-manage opioid withdrawal, or for its euphoric effects. But kratom carries several important risks, including addiction, serious adverse effects, and possibly death. In this article, we review the epidemiology and pharmacology of kratom, and provide some guidance for educating patients about this substance.

Widely used but not FDA approved

Although kratom is not regulated or approved by the FDA, 3 to 5 million Americans use it regularly.³ According to an internet survey, kratom users are mostly college-educated, employed white men, age 31 to 50, who take the substance to manage pain or to treat general anxiety and mood disorders.⁴ Some individuals use kratom as an opioid substitute to reduce symptoms of opioid withdrawal.⁴

Kratom is available from a wide range of manufacturers in various formulations, including powders, tablets, liquids, and gum. It is sometimes sold in combination with other agents as a single product. Low-cost, over-the-counter kratom products are available as “dietary supplements” in retail stores or online. Although the product packaging sometimes recommends a specific dose, the amount of active ingredients (as well as other agents) is unknown. Kratom is illegal in several states (Box⁵).

Box

The 2 alkaloids of interest

More than 40 alkaloids have been isolated from kratom leaves. The proportions of these alkaloids vary significantly depending on the environment in which the plant is grown, the breeding and harvesting techniques, and the age of the plant.⁶ Two alkaloids of significant interest are mitragynine (Figure 1) and 7-hydroxymitragynine (Figure 2), both of which are unique to M. speciosa and have opioid-like properties. Administering these alkaloids to morphine-dependent rats resulted in cross-tolerance and precipitated withdrawal when the rats were given naloxone.⁷ The potency of kratom at the mu opioid receptor has been found to exceed that of morphine.

Competitive binding studies that examined the affinity of mitragynine and 7-hydroxymitragynine at the various opioid receptor subtypes found a preference for the kappa receptors (antagonism), followed by mu (partial agonism), and lastly delta. This profile of mitragynine is very similar to that of buprenorphine.⁸ The affinity of 7-hydroxymitragynine for the mu receptor (agonism) is significantly greater than that of mitragynine.⁹ Mitragynine also interacts with noradrenergic and serotonergic pathways by stimulating postsynaptic alpha-2 adrenergic receptors and inhibiting 5-HT2A receptors.⁹ These properties are responsible for kratom’s ability to manage opioid withdrawal symptoms, which are generally attributed to a hyperactive noradrenergic system. There also is evidence that the hepatic metabolite 7-hydroxymitragynine is important in mediating the analgesic component of mitragynine.¹⁰

The initial effects of kratom typically begin within 10 to 20 minutes of consumption, and the full effects are experienced in 30 to 60 minutes.¹ The half-life of mitragynine in humans has not yet been determined, but is believed to be relatively short.¹¹ In rats, the half-life of mitragynine is 2 to 3 hours.¹² Individuals who use kratom to prevent opioid withdrawal have reported taking it as often as every 6 to 12 hours.¹³

Continue to: Metabolism of mitragynine...

Metabolism of mitragynine is predominantly carried out through cytochrome P450 (CYP) 3A4, with minor contributions by 2D6 and 2C9. A total of 13 metabolites are produced, including 7-hydroxymitragynine.¹⁴ Kratom’s constituents also interact with the CYP system, inhibiting 2C9, 2D6, and 3A4 isoenzymes, and to some extent, 1A2.

Adverse effects can be fatal

An animal study revealed that when administered intravenously, mitragynine and 7-hydroxymitragynine have a similar toxicity profile to heroin.¹⁵ When these alkaloids were administered in ascending doses, increases in blood pressure and elevations in liver function tests and creatinine levels from baseline were observed.

Chronic kratom use can result in weight loss, insomnia, constipation, dehydration, skin hyperpigmentation, and extreme fatigue.¹⁶ There have also been reports of seizures, delusions, hallucinations, respiratory depression, hepatotoxicity, coma, and death.^17,18 An emerging concern is the potential development of fatty liver infiltrates leading to cholestatic liver damage.^19-25 One case report described a young man who developed a serum aspartate aminotransferase level of 1,300 IU/L (reference range: 5 to 45 IU/L) and a serum alanine aminotransaminase level of 3,700 IU/L (reference range: 5 to 60 IU/L) after he ingested a kratom product.²⁶ Histologically, the pattern of liver injury mimics primary biliary cholangitis.²⁷

In recent years, calls to poison control centers in the United States related to kratom exposure have risen. Between 2011 and 2017, the number of calls increased from 1 a month to 2 each day.²⁸ The US National Poison Data System has also noted an increase in the number of calls in reference to kratom. It received 2,312 calls from January 2011 through July 2018, with 18 calls occurring in 2011, and 357 within the first 7 months of 2018.²⁹

As of February 2018, the FDA had received reports of 44 deaths associated with kratom.³⁰ There have been reports of fatal overdoses involving kratom, particularly when kratom is co-ingested or used with adulterated and/or combination agents, including one case that involved quetiapine.^31-33 There have been reports of deaths believed to be attributed to the use of kratom alone; in one such case, a 35-year-old man experienced a fatal cardiac arrest due to kratom use with no other coingestants.³⁴ Among the reports of deaths in which kratom was the only substance consumed, the mitragynine blood levels of the deceased individuals were found to be higher than the levels associated with individuals who had consumed traditional kratom teas.²⁹

Continue to: There is a lack of quality control...

There is a lack of quality control of commercially available kratom preparations. The FDA has found kratom products that exceeded the level of safe exposure to nickel and lead.³⁵ There have also been reports of Salmonella outbreaks associated with kratom products.³⁶

Detecting kratom use

Mitragynine is a lipophilic alkaloid that is poorly soluble in water³⁷ and eliminated primarily in urine.¹² Based on data from treatment center admissions, kratom can be detected in urine samples for 5 to 6 days after use.^24,38,39 However, kratom is not detectable by a standard urine toxicology screen; therefore, a high degree of suspicion and special confirmatory testing are necessary. The breakdown products of mitragynine can be detected through gas chromatography coupled with mass spectrometry (GC/MS), liquid chromatography with linear ion trap mass spectrometry, or electrospray tandem mass spectrometry.^40-42

A familiar withdrawal syndrome

Abrupt discontinuation of high-dose, long-term kratom use can produce withdrawal symptoms.¹³ Symptoms of kratom withdrawal resemble those of opioid withdrawal. These include physiological symptoms (mydriasis, nausea, sweating and chills, muscle and body aches, tremors and twitches, diarrhea, rhinorrhea, and lacrimation) and psychological symptoms (insomnia, restlessness, irritability/hostility, fatigue, anxiety, mood disturbances, and hallucinations).¹³ Symptoms are first noted starting 12 hours after the last use of kratom, and can last up to 7 days.⁴³ Withdrawal intensity has been positively correlated with the daily amount of kratom consumed, as well as the duration and frequency of use.^13,16

In 2 case reports, the newborns of women who used kratom during pregnancy experienced neonatal abstinence syndrome.^44,45 In these 2 reports, symptoms such as jitteriness, irritability, feeding intolerance, and vomiting emerged on postpartum Day 2. The newborns were admitted to a neonatal ICU and started on a standard opioid protocol with IV morphine and subsequently tapered with an oral formulation over 5 days.^44,45

Helping patients who use kratom

The best approach to treating a patient who is experiencing kratom withdrawal is symptomatic management, as would be appropriate for a patient experiencing opioid withdrawal.¹³ However, the use of agents such as methadone or buprenorphine for patients undergoing kratom withdrawal has not been thoroughly evaluated; very few reports have been published.^46,47

Continue to: Similarly, while the standard of care...

Similarly, while the standard of care for treating a patient with opioid use disorder is medication-assisted treatment in combination with counseling and behavioral therapies, there is little evidence on the efficacy of such treatments for patients who use kratom. There are no specific guidelines, and the risk of relapsing to kratom use is high.^48,49 Nonetheless, some clinicians have used the same protocol for patients with opioid use disorder to treat patients using kratom, and several published case reports describe this approach.^50,51 Because administering buprenorphine/naltrexone to a patient who is dependent on kratom can precipitate withdrawal, clinicians should follow a similar initiation protocol as for opioid dependence when starting a patient on these agents (ie, a washout period with a challenge test would be prudent prior to starting naltrexone).

In cases of kratom overdose, naloxone has been shown to reverse the analgesic effects of mitragynine in rats. However, in a case report of an individual who accidently overdosed on a kratom product, naloxone had a modest effect.⁵²

Bottom Line

Kratom is a botanical substance that acts like a stimulant at low doses and an opioid at higher doses. Patients might use it to treat mood-related symptoms, relieve pain, or manage opioid withdrawal. Kratom use has been associated with the development of addiction as well as a multitude of serious adverse effects, including hepatotoxicity and overdose. Long-term management may be required for a patient who uses kratom.

Related Resources

• White CM. Pharmacologic and clinical assessment of kratom: an update. Am J Health Syst Pharm. 2019;76(23):1915-1925.
• Smith KE, Lawson T. Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend. 2017;180:340-348.

Drug Brand Names

Buprenorphine • Subutex, Sublocade
Buprenorphine/naltrexone • Suboxone
Methadone • Methadose
Naltrexone • Revia
Naloxone • Narcan
Quetiapine • Seroquel