Key clinical point: The compound APR‐246 (PRIMA‐1Met/Eprenetapopt) caused synergistic tumor death in myelodysplastic syndrome with combined with inhibitors of efflux pump MRP1/ABCC1.

Major finding: A combination of combination of APR‐246 with the MRP1 inhibitor MK‐571 significantly reduced IC₅₀ values in 21 cell lines (P < 0.0001).

Study details: The data come from a combination of in vitro, ex vivo, and in vivo models, using combined treatment of APR‐246 and inhibitors of efflux pump MRP1/ABCC1. 

Disclosures: The study was funded by multiple organizations including Vetenskapsrådet, Cancerfonden (Swedish Cancer Society), Barncancerfonden (Swedish Childhood Cancer Foundation), Radiumhemmets Forskningsfonder (Cancer Research Foundations of Radiumhemmet, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation), Aprea Therapeutics, Karolinska Institutet (KI), Department of Health, Australian Government/National Health and Medical Research Council (NHMRC), Department of Health and Human Services, State Government of Victoria (DHHS), Tour de Cure Foundation, UKRI/Medical Research Council (MRC), Australian Cancer Research Foundation (ACRF), Australian Government’s National Collaborative Research Infrastructure Strategy (NCRIS) program, Peter MacCallum Cancer Centre Foundation, University of Melbourne Research Collaborative Infrastructure Program (MCRIP), and Cancer Research UK.

Source: Ceder S et al. EMBO Mol Med. 2020 Dec 14. doi: 10.15252/emmm.201910852.

Key clinical point: The compound APR‐246 (PRIMA‐1Met/Eprenetapopt) caused synergistic tumor death in myelodysplastic syndrome with combined with inhibitors of efflux pump MRP1/ABCC1.

Major finding: A combination of combination of APR‐246 with the MRP1 inhibitor MK‐571 significantly reduced IC₅₀ values in 21 cell lines (P < 0.0001).

Study details: The data come from a combination of in vitro, ex vivo, and in vivo models, using combined treatment of APR‐246 and inhibitors of efflux pump MRP1/ABCC1. 

Disclosures: The study was funded by multiple organizations including Vetenskapsrådet, Cancerfonden (Swedish Cancer Society), Barncancerfonden (Swedish Childhood Cancer Foundation), Radiumhemmets Forskningsfonder (Cancer Research Foundations of Radiumhemmet, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation), Aprea Therapeutics, Karolinska Institutet (KI), Department of Health, Australian Government/National Health and Medical Research Council (NHMRC), Department of Health and Human Services, State Government of Victoria (DHHS), Tour de Cure Foundation, UKRI/Medical Research Council (MRC), Australian Cancer Research Foundation (ACRF), Australian Government’s National Collaborative Research Infrastructure Strategy (NCRIS) program, Peter MacCallum Cancer Centre Foundation, University of Melbourne Research Collaborative Infrastructure Program (MCRIP), and Cancer Research UK.

Source: Ceder S et al. EMBO Mol Med. 2020 Dec 14. doi: 10.15252/emmm.201910852.

Key clinical point: The compound APR‐246 (PRIMA‐1Met/Eprenetapopt) caused synergistic tumor death in myelodysplastic syndrome with combined with inhibitors of efflux pump MRP1/ABCC1.

Major finding: A combination of combination of APR‐246 with the MRP1 inhibitor MK‐571 significantly reduced IC₅₀ values in 21 cell lines (P < 0.0001).

Study details: The data come from a combination of in vitro, ex vivo, and in vivo models, using combined treatment of APR‐246 and inhibitors of efflux pump MRP1/ABCC1. 

Disclosures: The study was funded by multiple organizations including Vetenskapsrådet, Cancerfonden (Swedish Cancer Society), Barncancerfonden (Swedish Childhood Cancer Foundation), Radiumhemmets Forskningsfonder (Cancer Research Foundations of Radiumhemmet, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation), Aprea Therapeutics, Karolinska Institutet (KI), Department of Health, Australian Government/National Health and Medical Research Council (NHMRC), Department of Health and Human Services, State Government of Victoria (DHHS), Tour de Cure Foundation, UKRI/Medical Research Council (MRC), Australian Cancer Research Foundation (ACRF), Australian Government’s National Collaborative Research Infrastructure Strategy (NCRIS) program, Peter MacCallum Cancer Centre Foundation, University of Melbourne Research Collaborative Infrastructure Program (MCRIP), and Cancer Research UK.

Source: Ceder S et al. EMBO Mol Med. 2020 Dec 14. doi: 10.15252/emmm.201910852.

Key clinical point: Researchers developed a flow score based on three variables: developed a “flow score” with the three variables percentage of myeloid CD34⁺ cells > 2%; percentage of B-cell progenitors < 0.05%; and CD16⁺ monocytes/TNCs > 1.0%.

Major finding: Of the 95 patients in the study, 23 remained alive after the end of the study period. A high percentage of CD16⁺ monocytes/TNCs > 1.0% (in the highest quartile) was associated with significantly worse survival.

Study details: The data come from 95 adult patients with newly diagnosed myelodysplastic syndrome seen at a single center and followed for an average of 42 months.

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

Source: Vido-Marques JR et al. Sci Rep. 2020 Nov 20. doi: 10.1038/s41598-020-77158-z.

Key clinical point: Researchers developed a flow score based on three variables: developed a “flow score” with the three variables percentage of myeloid CD34⁺ cells > 2%; percentage of B-cell progenitors < 0.05%; and CD16⁺ monocytes/TNCs > 1.0%.

Major finding: Of the 95 patients in the study, 23 remained alive after the end of the study period. A high percentage of CD16⁺ monocytes/TNCs > 1.0% (in the highest quartile) was associated with significantly worse survival.

Study details: The data come from 95 adult patients with newly diagnosed myelodysplastic syndrome seen at a single center and followed for an average of 42 months.

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

Source: Vido-Marques JR et al. Sci Rep. 2020 Nov 20. doi: 10.1038/s41598-020-77158-z.

Key clinical point: Researchers developed a flow score based on three variables: developed a “flow score” with the three variables percentage of myeloid CD34⁺ cells > 2%; percentage of B-cell progenitors < 0.05%; and CD16⁺ monocytes/TNCs > 1.0%.

Major finding: Of the 95 patients in the study, 23 remained alive after the end of the study period. A high percentage of CD16⁺ monocytes/TNCs > 1.0% (in the highest quartile) was associated with significantly worse survival.

Study details: The data come from 95 adult patients with newly diagnosed myelodysplastic syndrome seen at a single center and followed for an average of 42 months.

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

Source: Vido-Marques JR et al. Sci Rep. 2020 Nov 20. doi: 10.1038/s41598-020-77158-z.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Ted Howard started taking Truvada a few years ago because he wanted to protect himself against HIV, the virus that causes AIDS. But the daily pill was so pricey he was seriously thinking about giving it up.

Under his insurance plan, the former flight attendant and customer service instructor owed $500 in copayments every month for the drug and an additional $250 every three months for lab work and clinic visits.

Luckily for Howard, his doctor at Las Vegas’ Huntridge Family Clinic, which specializes in LGBTQ care, enrolled him in a clinical trial that covered his medication and other costs in full.

“If I hadn’t been able to get into the trial, I wouldn’t have kept taking PrEP,” said Howard, 68, using the shorthand term for “preexposure prophylaxis.” Taken daily, these drugs — like Truvada — are more than 90% effective at preventing infection with HIV.

Starting in January of 2021, most people with private insurance will no longer have to decide whether they can afford to protect themselves against HIV. Most health plans must begin to cover the drugs then without charging consumers anything out-of-pocket (some plans already began doing so last year).

Drugs in this category — Truvada, Descovy and, newly available, a generic version of Truvada — received an “A” recommendation by the U.S. Preventive Services Task Force. Under the Affordable Care Act, preventive services that receive an “A” or “B” rating by the task force, a group of medical experts in prevention and primary care, must be covered by most private health plans without making members share the cost, usually through copayments or deductibles. Only plans that are grandfathered under the health law are exempt.

The task force recommended PrEP for people at high risk of HIV infection, including men who have sex with men and injection drug users.

In the United States, more than 1 million people live with HIV, and nearly 40,000 new HIV cases are diagnosed every year. Yet fewer than 10% of people who could benefit from PrEP are taking it. One key reason is that out-of-pocket costs can exceed $1,000 annually, according to a study published in the American Journal of Public Health last year. Required periodic blood tests and doctor visits can add hundreds of dollars to the cost of the drug, and it’s not clear if insurers are required to pick up all those costs.

“Cost sharing has been a problem,” said Michael Crews, policy director at One Colorado, an advocacy group for the LGBTQ community. “It’s not just getting on PrEP and taking a pill. It’s the lab and clinical services. That’s a huge barrier for folks.”

Whether you’re shopping for a new plan during open enrollment or want to check out what your current plan covers, here are answers to questions you may have about the new preventive coverage requirement.
 

Q: How can people find out whether their health plan covers PrEP medications without charge?

The plan’s list of covered drugs, called a formulary, should spell out which drugs are covered, along with details about which drug tier they fall into. Drugs placed in higher tiers generally have higher cost sharing. That list should be online with the plan documents that give coverage details.

Sorting out coverage and cost sharing can be tricky. Both Truvada and Descovy can also be used to treat HIV, and if they are taken for that purpose, a plan may require members to pay some of the cost. But if the drugs are taken to prevent HIV infection, patients shouldn’t owe anything out-of-pocket, no matter which tier they are on.

In a recent analysis of online formularies for plans sold on the ACA marketplaces, Carl Schmid, executive director of the HIV + Hepatitis Policy Institute, found that many plans seemed out of compliance with the requirement to cover PrEP without cost sharing this year.

But representatives for Oscar and Kaiser Permanente, two insurers that were called out in the analysis for lack of compliance, said the drugs are covered without cost sharing in plans nationwide if they are taken to prevent HIV. Schmid later revised his analysis to reflect Oscar’s coverage.

Coverage and cost-sharing information needs to be transparent and easy to find, Schmid said.

“I acted like a shopper of insurance, just like any person would do,” he said. “Even when the information is correct, [it’s so] difficult to find [and there’s] no uniformity.”

It may be necessary to call the insurer directly to confirm coverage details if information on the website is unclear.
 

Q: Are all three drugs covered without cost sharing?

Health plans have to cover at least one of the drugs in this category — Descovy and the brand and generic versions of Truvada — without cost sharing. People may have to jump through some hoops to get approval for a specific drug, however. For example, Oscar plans sold in 18 states cover the three PrEP options without cost sharing. The generic version of Truvada doesn’t require prior authorization by the insurer. But if someone wants to take the name-brand drug, that person has to go through an approval process. Descovy, a newer drug, is available without cost sharing only if people are unable to use Truvada or its generic version because of clinical intolerance or other issues.
 

Q: What about the lab work and clinical visits that are necessary while taking PrEP? Are those services also covered without cost sharing?

That is the thousand-dollar question. People who are taking drugs to prevent HIV infection need to meet with a clinician and have blood work every three months to test for HIV, hepatitis B and sexually transmitted infections, and to check their kidney function.

The task force recommendation doesn’t specify whether these services must also be covered without cost sharing, and advocates say federal guidance is necessary to ensure they are free.

“If you’ve got a high-deductible plan and you’ve got to meet it before those services are covered, that’s going to add up,” said Amy Killelea, senior director of health systems and policy at the National Alliance of State & Territorial AIDS Directors. “We’re trying to emphasize that it’s integral to the intervention itself.”

A handful of states have programs that help people cover their out-of-pocket costs for lab and clinical visits, generally based on income.

There is precedent for including free ancillary care as part of a recommended preventive service. After consumers and advocates complained, the Centers for Medicare & Medicaid Services (CMS) clarified that under the ACA removing a polyp during a screening colonoscopy is considered an integral part of the procedure and patients shouldn’t be charged for it.

CMS officials declined to clarify whether PrEP services such as lab work and clinical visits are to be covered without cost sharing as part of the preventive service and noted that states generally enforce such insurance requirements. “CMS intends to contact state regulators, as appropriate, to discuss issuer’s compliance with the federal requirements and whether issuers need further guidance on which services associated with PrEP must be covered without cost sharing,” the agency said in a statement.
 

Q: What if someone runs into roadblocks getting a plan to cover PrEP or related services without cost sharing?

If an insurer charges for the medication or a follow-up visit, people may have to go through an appeals process to fight it.

“They’d have to appeal to the insurance company and then to the state if they don’t succeed,” said Nadeen Israel, vice president of policy and advocacy at the AIDS Foundation of Chicago. “Most people don’t know to do that.”
 

Q: Are uninsured people also protected by this new cost-sharing change for PrEP?

Unfortunately, no. The ACA requirement to cover recommended preventive services without charging patients applies only to private insurance plans. People without insurance don’t benefit. Gilead, which makes both Truvada and Descovy, has a patient assistance program for the uninsured.
 

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

Ted Howard started taking Truvada a few years ago because he wanted to protect himself against HIV, the virus that causes AIDS. But the daily pill was so pricey he was seriously thinking about giving it up.

Under his insurance plan, the former flight attendant and customer service instructor owed $500 in copayments every month for the drug and an additional $250 every three months for lab work and clinic visits.

Luckily for Howard, his doctor at Las Vegas’ Huntridge Family Clinic, which specializes in LGBTQ care, enrolled him in a clinical trial that covered his medication and other costs in full.

“If I hadn’t been able to get into the trial, I wouldn’t have kept taking PrEP,” said Howard, 68, using the shorthand term for “preexposure prophylaxis.” Taken daily, these drugs — like Truvada — are more than 90% effective at preventing infection with HIV.

Starting in January of 2021, most people with private insurance will no longer have to decide whether they can afford to protect themselves against HIV. Most health plans must begin to cover the drugs then without charging consumers anything out-of-pocket (some plans already began doing so last year).

Drugs in this category — Truvada, Descovy and, newly available, a generic version of Truvada — received an “A” recommendation by the U.S. Preventive Services Task Force. Under the Affordable Care Act, preventive services that receive an “A” or “B” rating by the task force, a group of medical experts in prevention and primary care, must be covered by most private health plans without making members share the cost, usually through copayments or deductibles. Only plans that are grandfathered under the health law are exempt.

The task force recommended PrEP for people at high risk of HIV infection, including men who have sex with men and injection drug users.

In the United States, more than 1 million people live with HIV, and nearly 40,000 new HIV cases are diagnosed every year. Yet fewer than 10% of people who could benefit from PrEP are taking it. One key reason is that out-of-pocket costs can exceed $1,000 annually, according to a study published in the American Journal of Public Health last year. Required periodic blood tests and doctor visits can add hundreds of dollars to the cost of the drug, and it’s not clear if insurers are required to pick up all those costs.

“Cost sharing has been a problem,” said Michael Crews, policy director at One Colorado, an advocacy group for the LGBTQ community. “It’s not just getting on PrEP and taking a pill. It’s the lab and clinical services. That’s a huge barrier for folks.”

Whether you’re shopping for a new plan during open enrollment or want to check out what your current plan covers, here are answers to questions you may have about the new preventive coverage requirement.
 

Q: How can people find out whether their health plan covers PrEP medications without charge?

The plan’s list of covered drugs, called a formulary, should spell out which drugs are covered, along with details about which drug tier they fall into. Drugs placed in higher tiers generally have higher cost sharing. That list should be online with the plan documents that give coverage details.

Sorting out coverage and cost sharing can be tricky. Both Truvada and Descovy can also be used to treat HIV, and if they are taken for that purpose, a plan may require members to pay some of the cost. But if the drugs are taken to prevent HIV infection, patients shouldn’t owe anything out-of-pocket, no matter which tier they are on.

In a recent analysis of online formularies for plans sold on the ACA marketplaces, Carl Schmid, executive director of the HIV + Hepatitis Policy Institute, found that many plans seemed out of compliance with the requirement to cover PrEP without cost sharing this year.

But representatives for Oscar and Kaiser Permanente, two insurers that were called out in the analysis for lack of compliance, said the drugs are covered without cost sharing in plans nationwide if they are taken to prevent HIV. Schmid later revised his analysis to reflect Oscar’s coverage.

Coverage and cost-sharing information needs to be transparent and easy to find, Schmid said.

“I acted like a shopper of insurance, just like any person would do,” he said. “Even when the information is correct, [it’s so] difficult to find [and there’s] no uniformity.”

It may be necessary to call the insurer directly to confirm coverage details if information on the website is unclear.
 

Q: Are all three drugs covered without cost sharing?

Health plans have to cover at least one of the drugs in this category — Descovy and the brand and generic versions of Truvada — without cost sharing. People may have to jump through some hoops to get approval for a specific drug, however. For example, Oscar plans sold in 18 states cover the three PrEP options without cost sharing. The generic version of Truvada doesn’t require prior authorization by the insurer. But if someone wants to take the name-brand drug, that person has to go through an approval process. Descovy, a newer drug, is available without cost sharing only if people are unable to use Truvada or its generic version because of clinical intolerance or other issues.
 

Q: What about the lab work and clinical visits that are necessary while taking PrEP? Are those services also covered without cost sharing?

That is the thousand-dollar question. People who are taking drugs to prevent HIV infection need to meet with a clinician and have blood work every three months to test for HIV, hepatitis B and sexually transmitted infections, and to check their kidney function.

The task force recommendation doesn’t specify whether these services must also be covered without cost sharing, and advocates say federal guidance is necessary to ensure they are free.

“If you’ve got a high-deductible plan and you’ve got to meet it before those services are covered, that’s going to add up,” said Amy Killelea, senior director of health systems and policy at the National Alliance of State & Territorial AIDS Directors. “We’re trying to emphasize that it’s integral to the intervention itself.”

A handful of states have programs that help people cover their out-of-pocket costs for lab and clinical visits, generally based on income.

There is precedent for including free ancillary care as part of a recommended preventive service. After consumers and advocates complained, the Centers for Medicare & Medicaid Services (CMS) clarified that under the ACA removing a polyp during a screening colonoscopy is considered an integral part of the procedure and patients shouldn’t be charged for it.

CMS officials declined to clarify whether PrEP services such as lab work and clinical visits are to be covered without cost sharing as part of the preventive service and noted that states generally enforce such insurance requirements. “CMS intends to contact state regulators, as appropriate, to discuss issuer’s compliance with the federal requirements and whether issuers need further guidance on which services associated with PrEP must be covered without cost sharing,” the agency said in a statement.
 

Q: What if someone runs into roadblocks getting a plan to cover PrEP or related services without cost sharing?

If an insurer charges for the medication or a follow-up visit, people may have to go through an appeals process to fight it.

“They’d have to appeal to the insurance company and then to the state if they don’t succeed,” said Nadeen Israel, vice president of policy and advocacy at the AIDS Foundation of Chicago. “Most people don’t know to do that.”
 

Q: Are uninsured people also protected by this new cost-sharing change for PrEP?

Unfortunately, no. The ACA requirement to cover recommended preventive services without charging patients applies only to private insurance plans. People without insurance don’t benefit. Gilead, which makes both Truvada and Descovy, has a patient assistance program for the uninsured.
 

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

Ted Howard started taking Truvada a few years ago because he wanted to protect himself against HIV, the virus that causes AIDS. But the daily pill was so pricey he was seriously thinking about giving it up.

Under his insurance plan, the former flight attendant and customer service instructor owed $500 in copayments every month for the drug and an additional $250 every three months for lab work and clinic visits.

Luckily for Howard, his doctor at Las Vegas’ Huntridge Family Clinic, which specializes in LGBTQ care, enrolled him in a clinical trial that covered his medication and other costs in full.

“If I hadn’t been able to get into the trial, I wouldn’t have kept taking PrEP,” said Howard, 68, using the shorthand term for “preexposure prophylaxis.” Taken daily, these drugs — like Truvada — are more than 90% effective at preventing infection with HIV.

Starting in January of 2021, most people with private insurance will no longer have to decide whether they can afford to protect themselves against HIV. Most health plans must begin to cover the drugs then without charging consumers anything out-of-pocket (some plans already began doing so last year).

Drugs in this category — Truvada, Descovy and, newly available, a generic version of Truvada — received an “A” recommendation by the U.S. Preventive Services Task Force. Under the Affordable Care Act, preventive services that receive an “A” or “B” rating by the task force, a group of medical experts in prevention and primary care, must be covered by most private health plans without making members share the cost, usually through copayments or deductibles. Only plans that are grandfathered under the health law are exempt.

The task force recommended PrEP for people at high risk of HIV infection, including men who have sex with men and injection drug users.

In the United States, more than 1 million people live with HIV, and nearly 40,000 new HIV cases are diagnosed every year. Yet fewer than 10% of people who could benefit from PrEP are taking it. One key reason is that out-of-pocket costs can exceed $1,000 annually, according to a study published in the American Journal of Public Health last year. Required periodic blood tests and doctor visits can add hundreds of dollars to the cost of the drug, and it’s not clear if insurers are required to pick up all those costs.

“Cost sharing has been a problem,” said Michael Crews, policy director at One Colorado, an advocacy group for the LGBTQ community. “It’s not just getting on PrEP and taking a pill. It’s the lab and clinical services. That’s a huge barrier for folks.”

Whether you’re shopping for a new plan during open enrollment or want to check out what your current plan covers, here are answers to questions you may have about the new preventive coverage requirement.
 

Q: How can people find out whether their health plan covers PrEP medications without charge?

The plan’s list of covered drugs, called a formulary, should spell out which drugs are covered, along with details about which drug tier they fall into. Drugs placed in higher tiers generally have higher cost sharing. That list should be online with the plan documents that give coverage details.

Sorting out coverage and cost sharing can be tricky. Both Truvada and Descovy can also be used to treat HIV, and if they are taken for that purpose, a plan may require members to pay some of the cost. But if the drugs are taken to prevent HIV infection, patients shouldn’t owe anything out-of-pocket, no matter which tier they are on.

In a recent analysis of online formularies for plans sold on the ACA marketplaces, Carl Schmid, executive director of the HIV + Hepatitis Policy Institute, found that many plans seemed out of compliance with the requirement to cover PrEP without cost sharing this year.

But representatives for Oscar and Kaiser Permanente, two insurers that were called out in the analysis for lack of compliance, said the drugs are covered without cost sharing in plans nationwide if they are taken to prevent HIV. Schmid later revised his analysis to reflect Oscar’s coverage.

Coverage and cost-sharing information needs to be transparent and easy to find, Schmid said.

“I acted like a shopper of insurance, just like any person would do,” he said. “Even when the information is correct, [it’s so] difficult to find [and there’s] no uniformity.”

It may be necessary to call the insurer directly to confirm coverage details if information on the website is unclear.
 

Q: Are all three drugs covered without cost sharing?

Health plans have to cover at least one of the drugs in this category — Descovy and the brand and generic versions of Truvada — without cost sharing. People may have to jump through some hoops to get approval for a specific drug, however. For example, Oscar plans sold in 18 states cover the three PrEP options without cost sharing. The generic version of Truvada doesn’t require prior authorization by the insurer. But if someone wants to take the name-brand drug, that person has to go through an approval process. Descovy, a newer drug, is available without cost sharing only if people are unable to use Truvada or its generic version because of clinical intolerance or other issues.
 

Q: What about the lab work and clinical visits that are necessary while taking PrEP? Are those services also covered without cost sharing?

That is the thousand-dollar question. People who are taking drugs to prevent HIV infection need to meet with a clinician and have blood work every three months to test for HIV, hepatitis B and sexually transmitted infections, and to check their kidney function.

The task force recommendation doesn’t specify whether these services must also be covered without cost sharing, and advocates say federal guidance is necessary to ensure they are free.

“If you’ve got a high-deductible plan and you’ve got to meet it before those services are covered, that’s going to add up,” said Amy Killelea, senior director of health systems and policy at the National Alliance of State & Territorial AIDS Directors. “We’re trying to emphasize that it’s integral to the intervention itself.”

A handful of states have programs that help people cover their out-of-pocket costs for lab and clinical visits, generally based on income.

There is precedent for including free ancillary care as part of a recommended preventive service. After consumers and advocates complained, the Centers for Medicare & Medicaid Services (CMS) clarified that under the ACA removing a polyp during a screening colonoscopy is considered an integral part of the procedure and patients shouldn’t be charged for it.

CMS officials declined to clarify whether PrEP services such as lab work and clinical visits are to be covered without cost sharing as part of the preventive service and noted that states generally enforce such insurance requirements. “CMS intends to contact state regulators, as appropriate, to discuss issuer’s compliance with the federal requirements and whether issuers need further guidance on which services associated with PrEP must be covered without cost sharing,” the agency said in a statement.
 

Q: What if someone runs into roadblocks getting a plan to cover PrEP or related services without cost sharing?

If an insurer charges for the medication or a follow-up visit, people may have to go through an appeals process to fight it.

“They’d have to appeal to the insurance company and then to the state if they don’t succeed,” said Nadeen Israel, vice president of policy and advocacy at the AIDS Foundation of Chicago. “Most people don’t know to do that.”
 

Q: Are uninsured people also protected by this new cost-sharing change for PrEP?

Unfortunately, no. The ACA requirement to cover recommended preventive services without charging patients applies only to private insurance plans. People without insurance don’t benefit. Gilead, which makes both Truvada and Descovy, has a patient assistance program for the uninsured.
 

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of Kaiser Family Foundation, which is not affiliated with Kaiser Permanente.

The role of imaging in diagnosing progressive multiple sclerosis (MS) and in assessing prognosis is the subject of a new review.

MRI is central in the diagnostic work-up of patients suspected of having MS, given its high sensitivity in detecting disease dissemination in space and over time and its notable ability to exclude mimics of MS, the authors noted. However, diagnosis of primary progressive MS remains challenging and is only possible retrospectively on the basis of clinical assessment.

Identification of imaging features associated with primary progressive MS and features that predict evolution from relapsing remitting MS to secondary progressive MS is an important, unmet need, they wrote.

Diagnosis of progressive MS is limited by difficulties in distinguishing accumulating disability caused by inflammatory disease activity from that attributable to degenerative processes associated with secondary progressive MS. Moreover, there are no accepted clinical criteria for diagnosing secondary progressive MS, the authors explained.

This need has promoted extensive research in the field of imaging, facilitated by definition of novel MRI sequences, to identify imaging features reflecting pathophysiological mechanisms relevant to the pathobiology of progressive MS, the authors said.

The current review reports the conclusions of a workshop held in Milan in November 2019, at which an expert panel of neurologists and neuroradiologists addressed the role of MRI in progressive MS.

Massimo Filippi, MD, IRCCS San Raffaele Scientific Institute, Milan, was the lead author of the review, which was published online Dec. 14, 2020, in JAMA Neurology.

The authors concluded that no definitive, qualitative clinical, immunologic, histopathologic, or neuroimaging features differentiate primary progressive and secondary progressive forms of MS; both are characterized by neurodegenerative phenomena and a gradual and irreversible accumulation of clinical disability, which is also affected by aging and comorbidities.

A definitive diagnosis of primary progressive MS is more difficult than a diagnosis of relapsing remitting MS; in part, primary progressive MS is a diagnosis of exclusion because it can be mimicked by other conditions clinically and radiologically, the authors noted.

The writers did report that, although nonspecific, some spinal cord imaging features are typical of primary progressive MS. These include diffuse abnormalities and lesions involving gray matter and two or more white-matter columns, but confirmation of this is required.

In patients with primary progressive MS and those with relapse-onset MS, MRI features at disease onset predict long-term disability and a progressive disease course. These features include lesions in critical central nervous system regions (i.e., spinal cord, infratentorial regions, and gray matter) and high inflammatory activity in the first years after disease onset. These measures are evaluable in clinical practice, the authors said.

In patients with established MS, gray-matter involvement and neurodegeneration are associated with accelerated clinical worsening; however, detection validation and standardization need to be implemented at the individual patient level, they commented.

Novel candidate imaging biomarkers, such as subpial demyelination, and the presence of slowly expanding lesions or paramagnetic rim lesions may identify progressive MS but should be further investigated, they added.

Discovery of MRI markers capable of detecting evolution from relapsing-remitting to secondary progressive MS remains an unmet need that will probably require multiparametric MRI studies, because it is unlikely that a single MRI method will be able to allow clinicians to optimally distinguish among these stages, the authors said.

The contribution of these promising MRI measures combined with other biomarkers, such as quantification of serum neurofilament light chain levels or optical coherence tomography assessment, should be explored to improve the identification of patients with progressive MS, they concluded.
 

‘A comprehensive review’

In a comment, Jeffrey A. Cohen, MD, director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research, said the article is a comprehensive review of the pathologic mechanisms that underlie progression in MS and the proxy measures of those processes (brain and spinal cord MRI, PET, optical coherence tomography, and biomarkers).

“The paper reports there is no qualitative difference between relapsing remitting and progressive MS; rather, the difference is quantitative,” Dr. Cohen noted. “In other words, the processes that underlie progression are present from the earliest stages of MS, becoming more prominent over time.”

The apparent transition to progressive MS, he added, “rather than representing a ‘transition,’ instead results from the accumulation of pathology over time, a shift from focal lesions to diffuse inflammation and damage, and unmasking of the damage due to decreased resiliency due to aging and failure of compensatory mechanisms (neuroplasticity and remyelination).”

Also commenting, Edward Fox, MD, director, MS Clinic of Central Texas and clinical associate professor, University of Texas, Austin, explained that loss of tissue is the main driver of progressive MS.

“We all look at imaging to confirm that the progressive symptoms expressed by the patient are related to demyelinating disease,” he said. “When I see MRI of the spinal cord showing multifocal lesions, especially if localized atrophy is seen in a region of the cord, I expect to hear a history of progressive deficits in gait and other signs of disability.”

Dr. Fox noted that, on MRI of the brain, gray matter atrophy both cortically and in the deep gray structures usually manifests as cognitive slowing and poorer performance in work and social situations.

“We hope that other biomarkers, such as neurofilament light chain, will add to this body of knowledge and give us a better grasp of the definition of neurodegeneration to confirm the clinical and radiographic findings,” he added.

Dr. Filippi has received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi, Genzyme, Takeda, and Teva Pharmaceutical Industries; and research support from ARiSLA, Biogen Idec, Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Merck Serono, Novartis, Roche, and Teva.

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

The role of imaging in diagnosing progressive multiple sclerosis (MS) and in assessing prognosis is the subject of a new review.

MRI is central in the diagnostic work-up of patients suspected of having MS, given its high sensitivity in detecting disease dissemination in space and over time and its notable ability to exclude mimics of MS, the authors noted. However, diagnosis of primary progressive MS remains challenging and is only possible retrospectively on the basis of clinical assessment.

Identification of imaging features associated with primary progressive MS and features that predict evolution from relapsing remitting MS to secondary progressive MS is an important, unmet need, they wrote.

Diagnosis of progressive MS is limited by difficulties in distinguishing accumulating disability caused by inflammatory disease activity from that attributable to degenerative processes associated with secondary progressive MS. Moreover, there are no accepted clinical criteria for diagnosing secondary progressive MS, the authors explained.

This need has promoted extensive research in the field of imaging, facilitated by definition of novel MRI sequences, to identify imaging features reflecting pathophysiological mechanisms relevant to the pathobiology of progressive MS, the authors said.

The current review reports the conclusions of a workshop held in Milan in November 2019, at which an expert panel of neurologists and neuroradiologists addressed the role of MRI in progressive MS.

Massimo Filippi, MD, IRCCS San Raffaele Scientific Institute, Milan, was the lead author of the review, which was published online Dec. 14, 2020, in JAMA Neurology.

The authors concluded that no definitive, qualitative clinical, immunologic, histopathologic, or neuroimaging features differentiate primary progressive and secondary progressive forms of MS; both are characterized by neurodegenerative phenomena and a gradual and irreversible accumulation of clinical disability, which is also affected by aging and comorbidities.

A definitive diagnosis of primary progressive MS is more difficult than a diagnosis of relapsing remitting MS; in part, primary progressive MS is a diagnosis of exclusion because it can be mimicked by other conditions clinically and radiologically, the authors noted.

The writers did report that, although nonspecific, some spinal cord imaging features are typical of primary progressive MS. These include diffuse abnormalities and lesions involving gray matter and two or more white-matter columns, but confirmation of this is required.

In patients with primary progressive MS and those with relapse-onset MS, MRI features at disease onset predict long-term disability and a progressive disease course. These features include lesions in critical central nervous system regions (i.e., spinal cord, infratentorial regions, and gray matter) and high inflammatory activity in the first years after disease onset. These measures are evaluable in clinical practice, the authors said.

In patients with established MS, gray-matter involvement and neurodegeneration are associated with accelerated clinical worsening; however, detection validation and standardization need to be implemented at the individual patient level, they commented.

Novel candidate imaging biomarkers, such as subpial demyelination, and the presence of slowly expanding lesions or paramagnetic rim lesions may identify progressive MS but should be further investigated, they added.

Discovery of MRI markers capable of detecting evolution from relapsing-remitting to secondary progressive MS remains an unmet need that will probably require multiparametric MRI studies, because it is unlikely that a single MRI method will be able to allow clinicians to optimally distinguish among these stages, the authors said.

The contribution of these promising MRI measures combined with other biomarkers, such as quantification of serum neurofilament light chain levels or optical coherence tomography assessment, should be explored to improve the identification of patients with progressive MS, they concluded.
 

‘A comprehensive review’

In a comment, Jeffrey A. Cohen, MD, director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research, said the article is a comprehensive review of the pathologic mechanisms that underlie progression in MS and the proxy measures of those processes (brain and spinal cord MRI, PET, optical coherence tomography, and biomarkers).

“The paper reports there is no qualitative difference between relapsing remitting and progressive MS; rather, the difference is quantitative,” Dr. Cohen noted. “In other words, the processes that underlie progression are present from the earliest stages of MS, becoming more prominent over time.”

The apparent transition to progressive MS, he added, “rather than representing a ‘transition,’ instead results from the accumulation of pathology over time, a shift from focal lesions to diffuse inflammation and damage, and unmasking of the damage due to decreased resiliency due to aging and failure of compensatory mechanisms (neuroplasticity and remyelination).”

Also commenting, Edward Fox, MD, director, MS Clinic of Central Texas and clinical associate professor, University of Texas, Austin, explained that loss of tissue is the main driver of progressive MS.

“We all look at imaging to confirm that the progressive symptoms expressed by the patient are related to demyelinating disease,” he said. “When I see MRI of the spinal cord showing multifocal lesions, especially if localized atrophy is seen in a region of the cord, I expect to hear a history of progressive deficits in gait and other signs of disability.”

Dr. Fox noted that, on MRI of the brain, gray matter atrophy both cortically and in the deep gray structures usually manifests as cognitive slowing and poorer performance in work and social situations.

“We hope that other biomarkers, such as neurofilament light chain, will add to this body of knowledge and give us a better grasp of the definition of neurodegeneration to confirm the clinical and radiographic findings,” he added.

Dr. Filippi has received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi, Genzyme, Takeda, and Teva Pharmaceutical Industries; and research support from ARiSLA, Biogen Idec, Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Merck Serono, Novartis, Roche, and Teva.

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

The role of imaging in diagnosing progressive multiple sclerosis (MS) and in assessing prognosis is the subject of a new review.

MRI is central in the diagnostic work-up of patients suspected of having MS, given its high sensitivity in detecting disease dissemination in space and over time and its notable ability to exclude mimics of MS, the authors noted. However, diagnosis of primary progressive MS remains challenging and is only possible retrospectively on the basis of clinical assessment.

Identification of imaging features associated with primary progressive MS and features that predict evolution from relapsing remitting MS to secondary progressive MS is an important, unmet need, they wrote.

Diagnosis of progressive MS is limited by difficulties in distinguishing accumulating disability caused by inflammatory disease activity from that attributable to degenerative processes associated with secondary progressive MS. Moreover, there are no accepted clinical criteria for diagnosing secondary progressive MS, the authors explained.

This need has promoted extensive research in the field of imaging, facilitated by definition of novel MRI sequences, to identify imaging features reflecting pathophysiological mechanisms relevant to the pathobiology of progressive MS, the authors said.

The current review reports the conclusions of a workshop held in Milan in November 2019, at which an expert panel of neurologists and neuroradiologists addressed the role of MRI in progressive MS.

Massimo Filippi, MD, IRCCS San Raffaele Scientific Institute, Milan, was the lead author of the review, which was published online Dec. 14, 2020, in JAMA Neurology.

The authors concluded that no definitive, qualitative clinical, immunologic, histopathologic, or neuroimaging features differentiate primary progressive and secondary progressive forms of MS; both are characterized by neurodegenerative phenomena and a gradual and irreversible accumulation of clinical disability, which is also affected by aging and comorbidities.

A definitive diagnosis of primary progressive MS is more difficult than a diagnosis of relapsing remitting MS; in part, primary progressive MS is a diagnosis of exclusion because it can be mimicked by other conditions clinically and radiologically, the authors noted.

The writers did report that, although nonspecific, some spinal cord imaging features are typical of primary progressive MS. These include diffuse abnormalities and lesions involving gray matter and two or more white-matter columns, but confirmation of this is required.

In patients with primary progressive MS and those with relapse-onset MS, MRI features at disease onset predict long-term disability and a progressive disease course. These features include lesions in critical central nervous system regions (i.e., spinal cord, infratentorial regions, and gray matter) and high inflammatory activity in the first years after disease onset. These measures are evaluable in clinical practice, the authors said.

In patients with established MS, gray-matter involvement and neurodegeneration are associated with accelerated clinical worsening; however, detection validation and standardization need to be implemented at the individual patient level, they commented.

Novel candidate imaging biomarkers, such as subpial demyelination, and the presence of slowly expanding lesions or paramagnetic rim lesions may identify progressive MS but should be further investigated, they added.

Discovery of MRI markers capable of detecting evolution from relapsing-remitting to secondary progressive MS remains an unmet need that will probably require multiparametric MRI studies, because it is unlikely that a single MRI method will be able to allow clinicians to optimally distinguish among these stages, the authors said.

The contribution of these promising MRI measures combined with other biomarkers, such as quantification of serum neurofilament light chain levels or optical coherence tomography assessment, should be explored to improve the identification of patients with progressive MS, they concluded.
 

‘A comprehensive review’

In a comment, Jeffrey A. Cohen, MD, director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research, said the article is a comprehensive review of the pathologic mechanisms that underlie progression in MS and the proxy measures of those processes (brain and spinal cord MRI, PET, optical coherence tomography, and biomarkers).

“The paper reports there is no qualitative difference between relapsing remitting and progressive MS; rather, the difference is quantitative,” Dr. Cohen noted. “In other words, the processes that underlie progression are present from the earliest stages of MS, becoming more prominent over time.”

The apparent transition to progressive MS, he added, “rather than representing a ‘transition,’ instead results from the accumulation of pathology over time, a shift from focal lesions to diffuse inflammation and damage, and unmasking of the damage due to decreased resiliency due to aging and failure of compensatory mechanisms (neuroplasticity and remyelination).”

Also commenting, Edward Fox, MD, director, MS Clinic of Central Texas and clinical associate professor, University of Texas, Austin, explained that loss of tissue is the main driver of progressive MS.

“We all look at imaging to confirm that the progressive symptoms expressed by the patient are related to demyelinating disease,” he said. “When I see MRI of the spinal cord showing multifocal lesions, especially if localized atrophy is seen in a region of the cord, I expect to hear a history of progressive deficits in gait and other signs of disability.”

Dr. Fox noted that, on MRI of the brain, gray matter atrophy both cortically and in the deep gray structures usually manifests as cognitive slowing and poorer performance in work and social situations.

“We hope that other biomarkers, such as neurofilament light chain, will add to this body of knowledge and give us a better grasp of the definition of neurodegeneration to confirm the clinical and radiographic findings,” he added.

Dr. Filippi has received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi, Genzyme, Takeda, and Teva Pharmaceutical Industries; and research support from ARiSLA, Biogen Idec, Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health, Merck Serono, Novartis, Roche, and Teva.

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

Researchers in Italy have identified microplastic (MP) fragments in four human placentas that were donated for study after delivery.

curtoicurto/Getty Images

“The presence of MPs in the placenta tissue requires the reconsideration of the immunological mechanism of self-tolerance,” wrote Antonio Ragusa, MD, of San Giovanni Calibita Fatebenefratelli Hospital, Rome, and colleagues. “Placenta represents the interface between the fetus and the environment.”

In a pilot observational study published in Environment International, the researchers used Raman microspectroscopy to analyze placentas from six women with physiological pregnancies for the presence of MPs. MPs were defined as particles smaller than 5 mm resulting from the degradation of plastic in the environment, such as plastic objects, coatings, adhesives, paints, and personal care products. Data from previous studies have shown that MPs can move into living organisms, but this study is the first to identify MPs in human placentas, the researchers said.
 

Polypropylene and pigments identified

A total of 12 microplastic fragments were identified in tissue from the placentas of four women; 5 in the fetal side, 4 in the maternal side, and 3 in the chorioamniotic membranes, which suggests that MPs can reach all levels of placental tissue, the researchers said. Most of the MPs were approximately 10 mcm in size, but two were roughly 5 mcm.

All 12 of the MPs were pigmented; of these, 3 were identified as stained polypropylene and the other 9 contained pigments used in a variety of items including coatings, paints, adhesives, plasters, finger paints, polymers and cosmetics, and personal care products. The researchers used a software program to analyze the pigments and matched them with information from the European Chemical Agency for identification of the commercial name, chemical formula, International Union of Pure and Applied Chemistry name, and Color Index Constitution Number.

The mechanism by which MPs may enter the bloodstream and access the placenta remains unclear, the researchers said. “The most probable transport route for MPs is a mechanism of particle uptake and translocation, already described for the internalization from the gastrointestinal tract. Once MPs have reached the maternal surface of the placenta, as other exogenous materials, they can invade the tissue in depth by several transport mechanisms, both active and passive, that are not clearly understood yet.”

The range in location and characteristics of the particles found in the study suggest that passage of MPs into the placenta may be affected by physiological conditions and genetics, as well as food and lifestyle habits of the patients, the researchers said.

The study findings were limited by several factors including the small sample size and observational study design.

However, the presence of MPs in the placenta could affect the pregnancy in various ways, including immunity, growth factor signaling, maternal-fetal communication, and trafficking of various cell types and macrophages, the researchers wrote. In addition, MPs could have a transgenerational effect on metabolism and reproduction.

“Further studies need to be performed to assess if the presence of MPs in human placenta may trigger immune responses or may lead to the release of toxic contaminants, resulting harmful for pregnancy,” they concluded.
 

Cause for concern, but research gaps remain

“Microplastics are ubiquitous in the environment and are detectable in tissues of humans and wildlife,” Andrea C. Gore, PhD, of the University of Texas, Austin, said in an interview. “To my knowledge, this was never previously shown in the placenta.

“There are two reasons why detection of microplastics in placenta would be concerning,” Dr. Gore explained. “First, microplastics may be endocrine-disrupting chemicals (EDCs), or they may concentrate other chemicals that are EDCs. Second, the developing fetus is exquisitely sensitive to natural hormones, and disruptions by EDCs may lead to both immediate as well as latent health problems.

“Clinicians should be concerned about particulate matter in the placenta, “although the number of particles was very small,” said Dr. Gore. “Out of six women, four had particles in their placentas (total of 12) of which one was confirmed to be a plastic (polypropylene). For the other 11 particles, only the pigments could be identified, so more work is needed to confirm whether they were plastics.

“If I were a clinician discussing this article with my patients, I would point out that, although it is concerning that microparticles are present in placenta, few of them were found, and it is not known whether any chemical is released from the particles or actually reaches the fetal circulation,” Dr. Gore said. “I would use it as a starting point for a conversation about lifestyle during pregnancy and encouraging pregnant women to avoid eating foods stored and/or prepared in plastics.”

The limitations of the study include not only the small sample size, but also that “the type of chemicals in the microplastics is for the most part unknown, making it difficult to assess which (if any) might be EDCs,” Dr. Gore emphasized. In addition, “lifestyle and diet can greatly affect exposures to chemicals, so this needs to be carefully factored into the analysis.” Also, “most of the detected particles are pigments, so connections to plastics (other than the one polypropylene particle) need to be strengthened,” she explained.

“The pathways by which microplastics might get into tissues are still rather speculative, and the mechanisms proposed by the authors (endocytosis, paracellular diffusion, entry via airways) need to be demonstrated,” Dr. Gore concluded.

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

SOURCE: Ragusa A et al. Environ Int. 2020 Dec 2. doi: 10.1016/j.envint.2020.106274.

Researchers in Italy have identified microplastic (MP) fragments in four human placentas that were donated for study after delivery.

curtoicurto/Getty Images

“The presence of MPs in the placenta tissue requires the reconsideration of the immunological mechanism of self-tolerance,” wrote Antonio Ragusa, MD, of San Giovanni Calibita Fatebenefratelli Hospital, Rome, and colleagues. “Placenta represents the interface between the fetus and the environment.”

In a pilot observational study published in Environment International, the researchers used Raman microspectroscopy to analyze placentas from six women with physiological pregnancies for the presence of MPs. MPs were defined as particles smaller than 5 mm resulting from the degradation of plastic in the environment, such as plastic objects, coatings, adhesives, paints, and personal care products. Data from previous studies have shown that MPs can move into living organisms, but this study is the first to identify MPs in human placentas, the researchers said.
 

Polypropylene and pigments identified

A total of 12 microplastic fragments were identified in tissue from the placentas of four women; 5 in the fetal side, 4 in the maternal side, and 3 in the chorioamniotic membranes, which suggests that MPs can reach all levels of placental tissue, the researchers said. Most of the MPs were approximately 10 mcm in size, but two were roughly 5 mcm.

All 12 of the MPs were pigmented; of these, 3 were identified as stained polypropylene and the other 9 contained pigments used in a variety of items including coatings, paints, adhesives, plasters, finger paints, polymers and cosmetics, and personal care products. The researchers used a software program to analyze the pigments and matched them with information from the European Chemical Agency for identification of the commercial name, chemical formula, International Union of Pure and Applied Chemistry name, and Color Index Constitution Number.

The mechanism by which MPs may enter the bloodstream and access the placenta remains unclear, the researchers said. “The most probable transport route for MPs is a mechanism of particle uptake and translocation, already described for the internalization from the gastrointestinal tract. Once MPs have reached the maternal surface of the placenta, as other exogenous materials, they can invade the tissue in depth by several transport mechanisms, both active and passive, that are not clearly understood yet.”

The range in location and characteristics of the particles found in the study suggest that passage of MPs into the placenta may be affected by physiological conditions and genetics, as well as food and lifestyle habits of the patients, the researchers said.

The study findings were limited by several factors including the small sample size and observational study design.

However, the presence of MPs in the placenta could affect the pregnancy in various ways, including immunity, growth factor signaling, maternal-fetal communication, and trafficking of various cell types and macrophages, the researchers wrote. In addition, MPs could have a transgenerational effect on metabolism and reproduction.

“Further studies need to be performed to assess if the presence of MPs in human placenta may trigger immune responses or may lead to the release of toxic contaminants, resulting harmful for pregnancy,” they concluded.
 

Cause for concern, but research gaps remain

“Microplastics are ubiquitous in the environment and are detectable in tissues of humans and wildlife,” Andrea C. Gore, PhD, of the University of Texas, Austin, said in an interview. “To my knowledge, this was never previously shown in the placenta.

“There are two reasons why detection of microplastics in placenta would be concerning,” Dr. Gore explained. “First, microplastics may be endocrine-disrupting chemicals (EDCs), or they may concentrate other chemicals that are EDCs. Second, the developing fetus is exquisitely sensitive to natural hormones, and disruptions by EDCs may lead to both immediate as well as latent health problems.

“Clinicians should be concerned about particulate matter in the placenta, “although the number of particles was very small,” said Dr. Gore. “Out of six women, four had particles in their placentas (total of 12) of which one was confirmed to be a plastic (polypropylene). For the other 11 particles, only the pigments could be identified, so more work is needed to confirm whether they were plastics.

“If I were a clinician discussing this article with my patients, I would point out that, although it is concerning that microparticles are present in placenta, few of them were found, and it is not known whether any chemical is released from the particles or actually reaches the fetal circulation,” Dr. Gore said. “I would use it as a starting point for a conversation about lifestyle during pregnancy and encouraging pregnant women to avoid eating foods stored and/or prepared in plastics.”

The limitations of the study include not only the small sample size, but also that “the type of chemicals in the microplastics is for the most part unknown, making it difficult to assess which (if any) might be EDCs,” Dr. Gore emphasized. In addition, “lifestyle and diet can greatly affect exposures to chemicals, so this needs to be carefully factored into the analysis.” Also, “most of the detected particles are pigments, so connections to plastics (other than the one polypropylene particle) need to be strengthened,” she explained.

“The pathways by which microplastics might get into tissues are still rather speculative, and the mechanisms proposed by the authors (endocytosis, paracellular diffusion, entry via airways) need to be demonstrated,” Dr. Gore concluded.

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

SOURCE: Ragusa A et al. Environ Int. 2020 Dec 2. doi: 10.1016/j.envint.2020.106274.

Researchers in Italy have identified microplastic (MP) fragments in four human placentas that were donated for study after delivery.

curtoicurto/Getty Images

“The presence of MPs in the placenta tissue requires the reconsideration of the immunological mechanism of self-tolerance,” wrote Antonio Ragusa, MD, of San Giovanni Calibita Fatebenefratelli Hospital, Rome, and colleagues. “Placenta represents the interface between the fetus and the environment.”

In a pilot observational study published in Environment International, the researchers used Raman microspectroscopy to analyze placentas from six women with physiological pregnancies for the presence of MPs. MPs were defined as particles smaller than 5 mm resulting from the degradation of plastic in the environment, such as plastic objects, coatings, adhesives, paints, and personal care products. Data from previous studies have shown that MPs can move into living organisms, but this study is the first to identify MPs in human placentas, the researchers said.
 

Polypropylene and pigments identified

A total of 12 microplastic fragments were identified in tissue from the placentas of four women; 5 in the fetal side, 4 in the maternal side, and 3 in the chorioamniotic membranes, which suggests that MPs can reach all levels of placental tissue, the researchers said. Most of the MPs were approximately 10 mcm in size, but two were roughly 5 mcm.

All 12 of the MPs were pigmented; of these, 3 were identified as stained polypropylene and the other 9 contained pigments used in a variety of items including coatings, paints, adhesives, plasters, finger paints, polymers and cosmetics, and personal care products. The researchers used a software program to analyze the pigments and matched them with information from the European Chemical Agency for identification of the commercial name, chemical formula, International Union of Pure and Applied Chemistry name, and Color Index Constitution Number.

The mechanism by which MPs may enter the bloodstream and access the placenta remains unclear, the researchers said. “The most probable transport route for MPs is a mechanism of particle uptake and translocation, already described for the internalization from the gastrointestinal tract. Once MPs have reached the maternal surface of the placenta, as other exogenous materials, they can invade the tissue in depth by several transport mechanisms, both active and passive, that are not clearly understood yet.”

The range in location and characteristics of the particles found in the study suggest that passage of MPs into the placenta may be affected by physiological conditions and genetics, as well as food and lifestyle habits of the patients, the researchers said.

The study findings were limited by several factors including the small sample size and observational study design.

However, the presence of MPs in the placenta could affect the pregnancy in various ways, including immunity, growth factor signaling, maternal-fetal communication, and trafficking of various cell types and macrophages, the researchers wrote. In addition, MPs could have a transgenerational effect on metabolism and reproduction.

“Further studies need to be performed to assess if the presence of MPs in human placenta may trigger immune responses or may lead to the release of toxic contaminants, resulting harmful for pregnancy,” they concluded.
 

Cause for concern, but research gaps remain

“Microplastics are ubiquitous in the environment and are detectable in tissues of humans and wildlife,” Andrea C. Gore, PhD, of the University of Texas, Austin, said in an interview. “To my knowledge, this was never previously shown in the placenta.

“There are two reasons why detection of microplastics in placenta would be concerning,” Dr. Gore explained. “First, microplastics may be endocrine-disrupting chemicals (EDCs), or they may concentrate other chemicals that are EDCs. Second, the developing fetus is exquisitely sensitive to natural hormones, and disruptions by EDCs may lead to both immediate as well as latent health problems.

“Clinicians should be concerned about particulate matter in the placenta, “although the number of particles was very small,” said Dr. Gore. “Out of six women, four had particles in their placentas (total of 12) of which one was confirmed to be a plastic (polypropylene). For the other 11 particles, only the pigments could be identified, so more work is needed to confirm whether they were plastics.

“If I were a clinician discussing this article with my patients, I would point out that, although it is concerning that microparticles are present in placenta, few of them were found, and it is not known whether any chemical is released from the particles or actually reaches the fetal circulation,” Dr. Gore said. “I would use it as a starting point for a conversation about lifestyle during pregnancy and encouraging pregnant women to avoid eating foods stored and/or prepared in plastics.”

The limitations of the study include not only the small sample size, but also that “the type of chemicals in the microplastics is for the most part unknown, making it difficult to assess which (if any) might be EDCs,” Dr. Gore emphasized. In addition, “lifestyle and diet can greatly affect exposures to chemicals, so this needs to be carefully factored into the analysis.” Also, “most of the detected particles are pigments, so connections to plastics (other than the one polypropylene particle) need to be strengthened,” she explained.

“The pathways by which microplastics might get into tissues are still rather speculative, and the mechanisms proposed by the authors (endocytosis, paracellular diffusion, entry via airways) need to be demonstrated,” Dr. Gore concluded.

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

SOURCE: Ragusa A et al. Environ Int. 2020 Dec 2. doi: 10.1016/j.envint.2020.106274.

The first month of the coronavirus pandemic created almost as much psychological distress among American adults as they had experienced in the year before February 2019, according to the results of two representative surveys.

“The 30-day prevalence of SD [serious distress] in May 2020 did not differ from the past-year prevalence of SD assessed with the same instrument [the Kessler-6 distress scale] in February 2019. In other words, equal numbers of people experienced SD in 30-days during the pandemic as experienced SD over an entire year prior to the pandemic,” Joshua Breslau, PhD, and associates at the Rand Corporation wrote in Preventive Medicine.

In May of 2020, the prevalence of SD was 10.1% in the previous month among 1,870 adults aged 20 years and older who had participated in the two Rand American Life Panel surveys, the first occurring in February 2019. In that earlier poll, 10.9% of the 2,555 respondents said that they experienced SD in the worst month of the previous year, the investigators said.

The prevalence of overall psychological distress increased by 12.8% from February 2019 to May 2020, with increases higher among women (17.7%) than men (10.6%); adults under age 60 years, compared with those over 60 (see graph); and Hispanics, compared with other races/ethnicities. Disparities also were seen among income groups: Distress rose 10.2% for those earning over $100,000, compared with 15.4% for those making less than $35,000 and 18.2% for Americans earning between $35,000 and $60,000, the researchers reported.

A high level of stress in the prepandemic survey strongly predicted serious distress during the pandemic. “Risk for SD during the pandemic among those with SD during a year before the pandemic was almost 3 times higher than among those reporting mild/moderate distress and 15 times higher than among those reporting no/low distress during the prepandemic year,” they noted.

Distress levels often return to normal after a disaster, Dr. Breslau and associates pointed out, but “the pandemic’s influence on economic stressors, disruption of usual activities and subsequent effects on population health may continue for an extended period and affect different regions of the country at different points in time.”

[email protected]

SOURCE: Breslau J et al. Prev Med. 2020 Dec 31. doi: 10.1016/j.ypmed.2020.106362.

The first month of the coronavirus pandemic created almost as much psychological distress among American adults as they had experienced in the year before February 2019, according to the results of two representative surveys.

“The 30-day prevalence of SD [serious distress] in May 2020 did not differ from the past-year prevalence of SD assessed with the same instrument [the Kessler-6 distress scale] in February 2019. In other words, equal numbers of people experienced SD in 30-days during the pandemic as experienced SD over an entire year prior to the pandemic,” Joshua Breslau, PhD, and associates at the Rand Corporation wrote in Preventive Medicine.

In May of 2020, the prevalence of SD was 10.1% in the previous month among 1,870 adults aged 20 years and older who had participated in the two Rand American Life Panel surveys, the first occurring in February 2019. In that earlier poll, 10.9% of the 2,555 respondents said that they experienced SD in the worst month of the previous year, the investigators said.

The prevalence of overall psychological distress increased by 12.8% from February 2019 to May 2020, with increases higher among women (17.7%) than men (10.6%); adults under age 60 years, compared with those over 60 (see graph); and Hispanics, compared with other races/ethnicities. Disparities also were seen among income groups: Distress rose 10.2% for those earning over $100,000, compared with 15.4% for those making less than $35,000 and 18.2% for Americans earning between $35,000 and $60,000, the researchers reported.

A high level of stress in the prepandemic survey strongly predicted serious distress during the pandemic. “Risk for SD during the pandemic among those with SD during a year before the pandemic was almost 3 times higher than among those reporting mild/moderate distress and 15 times higher than among those reporting no/low distress during the prepandemic year,” they noted.

Distress levels often return to normal after a disaster, Dr. Breslau and associates pointed out, but “the pandemic’s influence on economic stressors, disruption of usual activities and subsequent effects on population health may continue for an extended period and affect different regions of the country at different points in time.”

[email protected]

SOURCE: Breslau J et al. Prev Med. 2020 Dec 31. doi: 10.1016/j.ypmed.2020.106362.

The first month of the coronavirus pandemic created almost as much psychological distress among American adults as they had experienced in the year before February 2019, according to the results of two representative surveys.

“The 30-day prevalence of SD [serious distress] in May 2020 did not differ from the past-year prevalence of SD assessed with the same instrument [the Kessler-6 distress scale] in February 2019. In other words, equal numbers of people experienced SD in 30-days during the pandemic as experienced SD over an entire year prior to the pandemic,” Joshua Breslau, PhD, and associates at the Rand Corporation wrote in Preventive Medicine.

In May of 2020, the prevalence of SD was 10.1% in the previous month among 1,870 adults aged 20 years and older who had participated in the two Rand American Life Panel surveys, the first occurring in February 2019. In that earlier poll, 10.9% of the 2,555 respondents said that they experienced SD in the worst month of the previous year, the investigators said.

The prevalence of overall psychological distress increased by 12.8% from February 2019 to May 2020, with increases higher among women (17.7%) than men (10.6%); adults under age 60 years, compared with those over 60 (see graph); and Hispanics, compared with other races/ethnicities. Disparities also were seen among income groups: Distress rose 10.2% for those earning over $100,000, compared with 15.4% for those making less than $35,000 and 18.2% for Americans earning between $35,000 and $60,000, the researchers reported.

A high level of stress in the prepandemic survey strongly predicted serious distress during the pandemic. “Risk for SD during the pandemic among those with SD during a year before the pandemic was almost 3 times higher than among those reporting mild/moderate distress and 15 times higher than among those reporting no/low distress during the prepandemic year,” they noted.

Distress levels often return to normal after a disaster, Dr. Breslau and associates pointed out, but “the pandemic’s influence on economic stressors, disruption of usual activities and subsequent effects on population health may continue for an extended period and affect different regions of the country at different points in time.”

[email protected]

SOURCE: Breslau J et al. Prev Med. 2020 Dec 31. doi: 10.1016/j.ypmed.2020.106362.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Exercise and a hypocaloric, Mediterranean-style diet remain first-line interventions that can benefit all patients with nonalcoholic fatty liver disease (NAFLD), according to a clinical practice update from the American Gastroenterological Association.

“[W]eight loss is associated with a reduction in liver fat, which provides a potential for reversal of disease progression,” wrote Zobair M. Younossi, MD, MPH, of Inova Fairfax Medical Campus in Falls Church, Va., with his associates. Lifestyle modifications remain “the cornerstone for management” because, even though NAFLD affects approximately 25% of individuals worldwide according to one meta-analytic assessment, interventions such as medications, bariatric endoscopy, and surgery are usually reserved for the subset of patients with severe obesity, comorbid diabetes, or nonalcoholic steatohepatitis (NASH) with at least stage 2 fibrosis, the experts wrote in Gastroenterology.

They note that clinically significant weight loss typically requires a hypocaloric diet of 1,200-1,500 kilocalories/day or a decrease of 500-1,000 kilocalories/day from baseline. A Mediterranean diet of fresh vegetables, fruits, legumes, minimally processed whole grains, fish, olive oil, nuts, and seeds is recommended because its antioxidant, anti-inflammatory effects may slow NAFLD progression. This diet minimizes or eliminates sweets, refined grains, and red and processed meats. Fructose from fruit is not associated with NAFLD, but patients should consume little or no commercially prepared fructose, which has been linked to visceral adiposity, insulin resistance, hepatic inflammation, and fibrosis progression. Other hypocaloric diets have not been studied enough to support their routine use in NAFLD treatment, according to the clinical practice update.

For patients with NASH, which is the more severe form of NAFLD and is associated with significant morbidity and mortality caused by complications from cirrhosis, hepatic decompensation, and hepatocellular carcinoma, weight loss also has a big impact: Losing at least 5% of total body weight can decrease hepatic steatosis, losing at least 7% can resolve NASH, and losing at least 10% can lessen or stabilize hepatic fibrosis, according to level 1 evidence cited by the update. Weight loss “can significantly impact all aspects of NAFLD histology including fibrosis, but a goal of 10% total body weight loss should be considered for patients with overweight or obese NAFLD,” the authors wrote. Fat loss also improves liver histology in patients with lean NAFLD (body mass index, 26 kg/m² in non-Asian patients or 24 in Asians), for whom a hypocaloric diet targeting a more modest 3%-5% total body weight loss is recommended.

Because aerobic exercise reduces hepatic fat levels independently of hypocaloric diet, patients with NAFLD should consider a weekly regimen of 150-300 minutes of moderate-intensity exercise or 75-150 minutes of vigorous activity. Resistance training can complement aerobic exercise “but [is] not a replacement,” the authors noted. In addition, patients with NAFLD should restrict alcohol consumption to reduce the risk for liver-related events, and those with advanced hepatic fibrosis should “avoid alcohol entirely.” These recommendations reflect the findings of a large prospective study in which the consumption of even low amounts of alcohol led to worse liver-related outcomes among patients with NAFLD.

Clinicians should screen for and “aggressively” manage common NAFLD comorbidities, including diabetes mellitus, hypertension, and obstructive sleep apnea, according to the clinical practice update. Patients with coexisting metabolic conditions should be risk-stratified for cardiovascular disease and treated based on guidelines from the American College of Cardiology and the American Heart Association.

It is believed that sarcopenia affects patients with NASH cirrhosis because their livers cannot effectively store, metabolize, or mobilize carbohydrates, which leads to a catabolic state in which protein and fat are used as energy sources, according to the update. To avoid exacerbations, these patients may need to optimize their protein intake – a minimum of 1.2-1.5 g/kg of body weight is recommended – from sources of branched-chain amino acids, such as chicken, fish, eggs, nuts, lentils, or soy. Patients with sarcopenic NAFLD also should consume small, frequent meals spaced no more than 4-6 hours apart. When possible, they should consult with a specialized nutritionist. Moderate-intensity exercise may also benefit patients experiencing sarcopenia.

The researchers disclosed ties to Gilead Sciences, Intercept, Bristol Myers Squibb, Novo Nordisk, and several other companies. The review was commissioned and approved by the AGA Institute’s Clinical Practice Updates Committee and the AGA Governing Board.

SOURCE: Younossi ZM et al. Gastroenterology. 2020 Dec 8. doi: 10.1053/j.gastro.2020.11.051.

This article was updated Feb. 10, 2021.

Nickel is unrivaled as the most common cause of contact allergy worldwide.¹ Nickel is commonly used as a hardening agent in metal products, and complete avoidance is challenging due to numerous potential exposures (eg, direct contact, airborne, dietary, medical implantation). Allergic contact dermatitis to nickel (Ni-ACD) can lead to decreased quality of life, inability to work, and considerable health care expenses.¹ Here, we review the epidemiology of nickel allergy, regulation of nickel in the United States and Europe, common clinical presentations, and pearls on avoidance.

Epidemiology

Nickel continues to be the most common cause of contact allergy worldwide. Data from the 2015-2016 North American Contact Dermatitis Group patch test cycle (N=5597) showed nickel sulfate to be positive in 17.5% of patients patch tested to nickel.² The prevalence of nickel allergy has been relatively stable in North America since 2005 (Figure 1). Although Ni-ACD historically was identified as an occupational disease of the hands in male nickel platers, the epidemiology of nickel allergy has shifted.¹ Today, most cases are nonoccupational and affect women more often than men,³ in part due to improved industrial hygiene, pervasive incorporation of nickel in consumer items, and differences in cultural practices such as piercings.^1,3 Piercings in particular have been implicated as important sources of nickel exposure, as this practice disrupts normal skin barrier function and is a potentially sensitizing event. Multiple studies including a large-scale epidemiologic analysis from 2017 have found piercings to be associated with an increased frequency of Ni-ACD (24.4% with piercing vs 9.6% without piercing). Interestingly, the degree of nickel sensitivity also was found to increase with the number of piercings (14.3% with 1 piercing vs 34.0% with ≥5 piercings).⁴

Regulation

Nickel content has been regulated in parts of the European Union (EU) since the 1990s, but regulation in the United States is lacking. In an attempt to reduce the prevalence of nickel allergy, the EU limits the level of nickel release from consumer items intended to be in direct and prolonged contact with the skin. These limits were first introduced in Denmark in 1990, followed closely by the EU Nickel Directive in 1994, which has resulted in consistent patterns of decreasing prevalence of Ni-ACD in multiple European countries.⁵ Notably, a Danish study comparing the prevalence of sensitization between girls with ears pierced before vs after implementation of nickel regulation found a decrease in prevalence from 17.1% to 3.9%.⁶ Additionally, this initiative has greatly reduced the economic burden of nickel dermatitis. It is estimated that Denmark alone has saved US $2 billion over a 20-year period in both direct and indirect health care costs.⁷

However, a policy is only effective if it is enforced, and it has been reported in the EU that 8% to 32% of tested jewelry exceeds the limit placed on nickel release, with imported jewelry being especially problematic.⁵ Also of interest, the 1 and 2 euro coins are known to release more nickel than pure nickel itself, releasing 240 to 320 times more than is allowed under the EU Nickel Directive (Figure 2).⁸ Although coins are not explicitly mentioned as items having prolonged contact with the skin, they can and do exacerbate allergic contact dermatitis of the hands, especially in occupational groups such as cashiers.⁹ Unsurprisingly, during the discussions to determine the composition of coins prior to the mass adoption of the euro in the EU in 2002, dermatologists and nickel industry experts remained divided in their recommendations.¹⁰ However, the EU regulation is considered a public health success overall, and the trends of Ni-ACD and economic burden are opposite of the United States, where legislation has yet to be adopted.

Patch Testing to Nickel

In North America, the 2 available patch test systems are the chamber method and the Thin-layer Rapid Use Epicutaneous (T.R.U.E.) test (SmartPractice). In the T.R.U.E. test, nickel sulfate is used to formulate the patch at 200 µg/cm² using hydroxypropyl cellulose as the gel vehicle. In the chamber method, nickel sulfate is used on either an aluminum or plastic chamber, most commonly at concentrations of 2.5% or 5% in petrolatum. Nickel sulfate 2.5% is most frequently used in US-based patch test clinics. A 2018 study (N=205) comparing the sensitivities of the 2.5% and 5% concentrations of nickel found 5% to be more sensitive; 31% of the cohort tested positive at 5% but only 20% at 2.5%, suggesting the 5% formulation is superior at detecting nickel allergy.¹¹

Similar to other metals, nickel may react later than other allergens. A 2019 analysis of the prevalence of new patch test reactions on day 7 showed that 17% of 607 patients were negative on day 3 but were positive on day 7, further emphasizing the importance of a properly timed delayed reading.¹²

Clinical Presentation

Localized
The classic presentation of Ni-ACD is a scaly erythematous dermatitis in a typical distribution (eg, earlobes [earrings], wrists [watch], periumbilical [belt]). These scenarios usually can be diagnosed by the astute clinician without patch testing; however, the source of exposure may be less obvious if the nickel-releasing item has intermittent contact with the skin (eg, coins in the pocket, furniture hardware, personal grooming devices).¹³ Other reported exposures include facial dermatitis from mobile phones, dermatitis of the ulnar hands from laptop use, and hand dermatitis from gaming controllers,^14-16 perhaps another reason for some to unplug.

Systemic
Sensitized individuals also may present with systemic contact dermatitis after airborne, oral, mucosal, or intravenous exposure. Presentations vary but have been reported to manifest as flare-up reactions in previously affected areas, pompholyx, diffuse dermatitis, flexural dermatitis, and baboon syndrome.¹⁷ Although it is unknown if airborne exposure alone is sufficient for sensitization, cases have been reported in occupational settings.¹⁸ One report described a man presenting with widespread dermatitis involving the extremities, chest, and genital area after his first day working at an electroplating plant.¹⁹

Systemic contact dermatitis from foods high in nickel (eg, chocolate, sunflower seeds, whole-grain flour, dried beans) and occasionally nonfood items (eg, coins) also has occurred. The so-called Easter egg hunt dermatitis has been described in children with Ni-ACD after candy ingestion.²⁰ Another case described an 8-year-old girl and budding illusionist with severe diffuse dermatitis; a thorough history revealed the dermatitis began after she ingested a coin while performing a magic trick.²¹

Cases of nickel systemic contact dermatitis have been reported following medical device implantation, including reactions to cardiac devices, orthopedic implants, neurosurgery materials, and others.²² In addition, both intraoral and extraoral manifestations following application of orthodontic materials and dental implants have been reported.^23,24 Although nickel-containing medical devices generally are well tolerated even in nickel-sensitive individuals, the development of systemic Ni-ACD has at times required device or hardware removal.^22,23

After the Patch Test: Avoidance of Nickel

Counseling patients on nickel avoidance is critical to clinical improvement. Common nickel-containing items include jewelry, metal on clothing (eg, zippers, clasps, grommets), belt buckles, watches, glasses, furniture, coins, and keys. Numerous personal care products may also contain nickel, including nail clippers, eyelash curlers, tweezers, mascara tubes, and razors.^25,26 Patients should be made aware that nickel-free alternatives are available for the majority of these products. Internet-based tips such as painting nail polish on products or iron-on patches tend to be of limited use in our experience. Patients may consider purchasing a nickel spot test to detect nickel in their environment; the dimethylglyoxime nickel spot test is inexpensive, rapid, and easy-to-use. To use the test, a small amount of the chemical is rubbed on the metal item using a cotton swab; a pink color indicates nickel release. Patients can be reassured that dimethylglyoxime does not harm jewelry.

Some general advice for patients regarding jewelry, the most common source of nickel exposure, is to only wear jewelry that is made from metals such as surgical-grade stainless steel, pure sterling silver, or platinum. If yellow gold is the preferred metal, it is prudent to be aware that lower karat items could potentially contain nickel. White gold should be avoided, as it often contains nickel to contribute to its color. Finally, gold-plated jewelry should be avoided, as the plating can wear off and expose a possibly nickel-containing base.

A low-nickel diet may be of benefit in select patients. A meta-analysis assessing systemic contact dermatitis from nickel ingestion found that 1% of nickel-sensitive individuals may be expected to react to nickel found in a normal diet.²⁷ However, as with any diet, adherence can be difficult. Thankfully, Mislankar and Zirwas²⁸ have developed a simple point-based system to help increase compliance. Additionally, a free mobile application is now available; Nickel Navigator can be used to track daily nickel intake and may be especially convenient for our more tech-savvy patients. In conjunction with a low-nickel diet, some authors also recommend eating meals high in vitamin C or supplementation with vitamin C, as co-ingestion has been shown to reduce nickel absorption.²⁹

Final Interpretation

Nickel allergy remains common, found in up to 17.5% of patch tested patients. Despite regulation in the EU, nickel continues to have high prevalence of positive patch test reactions around the world. Nickel is not only found in jewelry and belt buckles but also in personal care products, electronics, and food. Allergen avoidance is key and requires knowledge of common items containing nickel and a low nickel diet for select patients.

Nickel is unrivaled as the most common cause of contact allergy worldwide.¹ Nickel is commonly used as a hardening agent in metal products, and complete avoidance is challenging due to numerous potential exposures (eg, direct contact, airborne, dietary, medical implantation). Allergic contact dermatitis to nickel (Ni-ACD) can lead to decreased quality of life, inability to work, and considerable health care expenses.¹ Here, we review the epidemiology of nickel allergy, regulation of nickel in the United States and Europe, common clinical presentations, and pearls on avoidance.

Epidemiology

Nickel continues to be the most common cause of contact allergy worldwide. Data from the 2015-2016 North American Contact Dermatitis Group patch test cycle (N=5597) showed nickel sulfate to be positive in 17.5% of patients patch tested to nickel.² The prevalence of nickel allergy has been relatively stable in North America since 2005 (Figure 1). Although Ni-ACD historically was identified as an occupational disease of the hands in male nickel platers, the epidemiology of nickel allergy has shifted.¹ Today, most cases are nonoccupational and affect women more often than men,³ in part due to improved industrial hygiene, pervasive incorporation of nickel in consumer items, and differences in cultural practices such as piercings.^1,3 Piercings in particular have been implicated as important sources of nickel exposure, as this practice disrupts normal skin barrier function and is a potentially sensitizing event. Multiple studies including a large-scale epidemiologic analysis from 2017 have found piercings to be associated with an increased frequency of Ni-ACD (24.4% with piercing vs 9.6% without piercing). Interestingly, the degree of nickel sensitivity also was found to increase with the number of piercings (14.3% with 1 piercing vs 34.0% with ≥5 piercings).⁴

Regulation

Nickel content has been regulated in parts of the European Union (EU) since the 1990s, but regulation in the United States is lacking. In an attempt to reduce the prevalence of nickel allergy, the EU limits the level of nickel release from consumer items intended to be in direct and prolonged contact with the skin. These limits were first introduced in Denmark in 1990, followed closely by the EU Nickel Directive in 1994, which has resulted in consistent patterns of decreasing prevalence of Ni-ACD in multiple European countries.⁵ Notably, a Danish study comparing the prevalence of sensitization between girls with ears pierced before vs after implementation of nickel regulation found a decrease in prevalence from 17.1% to 3.9%.⁶ Additionally, this initiative has greatly reduced the economic burden of nickel dermatitis. It is estimated that Denmark alone has saved US $2 billion over a 20-year period in both direct and indirect health care costs.⁷

However, a policy is only effective if it is enforced, and it has been reported in the EU that 8% to 32% of tested jewelry exceeds the limit placed on nickel release, with imported jewelry being especially problematic.⁵ Also of interest, the 1 and 2 euro coins are known to release more nickel than pure nickel itself, releasing 240 to 320 times more than is allowed under the EU Nickel Directive (Figure 2).⁸ Although coins are not explicitly mentioned as items having prolonged contact with the skin, they can and do exacerbate allergic contact dermatitis of the hands, especially in occupational groups such as cashiers.⁹ Unsurprisingly, during the discussions to determine the composition of coins prior to the mass adoption of the euro in the EU in 2002, dermatologists and nickel industry experts remained divided in their recommendations.¹⁰ However, the EU regulation is considered a public health success overall, and the trends of Ni-ACD and economic burden are opposite of the United States, where legislation has yet to be adopted.

Patch Testing to Nickel

In North America, the 2 available patch test systems are the chamber method and the Thin-layer Rapid Use Epicutaneous (T.R.U.E.) test (SmartPractice). In the T.R.U.E. test, nickel sulfate is used to formulate the patch at 200 µg/cm² using hydroxypropyl cellulose as the gel vehicle. In the chamber method, nickel sulfate is used on either an aluminum or plastic chamber, most commonly at concentrations of 2.5% or 5% in petrolatum. Nickel sulfate 2.5% is most frequently used in US-based patch test clinics. A 2018 study (N=205) comparing the sensitivities of the 2.5% and 5% concentrations of nickel found 5% to be more sensitive; 31% of the cohort tested positive at 5% but only 20% at 2.5%, suggesting the 5% formulation is superior at detecting nickel allergy.¹¹

Similar to other metals, nickel may react later than other allergens. A 2019 analysis of the prevalence of new patch test reactions on day 7 showed that 17% of 607 patients were negative on day 3 but were positive on day 7, further emphasizing the importance of a properly timed delayed reading.¹²

Clinical Presentation

Localized
The classic presentation of Ni-ACD is a scaly erythematous dermatitis in a typical distribution (eg, earlobes [earrings], wrists [watch], periumbilical [belt]). These scenarios usually can be diagnosed by the astute clinician without patch testing; however, the source of exposure may be less obvious if the nickel-releasing item has intermittent contact with the skin (eg, coins in the pocket, furniture hardware, personal grooming devices).¹³ Other reported exposures include facial dermatitis from mobile phones, dermatitis of the ulnar hands from laptop use, and hand dermatitis from gaming controllers,^14-16 perhaps another reason for some to unplug.

Systemic
Sensitized individuals also may present with systemic contact dermatitis after airborne, oral, mucosal, or intravenous exposure. Presentations vary but have been reported to manifest as flare-up reactions in previously affected areas, pompholyx, diffuse dermatitis, flexural dermatitis, and baboon syndrome.¹⁷ Although it is unknown if airborne exposure alone is sufficient for sensitization, cases have been reported in occupational settings.¹⁸ One report described a man presenting with widespread dermatitis involving the extremities, chest, and genital area after his first day working at an electroplating plant.¹⁹

Systemic contact dermatitis from foods high in nickel (eg, chocolate, sunflower seeds, whole-grain flour, dried beans) and occasionally nonfood items (eg, coins) also has occurred. The so-called Easter egg hunt dermatitis has been described in children with Ni-ACD after candy ingestion.²⁰ Another case described an 8-year-old girl and budding illusionist with severe diffuse dermatitis; a thorough history revealed the dermatitis began after she ingested a coin while performing a magic trick.²¹

Cases of nickel systemic contact dermatitis have been reported following medical device implantation, including reactions to cardiac devices, orthopedic implants, neurosurgery materials, and others.²² In addition, both intraoral and extraoral manifestations following application of orthodontic materials and dental implants have been reported.^23,24 Although nickel-containing medical devices generally are well tolerated even in nickel-sensitive individuals, the development of systemic Ni-ACD has at times required device or hardware removal.^22,23

After the Patch Test: Avoidance of Nickel

Counseling patients on nickel avoidance is critical to clinical improvement. Common nickel-containing items include jewelry, metal on clothing (eg, zippers, clasps, grommets), belt buckles, watches, glasses, furniture, coins, and keys. Numerous personal care products may also contain nickel, including nail clippers, eyelash curlers, tweezers, mascara tubes, and razors.^25,26 Patients should be made aware that nickel-free alternatives are available for the majority of these products. Internet-based tips such as painting nail polish on products or iron-on patches tend to be of limited use in our experience. Patients may consider purchasing a nickel spot test to detect nickel in their environment; the dimethylglyoxime nickel spot test is inexpensive, rapid, and easy-to-use. To use the test, a small amount of the chemical is rubbed on the metal item using a cotton swab; a pink color indicates nickel release. Patients can be reassured that dimethylglyoxime does not harm jewelry.

Some general advice for patients regarding jewelry, the most common source of nickel exposure, is to only wear jewelry that is made from metals such as surgical-grade stainless steel, pure sterling silver, or platinum. If yellow gold is the preferred metal, it is prudent to be aware that lower karat items could potentially contain nickel. White gold should be avoided, as it often contains nickel to contribute to its color. Finally, gold-plated jewelry should be avoided, as the plating can wear off and expose a possibly nickel-containing base.

A low-nickel diet may be of benefit in select patients. A meta-analysis assessing systemic contact dermatitis from nickel ingestion found that 1% of nickel-sensitive individuals may be expected to react to nickel found in a normal diet.²⁷ However, as with any diet, adherence can be difficult. Thankfully, Mislankar and Zirwas²⁸ have developed a simple point-based system to help increase compliance. Additionally, a free mobile application is now available; Nickel Navigator can be used to track daily nickel intake and may be especially convenient for our more tech-savvy patients. In conjunction with a low-nickel diet, some authors also recommend eating meals high in vitamin C or supplementation with vitamin C, as co-ingestion has been shown to reduce nickel absorption.²⁹

Final Interpretation

Nickel allergy remains common, found in up to 17.5% of patch tested patients. Despite regulation in the EU, nickel continues to have high prevalence of positive patch test reactions around the world. Nickel is not only found in jewelry and belt buckles but also in personal care products, electronics, and food. Allergen avoidance is key and requires knowledge of common items containing nickel and a low nickel diet for select patients.

Nickel is unrivaled as the most common cause of contact allergy worldwide.¹ Nickel is commonly used as a hardening agent in metal products, and complete avoidance is challenging due to numerous potential exposures (eg, direct contact, airborne, dietary, medical implantation). Allergic contact dermatitis to nickel (Ni-ACD) can lead to decreased quality of life, inability to work, and considerable health care expenses.¹ Here, we review the epidemiology of nickel allergy, regulation of nickel in the United States and Europe, common clinical presentations, and pearls on avoidance.

Epidemiology

Nickel continues to be the most common cause of contact allergy worldwide. Data from the 2015-2016 North American Contact Dermatitis Group patch test cycle (N=5597) showed nickel sulfate to be positive in 17.5% of patients patch tested to nickel.² The prevalence of nickel allergy has been relatively stable in North America since 2005 (Figure 1). Although Ni-ACD historically was identified as an occupational disease of the hands in male nickel platers, the epidemiology of nickel allergy has shifted.¹ Today, most cases are nonoccupational and affect women more often than men,³ in part due to improved industrial hygiene, pervasive incorporation of nickel in consumer items, and differences in cultural practices such as piercings.^1,3 Piercings in particular have been implicated as important sources of nickel exposure, as this practice disrupts normal skin barrier function and is a potentially sensitizing event. Multiple studies including a large-scale epidemiologic analysis from 2017 have found piercings to be associated with an increased frequency of Ni-ACD (24.4% with piercing vs 9.6% without piercing). Interestingly, the degree of nickel sensitivity also was found to increase with the number of piercings (14.3% with 1 piercing vs 34.0% with ≥5 piercings).⁴

Regulation

Nickel content has been regulated in parts of the European Union (EU) since the 1990s, but regulation in the United States is lacking. In an attempt to reduce the prevalence of nickel allergy, the EU limits the level of nickel release from consumer items intended to be in direct and prolonged contact with the skin. These limits were first introduced in Denmark in 1990, followed closely by the EU Nickel Directive in 1994, which has resulted in consistent patterns of decreasing prevalence of Ni-ACD in multiple European countries.⁵ Notably, a Danish study comparing the prevalence of sensitization between girls with ears pierced before vs after implementation of nickel regulation found a decrease in prevalence from 17.1% to 3.9%.⁶ Additionally, this initiative has greatly reduced the economic burden of nickel dermatitis. It is estimated that Denmark alone has saved US $2 billion over a 20-year period in both direct and indirect health care costs.⁷

However, a policy is only effective if it is enforced, and it has been reported in the EU that 8% to 32% of tested jewelry exceeds the limit placed on nickel release, with imported jewelry being especially problematic.⁵ Also of interest, the 1 and 2 euro coins are known to release more nickel than pure nickel itself, releasing 240 to 320 times more than is allowed under the EU Nickel Directive (Figure 2).⁸ Although coins are not explicitly mentioned as items having prolonged contact with the skin, they can and do exacerbate allergic contact dermatitis of the hands, especially in occupational groups such as cashiers.⁹ Unsurprisingly, during the discussions to determine the composition of coins prior to the mass adoption of the euro in the EU in 2002, dermatologists and nickel industry experts remained divided in their recommendations.¹⁰ However, the EU regulation is considered a public health success overall, and the trends of Ni-ACD and economic burden are opposite of the United States, where legislation has yet to be adopted.

Patch Testing to Nickel

In North America, the 2 available patch test systems are the chamber method and the Thin-layer Rapid Use Epicutaneous (T.R.U.E.) test (SmartPractice). In the T.R.U.E. test, nickel sulfate is used to formulate the patch at 200 µg/cm² using hydroxypropyl cellulose as the gel vehicle. In the chamber method, nickel sulfate is used on either an aluminum or plastic chamber, most commonly at concentrations of 2.5% or 5% in petrolatum. Nickel sulfate 2.5% is most frequently used in US-based patch test clinics. A 2018 study (N=205) comparing the sensitivities of the 2.5% and 5% concentrations of nickel found 5% to be more sensitive; 31% of the cohort tested positive at 5% but only 20% at 2.5%, suggesting the 5% formulation is superior at detecting nickel allergy.¹¹

Similar to other metals, nickel may react later than other allergens. A 2019 analysis of the prevalence of new patch test reactions on day 7 showed that 17% of 607 patients were negative on day 3 but were positive on day 7, further emphasizing the importance of a properly timed delayed reading.¹²

Clinical Presentation

Localized
The classic presentation of Ni-ACD is a scaly erythematous dermatitis in a typical distribution (eg, earlobes [earrings], wrists [watch], periumbilical [belt]). These scenarios usually can be diagnosed by the astute clinician without patch testing; however, the source of exposure may be less obvious if the nickel-releasing item has intermittent contact with the skin (eg, coins in the pocket, furniture hardware, personal grooming devices).¹³ Other reported exposures include facial dermatitis from mobile phones, dermatitis of the ulnar hands from laptop use, and hand dermatitis from gaming controllers,^14-16 perhaps another reason for some to unplug.

Systemic
Sensitized individuals also may present with systemic contact dermatitis after airborne, oral, mucosal, or intravenous exposure. Presentations vary but have been reported to manifest as flare-up reactions in previously affected areas, pompholyx, diffuse dermatitis, flexural dermatitis, and baboon syndrome.¹⁷ Although it is unknown if airborne exposure alone is sufficient for sensitization, cases have been reported in occupational settings.¹⁸ One report described a man presenting with widespread dermatitis involving the extremities, chest, and genital area after his first day working at an electroplating plant.¹⁹

Systemic contact dermatitis from foods high in nickel (eg, chocolate, sunflower seeds, whole-grain flour, dried beans) and occasionally nonfood items (eg, coins) also has occurred. The so-called Easter egg hunt dermatitis has been described in children with Ni-ACD after candy ingestion.²⁰ Another case described an 8-year-old girl and budding illusionist with severe diffuse dermatitis; a thorough history revealed the dermatitis began after she ingested a coin while performing a magic trick.²¹

Cases of nickel systemic contact dermatitis have been reported following medical device implantation, including reactions to cardiac devices, orthopedic implants, neurosurgery materials, and others.²² In addition, both intraoral and extraoral manifestations following application of orthodontic materials and dental implants have been reported.^23,24 Although nickel-containing medical devices generally are well tolerated even in nickel-sensitive individuals, the development of systemic Ni-ACD has at times required device or hardware removal.^22,23

After the Patch Test: Avoidance of Nickel

Counseling patients on nickel avoidance is critical to clinical improvement. Common nickel-containing items include jewelry, metal on clothing (eg, zippers, clasps, grommets), belt buckles, watches, glasses, furniture, coins, and keys. Numerous personal care products may also contain nickel, including nail clippers, eyelash curlers, tweezers, mascara tubes, and razors.^25,26 Patients should be made aware that nickel-free alternatives are available for the majority of these products. Internet-based tips such as painting nail polish on products or iron-on patches tend to be of limited use in our experience. Patients may consider purchasing a nickel spot test to detect nickel in their environment; the dimethylglyoxime nickel spot test is inexpensive, rapid, and easy-to-use. To use the test, a small amount of the chemical is rubbed on the metal item using a cotton swab; a pink color indicates nickel release. Patients can be reassured that dimethylglyoxime does not harm jewelry.

Some general advice for patients regarding jewelry, the most common source of nickel exposure, is to only wear jewelry that is made from metals such as surgical-grade stainless steel, pure sterling silver, or platinum. If yellow gold is the preferred metal, it is prudent to be aware that lower karat items could potentially contain nickel. White gold should be avoided, as it often contains nickel to contribute to its color. Finally, gold-plated jewelry should be avoided, as the plating can wear off and expose a possibly nickel-containing base.

A low-nickel diet may be of benefit in select patients. A meta-analysis assessing systemic contact dermatitis from nickel ingestion found that 1% of nickel-sensitive individuals may be expected to react to nickel found in a normal diet.²⁷ However, as with any diet, adherence can be difficult. Thankfully, Mislankar and Zirwas²⁸ have developed a simple point-based system to help increase compliance. Additionally, a free mobile application is now available; Nickel Navigator can be used to track daily nickel intake and may be especially convenient for our more tech-savvy patients. In conjunction with a low-nickel diet, some authors also recommend eating meals high in vitamin C or supplementation with vitamin C, as co-ingestion has been shown to reduce nickel absorption.²⁹

Final Interpretation

Nickel allergy remains common, found in up to 17.5% of patch tested patients. Despite regulation in the EU, nickel continues to have high prevalence of positive patch test reactions around the world. Nickel is not only found in jewelry and belt buckles but also in personal care products, electronics, and food. Allergen avoidance is key and requires knowledge of common items containing nickel and a low nickel diet for select patients.

The management of delusional infestation (DI), also known as Morgellons disease or delusional parasitosis, can lead to some of the most difficult and stressful patient encounters in dermatology. As a specialty, dermatology providers are trained to respect scientific objectivity and pride themselves on their visual diagnostic acumen. Therefore, having to accommodate a patient’s erroneous ideations and potentially treat a psychiatric pathology poses a challenge for many dermatology providers because it requires shifting their mindset to where the subjective reality becomes the primary issue during the visit. This disconnect may lead to strife between the patient and the provider. All of these issues may make it difficult for dermatologists to connect with DI patients with the usual courtesy and consideration given to other patients. Moreover, some dermatologists find it difficult to respect the chief concern, which often is seen as purely psychological because there may be some lingering bias where psychological concerns perhaps are not seen as bona fide or legitimate disorders.

Is There a Biologic Basis for DI? A New Theory on the Etiology of Delusional Parasitosis

It is important to distinguish DI phenomenology into primary and secondary causes. Primary DI refers to cases where the delusion and formication occur spontaneously. In contrast, in secondary DI the delusion and other manifestations (eg, formication) happen secondarily to underlying broader diagnoses such as illicit substance abuse, primary psychiatric conditions including schizophrenia, organic brain syndrome, and vitamin B₁₂ deficiency.

It is well known that primary DI overwhelmingly occurs in older women, whereas secondary DI does not show this same predilection. It has been a big unanswered question as to why primary DI so often occurs not only in women but specifically in older women. The latest theory that has been advancing in Europe and is supported by some data, including magnetic resonance imaging of the brain, involves the dopamine transporter (DAT) system, which is important in making sure the dopamine level in the intersynaptic space is not excessive.¹ The DAT system is much more prominent in woman vs men and deteriorates with age due to declining estrogen levels. This age-related loss of striatal DAT is thought to be one possible etiology of DI. It has been hypothesized that decreased DAT functioning may cause an increase in extracellular striatal dopamine levels in the synapse that can lead to tactile hallucinations and delusions, which are hallmark symptoms seen in DI. Given that women experience a greater age-related DAT decline in striatal subregions than men, it is thought that primary DI mainly affects older women due to the decline of neuroprotective effects of estrogen on DAT activity with age.² Further studies should evaluate the possibility of estrogen replacement therapy for treatment of DI.

Improving Care of Psychodermatology Patients in Clinic

There are several medications that are known to be effective for the treatment of DI, including pimozide, risperidone, aripiprazole, and olanzapine, among others. Pimozide is uniquely accepted by DI patients because it has no official psychiatric indication from the US Food and Drug Administration (FDA); it is only indicated in the United States for Tourette syndrome, which is a neurologic disorder. Therefore, pimozide arguably can be disregarded as a true antipsychotic agent. The fact that its chemical structure is similar to those of bona fide antipsychotic medications does not necessarily put it in this same category, as there also are antiemetic and antitussive medications (eg, prochlorperazine, promethazine) with chemical structures similar to antipsychotics, but clinicians generally do not think of these drugs as antipsychotics despite the similarities. This nuanced and admittedly somewhat arbitrary categorization is critical to patient care; in our clinic, we have found that patients who categorically refuse to consider all psychiatric medications are much more willing to try pimozide for this very reason, that this medication can uniquely be presented to the DI patient as an agent not used in psychiatry. We have found great success in treatment with pimozide, even with relatively low doses.^3,4

One of the main reasons dermatologists are reluctant to prescribe antipsychotic medications or even pimozide is the concern for side effects, especially tardive dyskinesia (TD), which is thought to be irreversible and untreatable. However, after a half century of worldwide use of pimozide in dermatology, a PubMed search of English-language articles indexed for MEDLINE using the terms pimozide and tardive dyskinesia, tardive dyskinesia and delusions of parasitosis, tardive dyskinesia and dermatology, and tardive dyskinesia and delusional infestation/Morgellons disease yielded only 1 known case of TD reported in dermatologic use for DI.⁵ In this particular case, TD-like symptoms did not appear until after pimozide had been discontinued for 1 month. Therefore, it is not clear if this case was true TD or a condition known as withdrawal dyskinesia, which mimics TD and usually is self-limiting.⁵

The senior author (J.K.) has been using pimozide for treatment of DI for more than 30 years and has not encountered TD or any other notable side effects. The reason for this extremely low incidence of side effects may be due to its high efficacy in treating DI; hence, only a low dose of pimozide usually is needed. At the University of California, San Francisco, Psychodermatology Clinic, pimozide typically is used to treat DI at a low dose of 3 mg or less daily, starting with 0.5 or 1 mg and slowly titrating upward until a clinically effective dose is reached. Pimozide rarely is used long-term; after the resolution of symptoms, the dose usually is continued at the clinically effective dose for a few months and then is slowly tapered off. In contrast, for a condition such as schizophrenia, an antipsychotic medication often is needed at high doses for life, resulting in higher TD occurrences being reported. Therefore, even though the newer antipsychotic agents are preferable to pimozide because of their somewhat lower risk for TD, in actual clinical practice many, if not most, DI patients detest any suggestion of taking a medication for “crazy people.” Thus, we find that pimozide’s inherent superior acceptability among DI patients often is critical to enabling any effective treatment to occur at all due to the fact that the provider can honestly say that pimozide has no FDA psychiatric indication.

Still, one of the biggest apprehensions with initiating and continuing these medications in dermatology is fear of TD. Now, dermatologists can be made aware that if this very rare side effect occurs, there are medications approved to treat TD, even if the anti-TD therapy is administered by a neurologist. For the first time, 2 medications were approved by the FDA for treatment of TD in 2017, namely valbenazine and deutetrabenazine. These medications represent a class known as vesicular monoamine transporter type 2 inhibitors and function by ultimately reducing the amount of dopamine released from the presynaptic dopaminergic neurons. In phase 3 trials for valbenazine and deutetrabenazine, 40% (N=234) and 34% (N=222) of patients, respectively, achieved a response, which was defined as at least a 50% decrease from baseline on the abnormal involuntary movement scale dyskinesia score in 6 to 12 weeks compared to 9% and 12%, respectively, with placebo.Discontinuation because of an adverse event was seldom encountered with both medications.⁶

Conclusion

The recent developments in psychodermatology with regard to DI are encouraging. The advent of new evidence and theories suggestive of an organic basis for DI could help this condition become more respected in the eyes of the dermatologist as a bona fide disorder. Moreover, the new developments and availability of medications that can treat TD can further make it easier for dermatologists to consider offering DI patients truly meaningful treatment that they desperately need. Therefore, both of these developments are welcomed for our specialty.

The management of delusional infestation (DI), also known as Morgellons disease or delusional parasitosis, can lead to some of the most difficult and stressful patient encounters in dermatology. As a specialty, dermatology providers are trained to respect scientific objectivity and pride themselves on their visual diagnostic acumen. Therefore, having to accommodate a patient’s erroneous ideations and potentially treat a psychiatric pathology poses a challenge for many dermatology providers because it requires shifting their mindset to where the subjective reality becomes the primary issue during the visit. This disconnect may lead to strife between the patient and the provider. All of these issues may make it difficult for dermatologists to connect with DI patients with the usual courtesy and consideration given to other patients. Moreover, some dermatologists find it difficult to respect the chief concern, which often is seen as purely psychological because there may be some lingering bias where psychological concerns perhaps are not seen as bona fide or legitimate disorders.

Is There a Biologic Basis for DI? A New Theory on the Etiology of Delusional Parasitosis

It is important to distinguish DI phenomenology into primary and secondary causes. Primary DI refers to cases where the delusion and formication occur spontaneously. In contrast, in secondary DI the delusion and other manifestations (eg, formication) happen secondarily to underlying broader diagnoses such as illicit substance abuse, primary psychiatric conditions including schizophrenia, organic brain syndrome, and vitamin B₁₂ deficiency.

It is well known that primary DI overwhelmingly occurs in older women, whereas secondary DI does not show this same predilection. It has been a big unanswered question as to why primary DI so often occurs not only in women but specifically in older women. The latest theory that has been advancing in Europe and is supported by some data, including magnetic resonance imaging of the brain, involves the dopamine transporter (DAT) system, which is important in making sure the dopamine level in the intersynaptic space is not excessive.¹ The DAT system is much more prominent in woman vs men and deteriorates with age due to declining estrogen levels. This age-related loss of striatal DAT is thought to be one possible etiology of DI. It has been hypothesized that decreased DAT functioning may cause an increase in extracellular striatal dopamine levels in the synapse that can lead to tactile hallucinations and delusions, which are hallmark symptoms seen in DI. Given that women experience a greater age-related DAT decline in striatal subregions than men, it is thought that primary DI mainly affects older women due to the decline of neuroprotective effects of estrogen on DAT activity with age.² Further studies should evaluate the possibility of estrogen replacement therapy for treatment of DI.

Improving Care of Psychodermatology Patients in Clinic

There are several medications that are known to be effective for the treatment of DI, including pimozide, risperidone, aripiprazole, and olanzapine, among others. Pimozide is uniquely accepted by DI patients because it has no official psychiatric indication from the US Food and Drug Administration (FDA); it is only indicated in the United States for Tourette syndrome, which is a neurologic disorder. Therefore, pimozide arguably can be disregarded as a true antipsychotic agent. The fact that its chemical structure is similar to those of bona fide antipsychotic medications does not necessarily put it in this same category, as there also are antiemetic and antitussive medications (eg, prochlorperazine, promethazine) with chemical structures similar to antipsychotics, but clinicians generally do not think of these drugs as antipsychotics despite the similarities. This nuanced and admittedly somewhat arbitrary categorization is critical to patient care; in our clinic, we have found that patients who categorically refuse to consider all psychiatric medications are much more willing to try pimozide for this very reason, that this medication can uniquely be presented to the DI patient as an agent not used in psychiatry. We have found great success in treatment with pimozide, even with relatively low doses.^3,4

One of the main reasons dermatologists are reluctant to prescribe antipsychotic medications or even pimozide is the concern for side effects, especially tardive dyskinesia (TD), which is thought to be irreversible and untreatable. However, after a half century of worldwide use of pimozide in dermatology, a PubMed search of English-language articles indexed for MEDLINE using the terms pimozide and tardive dyskinesia, tardive dyskinesia and delusions of parasitosis, tardive dyskinesia and dermatology, and tardive dyskinesia and delusional infestation/Morgellons disease yielded only 1 known case of TD reported in dermatologic use for DI.⁵ In this particular case, TD-like symptoms did not appear until after pimozide had been discontinued for 1 month. Therefore, it is not clear if this case was true TD or a condition known as withdrawal dyskinesia, which mimics TD and usually is self-limiting.⁵

The senior author (J.K.) has been using pimozide for treatment of DI for more than 30 years and has not encountered TD or any other notable side effects. The reason for this extremely low incidence of side effects may be due to its high efficacy in treating DI; hence, only a low dose of pimozide usually is needed. At the University of California, San Francisco, Psychodermatology Clinic, pimozide typically is used to treat DI at a low dose of 3 mg or less daily, starting with 0.5 or 1 mg and slowly titrating upward until a clinically effective dose is reached. Pimozide rarely is used long-term; after the resolution of symptoms, the dose usually is continued at the clinically effective dose for a few months and then is slowly tapered off. In contrast, for a condition such as schizophrenia, an antipsychotic medication often is needed at high doses for life, resulting in higher TD occurrences being reported. Therefore, even though the newer antipsychotic agents are preferable to pimozide because of their somewhat lower risk for TD, in actual clinical practice many, if not most, DI patients detest any suggestion of taking a medication for “crazy people.” Thus, we find that pimozide’s inherent superior acceptability among DI patients often is critical to enabling any effective treatment to occur at all due to the fact that the provider can honestly say that pimozide has no FDA psychiatric indication.

Still, one of the biggest apprehensions with initiating and continuing these medications in dermatology is fear of TD. Now, dermatologists can be made aware that if this very rare side effect occurs, there are medications approved to treat TD, even if the anti-TD therapy is administered by a neurologist. For the first time, 2 medications were approved by the FDA for treatment of TD in 2017, namely valbenazine and deutetrabenazine. These medications represent a class known as vesicular monoamine transporter type 2 inhibitors and function by ultimately reducing the amount of dopamine released from the presynaptic dopaminergic neurons. In phase 3 trials for valbenazine and deutetrabenazine, 40% (N=234) and 34% (N=222) of patients, respectively, achieved a response, which was defined as at least a 50% decrease from baseline on the abnormal involuntary movement scale dyskinesia score in 6 to 12 weeks compared to 9% and 12%, respectively, with placebo.Discontinuation because of an adverse event was seldom encountered with both medications.⁶

Conclusion

The recent developments in psychodermatology with regard to DI are encouraging. The advent of new evidence and theories suggestive of an organic basis for DI could help this condition become more respected in the eyes of the dermatologist as a bona fide disorder. Moreover, the new developments and availability of medications that can treat TD can further make it easier for dermatologists to consider offering DI patients truly meaningful treatment that they desperately need. Therefore, both of these developments are welcomed for our specialty.

The management of delusional infestation (DI), also known as Morgellons disease or delusional parasitosis, can lead to some of the most difficult and stressful patient encounters in dermatology. As a specialty, dermatology providers are trained to respect scientific objectivity and pride themselves on their visual diagnostic acumen. Therefore, having to accommodate a patient’s erroneous ideations and potentially treat a psychiatric pathology poses a challenge for many dermatology providers because it requires shifting their mindset to where the subjective reality becomes the primary issue during the visit. This disconnect may lead to strife between the patient and the provider. All of these issues may make it difficult for dermatologists to connect with DI patients with the usual courtesy and consideration given to other patients. Moreover, some dermatologists find it difficult to respect the chief concern, which often is seen as purely psychological because there may be some lingering bias where psychological concerns perhaps are not seen as bona fide or legitimate disorders.

Is There a Biologic Basis for DI? A New Theory on the Etiology of Delusional Parasitosis

It is important to distinguish DI phenomenology into primary and secondary causes. Primary DI refers to cases where the delusion and formication occur spontaneously. In contrast, in secondary DI the delusion and other manifestations (eg, formication) happen secondarily to underlying broader diagnoses such as illicit substance abuse, primary psychiatric conditions including schizophrenia, organic brain syndrome, and vitamin B₁₂ deficiency.

It is well known that primary DI overwhelmingly occurs in older women, whereas secondary DI does not show this same predilection. It has been a big unanswered question as to why primary DI so often occurs not only in women but specifically in older women. The latest theory that has been advancing in Europe and is supported by some data, including magnetic resonance imaging of the brain, involves the dopamine transporter (DAT) system, which is important in making sure the dopamine level in the intersynaptic space is not excessive.¹ The DAT system is much more prominent in woman vs men and deteriorates with age due to declining estrogen levels. This age-related loss of striatal DAT is thought to be one possible etiology of DI. It has been hypothesized that decreased DAT functioning may cause an increase in extracellular striatal dopamine levels in the synapse that can lead to tactile hallucinations and delusions, which are hallmark symptoms seen in DI. Given that women experience a greater age-related DAT decline in striatal subregions than men, it is thought that primary DI mainly affects older women due to the decline of neuroprotective effects of estrogen on DAT activity with age.² Further studies should evaluate the possibility of estrogen replacement therapy for treatment of DI.

Improving Care of Psychodermatology Patients in Clinic

There are several medications that are known to be effective for the treatment of DI, including pimozide, risperidone, aripiprazole, and olanzapine, among others. Pimozide is uniquely accepted by DI patients because it has no official psychiatric indication from the US Food and Drug Administration (FDA); it is only indicated in the United States for Tourette syndrome, which is a neurologic disorder. Therefore, pimozide arguably can be disregarded as a true antipsychotic agent. The fact that its chemical structure is similar to those of bona fide antipsychotic medications does not necessarily put it in this same category, as there also are antiemetic and antitussive medications (eg, prochlorperazine, promethazine) with chemical structures similar to antipsychotics, but clinicians generally do not think of these drugs as antipsychotics despite the similarities. This nuanced and admittedly somewhat arbitrary categorization is critical to patient care; in our clinic, we have found that patients who categorically refuse to consider all psychiatric medications are much more willing to try pimozide for this very reason, that this medication can uniquely be presented to the DI patient as an agent not used in psychiatry. We have found great success in treatment with pimozide, even with relatively low doses.^3,4

One of the main reasons dermatologists are reluctant to prescribe antipsychotic medications or even pimozide is the concern for side effects, especially tardive dyskinesia (TD), which is thought to be irreversible and untreatable. However, after a half century of worldwide use of pimozide in dermatology, a PubMed search of English-language articles indexed for MEDLINE using the terms pimozide and tardive dyskinesia, tardive dyskinesia and delusions of parasitosis, tardive dyskinesia and dermatology, and tardive dyskinesia and delusional infestation/Morgellons disease yielded only 1 known case of TD reported in dermatologic use for DI.⁵ In this particular case, TD-like symptoms did not appear until after pimozide had been discontinued for 1 month. Therefore, it is not clear if this case was true TD or a condition known as withdrawal dyskinesia, which mimics TD and usually is self-limiting.⁵

The senior author (J.K.) has been using pimozide for treatment of DI for more than 30 years and has not encountered TD or any other notable side effects. The reason for this extremely low incidence of side effects may be due to its high efficacy in treating DI; hence, only a low dose of pimozide usually is needed. At the University of California, San Francisco, Psychodermatology Clinic, pimozide typically is used to treat DI at a low dose of 3 mg or less daily, starting with 0.5 or 1 mg and slowly titrating upward until a clinically effective dose is reached. Pimozide rarely is used long-term; after the resolution of symptoms, the dose usually is continued at the clinically effective dose for a few months and then is slowly tapered off. In contrast, for a condition such as schizophrenia, an antipsychotic medication often is needed at high doses for life, resulting in higher TD occurrences being reported. Therefore, even though the newer antipsychotic agents are preferable to pimozide because of their somewhat lower risk for TD, in actual clinical practice many, if not most, DI patients detest any suggestion of taking a medication for “crazy people.” Thus, we find that pimozide’s inherent superior acceptability among DI patients often is critical to enabling any effective treatment to occur at all due to the fact that the provider can honestly say that pimozide has no FDA psychiatric indication.

Still, one of the biggest apprehensions with initiating and continuing these medications in dermatology is fear of TD. Now, dermatologists can be made aware that if this very rare side effect occurs, there are medications approved to treat TD, even if the anti-TD therapy is administered by a neurologist. For the first time, 2 medications were approved by the FDA for treatment of TD in 2017, namely valbenazine and deutetrabenazine. These medications represent a class known as vesicular monoamine transporter type 2 inhibitors and function by ultimately reducing the amount of dopamine released from the presynaptic dopaminergic neurons. In phase 3 trials for valbenazine and deutetrabenazine, 40% (N=234) and 34% (N=222) of patients, respectively, achieved a response, which was defined as at least a 50% decrease from baseline on the abnormal involuntary movement scale dyskinesia score in 6 to 12 weeks compared to 9% and 12%, respectively, with placebo.Discontinuation because of an adverse event was seldom encountered with both medications.⁶

Conclusion

The recent developments in psychodermatology with regard to DI are encouraging. The advent of new evidence and theories suggestive of an organic basis for DI could help this condition become more respected in the eyes of the dermatologist as a bona fide disorder. Moreover, the new developments and availability of medications that can treat TD can further make it easier for dermatologists to consider offering DI patients truly meaningful treatment that they desperately need. Therefore, both of these developments are welcomed for our specialty.