Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.^1,2

Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.

The mechanics of erythropoiesis, hemoglobin, and oxygen transport

Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.³ Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.

Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.⁴ Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.

Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.^5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.

CASE Patient seeks treatment for HMB-associated symptoms

A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.

Untreated iron deficiency will progress to anemia

This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.³

Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.⁸ Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.

For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.⁹

Continue to: Managing iron deficiency and anemia...

 

 

Managing iron deficiency and anemia

Management of iron deficiency and iron deficiency anemia in the setting of HMB includes:

• workup for the etiology of the abnormal uterine bleeding (TABLE)
• reducing the source of blood loss, and
• iron supplementation to correct the iron deficiency state.

In most cases, workup, reduction, and repletion can occur simultaneously. The goal is not always complete cessation of menstrual bleeding; even short-term therapy can allow time to replenish iron storage. Use a shared decision-making process to assess what is important to the patient, and provide information about relative amounts of bleeding cessation that can be expected with various therapies.¹⁰

Treatment options

Medical treatments to decrease menstrual iron losses are recommended prior to proceeding with surgical interventions.¹¹ Hormonal treatments are the most consistently recommended, with many guidelines citing the 52-mg levonorgestrel-releasing intrauterine device (LNG IUD) as first-line treatment due to its substantial reduction in the amount of bleeding, HMB treatment indication approved by the US Food and Drug Administration (FDA), and evidence of success in those with HMB.¹²

Any progestin or combined hormonal medication with estrogen and a progestin will result in an approximately 60% to 90% bleeding reduction, thus providing many effective options for blood loss while considering patient preferences for bleeding pattern, route of administration, and concomitant benefits. While only 1 oral product (estradiol valerate/dienogest) is FDA approved for managementof HMB, use of any of the commercially available contraceptive products will provide substantial benefit.^11,13

Nonhormonal options, such as antifibrinolytics and nonsteroidal anti-inflammatory drugs (NSAIDs), tend to be listed as second-line therapies or for those who want to avoid hormonal medications. Antifibrinolytics, such as tranexamic acid, require frequent dosing of large pills and result in approximately 40% blood loss reduction, but they are a very successful and well-tolerated method for those seeking on-demand therapy.¹⁴ NSAIDs may result in a slight bleeding reduction, but they are far less effective than other therapies.¹⁵ Antifibrinolytics have a theoretical risk of thrombosis and a contraindication to use with hormonal contraceptives; therefore, concomitant use with estrogen-containing medications is reserved for patients with refractory heavy bleeding or for heavy bleeding days during the hormone-free interval, when benefits likely outweigh potential risk.^16,17

Guidelines for medical management of acute HMB typically cite 3 small comparative studies with high-dose regimens of parenteral conjugated estrogen, combined ethinyl estradiol and progestin, or oral medroxyprogesterone acetate.^18,19 Dosing recommendations for the oral medications include a loading dose followed by a taper regimen that is poorly tolerated and for which there is no evidence of superior effectiveness over the standard dose.^20,21 In most cases, initiation of the preferred long-term hormonal medication plan will reduce bleeding significantly within 2 to 3 days. Many clinicians who commonly treat acute HMB prescribe norethindrone acetate 5 mg daily (up to 3 times daily, if needed) for effective and safe menstrual suppression.²²

Iron replenishment: Dosing frequency, dietary iron, and multivitamins

Iron repletion is usually via the oral route unless surgery is imminent, anemia is severe, or the oral route is not tolerated or effective.²³ Oral iron has substantial adverse effects that limit tolerance, including nausea, epigastric pain, diarrhea, and constipation. Fortunately, evidence supports lower oral iron doses than previously used.⁴

Iron homeostasis is controlled by the peptide hormone hepcidin, produced by the liver, which controls mobilization of iron from the gut and spleen and aids iron absorption from the diet and supplements.²⁴ Hepcidin levels decrease in response to high circulating levels of iron, so the ideal iron repletion dose in iron-deficient nonanemic women was determined by assessing the dose response of hepcidin. Researchers compared iron 60 mg daily for 14 days versus every other day for 28 days and found that iron absorption was greater in the every-other-day group (21.8% vs 16.3%).²⁵ They concluded that changing iron administration to 60 mg or more in a single dose every other day is most efficient in those with iron deficiency without anemia. Since study participants did not have anemia, research is pending on whether different strategies (such as daily dosing) are more effective for more severe cases. The bottom line is that conventional high-dose divided daily oral iron administration results in reduced iron bioavailability compared with alternate-day dosing.

Increasing dietary iron is insufficient to treat low iron storage, iron deficiency, and iron deficiency anemia. Likewise, multivitamins, which contain very little elemental iron, are not recommended for repletion. Any iron salt with 60 to 120 mg of elemental iron can be used (for examples, ferrous sulfate, ferrous gluconate).²⁵ Once ingested, stomach and pancreatic acids release elemental iron from its bound form. For that reason, absorption may be improved by administering iron at least 1 hour before a meal and avoiding antacids, including milk. Meat proteins and ascorbic acid help maintain the soluble ferrous form and also aid absorption. Tea, coffee, and tannins prevent absorption when polyphenol compounds form an insoluble complex with iron (see box at end of article). Gastrointestinal adverse effects can be minimized by decreasing the dose and taking after meals, although with reduced efficacy.

Intravenous iron treatment raises hemoglobin levels significantly faster than oral administration but is limited by cost and availability, so it is reserved for individuals with a hemoglobin level less than 9 g/dL, prior gastrointestinal or bariatric surgery, imminent surgery, and intolerance, poor adherence, or nonresponse to oral iron therapy. Several approved formulations are available, all with equivalent effectiveness and similar safety profiles. Lower-dose formulations (such as iron sucrose) may require several infusions, but higher-dose intravenous iron products (ferric carboxymaltose, low-molecular weight iron dextran, etc) have a stable carbohydrate shell that inhibits free iron release and improves safety, allowing a single administration.²⁶

Common adverse effects of intravenous iron treatment include a metallic taste and headache during administration. More serious adverse effects, such as hypotension, arthralgia, malaise, and nausea, are usually self-limited. With mild infusion reactions (1 in 200), the infusion can be stopped until symptoms improve and can be resumed at a slower rate.²⁷

Continue to: The role of blood transfusion...

The role of blood transfusion

Blood transfusion is expensive and potentially hazardous, so its use is limited to treatment of acute blood loss or severe anemia.

A one-time red blood cell transfusion does not impact diagnostic criteria to assess for iron deficiency with ferritin, and it does not improve underlying iron deficiency.²⁸ Patients with acute blood loss anemia superimposed on chronic blood loss should be screened and treated for iron deficiency even after receiving a transfusion.

Since ferritin levels can rise significantly as an acute phase reactant, even following a hemorrhage, iron deficiency during inflammation is defined as ferritin less than 70 ng/mL.

The potential for iron overload

Since iron is never metabolized or excreted, it is possible to have iron overload following accidental overdose, transfusion dependency, and disorders of iron transport, such as hemochromatosis and thalassemia.

While a low ferritin level always indicates iron deficiency, high ferritin levels can be an acute phase reactant. Ferritin levels greater than 150 ng/mL in healthy menstruating individuals and greater than 500 ng/mL in unhealthy individuals should raise concern for excess iron and should prompt discontinuation of iron intake or workup for conditions at risk for overload.⁵

Oral iron supplements should be stored away from small children, who are at particular risk of toxicity.

How long to treat?

Treatment duration depends on the individual’s degree of iron deficiency, whether anemia is present, and the amount of ongoing blood loss. The main treatment goal is normalization and maintenance of serum ferritin.

Successful treatment should be confirmed with a complete blood count and ferritin level. Hemoglobin levels improve 2 g/dL after 3 weeks of oral iron therapy, but repletion may take 4 to 6 months.^23,29 The American College of Obstetricians and Gynecologists recommends 3 to 6 months of continued iron therapy after resolution of HMB.¹⁹

In a comparative study of treatment for HMB with the 52-mg LNG IUD versus hysterectomy, hemoglobin levels increased in both treatment groups but stayed lower in those with initial anemia.⁸ Ferritin levels normalized only after 5 years and were still lower in individuals with initial anemia.

Increase in hemoglobin is faster after intravenous iron administration but is equivalent to oral therapy by 12 weeks. If management to reduce menstrual losses is discontinued, periodic or maintenance iron repletion will be necessary.

CASE Management plan initiated

This 17-year-old patient with iron deficiency resulting from HMB requests management to reduce menstrual iron losses with a preference for predictable menses. We have already completed a basic workup, which could also include assessment for hypermobility with a Beighton score, as connective tissue disorders also are associated with HMB.³⁰ We discuss the options of cyclic hormonal therapy, antifibrinolytic treatment, and an LNG IUD. The patient is concerned about adherence and wants to avoid unscheduled bleeding, so she opts for a trial of tranexamic acid 1,300 mg 3 times daily for 5 days during menses. This regimen results in a 50% reduction in bleeding amount, which the patient finds satisfactory. Iron repletion with oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) is administered on alternating days with vitamin C taken 1 hour prior to dinner. Repeat laboratory test results at 3 weeks show improvement to a hemoglobin level of 14.2 g/dL and a ferritin level of 12 ng/mL. By 3 months, her ferritin levels are greater than 30 ng/mL and oral iron is administered only during menses.

Summing up

Chronic HMB results in a progressive net loss of iron and eventual anemia. Screening with complete blood count and ferritin and early treatment of low iron storage when ferritin is less than 30 ng/mL will help avoid symptoms. Any amount of reduction of menstrual blood loss can be beneficial, allowing a variety of effective hormonal and nonhormonal treatment options. ●

Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.^1,2

Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.

The mechanics of erythropoiesis, hemoglobin, and oxygen transport

Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.³ Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.

Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.⁴ Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.

Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.^5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.

CASE Patient seeks treatment for HMB-associated symptoms

A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.

Untreated iron deficiency will progress to anemia

This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.³

Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.⁸ Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.

For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.⁹

Continue to: Managing iron deficiency and anemia...

 

 

Managing iron deficiency and anemia

Management of iron deficiency and iron deficiency anemia in the setting of HMB includes:

• workup for the etiology of the abnormal uterine bleeding (TABLE)
• reducing the source of blood loss, and
• iron supplementation to correct the iron deficiency state.

In most cases, workup, reduction, and repletion can occur simultaneously. The goal is not always complete cessation of menstrual bleeding; even short-term therapy can allow time to replenish iron storage. Use a shared decision-making process to assess what is important to the patient, and provide information about relative amounts of bleeding cessation that can be expected with various therapies.¹⁰

Treatment options

Medical treatments to decrease menstrual iron losses are recommended prior to proceeding with surgical interventions.¹¹ Hormonal treatments are the most consistently recommended, with many guidelines citing the 52-mg levonorgestrel-releasing intrauterine device (LNG IUD) as first-line treatment due to its substantial reduction in the amount of bleeding, HMB treatment indication approved by the US Food and Drug Administration (FDA), and evidence of success in those with HMB.¹²

Any progestin or combined hormonal medication with estrogen and a progestin will result in an approximately 60% to 90% bleeding reduction, thus providing many effective options for blood loss while considering patient preferences for bleeding pattern, route of administration, and concomitant benefits. While only 1 oral product (estradiol valerate/dienogest) is FDA approved for managementof HMB, use of any of the commercially available contraceptive products will provide substantial benefit.^11,13

Nonhormonal options, such as antifibrinolytics and nonsteroidal anti-inflammatory drugs (NSAIDs), tend to be listed as second-line therapies or for those who want to avoid hormonal medications. Antifibrinolytics, such as tranexamic acid, require frequent dosing of large pills and result in approximately 40% blood loss reduction, but they are a very successful and well-tolerated method for those seeking on-demand therapy.¹⁴ NSAIDs may result in a slight bleeding reduction, but they are far less effective than other therapies.¹⁵ Antifibrinolytics have a theoretical risk of thrombosis and a contraindication to use with hormonal contraceptives; therefore, concomitant use with estrogen-containing medications is reserved for patients with refractory heavy bleeding or for heavy bleeding days during the hormone-free interval, when benefits likely outweigh potential risk.^16,17

Guidelines for medical management of acute HMB typically cite 3 small comparative studies with high-dose regimens of parenteral conjugated estrogen, combined ethinyl estradiol and progestin, or oral medroxyprogesterone acetate.^18,19 Dosing recommendations for the oral medications include a loading dose followed by a taper regimen that is poorly tolerated and for which there is no evidence of superior effectiveness over the standard dose.^20,21 In most cases, initiation of the preferred long-term hormonal medication plan will reduce bleeding significantly within 2 to 3 days. Many clinicians who commonly treat acute HMB prescribe norethindrone acetate 5 mg daily (up to 3 times daily, if needed) for effective and safe menstrual suppression.²²

Iron replenishment: Dosing frequency, dietary iron, and multivitamins

Iron repletion is usually via the oral route unless surgery is imminent, anemia is severe, or the oral route is not tolerated or effective.²³ Oral iron has substantial adverse effects that limit tolerance, including nausea, epigastric pain, diarrhea, and constipation. Fortunately, evidence supports lower oral iron doses than previously used.⁴

Iron homeostasis is controlled by the peptide hormone hepcidin, produced by the liver, which controls mobilization of iron from the gut and spleen and aids iron absorption from the diet and supplements.²⁴ Hepcidin levels decrease in response to high circulating levels of iron, so the ideal iron repletion dose in iron-deficient nonanemic women was determined by assessing the dose response of hepcidin. Researchers compared iron 60 mg daily for 14 days versus every other day for 28 days and found that iron absorption was greater in the every-other-day group (21.8% vs 16.3%).²⁵ They concluded that changing iron administration to 60 mg or more in a single dose every other day is most efficient in those with iron deficiency without anemia. Since study participants did not have anemia, research is pending on whether different strategies (such as daily dosing) are more effective for more severe cases. The bottom line is that conventional high-dose divided daily oral iron administration results in reduced iron bioavailability compared with alternate-day dosing.

Increasing dietary iron is insufficient to treat low iron storage, iron deficiency, and iron deficiency anemia. Likewise, multivitamins, which contain very little elemental iron, are not recommended for repletion. Any iron salt with 60 to 120 mg of elemental iron can be used (for examples, ferrous sulfate, ferrous gluconate).²⁵ Once ingested, stomach and pancreatic acids release elemental iron from its bound form. For that reason, absorption may be improved by administering iron at least 1 hour before a meal and avoiding antacids, including milk. Meat proteins and ascorbic acid help maintain the soluble ferrous form and also aid absorption. Tea, coffee, and tannins prevent absorption when polyphenol compounds form an insoluble complex with iron (see box at end of article). Gastrointestinal adverse effects can be minimized by decreasing the dose and taking after meals, although with reduced efficacy.

Intravenous iron treatment raises hemoglobin levels significantly faster than oral administration but is limited by cost and availability, so it is reserved for individuals with a hemoglobin level less than 9 g/dL, prior gastrointestinal or bariatric surgery, imminent surgery, and intolerance, poor adherence, or nonresponse to oral iron therapy. Several approved formulations are available, all with equivalent effectiveness and similar safety profiles. Lower-dose formulations (such as iron sucrose) may require several infusions, but higher-dose intravenous iron products (ferric carboxymaltose, low-molecular weight iron dextran, etc) have a stable carbohydrate shell that inhibits free iron release and improves safety, allowing a single administration.²⁶

Common adverse effects of intravenous iron treatment include a metallic taste and headache during administration. More serious adverse effects, such as hypotension, arthralgia, malaise, and nausea, are usually self-limited. With mild infusion reactions (1 in 200), the infusion can be stopped until symptoms improve and can be resumed at a slower rate.²⁷

Continue to: The role of blood transfusion...

The role of blood transfusion

Blood transfusion is expensive and potentially hazardous, so its use is limited to treatment of acute blood loss or severe anemia.

A one-time red blood cell transfusion does not impact diagnostic criteria to assess for iron deficiency with ferritin, and it does not improve underlying iron deficiency.²⁸ Patients with acute blood loss anemia superimposed on chronic blood loss should be screened and treated for iron deficiency even after receiving a transfusion.

Since ferritin levels can rise significantly as an acute phase reactant, even following a hemorrhage, iron deficiency during inflammation is defined as ferritin less than 70 ng/mL.

The potential for iron overload

Since iron is never metabolized or excreted, it is possible to have iron overload following accidental overdose, transfusion dependency, and disorders of iron transport, such as hemochromatosis and thalassemia.

While a low ferritin level always indicates iron deficiency, high ferritin levels can be an acute phase reactant. Ferritin levels greater than 150 ng/mL in healthy menstruating individuals and greater than 500 ng/mL in unhealthy individuals should raise concern for excess iron and should prompt discontinuation of iron intake or workup for conditions at risk for overload.⁵

Oral iron supplements should be stored away from small children, who are at particular risk of toxicity.

How long to treat?

Treatment duration depends on the individual’s degree of iron deficiency, whether anemia is present, and the amount of ongoing blood loss. The main treatment goal is normalization and maintenance of serum ferritin.

Successful treatment should be confirmed with a complete blood count and ferritin level. Hemoglobin levels improve 2 g/dL after 3 weeks of oral iron therapy, but repletion may take 4 to 6 months.^23,29 The American College of Obstetricians and Gynecologists recommends 3 to 6 months of continued iron therapy after resolution of HMB.¹⁹

In a comparative study of treatment for HMB with the 52-mg LNG IUD versus hysterectomy, hemoglobin levels increased in both treatment groups but stayed lower in those with initial anemia.⁸ Ferritin levels normalized only after 5 years and were still lower in individuals with initial anemia.

Increase in hemoglobin is faster after intravenous iron administration but is equivalent to oral therapy by 12 weeks. If management to reduce menstrual losses is discontinued, periodic or maintenance iron repletion will be necessary.

CASE Management plan initiated

This 17-year-old patient with iron deficiency resulting from HMB requests management to reduce menstrual iron losses with a preference for predictable menses. We have already completed a basic workup, which could also include assessment for hypermobility with a Beighton score, as connective tissue disorders also are associated with HMB.³⁰ We discuss the options of cyclic hormonal therapy, antifibrinolytic treatment, and an LNG IUD. The patient is concerned about adherence and wants to avoid unscheduled bleeding, so she opts for a trial of tranexamic acid 1,300 mg 3 times daily for 5 days during menses. This regimen results in a 50% reduction in bleeding amount, which the patient finds satisfactory. Iron repletion with oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) is administered on alternating days with vitamin C taken 1 hour prior to dinner. Repeat laboratory test results at 3 weeks show improvement to a hemoglobin level of 14.2 g/dL and a ferritin level of 12 ng/mL. By 3 months, her ferritin levels are greater than 30 ng/mL and oral iron is administered only during menses.

Summing up

Chronic HMB results in a progressive net loss of iron and eventual anemia. Screening with complete blood count and ferritin and early treatment of low iron storage when ferritin is less than 30 ng/mL will help avoid symptoms. Any amount of reduction of menstrual blood loss can be beneficial, allowing a variety of effective hormonal and nonhormonal treatment options. ●

Recurrent episodic blood loss from normal menstruation is not expected to result in anemia. But without treatment, chronic heavy periods will progress through the stages of low iron stores to iron deficiency and then to anemia. When iron storage levels are low, the bone marrow’s blood cell factory cannot keep up with continued losses. Every patient with heavy menstrual bleeding (HMB) or prolonged menstrual episodes should be tested and treated for iron deficiency and anemia.^1,2

Particular attention should be paid to assessment of iron storage levels with serum ferritin, recognizing that low iron levels progress to anemia once the storage is depleted. Recovery from anemia is much slower in individuals with iron deficiency, so assessment for iron storage also should be included in preoperative assessments and following a diagnosis of acute blood loss anemia.

The mechanics of erythropoiesis, hemoglobin, and oxygen transport

Red blood cells (erythrocytes) have a short life cycle and require constant replacement. Erythrocytes are generated on demand in erythropoiesis by a hormonal signaling process, regardless of whether sufficient components are available.³ Hemoglobin, the main intracellular component of erythrocytes, is comprised of 4 globin chains, which each contain 1 iron atom bound to a heme molecule. After erythrocytes are assembled, they are sent out into circulation for approximately 120 days. A hemoglobin level measures the oxygen-carrying capacity of erythrocytes, and anemia is defined as hemoglobin less than 12 g/dL.

Unless erythrocytes are lost from bleeding, they are decommissioned—that is, the heme molecule is metabolized into bilirubin and excreted, and the iron atoms are recycled back to the bone marrow or to storage.⁴ Ferritin is the storage molecule that binds to iron, a glycoprotein with numerous subunits around a core that can contain about 4,000 iron atoms. Most ferritin is intracellular, but a small proportion is present in serum, where it can be measured.

Serum ferritin is a good marker for the iron supply in healthy individuals because it has high correlation to iron in the bone marrow and correlates to total intracellular storage unless there is inflammation, when mobilization to serum increases. The ferritin level at which the iron supply is deficient to meet demand, defined as iron deficiency, is hotly debated and ranges from less than 15 to 50 ng/mL in menstruating individuals, with higher thresholds based on onset of erythropoiesis signaling and the lower threshold being the World Health Organization recommendation.^5-7 When iron atoms are in short supply, erythrocytes still are generated but they have lower amounts of intracellular hemoglobin, which makes them thinner, smaller, and paler—and less effective at oxygen transport.

CASE Patient seeks treatment for HMB-associated symptoms

A 17-year-old patient presents with HMB, fatigue, and difficulty with concentration. She reports that her periods have been regular and lasting 7 days since menarche at age 13. While they are manageable, they seem to be getting heavier, soaking pads in 2 to 3 hours. The patient reports that she would like to start treatment for her progressively heavy bleeding and prefers lighter scheduled bleeding; she currently does not desire contraception. The patient has no family history of bleeding problems and self-reports no personal history of epistaxis or bleeding with tooth extraction or tonsillectomy. Laboratory tests confirm iron deficiency with a hemoglobin level of 12.5 g/dL (reference range, 12.0–17.5 g/dL) and a serum ferritin level of 8 ng/mL (reference range, 50–420 ng/mL). Results from a coagulopathy panel are normal, as are von Willebrand factor levels.

Untreated iron deficiency will progress to anemia

This patient has iron deficiency without anemia, which warrants significant attention in HMB because without treatment it eventually will progress to anemia. The prevalence of iron deficiency, which makes up half of all causes of anemia, is at least double that of iron deficiency anemia.³

Adult bodies usually contain about 3 to 4 g of iron, with two-thirds in erythrocytes as hemoglobin.⁸ Approximately 40 to 60 mg of iron is recycled daily, 1 to 2 mg/day is lost from sloughed cells and sweat, and at least 1 mg/day is lost during normal menstruation. These losses are balanced with gastrointestinal uptake of 1 to 2 mg/day until bleeding exceeds about 10 mL/day. In this 17-year-old patient, iron stores have likely been on a progressive decline since menarche.

For normally menstruating individuals to maintain iron homeostasis, the daily dietary iron requirement is 18 mg/day. Iron requirements also increase during periods of illness or inflammation due to hormonal signaling in the iron absorption and transport pathway, in athletes due to sweating, foot strike hemolysis and bruising, and during growth spurts.⁹

Continue to: Managing iron deficiency and anemia...

 

 

Managing iron deficiency and anemia

Management of iron deficiency and iron deficiency anemia in the setting of HMB includes:

• workup for the etiology of the abnormal uterine bleeding (TABLE)
• reducing the source of blood loss, and
• iron supplementation to correct the iron deficiency state.

In most cases, workup, reduction, and repletion can occur simultaneously. The goal is not always complete cessation of menstrual bleeding; even short-term therapy can allow time to replenish iron storage. Use a shared decision-making process to assess what is important to the patient, and provide information about relative amounts of bleeding cessation that can be expected with various therapies.¹⁰

Treatment options

Medical treatments to decrease menstrual iron losses are recommended prior to proceeding with surgical interventions.¹¹ Hormonal treatments are the most consistently recommended, with many guidelines citing the 52-mg levonorgestrel-releasing intrauterine device (LNG IUD) as first-line treatment due to its substantial reduction in the amount of bleeding, HMB treatment indication approved by the US Food and Drug Administration (FDA), and evidence of success in those with HMB.¹²

Any progestin or combined hormonal medication with estrogen and a progestin will result in an approximately 60% to 90% bleeding reduction, thus providing many effective options for blood loss while considering patient preferences for bleeding pattern, route of administration, and concomitant benefits. While only 1 oral product (estradiol valerate/dienogest) is FDA approved for managementof HMB, use of any of the commercially available contraceptive products will provide substantial benefit.^11,13

Nonhormonal options, such as antifibrinolytics and nonsteroidal anti-inflammatory drugs (NSAIDs), tend to be listed as second-line therapies or for those who want to avoid hormonal medications. Antifibrinolytics, such as tranexamic acid, require frequent dosing of large pills and result in approximately 40% blood loss reduction, but they are a very successful and well-tolerated method for those seeking on-demand therapy.¹⁴ NSAIDs may result in a slight bleeding reduction, but they are far less effective than other therapies.¹⁵ Antifibrinolytics have a theoretical risk of thrombosis and a contraindication to use with hormonal contraceptives; therefore, concomitant use with estrogen-containing medications is reserved for patients with refractory heavy bleeding or for heavy bleeding days during the hormone-free interval, when benefits likely outweigh potential risk.^16,17

Guidelines for medical management of acute HMB typically cite 3 small comparative studies with high-dose regimens of parenteral conjugated estrogen, combined ethinyl estradiol and progestin, or oral medroxyprogesterone acetate.^18,19 Dosing recommendations for the oral medications include a loading dose followed by a taper regimen that is poorly tolerated and for which there is no evidence of superior effectiveness over the standard dose.^20,21 In most cases, initiation of the preferred long-term hormonal medication plan will reduce bleeding significantly within 2 to 3 days. Many clinicians who commonly treat acute HMB prescribe norethindrone acetate 5 mg daily (up to 3 times daily, if needed) for effective and safe menstrual suppression.²²

Iron replenishment: Dosing frequency, dietary iron, and multivitamins

Iron repletion is usually via the oral route unless surgery is imminent, anemia is severe, or the oral route is not tolerated or effective.²³ Oral iron has substantial adverse effects that limit tolerance, including nausea, epigastric pain, diarrhea, and constipation. Fortunately, evidence supports lower oral iron doses than previously used.⁴

Iron homeostasis is controlled by the peptide hormone hepcidin, produced by the liver, which controls mobilization of iron from the gut and spleen and aids iron absorption from the diet and supplements.²⁴ Hepcidin levels decrease in response to high circulating levels of iron, so the ideal iron repletion dose in iron-deficient nonanemic women was determined by assessing the dose response of hepcidin. Researchers compared iron 60 mg daily for 14 days versus every other day for 28 days and found that iron absorption was greater in the every-other-day group (21.8% vs 16.3%).²⁵ They concluded that changing iron administration to 60 mg or more in a single dose every other day is most efficient in those with iron deficiency without anemia. Since study participants did not have anemia, research is pending on whether different strategies (such as daily dosing) are more effective for more severe cases. The bottom line is that conventional high-dose divided daily oral iron administration results in reduced iron bioavailability compared with alternate-day dosing.

Increasing dietary iron is insufficient to treat low iron storage, iron deficiency, and iron deficiency anemia. Likewise, multivitamins, which contain very little elemental iron, are not recommended for repletion. Any iron salt with 60 to 120 mg of elemental iron can be used (for examples, ferrous sulfate, ferrous gluconate).²⁵ Once ingested, stomach and pancreatic acids release elemental iron from its bound form. For that reason, absorption may be improved by administering iron at least 1 hour before a meal and avoiding antacids, including milk. Meat proteins and ascorbic acid help maintain the soluble ferrous form and also aid absorption. Tea, coffee, and tannins prevent absorption when polyphenol compounds form an insoluble complex with iron (see box at end of article). Gastrointestinal adverse effects can be minimized by decreasing the dose and taking after meals, although with reduced efficacy.

Intravenous iron treatment raises hemoglobin levels significantly faster than oral administration but is limited by cost and availability, so it is reserved for individuals with a hemoglobin level less than 9 g/dL, prior gastrointestinal or bariatric surgery, imminent surgery, and intolerance, poor adherence, or nonresponse to oral iron therapy. Several approved formulations are available, all with equivalent effectiveness and similar safety profiles. Lower-dose formulations (such as iron sucrose) may require several infusions, but higher-dose intravenous iron products (ferric carboxymaltose, low-molecular weight iron dextran, etc) have a stable carbohydrate shell that inhibits free iron release and improves safety, allowing a single administration.²⁶

Common adverse effects of intravenous iron treatment include a metallic taste and headache during administration. More serious adverse effects, such as hypotension, arthralgia, malaise, and nausea, are usually self-limited. With mild infusion reactions (1 in 200), the infusion can be stopped until symptoms improve and can be resumed at a slower rate.²⁷

Continue to: The role of blood transfusion...

The role of blood transfusion

Blood transfusion is expensive and potentially hazardous, so its use is limited to treatment of acute blood loss or severe anemia.

A one-time red blood cell transfusion does not impact diagnostic criteria to assess for iron deficiency with ferritin, and it does not improve underlying iron deficiency.²⁸ Patients with acute blood loss anemia superimposed on chronic blood loss should be screened and treated for iron deficiency even after receiving a transfusion.

Since ferritin levels can rise significantly as an acute phase reactant, even following a hemorrhage, iron deficiency during inflammation is defined as ferritin less than 70 ng/mL.

The potential for iron overload

Since iron is never metabolized or excreted, it is possible to have iron overload following accidental overdose, transfusion dependency, and disorders of iron transport, such as hemochromatosis and thalassemia.

While a low ferritin level always indicates iron deficiency, high ferritin levels can be an acute phase reactant. Ferritin levels greater than 150 ng/mL in healthy menstruating individuals and greater than 500 ng/mL in unhealthy individuals should raise concern for excess iron and should prompt discontinuation of iron intake or workup for conditions at risk for overload.⁵

Oral iron supplements should be stored away from small children, who are at particular risk of toxicity.

How long to treat?

Treatment duration depends on the individual’s degree of iron deficiency, whether anemia is present, and the amount of ongoing blood loss. The main treatment goal is normalization and maintenance of serum ferritin.

Successful treatment should be confirmed with a complete blood count and ferritin level. Hemoglobin levels improve 2 g/dL after 3 weeks of oral iron therapy, but repletion may take 4 to 6 months.^23,29 The American College of Obstetricians and Gynecologists recommends 3 to 6 months of continued iron therapy after resolution of HMB.¹⁹

In a comparative study of treatment for HMB with the 52-mg LNG IUD versus hysterectomy, hemoglobin levels increased in both treatment groups but stayed lower in those with initial anemia.⁸ Ferritin levels normalized only after 5 years and were still lower in individuals with initial anemia.

Increase in hemoglobin is faster after intravenous iron administration but is equivalent to oral therapy by 12 weeks. If management to reduce menstrual losses is discontinued, periodic or maintenance iron repletion will be necessary.

CASE Management plan initiated

This 17-year-old patient with iron deficiency resulting from HMB requests management to reduce menstrual iron losses with a preference for predictable menses. We have already completed a basic workup, which could also include assessment for hypermobility with a Beighton score, as connective tissue disorders also are associated with HMB.³⁰ We discuss the options of cyclic hormonal therapy, antifibrinolytic treatment, and an LNG IUD. The patient is concerned about adherence and wants to avoid unscheduled bleeding, so she opts for a trial of tranexamic acid 1,300 mg 3 times daily for 5 days during menses. This regimen results in a 50% reduction in bleeding amount, which the patient finds satisfactory. Iron repletion with oral ferrous sulfate 325 mg (containing 65 mg of elemental iron) is administered on alternating days with vitamin C taken 1 hour prior to dinner. Repeat laboratory test results at 3 weeks show improvement to a hemoglobin level of 14.2 g/dL and a ferritin level of 12 ng/mL. By 3 months, her ferritin levels are greater than 30 ng/mL and oral iron is administered only during menses.

Summing up

Chronic HMB results in a progressive net loss of iron and eventual anemia. Screening with complete blood count and ferritin and early treatment of low iron storage when ferritin is less than 30 ng/mL will help avoid symptoms. Any amount of reduction of menstrual blood loss can be beneficial, allowing a variety of effective hormonal and nonhormonal treatment options. ●

NEW ORLEANS – Assessing underlying mechanisms for the effects of age, mean platelet volume (MPV), and tryptase may help identify pediatric patients with chronic spontaneous urticaria (CSU) who will respond to different treatment options, results from a single-center prospective study showed.

“Given that the majority of CSU cases in adults are due to autoimmunity and there being very [few] studies on biomarkers for CSU in children, our study furthers our current understanding of the role of different biomarkers in treatment response,” lead study author Alex Nguyen, MsC, said in an interview at the annual meeting of the American Academy of Dermatology, where the study was presented during a poster session.

NEW ORLEANS – Assessing underlying mechanisms for the effects of age, mean platelet volume (MPV), and tryptase may help identify pediatric patients with chronic spontaneous urticaria (CSU) who will respond to different treatment options, results from a single-center prospective study showed.

“Given that the majority of CSU cases in adults are due to autoimmunity and there being very [few] studies on biomarkers for CSU in children, our study furthers our current understanding of the role of different biomarkers in treatment response,” lead study author Alex Nguyen, MsC, said in an interview at the annual meeting of the American Academy of Dermatology, where the study was presented during a poster session.

NEW ORLEANS – Assessing underlying mechanisms for the effects of age, mean platelet volume (MPV), and tryptase may help identify pediatric patients with chronic spontaneous urticaria (CSU) who will respond to different treatment options, results from a single-center prospective study showed.

“Given that the majority of CSU cases in adults are due to autoimmunity and there being very [few] studies on biomarkers for CSU in children, our study furthers our current understanding of the role of different biomarkers in treatment response,” lead study author Alex Nguyen, MsC, said in an interview at the annual meeting of the American Academy of Dermatology, where the study was presented during a poster session.

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

NEW ORLEANS – All but one Janus kinase (JAK) inhibitor with dermatologic indications carries a boxed warning that lists multiple risks for drugs in this class, including the risk of major adverse cardiac events (MACE), even though the basis for all the risks is a rheumatoid arthritis study, according to a critical review at the annual meeting of the American Academy of Dermatology.  

Given the fact that the postmarketing RA study was specifically enriched with high-risk patients by requiring an age at enrollment of at least 50 years and the presence of at least one cardiovascular risk factor, the extrapolation of these risks to dermatologic indications is “not necessarily data-driven,” said Brett A. King, MD, PhD, associate professor of dermatology, Yale University, New Haven, Conn.

The recently approved deucravacitinib is the only JAK inhibitor that has so far been exempt from these warnings. Instead, based on the ORAL Surveillance study, published in the New England Journal of Medicine, the Food and Drug Administration requires a boxed warning in nearly identical language for all the other JAK inhibitors. Relative to tofacitinib, the JAK inhibitor tested in ORAL Surveillance, many of these drugs differ by JAK selectivity and other characteristics that are likely relevant to risk of adverse events, Dr. King said. The same language has even been applied to topical ruxolitinib cream. 
 

Basis of boxed warnings

In ORAL Surveillance, about 4,300 high-risk patients with RA were randomized to one of two doses of tofacitinib (5 mg or 10 mg) twice daily or a tumor necrosis factor (TNF) inhibitor. All patients in the trial were taking methotrexate, and almost 60% were taking concomitant corticosteroids. The average body mass index of the study population was about 30 kg/m².

After a median 4 years of follow-up (about 5,000 patient-years), the incidence of many of the adverse events tracked in the study were higher in the tofacitinib groups, including serious infections, MACE, thromboembolic events, and cancer. Dr. King did not challenge the importance of these data, but he questioned whether they are reasonably extrapolated to dermatologic indications, particularly as many of those treated are younger than those common to an RA population.

In fact, despite a study enriched for a higher risk of many events tracked, most adverse events were only slightly elevated, Dr. King pointed out. For example, the incidence of MACE over the 4 years of follow-up was 3.4% among those taking any dose of tofacitinib versus 2.5% of those randomized to TNF inhibitor. Rates of cancer were 4.2% versus 2.9%, respectively. There were also absolute increases in the number of serious infections and thromboembolic events for tofacitinib relative to TNF inhibitor.

Dr. King acknowledged that the numbers in ORAL Surveillance associated tofacitinib with a higher risk of serious events than TNF inhibitor in patients with RA, but he believes that “JAK inhibitor safety is almost certainly not the same in dermatology as it is in rheumatology patients.”
 

Evidence of difference in dermatology

There is some evidence to back this up. Dr. King cited a recently published study in RMD Open that evaluated the safety profile of the JAK inhibitor upadacitinib in nearly 7,000 patients over 15,000 patient-years of follow-up. Drug safety data were evaluated with up to 5.5 years of follow-up from 12 clinical trials of the four diseases for which upadacitinib is now indicated. Three were rheumatologic (RA, psoriatic arthritis, and ankylosing spondylitis), and the fourth was atopic dermatitis (AD). Fourteen outcomes, including numerous types of infection, MACE, hepatic complications, and malignancy, were compared with methotrexate and the TNF inhibitor adalimumab.

For the RA diseases, upadacitinib was associated with a greater risk than comparators for several outcomes, including serious infections. But in AD, there was a smaller increased risk of adverse outcomes for the JAK inhibitor relative to comparators.

When evaluated by risk of adverse events across indications, for MACE, the exposure-adjusted event rates for upadacitinib were less than 0.1 in patients treated for AD over the observation period versus 0.3 and 0.4 for RA and psoriatic arthritis, respectively. Similarly, for venous thromboembolism, the rates for upadacitinib were again less than 0.1 in patients with AD versus 0.4 and 0.2 in RA and psoriatic arthritis, respectively.

Referring back to the postmarketing study, Dr. King emphasized that it is essential to consider how the boxed warning for JAK inhibitors was generated before applying them to dermatologic indications.

“Is a 30-year-old patient with a dermatologic disorder possibly at the same risk as the patients in the study from which we got the boxed warning? The answer is simply no,” he said.

Like the tofacitinib data in the ORAL Surveillance study, the upadacitinib clinical trial data are not necessarily relevant to other JAK inhibitors. In fact, Dr. King pointed out that the safety profiles of the available JAK inhibitors are not identical, an observation that is consistent with differences in JAK inhibitor selectivity that has implications for off-target events.  

Dr. King does not dismiss the potential risks outlined in the current regulatory cautions about the use of JAK inhibitors, but he believes that dermatologists should be cognizant of “where the black box warning comes from.”

“We need to think carefully about the risk-to-benefit ratio in older patients or patients with risk factors, such as obesity and diabetes,” he said. But the safety profile of JAK inhibitors “is almost certainly better” than the profile suggested in boxed warnings applied to JAK inhibitors for dermatologic indications, he advised.
 

Risk-benefit considerations in dermatology

This position was supported by numerous other experts when asked for their perspectives. “I fully agree,” said Emma Guttman-Yassky, MD, PhD, system chair of dermatology and immunology, Icahn School of Medicine, Mount Sinai, New York.

Like Dr. King, Dr. Guttman-Yassky did not dismiss the potential risks of JAK inhibitors when treating dermatologic diseases.

“While JAK inhibitors need monitoring as advised, adopting a boxed warning from an RA study for patients who are older [is problematic],” she commented. A study with the nonselective tofacitinib in this population “cannot be compared to more selective inhibitors in a much younger population, such as those treated [for] alopecia areata or atopic dermatitis.”

George Z. Han, MD, PhD, an associate professor of dermatology, Zucker School of Medicine, Hofstra, Northwell Medical Center, New Hyde Park, New York, also agreed but added some caveats.

“The comments about the ORAL Surveillance study are salient,” he said in an interview. “This kind of data should not directly be extrapolated to other patient types or to other medications.” However, one of Dr. Han’s most important caveats involves long-term use.

“JAK inhibitors are still relatively narrow-therapeutic-window drugs that in a dose-dependent fashion could lead to negative effects, including thromboembolic events, abnormalities in red blood cells, white blood cells, platelets, and lipids,” he said. While doses used in dermatology “are generally below the level of any major concern,” Dr. Han cautioned that “we lack definitive data” on long-term use, and this is important for understanding “any potential small risk of rare events, such as malignancy or thromboembolism.”

Saakshi Khattri, MD, a colleague of Dr. Guttman-Yassky at Mount Sinai, said the risks of JAK inhibitors should not be underestimated, but she also agreed that risk “needs to be delivered in the right context.” Dr. Khattri, who is board certified in both dermatology and rheumatology, noted the safety profiles of available JAK inhibitors differ and that extrapolating safety from an RA study to dermatologic indications does not make sense. “Different diseases, different age groups,” she said.

Dr. King has reported financial relationships with more than 15 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Han reports financial relationships with Amgen, Athenex, Boehringer Ingelheim, Bond Avillion, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, PellePharm, Pfizer, and UCB. Dr. Khattri has reported financial relationships with AbbVie, Arcutis, Bristol-Myers Squibb, Janssen, Leo, Lilly, Novartis, Pfizer, and UCB.

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

The only true wisdom is in knowing you know nothing. – Socrates

At what age is one supposed to be wise? I feel like I’m falling behind. I’ve crossed the middle of life and can check the prerequisite experiences: Joy, tragedy, love, adventure, love again. I lived a jetsetter life with an overnight bag always packed. I’ve sported the “Dad AF” tee with a fully loaded dad-pack. I’ve seen the 50 states and had my picture wrapped on a city bus (super-weird when you pull up next to one). Yet, when a moment arrives to pop in pithy advice for a resident or drop a few reassuring lines for a grieving friend, I’m often unable to find the words. If life were a video game, I’ve not earned the wisdom level yet.

Who are the wise men and women in your life? It’s difficult to list them. This is because it’s a complex attribute and hard to explain. It’s also because the wise who walk among us are rare. Wise is more than being brilliant at bullous diseases or knowing how to sleep train a baby. Nor is wise the buddy who purchased $1,000 of Bitcoin in 2010 (although stay close with him, he probably owns a jet). Neither content experts nor lucky friends rise to the appellation. To be wise you have to not only make good decisions, but also offer good advice. You need both knowledge and insight. Both experience and empathy.

Public domain/Wikimedia Commons

The ancients considered wisdom to be one of the vital virtues. It was personified in high-profile gods like Apollo and Athena. It’s rare and important enough to be seen as spiritual. It features heavily in the Bible, the Bhagavad Gita, the Meditations of Marcus Aurelius. In some cultures the wise are called elders or sages. In all cultures they are helpful, respected, sought after, appreciated. We need more wise people in this game of life. I want to be one. But there’s no Coursera for it.

To become wise you have to pass through many levels, put in a lot of reps, suffer through many sleepless nights. Like the third molar, also known as the wisdom tooth, it takes years. You also have to emerge stronger and smarter through those experiences. FDR would not have become one of the wisest presidents in history had it not been for his trials, and victories, over polio. Osler missed Cushing syndrome multiple times before he got it right. It seems you have to go to the mountain, like Batman, and fight a few battles to realize your full wisdom potential.

You must also reflect on your experiences and hone your insight. The management sage Peter Drucker would write what he expected to happen after a decision. Then he’d return to it to hone his intuition and judgment.

Lastly, you have to use your powers for good. Using insight to win your NCAA bracket pool isn’t wisdom. Helping a friend whose marriage is falling apart or colleague whose patient is suing them or a resident whose excision hit an arteriole surely is.

I’ve got a ways to go before anyone puts me on their wise friend list. I’m working on it though. Perhaps you will too – we are desperately short-staffed in this area. For now, I can start with writing better condolences.



“Who maintains that it is not a heavy blow? But it is part of being human.” – Seneca

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

The only true wisdom is in knowing you know nothing. – Socrates

At what age is one supposed to be wise? I feel like I’m falling behind. I’ve crossed the middle of life and can check the prerequisite experiences: Joy, tragedy, love, adventure, love again. I lived a jetsetter life with an overnight bag always packed. I’ve sported the “Dad AF” tee with a fully loaded dad-pack. I’ve seen the 50 states and had my picture wrapped on a city bus (super-weird when you pull up next to one). Yet, when a moment arrives to pop in pithy advice for a resident or drop a few reassuring lines for a grieving friend, I’m often unable to find the words. If life were a video game, I’ve not earned the wisdom level yet.

Who are the wise men and women in your life? It’s difficult to list them. This is because it’s a complex attribute and hard to explain. It’s also because the wise who walk among us are rare. Wise is more than being brilliant at bullous diseases or knowing how to sleep train a baby. Nor is wise the buddy who purchased $1,000 of Bitcoin in 2010 (although stay close with him, he probably owns a jet). Neither content experts nor lucky friends rise to the appellation. To be wise you have to not only make good decisions, but also offer good advice. You need both knowledge and insight. Both experience and empathy.

Public domain/Wikimedia Commons

The ancients considered wisdom to be one of the vital virtues. It was personified in high-profile gods like Apollo and Athena. It’s rare and important enough to be seen as spiritual. It features heavily in the Bible, the Bhagavad Gita, the Meditations of Marcus Aurelius. In some cultures the wise are called elders or sages. In all cultures they are helpful, respected, sought after, appreciated. We need more wise people in this game of life. I want to be one. But there’s no Coursera for it.

To become wise you have to pass through many levels, put in a lot of reps, suffer through many sleepless nights. Like the third molar, also known as the wisdom tooth, it takes years. You also have to emerge stronger and smarter through those experiences. FDR would not have become one of the wisest presidents in history had it not been for his trials, and victories, over polio. Osler missed Cushing syndrome multiple times before he got it right. It seems you have to go to the mountain, like Batman, and fight a few battles to realize your full wisdom potential.

You must also reflect on your experiences and hone your insight. The management sage Peter Drucker would write what he expected to happen after a decision. Then he’d return to it to hone his intuition and judgment.

Lastly, you have to use your powers for good. Using insight to win your NCAA bracket pool isn’t wisdom. Helping a friend whose marriage is falling apart or colleague whose patient is suing them or a resident whose excision hit an arteriole surely is.

I’ve got a ways to go before anyone puts me on their wise friend list. I’m working on it though. Perhaps you will too – we are desperately short-staffed in this area. For now, I can start with writing better condolences.



“Who maintains that it is not a heavy blow? But it is part of being human.” – Seneca

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

The only true wisdom is in knowing you know nothing. – Socrates

At what age is one supposed to be wise? I feel like I’m falling behind. I’ve crossed the middle of life and can check the prerequisite experiences: Joy, tragedy, love, adventure, love again. I lived a jetsetter life with an overnight bag always packed. I’ve sported the “Dad AF” tee with a fully loaded dad-pack. I’ve seen the 50 states and had my picture wrapped on a city bus (super-weird when you pull up next to one). Yet, when a moment arrives to pop in pithy advice for a resident or drop a few reassuring lines for a grieving friend, I’m often unable to find the words. If life were a video game, I’ve not earned the wisdom level yet.

Who are the wise men and women in your life? It’s difficult to list them. This is because it’s a complex attribute and hard to explain. It’s also because the wise who walk among us are rare. Wise is more than being brilliant at bullous diseases or knowing how to sleep train a baby. Nor is wise the buddy who purchased $1,000 of Bitcoin in 2010 (although stay close with him, he probably owns a jet). Neither content experts nor lucky friends rise to the appellation. To be wise you have to not only make good decisions, but also offer good advice. You need both knowledge and insight. Both experience and empathy.

Public domain/Wikimedia Commons

The ancients considered wisdom to be one of the vital virtues. It was personified in high-profile gods like Apollo and Athena. It’s rare and important enough to be seen as spiritual. It features heavily in the Bible, the Bhagavad Gita, the Meditations of Marcus Aurelius. In some cultures the wise are called elders or sages. In all cultures they are helpful, respected, sought after, appreciated. We need more wise people in this game of life. I want to be one. But there’s no Coursera for it.

To become wise you have to pass through many levels, put in a lot of reps, suffer through many sleepless nights. Like the third molar, also known as the wisdom tooth, it takes years. You also have to emerge stronger and smarter through those experiences. FDR would not have become one of the wisest presidents in history had it not been for his trials, and victories, over polio. Osler missed Cushing syndrome multiple times before he got it right. It seems you have to go to the mountain, like Batman, and fight a few battles to realize your full wisdom potential.

You must also reflect on your experiences and hone your insight. The management sage Peter Drucker would write what he expected to happen after a decision. Then he’d return to it to hone his intuition and judgment.

Lastly, you have to use your powers for good. Using insight to win your NCAA bracket pool isn’t wisdom. Helping a friend whose marriage is falling apart or colleague whose patient is suing them or a resident whose excision hit an arteriole surely is.

I’ve got a ways to go before anyone puts me on their wise friend list. I’m working on it though. Perhaps you will too – we are desperately short-staffed in this area. For now, I can start with writing better condolences.



“Who maintains that it is not a heavy blow? But it is part of being human.” – Seneca

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

Lanolin, known mainly for its emollient properties, has been named by the American Contact Dermatitis Society as the Contact Allergen of the Year for 2023.

Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.

Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.

“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.

“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”

And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.

“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
 

Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.

Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.

Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
 

Consider high-risk groups

Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.

Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.

Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”

Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.

Lanolin, known mainly for its emollient properties, has been named by the American Contact Dermatitis Society as the Contact Allergen of the Year for 2023.

Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.

Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.

“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.

“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”

And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.

“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
 

Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.

Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.

Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
 

Consider high-risk groups

Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.

Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.

Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”

Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.

Lanolin, known mainly for its emollient properties, has been named by the American Contact Dermatitis Society as the Contact Allergen of the Year for 2023.

Lanolin is a complex and varying mixture of high molecular weight esters, aliphatic alcohols, sterols, fatty acids, and hydrocarbons, but the allergic components are mainly the free lanolin alcohols, especially alkanediols, said Donald V. Belsito, MD, professor of dermatology, Columbia University, New York, who announced the Allergen of the Year at the society’s annual meeting.

Criteria for selection can include a known allergen with a new twist or increasing frequency or a newly reported allergen with mini-epidemics that may have been missed for years, Dr. Belsito said.

“The prevalence and severity of allergy to ‘lanolin’ have been hotly debated” since a potential case was first reported in the 1920s, wrote Dr. Belsito and Blair A. Jenkins, MD, PhD, a dermatology resident at New York–Presbyterian Hospital, Columbia Campus, in a review published in Dermatitis.

“ ‘Lanolin’ is indeed a paradox allergen,” wrote Dr. Jenkins and Dr. Belsito. “The most appropriate patch test preparation(s) for detecting allergy remain disputed. Detection of lanolin-induced contact dermatitis in diseased skin by patch testing on normal skin may lead to false negative results.”

And those who test positive for a lanolin allergy on diseased skin may be able to use lanolin products on normal skin, they wrote.

“From my perspective, this was a timely year to think about lanolin, as there is significant ongoing controversy about whether it is allergenic,” Dr. Jenkins said in an interview. “Numerous companies market lanolin-containing topicals as safe and effective emollients,” she said.
 

Medical grade and highly purified anhydrous lanolin, which contain less than 2.5% and less than 1.5% of free alcohols, respectively, can still elicit or induce a contact allergy, Dr. Belsito said in his presentation. Hydrogenated lanolin has shown more allergenicity than lanolin alcohol, while lanolin wax, lanolin acid, and lanolin esters possess lower allergenicity than lanolin alcohol, he said.

Notably, modern wool textiles do not contain lanolin, and lanolin-allergic patients need not avoid wool, Dr. Belsito added.

Amerchol L-101, a common trade name on products containing lanolin, contains 10% wool wax alcohols obtained from the hydrolysis of wool fat dissolved in mineral oil at a 1:1 ratio, said Dr. Belsito. He recommended testing lanolin alcohols (in 30% petrolatum) and Amerchol L-101 (in 50% petrolatum) simultaneously with or without other lanolin derivatives and/or the patient’s products in cases of possible allergy, he said.
 

Consider high-risk groups

Current evidence suggests that the prevalence of contact allergy in the western European population is 0.4%, wrote Dr. Jenkins and Dr. Belsito.

Although the frequency of lanolin allergy is relatively low, certain conditions convey greater risk, such as stasis dermatitis, leg ulcers, perianal/genital dermatitis, and atopic dermatitis, they wrote. Older adults and children are at increased risk because they are more likely to have these conditions. Demographic data also suggest that lanolin allergy is more common in non-Hispanic Whites than in non-Hispanic Blacks, they wrote.

Looking ahead, “I think further exploration of allergy across different skin types and ethnicities is warranted,” Dr. Jenkins said. “Further investigation of ideal [lanolin] allergens for patch testing is also needed.”

Dr. Jenkins and Dr. Belsito said they had no relevant financial conflicts to disclose.

NEW ORLEANS – Among the 10 most viewed YouTube videos regarding topical steroid withdrawal, patient testimonials had the poorest quality and reliability of all information sources, results from a novel analysis showed.

“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”

Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.

Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”

The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.

“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.

Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.

Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”

One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”

Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.

NEW ORLEANS – Among the 10 most viewed YouTube videos regarding topical steroid withdrawal, patient testimonials had the poorest quality and reliability of all information sources, results from a novel analysis showed.

“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”

Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.

Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”

The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.

“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.

Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.

Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”

One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”

Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.

NEW ORLEANS – Among the 10 most viewed YouTube videos regarding topical steroid withdrawal, patient testimonials had the poorest quality and reliability of all information sources, results from a novel analysis showed.

“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”

Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.

Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”

The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.

“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.

Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.

Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”

One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”

Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.

A common chemical that is used in correction fluid, paint removers, gun cleaners, aerosol cleaning products, and dry cleaning may be the key culprit behind the dramatic increase in Parkinson’s disease (PD), researchers say.

An international team of researchers reviewed previous research and cited data that suggest the chemical trichloroethylene (TCE) is associated with as much as a 500% increased risk for Parkinson’s disease (PD).

Lead investigator Ray Dorsey, MD, professor of neurology, University of Rochester, N.Y., called PD “the world’s fastest-growing brain disease,” and told this news organization that it “may be largely preventable.”

“Countless people have died over generations from cancer and other disease linked to TCE [and] Parkinson’s may be the latest,” he said. “Banning these chemicals, containing contaminated sites, and protecting homes, schools, and buildings at risk may all create a world where Parkinson’s is increasingly rare, not common.”

The paper was published online in the Journal of Parkinson’s Disease.
 

Invisible, ubiquitous

TCE was first synthesized in a lab in 1864, with commercial production beginning in 1920, the researchers noted.

“Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications,” including producing refrigerants, cleaning electronics, and degreasing engine parts.

In addition, it’s been used in dry cleaning, although a similar chemical (perchloroethylene [PCE]) is currently more widely used for that purpose. Nevertheless, the authors noted, in anaerobic conditions, perchloroethylene often transforms into TCE “and their toxicity may be similar.”

Consumer products in which TCE is found include typewriter correction fluid, paint removers, gun cleaners, and aerosol cleaning products. Up until the 1970s, it was used to decaffeinate coffee.

TCE exposure isn’t confined to those who work with it. It also pollutes outdoor air, taints groundwater, and contaminates indoor air. It’s present in a substantial amount of groundwater in the United States and it “evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected,” the researchers noted.

“Exposure can come via occupation or the environment and is often largely unknown at the time it occurs,” Dr. Dorsey said.

He noted that the rapid increase in PD incidence cannot be explained by genetic factors alone, which affect only about 15% of patients with PD, nor can it be explained by aging alone. “Certain pesticides ... are likely causes but would not explain the high prevalence of PD in urban areas, as is the case in the U.S.” Rather, “other factors” are involved, and “TCE is likely one such factor.”

Yet, “despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited.”

To fill this knowledge gap, Dr. Dorsey and his coauthors of the book, “Ending Parkinson’s Disease: A Prescription for Action,” took a deep dive into studies focusing on the potential association of TCE and PD and presented seven cases to illustrate the association.

“Like many genetic mutations (e.g., Parkin) and other environmental toxicants ... TCE damages the energy-producing parts of cells, i.e., the mitochondria,” said Dr. Dorsey.

TCE and PCE “likely mediate their toxicity through a common metabolite.” Because both are lipophilic, they “readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses,” the researchers hypothesized.

Dopaminergic neurons are particularly sensitive to mitochondrial neurotoxicants, so this might “partially explain the link to PD.”

Animal studies have shown that TCE “caused selective loss of dopaminergic neurons.” Moreover, PD-related neuropathology was found in the substantia nigra of rodents exposed to TCE over time. In addition, studies as early as 1960 were showing an association between TCE and parkinsonism.

The authors describe TCE as “ubiquitous” in the 1970s, with 10 million Americans working with the chemical or other organic solvents daily. The review details an extensive list of industries and occupations in which TCE exposure continues to occur.

People working with TCE might inhale it or touch it; but “millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution.”

They noted that TCE contaminates up to one-third of U.S. drinking water, has polluted the groundwater in more than 20 different countries on five continents, and is found in half of the 1,300 most toxic “Superfund” sites that are “part of a federal clean-up program, including 15 in California’s Silicon Valley, where TCE was used to clean electronics.”

Although the U.S. military stopped using TCE, numerous sites have been contaminated, including Marine Corps Base Camp Lejeune in North Carolina, where TCE and PCE were found in drinking water at 280 times the recommended safety standards.

The researchers highlighted seven cases of individuals who developed PD after likely exposure to TCE, including NBA basketball player Brian Grant, who developed symptoms of PD in 2006 at the age of 34.

Mr. Grant and his family had lived in Camp Lejeune when he was a child, during which time he drank, bathed, and swam in contaminated water, “unaware of its toxicity.” His father also died of esophageal cancer, “which is linked to TCE,” the authors of the study wrote. Mr. Grant has created a foundation to inspire and support patients with PD.

All of the individuals either grew up in or spent time in an area where they were extensively exposed to TCE, PCE, or other chemicals, or experienced occupational exposure.

The authors acknowledged that the role of TCE in PD, as illustrated by the cases, is “far from definitive.” For example, exposure to TCE is often combined with exposure to other toxins, or with unmeasured genetic risk factors.

They highlighted the need for more research and called for cleaning and containing contaminated sites, monitoring TCE levels, and publicly communicating risk and a ban on TCE.
 

Recall bias?

Commenting for this news organization, Rebecca Gilbert, MD, PhD, chief scientific officer, American Parkinson Disease Association (APDA), noted that the authors “are very frank about the limitations of this approach [illustrative cases] as proof of causation between PD and TCE exposure.”

Another limitation is that TCE exposure is very common, “as argued in the paper.” But “most people with exposure do not develop PD,” Dr. Gilbert pointed out. “By probing the TCE exposure of those who already have PD, there is a danger of recall bias.”

Dr. Gilbert, associate professor of neurology at NYU Langone Health, who was not involved with the study, acknowledged that the authors “present their work as hypothesis and clearly state that more work is needed to understand the connection between TCE and PD.”

In the meantime, however, there are “well-established health risks of TCE exposure, including development of various cancers,” she said. Therefore, the authors’ goals appear to be educating the public about known health risks, working to clean up known sites of contamination, and advocating to ban future use of TCE.

These goals “do not need to wait for [proof of] firm causation between TCE and PD,” she stated.

Dr. Dorsey reported he has received honoraria for speaking at the American Academy of Neurology and at multiple other societies and foundations and has received compensation for consulting services from pharmaceutical companies, foundations, medical education companies, and medical publications; he owns stock in several companies. The other authors’ disclosures can be found in the original paper. Dr. Gilbert is employed by the American Parkinson Disease Association and Bellevue Hospital Center in New York City.
 

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

A common chemical that is used in correction fluid, paint removers, gun cleaners, aerosol cleaning products, and dry cleaning may be the key culprit behind the dramatic increase in Parkinson’s disease (PD), researchers say.

An international team of researchers reviewed previous research and cited data that suggest the chemical trichloroethylene (TCE) is associated with as much as a 500% increased risk for Parkinson’s disease (PD).

Lead investigator Ray Dorsey, MD, professor of neurology, University of Rochester, N.Y., called PD “the world’s fastest-growing brain disease,” and told this news organization that it “may be largely preventable.”

“Countless people have died over generations from cancer and other disease linked to TCE [and] Parkinson’s may be the latest,” he said. “Banning these chemicals, containing contaminated sites, and protecting homes, schools, and buildings at risk may all create a world where Parkinson’s is increasingly rare, not common.”

The paper was published online in the Journal of Parkinson’s Disease.
 

Invisible, ubiquitous

TCE was first synthesized in a lab in 1864, with commercial production beginning in 1920, the researchers noted.

“Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications,” including producing refrigerants, cleaning electronics, and degreasing engine parts.

In addition, it’s been used in dry cleaning, although a similar chemical (perchloroethylene [PCE]) is currently more widely used for that purpose. Nevertheless, the authors noted, in anaerobic conditions, perchloroethylene often transforms into TCE “and their toxicity may be similar.”

Consumer products in which TCE is found include typewriter correction fluid, paint removers, gun cleaners, and aerosol cleaning products. Up until the 1970s, it was used to decaffeinate coffee.

TCE exposure isn’t confined to those who work with it. It also pollutes outdoor air, taints groundwater, and contaminates indoor air. It’s present in a substantial amount of groundwater in the United States and it “evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected,” the researchers noted.

“Exposure can come via occupation or the environment and is often largely unknown at the time it occurs,” Dr. Dorsey said.

He noted that the rapid increase in PD incidence cannot be explained by genetic factors alone, which affect only about 15% of patients with PD, nor can it be explained by aging alone. “Certain pesticides ... are likely causes but would not explain the high prevalence of PD in urban areas, as is the case in the U.S.” Rather, “other factors” are involved, and “TCE is likely one such factor.”

Yet, “despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited.”

To fill this knowledge gap, Dr. Dorsey and his coauthors of the book, “Ending Parkinson’s Disease: A Prescription for Action,” took a deep dive into studies focusing on the potential association of TCE and PD and presented seven cases to illustrate the association.

“Like many genetic mutations (e.g., Parkin) and other environmental toxicants ... TCE damages the energy-producing parts of cells, i.e., the mitochondria,” said Dr. Dorsey.

TCE and PCE “likely mediate their toxicity through a common metabolite.” Because both are lipophilic, they “readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses,” the researchers hypothesized.

Dopaminergic neurons are particularly sensitive to mitochondrial neurotoxicants, so this might “partially explain the link to PD.”

Animal studies have shown that TCE “caused selective loss of dopaminergic neurons.” Moreover, PD-related neuropathology was found in the substantia nigra of rodents exposed to TCE over time. In addition, studies as early as 1960 were showing an association between TCE and parkinsonism.

The authors describe TCE as “ubiquitous” in the 1970s, with 10 million Americans working with the chemical or other organic solvents daily. The review details an extensive list of industries and occupations in which TCE exposure continues to occur.

People working with TCE might inhale it or touch it; but “millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution.”

They noted that TCE contaminates up to one-third of U.S. drinking water, has polluted the groundwater in more than 20 different countries on five continents, and is found in half of the 1,300 most toxic “Superfund” sites that are “part of a federal clean-up program, including 15 in California’s Silicon Valley, where TCE was used to clean electronics.”

Although the U.S. military stopped using TCE, numerous sites have been contaminated, including Marine Corps Base Camp Lejeune in North Carolina, where TCE and PCE were found in drinking water at 280 times the recommended safety standards.

The researchers highlighted seven cases of individuals who developed PD after likely exposure to TCE, including NBA basketball player Brian Grant, who developed symptoms of PD in 2006 at the age of 34.

Mr. Grant and his family had lived in Camp Lejeune when he was a child, during which time he drank, bathed, and swam in contaminated water, “unaware of its toxicity.” His father also died of esophageal cancer, “which is linked to TCE,” the authors of the study wrote. Mr. Grant has created a foundation to inspire and support patients with PD.

All of the individuals either grew up in or spent time in an area where they were extensively exposed to TCE, PCE, or other chemicals, or experienced occupational exposure.

The authors acknowledged that the role of TCE in PD, as illustrated by the cases, is “far from definitive.” For example, exposure to TCE is often combined with exposure to other toxins, or with unmeasured genetic risk factors.

They highlighted the need for more research and called for cleaning and containing contaminated sites, monitoring TCE levels, and publicly communicating risk and a ban on TCE.
 

Recall bias?

Commenting for this news organization, Rebecca Gilbert, MD, PhD, chief scientific officer, American Parkinson Disease Association (APDA), noted that the authors “are very frank about the limitations of this approach [illustrative cases] as proof of causation between PD and TCE exposure.”

Another limitation is that TCE exposure is very common, “as argued in the paper.” But “most people with exposure do not develop PD,” Dr. Gilbert pointed out. “By probing the TCE exposure of those who already have PD, there is a danger of recall bias.”

Dr. Gilbert, associate professor of neurology at NYU Langone Health, who was not involved with the study, acknowledged that the authors “present their work as hypothesis and clearly state that more work is needed to understand the connection between TCE and PD.”

In the meantime, however, there are “well-established health risks of TCE exposure, including development of various cancers,” she said. Therefore, the authors’ goals appear to be educating the public about known health risks, working to clean up known sites of contamination, and advocating to ban future use of TCE.

These goals “do not need to wait for [proof of] firm causation between TCE and PD,” she stated.

Dr. Dorsey reported he has received honoraria for speaking at the American Academy of Neurology and at multiple other societies and foundations and has received compensation for consulting services from pharmaceutical companies, foundations, medical education companies, and medical publications; he owns stock in several companies. The other authors’ disclosures can be found in the original paper. Dr. Gilbert is employed by the American Parkinson Disease Association and Bellevue Hospital Center in New York City.
 

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

A common chemical that is used in correction fluid, paint removers, gun cleaners, aerosol cleaning products, and dry cleaning may be the key culprit behind the dramatic increase in Parkinson’s disease (PD), researchers say.

An international team of researchers reviewed previous research and cited data that suggest the chemical trichloroethylene (TCE) is associated with as much as a 500% increased risk for Parkinson’s disease (PD).

Lead investigator Ray Dorsey, MD, professor of neurology, University of Rochester, N.Y., called PD “the world’s fastest-growing brain disease,” and told this news organization that it “may be largely preventable.”

“Countless people have died over generations from cancer and other disease linked to TCE [and] Parkinson’s may be the latest,” he said. “Banning these chemicals, containing contaminated sites, and protecting homes, schools, and buildings at risk may all create a world where Parkinson’s is increasingly rare, not common.”

The paper was published online in the Journal of Parkinson’s Disease.
 

Invisible, ubiquitous

TCE was first synthesized in a lab in 1864, with commercial production beginning in 1920, the researchers noted.

“Because of its unique properties, TCE has had countless industrial, commercial, military, and medical applications,” including producing refrigerants, cleaning electronics, and degreasing engine parts.

In addition, it’s been used in dry cleaning, although a similar chemical (perchloroethylene [PCE]) is currently more widely used for that purpose. Nevertheless, the authors noted, in anaerobic conditions, perchloroethylene often transforms into TCE “and their toxicity may be similar.”

Consumer products in which TCE is found include typewriter correction fluid, paint removers, gun cleaners, and aerosol cleaning products. Up until the 1970s, it was used to decaffeinate coffee.

TCE exposure isn’t confined to those who work with it. It also pollutes outdoor air, taints groundwater, and contaminates indoor air. It’s present in a substantial amount of groundwater in the United States and it “evaporates from underlying soil and groundwater and enters homes, workplaces, or schools, often undetected,” the researchers noted.

“Exposure can come via occupation or the environment and is often largely unknown at the time it occurs,” Dr. Dorsey said.

He noted that the rapid increase in PD incidence cannot be explained by genetic factors alone, which affect only about 15% of patients with PD, nor can it be explained by aging alone. “Certain pesticides ... are likely causes but would not explain the high prevalence of PD in urban areas, as is the case in the U.S.” Rather, “other factors” are involved, and “TCE is likely one such factor.”

Yet, “despite widespread contamination and increasing industrial, commercial, and military use, clinical investigations of TCE and PD have been limited.”

To fill this knowledge gap, Dr. Dorsey and his coauthors of the book, “Ending Parkinson’s Disease: A Prescription for Action,” took a deep dive into studies focusing on the potential association of TCE and PD and presented seven cases to illustrate the association.

“Like many genetic mutations (e.g., Parkin) and other environmental toxicants ... TCE damages the energy-producing parts of cells, i.e., the mitochondria,” said Dr. Dorsey.

TCE and PCE “likely mediate their toxicity through a common metabolite.” Because both are lipophilic, they “readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses,” the researchers hypothesized.

Dopaminergic neurons are particularly sensitive to mitochondrial neurotoxicants, so this might “partially explain the link to PD.”

Animal studies have shown that TCE “caused selective loss of dopaminergic neurons.” Moreover, PD-related neuropathology was found in the substantia nigra of rodents exposed to TCE over time. In addition, studies as early as 1960 were showing an association between TCE and parkinsonism.

The authors describe TCE as “ubiquitous” in the 1970s, with 10 million Americans working with the chemical or other organic solvents daily. The review details an extensive list of industries and occupations in which TCE exposure continues to occur.

People working with TCE might inhale it or touch it; but “millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution.”

They noted that TCE contaminates up to one-third of U.S. drinking water, has polluted the groundwater in more than 20 different countries on five continents, and is found in half of the 1,300 most toxic “Superfund” sites that are “part of a federal clean-up program, including 15 in California’s Silicon Valley, where TCE was used to clean electronics.”

Although the U.S. military stopped using TCE, numerous sites have been contaminated, including Marine Corps Base Camp Lejeune in North Carolina, where TCE and PCE were found in drinking water at 280 times the recommended safety standards.

The researchers highlighted seven cases of individuals who developed PD after likely exposure to TCE, including NBA basketball player Brian Grant, who developed symptoms of PD in 2006 at the age of 34.

Mr. Grant and his family had lived in Camp Lejeune when he was a child, during which time he drank, bathed, and swam in contaminated water, “unaware of its toxicity.” His father also died of esophageal cancer, “which is linked to TCE,” the authors of the study wrote. Mr. Grant has created a foundation to inspire and support patients with PD.

All of the individuals either grew up in or spent time in an area where they were extensively exposed to TCE, PCE, or other chemicals, or experienced occupational exposure.

The authors acknowledged that the role of TCE in PD, as illustrated by the cases, is “far from definitive.” For example, exposure to TCE is often combined with exposure to other toxins, or with unmeasured genetic risk factors.

They highlighted the need for more research and called for cleaning and containing contaminated sites, monitoring TCE levels, and publicly communicating risk and a ban on TCE.
 

Recall bias?

Commenting for this news organization, Rebecca Gilbert, MD, PhD, chief scientific officer, American Parkinson Disease Association (APDA), noted that the authors “are very frank about the limitations of this approach [illustrative cases] as proof of causation between PD and TCE exposure.”

Another limitation is that TCE exposure is very common, “as argued in the paper.” But “most people with exposure do not develop PD,” Dr. Gilbert pointed out. “By probing the TCE exposure of those who already have PD, there is a danger of recall bias.”

Dr. Gilbert, associate professor of neurology at NYU Langone Health, who was not involved with the study, acknowledged that the authors “present their work as hypothesis and clearly state that more work is needed to understand the connection between TCE and PD.”

In the meantime, however, there are “well-established health risks of TCE exposure, including development of various cancers,” she said. Therefore, the authors’ goals appear to be educating the public about known health risks, working to clean up known sites of contamination, and advocating to ban future use of TCE.

These goals “do not need to wait for [proof of] firm causation between TCE and PD,” she stated.

Dr. Dorsey reported he has received honoraria for speaking at the American Academy of Neurology and at multiple other societies and foundations and has received compensation for consulting services from pharmaceutical companies, foundations, medical education companies, and medical publications; he owns stock in several companies. The other authors’ disclosures can be found in the original paper. Dr. Gilbert is employed by the American Parkinson Disease Association and Bellevue Hospital Center in New York City.
 

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

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

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

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

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

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

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

From movies to billboards to magazine covers – media have been pushing impossible beauty ideals for decades. But the recent rise of social media brings that exposure to new levels, particularly for young people.

“Youth spend, on average, between 6 and 8 hours per day on screens, much of it on social media,” said senior study author Gary S. Goldfield, PhD, senior scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Canada. “Social media provides exposure to so many photo-edited pictures – including those of models, celebrities, and fitness instructors – that perpetuate an unattainable beauty standard that gets internalized by impressionable youth and young adults, leading to body dissatisfaction.”

Plenty of research has linked frequent social media use with body image issues and even eating disorders. But crucial gaps in our knowledge remain, Dr. Goldfield said.

Much of that research “is correlational,” Dr. Goldfield added. And studies don’t always focus on individuals who may be more vulnerable to social media’s harmful effects, such as those with ruminative or brooding cognitive styles, affecting results.

And none have explored an obvious question: Can cutting down on social media use also diminish its potential harms?

Dr. Goldfield and his colleagues found an answer: Yes, it can.  

Limiting social media use to 1 hour per day helped older teens and young adults feel much better about their weight and appearance after only 3 weeks, according to the study in Psychology of Popular Media, a journal of the American Psychological Association.

“Our randomized controlled design allowed us to show a stronger causal link between social media use and body image in youth, compared to previous research,” Dr. Goldfield said. “To our knowledge, this is the first study to show that social media use reduction leads to enhanced body image.”

Nancy Lee Zucker, PhD, professor of psychology and neuroscience at Duke University, Durham, N.C., and director of the Duke Center for Eating Disorders, said the results provide needed data that could help guide young people and parents on optimal social media use. Dr. Zucker was not involved in the study.
 

What the researchers did

For the study, Dr. Goldfield and colleagues recruited undergraduate psychology students aged 17-25 who averaged at least 2 hours per day of social media use on smartphones, and who had symptoms of depression or anxiety.

Participants were not told the purpose of the study, and their social media use was monitored by a screen time tracking program. At the beginning and end of the study, they answered questions such as “I’m pretty happy about the way I look,” and “I am satisfied with my weight,” on a 1 (never) to 5 (always) Likert scale.

During the first week, all 220 participants (76% female, 23% male, and 1% other) were told to use social media on their smartphones as they usually do. Over the next 3 weeks, 117 students were told to limit their social media use to 1 hour per day, while the rest were instructed to carry on as usual. In both groups, over 70% of participants were between age 17 and 19. 

The first group cut their social media use by about 50%, from a mean of around 168 minutes per day during week 1 to around 78 minutes per day by the end of week 4, while the unrestricted group went from around 181 minutes per day to 189.
 

Cutting use by around half yielded quick, significant improvements

The students who curbed their social media use saw significant improvements in their “appearance esteem” (from 2.95 to 3.15 points; P <.001) and their “weight esteem” (from 3.16 to 3.32 points; P < .001), whereas those who used social media freely saw no such changes (from 2.72 to 2.76; P = .992 and 3.01 to 3.02; P = .654, respectively). No gender differences between the groups were found.

The researchers are now studying possible reasons for these findings.

The changes in appearance scores “represent a small- to medium-effect size,” said child psychologist Sara R. Gould, PhD, director of the Eating Disorders Center at Children’s Mercy Kansas City in Missouri, who was not associated with the research.“ As such, these are clinically meaningful results, particularly since they were achieved in only 3 weeks. Even small impacts can be added to other changes to create larger impacts or have the potential to grow over time.”
 

The push to limit social media

As more and more experts scrutinize the impact of social media on young people’s mental health, social media companies have responded with features designed to limit the time young users spend on their platforms.

Just this year, Instagram rolled out “quiet mode,” which lets users shut down their direct messages (DMs) for a specified amount of time. To turn on quiet mode, users can navigate to their profiles, and select the triple line icon, “settings,” “notifications,” and “quiet mode.” Another option: Tap the triple line icon, “your activity,” and “time spent” to set reminders to take breaks after 10, 20, or 30 minutes of use.  

TikTok users under 18 will soon have their accounts defaulted to a 1-hour daily screen-time limit, TikTok has announced. Unlike other similar features, it will require users to turn it off rather than turn it on.

Leveraging built-in controls is “a good start to being more intentional about your screen time,” suggested lead author Helen Thai, a PhD student in clinical psychology at McGill University in Montreal. “Unfortunately, users can easily bypass these settings.”  

One reason for social’s magnetic pull: “FOMO – fear of missing out – on what friends are doing can make cutting back on social media use difficult,” said Dr. Zucker. To help prevent FOMO, parents may consider talking to parents of their children’s friends about reducing usage for all the children, Dr. Zucker suggested.

Mary E. Romano, MD, MPH, associate professor of pediatrics-adolescent medicine at Vanderbilt University, Nashville, Tenn., urges parents “to have very clear rules and expectations about social media use.” 

Dr. Romano, also not involved in the study, recommended the website Wait Until 8th to help parents band together to commit to delaying smartphone access until at least eighth grade.

Dr. Gould recommended the Family Media Plan, a tool from the American Academy of Pediatrics that lets users create a customized plan, complete with guidance tailored to each person’s age and the family’s goals. Sample tips: Designate a basket for holding devices during meals, and switch to audiobooks or relaxing music instead of videos to fall asleep at night.
 

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

From movies to billboards to magazine covers – media have been pushing impossible beauty ideals for decades. But the recent rise of social media brings that exposure to new levels, particularly for young people.

“Youth spend, on average, between 6 and 8 hours per day on screens, much of it on social media,” said senior study author Gary S. Goldfield, PhD, senior scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Canada. “Social media provides exposure to so many photo-edited pictures – including those of models, celebrities, and fitness instructors – that perpetuate an unattainable beauty standard that gets internalized by impressionable youth and young adults, leading to body dissatisfaction.”

Plenty of research has linked frequent social media use with body image issues and even eating disorders. But crucial gaps in our knowledge remain, Dr. Goldfield said.

Much of that research “is correlational,” Dr. Goldfield added. And studies don’t always focus on individuals who may be more vulnerable to social media’s harmful effects, such as those with ruminative or brooding cognitive styles, affecting results.

And none have explored an obvious question: Can cutting down on social media use also diminish its potential harms?

Dr. Goldfield and his colleagues found an answer: Yes, it can.  

Limiting social media use to 1 hour per day helped older teens and young adults feel much better about their weight and appearance after only 3 weeks, according to the study in Psychology of Popular Media, a journal of the American Psychological Association.

“Our randomized controlled design allowed us to show a stronger causal link between social media use and body image in youth, compared to previous research,” Dr. Goldfield said. “To our knowledge, this is the first study to show that social media use reduction leads to enhanced body image.”

Nancy Lee Zucker, PhD, professor of psychology and neuroscience at Duke University, Durham, N.C., and director of the Duke Center for Eating Disorders, said the results provide needed data that could help guide young people and parents on optimal social media use. Dr. Zucker was not involved in the study.
 

What the researchers did

For the study, Dr. Goldfield and colleagues recruited undergraduate psychology students aged 17-25 who averaged at least 2 hours per day of social media use on smartphones, and who had symptoms of depression or anxiety.

Participants were not told the purpose of the study, and their social media use was monitored by a screen time tracking program. At the beginning and end of the study, they answered questions such as “I’m pretty happy about the way I look,” and “I am satisfied with my weight,” on a 1 (never) to 5 (always) Likert scale.

During the first week, all 220 participants (76% female, 23% male, and 1% other) were told to use social media on their smartphones as they usually do. Over the next 3 weeks, 117 students were told to limit their social media use to 1 hour per day, while the rest were instructed to carry on as usual. In both groups, over 70% of participants were between age 17 and 19. 

The first group cut their social media use by about 50%, from a mean of around 168 minutes per day during week 1 to around 78 minutes per day by the end of week 4, while the unrestricted group went from around 181 minutes per day to 189.
 

Cutting use by around half yielded quick, significant improvements

The students who curbed their social media use saw significant improvements in their “appearance esteem” (from 2.95 to 3.15 points; P <.001) and their “weight esteem” (from 3.16 to 3.32 points; P < .001), whereas those who used social media freely saw no such changes (from 2.72 to 2.76; P = .992 and 3.01 to 3.02; P = .654, respectively). No gender differences between the groups were found.

The researchers are now studying possible reasons for these findings.

The changes in appearance scores “represent a small- to medium-effect size,” said child psychologist Sara R. Gould, PhD, director of the Eating Disorders Center at Children’s Mercy Kansas City in Missouri, who was not associated with the research.“ As such, these are clinically meaningful results, particularly since they were achieved in only 3 weeks. Even small impacts can be added to other changes to create larger impacts or have the potential to grow over time.”
 

The push to limit social media

As more and more experts scrutinize the impact of social media on young people’s mental health, social media companies have responded with features designed to limit the time young users spend on their platforms.

Just this year, Instagram rolled out “quiet mode,” which lets users shut down their direct messages (DMs) for a specified amount of time. To turn on quiet mode, users can navigate to their profiles, and select the triple line icon, “settings,” “notifications,” and “quiet mode.” Another option: Tap the triple line icon, “your activity,” and “time spent” to set reminders to take breaks after 10, 20, or 30 minutes of use.  

TikTok users under 18 will soon have their accounts defaulted to a 1-hour daily screen-time limit, TikTok has announced. Unlike other similar features, it will require users to turn it off rather than turn it on.

Leveraging built-in controls is “a good start to being more intentional about your screen time,” suggested lead author Helen Thai, a PhD student in clinical psychology at McGill University in Montreal. “Unfortunately, users can easily bypass these settings.”  

One reason for social’s magnetic pull: “FOMO – fear of missing out – on what friends are doing can make cutting back on social media use difficult,” said Dr. Zucker. To help prevent FOMO, parents may consider talking to parents of their children’s friends about reducing usage for all the children, Dr. Zucker suggested.

Mary E. Romano, MD, MPH, associate professor of pediatrics-adolescent medicine at Vanderbilt University, Nashville, Tenn., urges parents “to have very clear rules and expectations about social media use.” 

Dr. Romano, also not involved in the study, recommended the website Wait Until 8th to help parents band together to commit to delaying smartphone access until at least eighth grade.

Dr. Gould recommended the Family Media Plan, a tool from the American Academy of Pediatrics that lets users create a customized plan, complete with guidance tailored to each person’s age and the family’s goals. Sample tips: Designate a basket for holding devices during meals, and switch to audiobooks or relaxing music instead of videos to fall asleep at night.
 

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

From movies to billboards to magazine covers – media have been pushing impossible beauty ideals for decades. But the recent rise of social media brings that exposure to new levels, particularly for young people.

“Youth spend, on average, between 6 and 8 hours per day on screens, much of it on social media,” said senior study author Gary S. Goldfield, PhD, senior scientist at Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Canada. “Social media provides exposure to so many photo-edited pictures – including those of models, celebrities, and fitness instructors – that perpetuate an unattainable beauty standard that gets internalized by impressionable youth and young adults, leading to body dissatisfaction.”

Plenty of research has linked frequent social media use with body image issues and even eating disorders. But crucial gaps in our knowledge remain, Dr. Goldfield said.

Much of that research “is correlational,” Dr. Goldfield added. And studies don’t always focus on individuals who may be more vulnerable to social media’s harmful effects, such as those with ruminative or brooding cognitive styles, affecting results.

And none have explored an obvious question: Can cutting down on social media use also diminish its potential harms?

Dr. Goldfield and his colleagues found an answer: Yes, it can.  

Limiting social media use to 1 hour per day helped older teens and young adults feel much better about their weight and appearance after only 3 weeks, according to the study in Psychology of Popular Media, a journal of the American Psychological Association.

“Our randomized controlled design allowed us to show a stronger causal link between social media use and body image in youth, compared to previous research,” Dr. Goldfield said. “To our knowledge, this is the first study to show that social media use reduction leads to enhanced body image.”

Nancy Lee Zucker, PhD, professor of psychology and neuroscience at Duke University, Durham, N.C., and director of the Duke Center for Eating Disorders, said the results provide needed data that could help guide young people and parents on optimal social media use. Dr. Zucker was not involved in the study.
 

What the researchers did

For the study, Dr. Goldfield and colleagues recruited undergraduate psychology students aged 17-25 who averaged at least 2 hours per day of social media use on smartphones, and who had symptoms of depression or anxiety.

Participants were not told the purpose of the study, and their social media use was monitored by a screen time tracking program. At the beginning and end of the study, they answered questions such as “I’m pretty happy about the way I look,” and “I am satisfied with my weight,” on a 1 (never) to 5 (always) Likert scale.

During the first week, all 220 participants (76% female, 23% male, and 1% other) were told to use social media on their smartphones as they usually do. Over the next 3 weeks, 117 students were told to limit their social media use to 1 hour per day, while the rest were instructed to carry on as usual. In both groups, over 70% of participants were between age 17 and 19. 

The first group cut their social media use by about 50%, from a mean of around 168 minutes per day during week 1 to around 78 minutes per day by the end of week 4, while the unrestricted group went from around 181 minutes per day to 189.
 

Cutting use by around half yielded quick, significant improvements

The students who curbed their social media use saw significant improvements in their “appearance esteem” (from 2.95 to 3.15 points; P <.001) and their “weight esteem” (from 3.16 to 3.32 points; P < .001), whereas those who used social media freely saw no such changes (from 2.72 to 2.76; P = .992 and 3.01 to 3.02; P = .654, respectively). No gender differences between the groups were found.

The researchers are now studying possible reasons for these findings.

The changes in appearance scores “represent a small- to medium-effect size,” said child psychologist Sara R. Gould, PhD, director of the Eating Disorders Center at Children’s Mercy Kansas City in Missouri, who was not associated with the research.“ As such, these are clinically meaningful results, particularly since they were achieved in only 3 weeks. Even small impacts can be added to other changes to create larger impacts or have the potential to grow over time.”
 

The push to limit social media

As more and more experts scrutinize the impact of social media on young people’s mental health, social media companies have responded with features designed to limit the time young users spend on their platforms.

Just this year, Instagram rolled out “quiet mode,” which lets users shut down their direct messages (DMs) for a specified amount of time. To turn on quiet mode, users can navigate to their profiles, and select the triple line icon, “settings,” “notifications,” and “quiet mode.” Another option: Tap the triple line icon, “your activity,” and “time spent” to set reminders to take breaks after 10, 20, or 30 minutes of use.  

TikTok users under 18 will soon have their accounts defaulted to a 1-hour daily screen-time limit, TikTok has announced. Unlike other similar features, it will require users to turn it off rather than turn it on.

Leveraging built-in controls is “a good start to being more intentional about your screen time,” suggested lead author Helen Thai, a PhD student in clinical psychology at McGill University in Montreal. “Unfortunately, users can easily bypass these settings.”  

One reason for social’s magnetic pull: “FOMO – fear of missing out – on what friends are doing can make cutting back on social media use difficult,” said Dr. Zucker. To help prevent FOMO, parents may consider talking to parents of their children’s friends about reducing usage for all the children, Dr. Zucker suggested.

Mary E. Romano, MD, MPH, associate professor of pediatrics-adolescent medicine at Vanderbilt University, Nashville, Tenn., urges parents “to have very clear rules and expectations about social media use.” 

Dr. Romano, also not involved in the study, recommended the website Wait Until 8th to help parents band together to commit to delaying smartphone access until at least eighth grade.

Dr. Gould recommended the Family Media Plan, a tool from the American Academy of Pediatrics that lets users create a customized plan, complete with guidance tailored to each person’s age and the family’s goals. Sample tips: Designate a basket for holding devices during meals, and switch to audiobooks or relaxing music instead of videos to fall asleep at night.
 

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

The Environmental Protection Agency is proposing a new rule that would greatly limit the concentration of endocrine-disrupting “forever” chemicals in drinking water. 

The EPA on Tuesday announced the proposed National Primary Drinking Water Regulation (NPDWR) for six polyfluoroalkyl substances, more commonly known as PFAS, which are human-made chemicals used as oil and water repellents and coatings for common products including cookware, carpets, and textiles. Such substances are also widely used in cosmetics and food packaging.

curtoicurto/Getty Images

The Endocrine Society, which represents more than 18,000 doctors who treat hormone disorders, says it fully supports the new EPA proposal. It explains that these substances, also known as endocrine-disrupting chemicals, “do not break down when they are released into the environment, and they continue to accumulate over time. They pose health dangers at incredibly low levels and have been linked to endocrine disorders such as cancer, thyroid disruption, and reproductive difficulties.”

“This is the first time the government has regulated a new chemical in drinking water in more than 30 years,” the society notes, adding, this “will require major water treatment upgrades at utilities across the country.”

Robert F. Powelson, president and CEO of the National Association of Water Companies, says addressing the PFAS in the nation’s water supply will cost “billions of dollars.”

“It’s a burden that under the current structure will disproportionately fall on water and wastewater customers in small communities and low-income families,” Mr. Powelson says in a statement. He says the onus should instead fall on “the polluters” – those who manufacture and use PFAS chemicals, who “should be held directly responsible for the clean-up costs.” 

Although the EPA is proposing a health-based maximum contaminant level goal of zero for these chemicals in drinking water, it acknowledges that this is unenforceable and so has set what it considers an enforceable level, or maximum contaminant level (MCL), of 4 parts per trillion for two of the PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). 

A different standard has been proposed for the remaining four chemicals: perfluorononanoic acid (PFNA) and hexafluoropropylene oxide dimer acid (HFPO-DA) – known together as GenX chemicals – perfluorohexane sulfonic acid (PFHxS), and perfluorobutane sulfonic acid (PFBS).

Officials from the EPA told The Washington Post that these proposed limits would be as strong or stronger than limits from about a dozen states that have set their own drinking water standards in recent years. 

“The experts here felt this was the level of stringency required to protect public health, and that the law would allow for us,” EPA Administrator Michael Regan told the newspaper. “This is a transformative action that we’re taking.”

The EPA is requesting public comment on the proposed regulation and will hold a public hearing on May 4, which members of the public can register to attend and comment on the rule proposal. The last day to register is April 28. 

The EPA wants to finalize regulation by the end of 2023, although delays are common on new rules. 

If it is fully implemented, “the rule will prevent thousands of deaths and reduce tens of thousands of serious PFAS-attributable illnesses,” the EPA statement says.

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

The Environmental Protection Agency is proposing a new rule that would greatly limit the concentration of endocrine-disrupting “forever” chemicals in drinking water. 

The EPA on Tuesday announced the proposed National Primary Drinking Water Regulation (NPDWR) for six polyfluoroalkyl substances, more commonly known as PFAS, which are human-made chemicals used as oil and water repellents and coatings for common products including cookware, carpets, and textiles. Such substances are also widely used in cosmetics and food packaging.

curtoicurto/Getty Images

The Endocrine Society, which represents more than 18,000 doctors who treat hormone disorders, says it fully supports the new EPA proposal. It explains that these substances, also known as endocrine-disrupting chemicals, “do not break down when they are released into the environment, and they continue to accumulate over time. They pose health dangers at incredibly low levels and have been linked to endocrine disorders such as cancer, thyroid disruption, and reproductive difficulties.”

“This is the first time the government has regulated a new chemical in drinking water in more than 30 years,” the society notes, adding, this “will require major water treatment upgrades at utilities across the country.”

Robert F. Powelson, president and CEO of the National Association of Water Companies, says addressing the PFAS in the nation’s water supply will cost “billions of dollars.”

“It’s a burden that under the current structure will disproportionately fall on water and wastewater customers in small communities and low-income families,” Mr. Powelson says in a statement. He says the onus should instead fall on “the polluters” – those who manufacture and use PFAS chemicals, who “should be held directly responsible for the clean-up costs.” 

Although the EPA is proposing a health-based maximum contaminant level goal of zero for these chemicals in drinking water, it acknowledges that this is unenforceable and so has set what it considers an enforceable level, or maximum contaminant level (MCL), of 4 parts per trillion for two of the PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). 

A different standard has been proposed for the remaining four chemicals: perfluorononanoic acid (PFNA) and hexafluoropropylene oxide dimer acid (HFPO-DA) – known together as GenX chemicals – perfluorohexane sulfonic acid (PFHxS), and perfluorobutane sulfonic acid (PFBS).

Officials from the EPA told The Washington Post that these proposed limits would be as strong or stronger than limits from about a dozen states that have set their own drinking water standards in recent years. 

“The experts here felt this was the level of stringency required to protect public health, and that the law would allow for us,” EPA Administrator Michael Regan told the newspaper. “This is a transformative action that we’re taking.”

The EPA is requesting public comment on the proposed regulation and will hold a public hearing on May 4, which members of the public can register to attend and comment on the rule proposal. The last day to register is April 28. 

The EPA wants to finalize regulation by the end of 2023, although delays are common on new rules. 

If it is fully implemented, “the rule will prevent thousands of deaths and reduce tens of thousands of serious PFAS-attributable illnesses,” the EPA statement says.

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

The Environmental Protection Agency is proposing a new rule that would greatly limit the concentration of endocrine-disrupting “forever” chemicals in drinking water. 

The EPA on Tuesday announced the proposed National Primary Drinking Water Regulation (NPDWR) for six polyfluoroalkyl substances, more commonly known as PFAS, which are human-made chemicals used as oil and water repellents and coatings for common products including cookware, carpets, and textiles. Such substances are also widely used in cosmetics and food packaging.

curtoicurto/Getty Images

The Endocrine Society, which represents more than 18,000 doctors who treat hormone disorders, says it fully supports the new EPA proposal. It explains that these substances, also known as endocrine-disrupting chemicals, “do not break down when they are released into the environment, and they continue to accumulate over time. They pose health dangers at incredibly low levels and have been linked to endocrine disorders such as cancer, thyroid disruption, and reproductive difficulties.”

“This is the first time the government has regulated a new chemical in drinking water in more than 30 years,” the society notes, adding, this “will require major water treatment upgrades at utilities across the country.”

Robert F. Powelson, president and CEO of the National Association of Water Companies, says addressing the PFAS in the nation’s water supply will cost “billions of dollars.”

“It’s a burden that under the current structure will disproportionately fall on water and wastewater customers in small communities and low-income families,” Mr. Powelson says in a statement. He says the onus should instead fall on “the polluters” – those who manufacture and use PFAS chemicals, who “should be held directly responsible for the clean-up costs.” 

Although the EPA is proposing a health-based maximum contaminant level goal of zero for these chemicals in drinking water, it acknowledges that this is unenforceable and so has set what it considers an enforceable level, or maximum contaminant level (MCL), of 4 parts per trillion for two of the PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). 

A different standard has been proposed for the remaining four chemicals: perfluorononanoic acid (PFNA) and hexafluoropropylene oxide dimer acid (HFPO-DA) – known together as GenX chemicals – perfluorohexane sulfonic acid (PFHxS), and perfluorobutane sulfonic acid (PFBS).

Officials from the EPA told The Washington Post that these proposed limits would be as strong or stronger than limits from about a dozen states that have set their own drinking water standards in recent years. 

“The experts here felt this was the level of stringency required to protect public health, and that the law would allow for us,” EPA Administrator Michael Regan told the newspaper. “This is a transformative action that we’re taking.”

The EPA is requesting public comment on the proposed regulation and will hold a public hearing on May 4, which members of the public can register to attend and comment on the rule proposal. The last day to register is April 28. 

The EPA wants to finalize regulation by the end of 2023, although delays are common on new rules. 

If it is fully implemented, “the rule will prevent thousands of deaths and reduce tens of thousands of serious PFAS-attributable illnesses,” the EPA statement says.

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