Residents are confronted daily with situations in clinic that require a foundation in medical ethics to assist in decision-making. Attending physicians require health care services and at times may seek care from resident physicians. If the attending physician has direct oversight over the resident, however, the ethics of the resident treating them need to be addressed. Although patients have autonomy to choose whoever they want as a physician, nonmaleficence dictates that the resident may forego treatment due to concerns for providing suboptimal care; however, this same attending may be treated under specific circumstances. This column explores the ethical implications of both situations.

The Ethical Dilemma of Treating an Attending

Imagine this scenario: You are in your resident general dermatology clinic seeing patients with an attending overseeing your clinical decisions following each encounter. You look on your schedule and see that the next patient is one of your pediatric dermatology attendings for a total-body skin examination (TBSE). You have never treated a physician that oversees you, and you ponder whether you should perform the examination or fetch your attending to perform the encounter alone.

This conundrum then brings other questions to mind: Would changing the reason for the appointment (ie, an acute problem vs a TBSE) alter your decision as to whether or not you would treat this attending? Would the situation be different if this was an attending in a different department?

Ethics Curriculum for Residents

Medical providers face ethical dilemmas daily, and dermatologists and dermatology residents are not excluded. Dermatoethics can provide a framework for the best approach to this hypothetical situation. To equip residents with resources on ethics and a cognitive framework to approach similar situations, the American Board of Dermatology has created an ethics curriculum for residents to learn over their 3 years of training.¹

One study that analyzed the ethical themes portrayed in essays by fourth-year medical students showed that the most common themes included autonomy, social justice, nonmaleficence, beneficence, honesty, and respect.² These themes must be considered in different permutations throughout ethical conundrums.

In the situation of an attending physician who supervises a resident in another clinic voluntarily attending the resident clinic, the physician is aware of the resident’s skills and qualifications and knows that supervision is being provided by an attending physician, which allows informed consent to be made, as a study by Unruh et al³ shows. The patient’s autonomy allows them to choose their treating provider.

However, there are several reasons why the resident may be hesitant to enter the room. One concern may be that during a TBSE the provider usually examines the patient’s genitals, rectum, and breasts.⁴ Because the resident knows the individual personally, the patient and/or the provider may be uncomfortable checking these areas, leaving a portion of the examination unperformed. This neglect may harm the patient (eg, a genital melanoma is missed), violating the tenant of nonmaleficence.

The effect of the medical hierarchy also should be considered. The de facto hierarchy of attendings supervising residents, interns, and medical students, with each group having some oversight over the next, can have positive effects on education and appropriate patient management but also can prove to be detrimental to the patient and provider in some circumstances. Studies have shown that residents may be less willing to disagree with their superior’s opinions for fear of negative reactions and harmful effects on their future careers.^5-7 The hierarchy of medicine also can affect a resident’s moral judgement by intimidating the practitioner to perform tasks or make diagnoses they may not wish to make.^5,6,8,9 For example, the resident may send a prescription for a medication that the attending requested despite no clear indication of need. This mingling of patient and supervisor roles can result in a resident treating their attending physician inconsistently with their standard of care.

Navigating the Ethics of Treating Family Members

The American Medical Association Code of Medical Ethics Opinions on Patient-Physician Relationships highlights treating family members as an important ethical topic. Although most residents and attendings are not biologically related, a familial-style relationship exists in many dermatology programs between attendings and residents due to the close-knit nature of dermatology programs. Diagnostic and treatment accuracy may be diminished by the discomfort or disbelief that a condition could affect someone the resident cares about.¹⁰

The American Medical Association also states that a physician can treat family members in an emergency situation or for short-term minor problems. If these 2 exceptions were to be extrapolated to apply to situations involving residents and attendings in addition to family, there would be situations where a dermatology resident could ethically treat their attending physician.¹⁰ If the attending physician was worried about a problem that was deemed potentially life-threatening, such as a rapidly progressive bullous eruption concerning for Stevens-Johnson syndrome following the initiation of a new medication, and they wanted an urgent evaluation and biopsy, an ethicist could argue that urgent treatment is medically indicated as deferring treatment could have negative consequences on the patient’s health. In addition, if the attending found a splinter in their finger following yardwork and needed assistance in removal, this also could be treated by their resident, as it is minimally invasive and has a finite conclusion.

Treating Nonsupervisory Attendings

In the case of performing a TBSE on an attending from another specialty, it would be acceptable and less ethically ambiguous if no close personal relationship existed between the two practitioners, as this patient would have no direct oversight over the resident physician.

Final Thoughts

Each situation that residents face may carry ethical implications with perspectives from the patient, provider, and bystanders. The above scenarios highlight specific instances that a dermatology resident may face and provide insight into how they may approach the situations. At the same time, it is important to remember that every situation is different and requires a unique approach. Fortunately,physicians—specifically dermatologists—are provided many resources to help navigate challenging scenarios.

Acknowledgments—The author thanks Jane M. Grant-Kels, MD (Farmington, Connecticut), for reviewing this paper and providing feedback to improve its content, as well as Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and article.

Residents are confronted daily with situations in clinic that require a foundation in medical ethics to assist in decision-making. Attending physicians require health care services and at times may seek care from resident physicians. If the attending physician has direct oversight over the resident, however, the ethics of the resident treating them need to be addressed. Although patients have autonomy to choose whoever they want as a physician, nonmaleficence dictates that the resident may forego treatment due to concerns for providing suboptimal care; however, this same attending may be treated under specific circumstances. This column explores the ethical implications of both situations.

The Ethical Dilemma of Treating an Attending

Imagine this scenario: You are in your resident general dermatology clinic seeing patients with an attending overseeing your clinical decisions following each encounter. You look on your schedule and see that the next patient is one of your pediatric dermatology attendings for a total-body skin examination (TBSE). You have never treated a physician that oversees you, and you ponder whether you should perform the examination or fetch your attending to perform the encounter alone.

This conundrum then brings other questions to mind: Would changing the reason for the appointment (ie, an acute problem vs a TBSE) alter your decision as to whether or not you would treat this attending? Would the situation be different if this was an attending in a different department?

Ethics Curriculum for Residents

Medical providers face ethical dilemmas daily, and dermatologists and dermatology residents are not excluded. Dermatoethics can provide a framework for the best approach to this hypothetical situation. To equip residents with resources on ethics and a cognitive framework to approach similar situations, the American Board of Dermatology has created an ethics curriculum for residents to learn over their 3 years of training.¹

One study that analyzed the ethical themes portrayed in essays by fourth-year medical students showed that the most common themes included autonomy, social justice, nonmaleficence, beneficence, honesty, and respect.² These themes must be considered in different permutations throughout ethical conundrums.

In the situation of an attending physician who supervises a resident in another clinic voluntarily attending the resident clinic, the physician is aware of the resident’s skills and qualifications and knows that supervision is being provided by an attending physician, which allows informed consent to be made, as a study by Unruh et al³ shows. The patient’s autonomy allows them to choose their treating provider.

However, there are several reasons why the resident may be hesitant to enter the room. One concern may be that during a TBSE the provider usually examines the patient’s genitals, rectum, and breasts.⁴ Because the resident knows the individual personally, the patient and/or the provider may be uncomfortable checking these areas, leaving a portion of the examination unperformed. This neglect may harm the patient (eg, a genital melanoma is missed), violating the tenant of nonmaleficence.

The effect of the medical hierarchy also should be considered. The de facto hierarchy of attendings supervising residents, interns, and medical students, with each group having some oversight over the next, can have positive effects on education and appropriate patient management but also can prove to be detrimental to the patient and provider in some circumstances. Studies have shown that residents may be less willing to disagree with their superior’s opinions for fear of negative reactions and harmful effects on their future careers.^5-7 The hierarchy of medicine also can affect a resident’s moral judgement by intimidating the practitioner to perform tasks or make diagnoses they may not wish to make.^5,6,8,9 For example, the resident may send a prescription for a medication that the attending requested despite no clear indication of need. This mingling of patient and supervisor roles can result in a resident treating their attending physician inconsistently with their standard of care.

Navigating the Ethics of Treating Family Members

The American Medical Association Code of Medical Ethics Opinions on Patient-Physician Relationships highlights treating family members as an important ethical topic. Although most residents and attendings are not biologically related, a familial-style relationship exists in many dermatology programs between attendings and residents due to the close-knit nature of dermatology programs. Diagnostic and treatment accuracy may be diminished by the discomfort or disbelief that a condition could affect someone the resident cares about.¹⁰

The American Medical Association also states that a physician can treat family members in an emergency situation or for short-term minor problems. If these 2 exceptions were to be extrapolated to apply to situations involving residents and attendings in addition to family, there would be situations where a dermatology resident could ethically treat their attending physician.¹⁰ If the attending physician was worried about a problem that was deemed potentially life-threatening, such as a rapidly progressive bullous eruption concerning for Stevens-Johnson syndrome following the initiation of a new medication, and they wanted an urgent evaluation and biopsy, an ethicist could argue that urgent treatment is medically indicated as deferring treatment could have negative consequences on the patient’s health. In addition, if the attending found a splinter in their finger following yardwork and needed assistance in removal, this also could be treated by their resident, as it is minimally invasive and has a finite conclusion.

Treating Nonsupervisory Attendings

In the case of performing a TBSE on an attending from another specialty, it would be acceptable and less ethically ambiguous if no close personal relationship existed between the two practitioners, as this patient would have no direct oversight over the resident physician.

Final Thoughts

Each situation that residents face may carry ethical implications with perspectives from the patient, provider, and bystanders. The above scenarios highlight specific instances that a dermatology resident may face and provide insight into how they may approach the situations. At the same time, it is important to remember that every situation is different and requires a unique approach. Fortunately,physicians—specifically dermatologists—are provided many resources to help navigate challenging scenarios.

Acknowledgments—The author thanks Jane M. Grant-Kels, MD (Farmington, Connecticut), for reviewing this paper and providing feedback to improve its content, as well as Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and article.

Residents are confronted daily with situations in clinic that require a foundation in medical ethics to assist in decision-making. Attending physicians require health care services and at times may seek care from resident physicians. If the attending physician has direct oversight over the resident, however, the ethics of the resident treating them need to be addressed. Although patients have autonomy to choose whoever they want as a physician, nonmaleficence dictates that the resident may forego treatment due to concerns for providing suboptimal care; however, this same attending may be treated under specific circumstances. This column explores the ethical implications of both situations.

The Ethical Dilemma of Treating an Attending

Imagine this scenario: You are in your resident general dermatology clinic seeing patients with an attending overseeing your clinical decisions following each encounter. You look on your schedule and see that the next patient is one of your pediatric dermatology attendings for a total-body skin examination (TBSE). You have never treated a physician that oversees you, and you ponder whether you should perform the examination or fetch your attending to perform the encounter alone.

This conundrum then brings other questions to mind: Would changing the reason for the appointment (ie, an acute problem vs a TBSE) alter your decision as to whether or not you would treat this attending? Would the situation be different if this was an attending in a different department?

Ethics Curriculum for Residents

Medical providers face ethical dilemmas daily, and dermatologists and dermatology residents are not excluded. Dermatoethics can provide a framework for the best approach to this hypothetical situation. To equip residents with resources on ethics and a cognitive framework to approach similar situations, the American Board of Dermatology has created an ethics curriculum for residents to learn over their 3 years of training.¹

One study that analyzed the ethical themes portrayed in essays by fourth-year medical students showed that the most common themes included autonomy, social justice, nonmaleficence, beneficence, honesty, and respect.² These themes must be considered in different permutations throughout ethical conundrums.

In the situation of an attending physician who supervises a resident in another clinic voluntarily attending the resident clinic, the physician is aware of the resident’s skills and qualifications and knows that supervision is being provided by an attending physician, which allows informed consent to be made, as a study by Unruh et al³ shows. The patient’s autonomy allows them to choose their treating provider.

However, there are several reasons why the resident may be hesitant to enter the room. One concern may be that during a TBSE the provider usually examines the patient’s genitals, rectum, and breasts.⁴ Because the resident knows the individual personally, the patient and/or the provider may be uncomfortable checking these areas, leaving a portion of the examination unperformed. This neglect may harm the patient (eg, a genital melanoma is missed), violating the tenant of nonmaleficence.

The effect of the medical hierarchy also should be considered. The de facto hierarchy of attendings supervising residents, interns, and medical students, with each group having some oversight over the next, can have positive effects on education and appropriate patient management but also can prove to be detrimental to the patient and provider in some circumstances. Studies have shown that residents may be less willing to disagree with their superior’s opinions for fear of negative reactions and harmful effects on their future careers.^5-7 The hierarchy of medicine also can affect a resident’s moral judgement by intimidating the practitioner to perform tasks or make diagnoses they may not wish to make.^5,6,8,9 For example, the resident may send a prescription for a medication that the attending requested despite no clear indication of need. This mingling of patient and supervisor roles can result in a resident treating their attending physician inconsistently with their standard of care.

Navigating the Ethics of Treating Family Members

The American Medical Association Code of Medical Ethics Opinions on Patient-Physician Relationships highlights treating family members as an important ethical topic. Although most residents and attendings are not biologically related, a familial-style relationship exists in many dermatology programs between attendings and residents due to the close-knit nature of dermatology programs. Diagnostic and treatment accuracy may be diminished by the discomfort or disbelief that a condition could affect someone the resident cares about.¹⁰

The American Medical Association also states that a physician can treat family members in an emergency situation or for short-term minor problems. If these 2 exceptions were to be extrapolated to apply to situations involving residents and attendings in addition to family, there would be situations where a dermatology resident could ethically treat their attending physician.¹⁰ If the attending physician was worried about a problem that was deemed potentially life-threatening, such as a rapidly progressive bullous eruption concerning for Stevens-Johnson syndrome following the initiation of a new medication, and they wanted an urgent evaluation and biopsy, an ethicist could argue that urgent treatment is medically indicated as deferring treatment could have negative consequences on the patient’s health. In addition, if the attending found a splinter in their finger following yardwork and needed assistance in removal, this also could be treated by their resident, as it is minimally invasive and has a finite conclusion.

Treating Nonsupervisory Attendings

In the case of performing a TBSE on an attending from another specialty, it would be acceptable and less ethically ambiguous if no close personal relationship existed between the two practitioners, as this patient would have no direct oversight over the resident physician.

Final Thoughts

Each situation that residents face may carry ethical implications with perspectives from the patient, provider, and bystanders. The above scenarios highlight specific instances that a dermatology resident may face and provide insight into how they may approach the situations. At the same time, it is important to remember that every situation is different and requires a unique approach. Fortunately,physicians—specifically dermatologists—are provided many resources to help navigate challenging scenarios.

Acknowledgments—The author thanks Jane M. Grant-Kels, MD (Farmington, Connecticut), for reviewing this paper and providing feedback to improve its content, as well as Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and article.

The Food and Drug Administration today granted emergency use authorization to Omicron-specific COVID-19 vaccines made by Pfizer/BioNTech and Moderna.

The agency cited data to support the safety and efficacy of this next generation of mRNA vaccines targeted toward variants of concern.

The Pfizer EUA corresponds to the company’s combination booster shot that includes the original COVID-19 vaccine as well as a vaccine specifically designed to protect against the most recent Omicron variants, BA.4 and BA.5.

The Moderna combination vaccine will contain both the firm’s original COVID-19 vaccine and a vaccine to protect specifically against Omicron BA.4 and BA.5 subvariants.

As of Aug. 27, BA.4 and BA.4.6 account for about 11% of circulating variants and BA.5 accounts for almost all the remaining 89%, Centers for Disease Control and Prevention data show.

The next step will be review of the scientific data by the CDC’s Advisory Committee on Immunization Practices, which is set to meet Sept. 1 and 2. The final hurdle before distribution of the new vaccines will be sign-off on CDC recommendations for use by agency Director Rochelle Walensky, MD.

This is a developing story. A version of this article first appeared on WebMD.com.

The Food and Drug Administration today granted emergency use authorization to Omicron-specific COVID-19 vaccines made by Pfizer/BioNTech and Moderna.

The agency cited data to support the safety and efficacy of this next generation of mRNA vaccines targeted toward variants of concern.

The Pfizer EUA corresponds to the company’s combination booster shot that includes the original COVID-19 vaccine as well as a vaccine specifically designed to protect against the most recent Omicron variants, BA.4 and BA.5.

The Moderna combination vaccine will contain both the firm’s original COVID-19 vaccine and a vaccine to protect specifically against Omicron BA.4 and BA.5 subvariants.

As of Aug. 27, BA.4 and BA.4.6 account for about 11% of circulating variants and BA.5 accounts for almost all the remaining 89%, Centers for Disease Control and Prevention data show.

The next step will be review of the scientific data by the CDC’s Advisory Committee on Immunization Practices, which is set to meet Sept. 1 and 2. The final hurdle before distribution of the new vaccines will be sign-off on CDC recommendations for use by agency Director Rochelle Walensky, MD.

This is a developing story. A version of this article first appeared on WebMD.com.

The Food and Drug Administration today granted emergency use authorization to Omicron-specific COVID-19 vaccines made by Pfizer/BioNTech and Moderna.

The agency cited data to support the safety and efficacy of this next generation of mRNA vaccines targeted toward variants of concern.

The Pfizer EUA corresponds to the company’s combination booster shot that includes the original COVID-19 vaccine as well as a vaccine specifically designed to protect against the most recent Omicron variants, BA.4 and BA.5.

The Moderna combination vaccine will contain both the firm’s original COVID-19 vaccine and a vaccine to protect specifically against Omicron BA.4 and BA.5 subvariants.

As of Aug. 27, BA.4 and BA.4.6 account for about 11% of circulating variants and BA.5 accounts for almost all the remaining 89%, Centers for Disease Control and Prevention data show.

The next step will be review of the scientific data by the CDC’s Advisory Committee on Immunization Practices, which is set to meet Sept. 1 and 2. The final hurdle before distribution of the new vaccines will be sign-off on CDC recommendations for use by agency Director Rochelle Walensky, MD.

This is a developing story. A version of this article first appeared on WebMD.com.

The Diagnosis: Scleromyxedema

A punch biopsy of the upper back performed at an outside institution revealed increased histiocytes and abundant interstitial mucin confined to the papillary dermis (Figures 1 and 2), consistent with the lichen myxedematosus (LM) papules that may be seen in scleromyxedema. Serum protein electrophoresis revealed the presence of a protein of restricted mobility on the gamma region that occupied 5.3% of the total protein (0.3 g/dL). Urine protein electrophoresis showed free kappa light chain monoclonal protein in the gamma region. Immunofixation electrophoresis revealed the presence of IgG kappa monoclonal protein in the gamma region with 10% monotype kappa cells. The presence of Raynaud phenomenon and positive antinuclear antibody (1:320, speckled) was noted. Laboratory studies for thyroid-stimulating hormone, C-reactive protein, Scl-70 antibody, myositis panel, ribonucleoprotein antibody, Smith antibody, Sjögren syndrome–related antigens A and B antibodies, rheumatoid factor, and RNA polymerase III antibody all were within reference range. Our patient was treated with monthly intravenous immunoglobulin (IVIG), and he noted substantial improvement in skin findings after 3 months of IVIG.

Localized lichen myxedematosus is a rare idiopathic cutaneous disease that clinically is characterized by waxy indurated papules and histologically is characterized by diffuse mucin deposition and fibroblast proliferation in the upper dermis.¹ Scleromyxedema is a diffuse variant of LM in which the papules and plaques of LM are associated with skin thickening involving almost the entire body and associated systemic disease. The exact mechanism of this disease is unknown, but the most widely accepted hypothesis is that immunoglobulins and cytokines contribute to the synthesis of glycosaminoglycans and thereby the deposition of mucin in the dermis.² Scleromyxedema has a chronic course and generally responds poorly to existing treatments.¹ Partial improvement has been demonstrated in treatment with topical calcineurin inhibitors and topical steroids.²

The differential diagnosis in our patient included scleromyxedema, scleredema, scleroderma, LM, and reticular erythematosus mucinosis. He was diagnosed with scleromyxedema with kappa monoclonal gammopathy. Scleromyxedema is a rare disorder involving the deposition of mucinous material in the papillary dermis that causes the formation of infiltrative skin lesions.³ The etiology is unknown, but the presence of a monoclonal protein is an important characteristic of this disorder. It is important to rule out thyroid disease as a possible etiology before concluding that the disease process is driven by the monoclonal gammopathy; this will help determine appropriate therapies.^4,5 Usually the monoclonal protein is associated with the IgG lambda subtype. Intravenous immunoglobulin often is considered as a first-line treatment of scleromyxedema and usually is administered at a dosage of 2 g/kg divided over 2 to 5 consecutive days per month.³ Previously, our patient had been treated with IVIG for 3 years for chronic inflammatory demyelinating polyneuropathy and had stopped 1 to 2 years before his cutaneous symptoms started. Generally, scleromyxedema patients must stay on IVIG long-term to prevent relapse, typically every 6 to 8 weeks. Second-line treatments for scleromyxedema include systemic corticosteroids and thalidomide.⁶ Scleromyxedema and LM have several clinical and histopathologic features in common. Our patient’s biopsy revealed increased mucin deposition associated with fibroblast proliferation confined to the superficial dermis. These histologic changes can be seen in the setting of either LM or scleromyxedema. Our patient’s diffuse skin thickening and monoclonal gammopathy were more characteristic of scleromyxedema. In contrast, LM is a localized eruption with no internal organ manifestations and no associated systemic disease, such as monoclonal gammopathy and thyroid disease.

Scleredema adultorum of Buschke (also referred to as scleredema) is a rare idiopathic dermatologic condition characterized by thickening and tightening of the skin that leads to firm, nonpitting, woody edema that initially involves the upper back and neck but can spread to the face, scalp, and shoulders; importantly, scleredema spares the hands and feet.⁷ Scleredema has been associated with type 2 diabetes mellitus, streptococcal upper respiratory tract infections, and monoclonal gammopathy.⁸ Although our patient did have a monoclonal gammopathy, he also experienced prominent hand involvement with diffuse skin thickening, which is not typical of scleredema. Additionally, biopsy of scleredema would show increased mucin but would not show the proliferation of fibroblasts that was seen in our patient’s biopsy. Furthermore, scleredema has more profound diffuse superficial and deep mucin deposition compared to scleromyxedema. Scleroderma is an autoimmune cutaneous condition that is divided into 2 categories: localized scleroderma and systemic sclerosis (SSc).⁹ Localized scleroderma (also called morphea) often is characterized by indurated hyperpigmented or hypopigmented lesions. There is an absence of Raynaud phenomenon, telangiectasia, and systemic disease.⁹ Systemic sclerosis is further divided into 2 categories—limited cutaneous and diffuse cutaneous—which are differentiated by the extent of organ system involvement. Limited cutaneous SSc involves calcinosis, Raynaud phenomenon, esophageal dysmotility, skin sclerosis distal to the elbows and knees, and telangiectasia.⁹ Diffuse cutaneous SSc is characterized by Raynaud phenomenon; cutaneous sclerosis proximal to the elbows and knees; and fibrosis of the gastrointestinal, pulmonary, renal, and cardiac systems.9 Scl-70 antibodies are specific for diffuse cutaneous SSc, and centromere antibodies are specific for limited cutaneous SSc. Scleromyxedema shares many of the same clinical symptoms as scleroderma; therefore, histopathologic examination is important for differentiating these disorders. Histologically, scleroderma is characterized by thickened collagen bundles associated with a variable degree of perivascular and interstitial lymphoplasmacytic inflammation. No increased dermal mucin is present.⁹ Our patient did not have the clinical cutaneous features of localized scleroderma and lacked the signs of internal organ involvement that typically are found in SSc. He did have Raynaud phenomenon but did not have matlike telangiectases or Scl-70 or centromere antibodies.

Reticular erythematosus mucinosis (REM) is a rare inflammatory cutaneous disease that is characterized by diffuse reticular erythematous macules or papules that may be asymptomatic or associated with pruritus.¹⁰ Reticular erythematosus mucinosis most frequently affects middle-aged women and appears on the trunk.⁹ Our patient was not part of the demographic group most frequently affected by REM. More importantly, our patient’s lesions were not erythematous or reticular in appearance, making the diagnosis of REM unlikely. Furthermore, REM has no associated cutaneous sclerosis or induration.

The Diagnosis: Scleromyxedema

A punch biopsy of the upper back performed at an outside institution revealed increased histiocytes and abundant interstitial mucin confined to the papillary dermis (Figures 1 and 2), consistent with the lichen myxedematosus (LM) papules that may be seen in scleromyxedema. Serum protein electrophoresis revealed the presence of a protein of restricted mobility on the gamma region that occupied 5.3% of the total protein (0.3 g/dL). Urine protein electrophoresis showed free kappa light chain monoclonal protein in the gamma region. Immunofixation electrophoresis revealed the presence of IgG kappa monoclonal protein in the gamma region with 10% monotype kappa cells. The presence of Raynaud phenomenon and positive antinuclear antibody (1:320, speckled) was noted. Laboratory studies for thyroid-stimulating hormone, C-reactive protein, Scl-70 antibody, myositis panel, ribonucleoprotein antibody, Smith antibody, Sjögren syndrome–related antigens A and B antibodies, rheumatoid factor, and RNA polymerase III antibody all were within reference range. Our patient was treated with monthly intravenous immunoglobulin (IVIG), and he noted substantial improvement in skin findings after 3 months of IVIG.

Localized lichen myxedematosus is a rare idiopathic cutaneous disease that clinically is characterized by waxy indurated papules and histologically is characterized by diffuse mucin deposition and fibroblast proliferation in the upper dermis.¹ Scleromyxedema is a diffuse variant of LM in which the papules and plaques of LM are associated with skin thickening involving almost the entire body and associated systemic disease. The exact mechanism of this disease is unknown, but the most widely accepted hypothesis is that immunoglobulins and cytokines contribute to the synthesis of glycosaminoglycans and thereby the deposition of mucin in the dermis.² Scleromyxedema has a chronic course and generally responds poorly to existing treatments.¹ Partial improvement has been demonstrated in treatment with topical calcineurin inhibitors and topical steroids.²

The differential diagnosis in our patient included scleromyxedema, scleredema, scleroderma, LM, and reticular erythematosus mucinosis. He was diagnosed with scleromyxedema with kappa monoclonal gammopathy. Scleromyxedema is a rare disorder involving the deposition of mucinous material in the papillary dermis that causes the formation of infiltrative skin lesions.³ The etiology is unknown, but the presence of a monoclonal protein is an important characteristic of this disorder. It is important to rule out thyroid disease as a possible etiology before concluding that the disease process is driven by the monoclonal gammopathy; this will help determine appropriate therapies.^4,5 Usually the monoclonal protein is associated with the IgG lambda subtype. Intravenous immunoglobulin often is considered as a first-line treatment of scleromyxedema and usually is administered at a dosage of 2 g/kg divided over 2 to 5 consecutive days per month.³ Previously, our patient had been treated with IVIG for 3 years for chronic inflammatory demyelinating polyneuropathy and had stopped 1 to 2 years before his cutaneous symptoms started. Generally, scleromyxedema patients must stay on IVIG long-term to prevent relapse, typically every 6 to 8 weeks. Second-line treatments for scleromyxedema include systemic corticosteroids and thalidomide.⁶ Scleromyxedema and LM have several clinical and histopathologic features in common. Our patient’s biopsy revealed increased mucin deposition associated with fibroblast proliferation confined to the superficial dermis. These histologic changes can be seen in the setting of either LM or scleromyxedema. Our patient’s diffuse skin thickening and monoclonal gammopathy were more characteristic of scleromyxedema. In contrast, LM is a localized eruption with no internal organ manifestations and no associated systemic disease, such as monoclonal gammopathy and thyroid disease.

Scleredema adultorum of Buschke (also referred to as scleredema) is a rare idiopathic dermatologic condition characterized by thickening and tightening of the skin that leads to firm, nonpitting, woody edema that initially involves the upper back and neck but can spread to the face, scalp, and shoulders; importantly, scleredema spares the hands and feet.⁷ Scleredema has been associated with type 2 diabetes mellitus, streptococcal upper respiratory tract infections, and monoclonal gammopathy.⁸ Although our patient did have a monoclonal gammopathy, he also experienced prominent hand involvement with diffuse skin thickening, which is not typical of scleredema. Additionally, biopsy of scleredema would show increased mucin but would not show the proliferation of fibroblasts that was seen in our patient’s biopsy. Furthermore, scleredema has more profound diffuse superficial and deep mucin deposition compared to scleromyxedema. Scleroderma is an autoimmune cutaneous condition that is divided into 2 categories: localized scleroderma and systemic sclerosis (SSc).⁹ Localized scleroderma (also called morphea) often is characterized by indurated hyperpigmented or hypopigmented lesions. There is an absence of Raynaud phenomenon, telangiectasia, and systemic disease.⁹ Systemic sclerosis is further divided into 2 categories—limited cutaneous and diffuse cutaneous—which are differentiated by the extent of organ system involvement. Limited cutaneous SSc involves calcinosis, Raynaud phenomenon, esophageal dysmotility, skin sclerosis distal to the elbows and knees, and telangiectasia.⁹ Diffuse cutaneous SSc is characterized by Raynaud phenomenon; cutaneous sclerosis proximal to the elbows and knees; and fibrosis of the gastrointestinal, pulmonary, renal, and cardiac systems.9 Scl-70 antibodies are specific for diffuse cutaneous SSc, and centromere antibodies are specific for limited cutaneous SSc. Scleromyxedema shares many of the same clinical symptoms as scleroderma; therefore, histopathologic examination is important for differentiating these disorders. Histologically, scleroderma is characterized by thickened collagen bundles associated with a variable degree of perivascular and interstitial lymphoplasmacytic inflammation. No increased dermal mucin is present.⁹ Our patient did not have the clinical cutaneous features of localized scleroderma and lacked the signs of internal organ involvement that typically are found in SSc. He did have Raynaud phenomenon but did not have matlike telangiectases or Scl-70 or centromere antibodies.

Reticular erythematosus mucinosis (REM) is a rare inflammatory cutaneous disease that is characterized by diffuse reticular erythematous macules or papules that may be asymptomatic or associated with pruritus.¹⁰ Reticular erythematosus mucinosis most frequently affects middle-aged women and appears on the trunk.⁹ Our patient was not part of the demographic group most frequently affected by REM. More importantly, our patient’s lesions were not erythematous or reticular in appearance, making the diagnosis of REM unlikely. Furthermore, REM has no associated cutaneous sclerosis or induration.

The Diagnosis: Scleromyxedema

A punch biopsy of the upper back performed at an outside institution revealed increased histiocytes and abundant interstitial mucin confined to the papillary dermis (Figures 1 and 2), consistent with the lichen myxedematosus (LM) papules that may be seen in scleromyxedema. Serum protein electrophoresis revealed the presence of a protein of restricted mobility on the gamma region that occupied 5.3% of the total protein (0.3 g/dL). Urine protein electrophoresis showed free kappa light chain monoclonal protein in the gamma region. Immunofixation electrophoresis revealed the presence of IgG kappa monoclonal protein in the gamma region with 10% monotype kappa cells. The presence of Raynaud phenomenon and positive antinuclear antibody (1:320, speckled) was noted. Laboratory studies for thyroid-stimulating hormone, C-reactive protein, Scl-70 antibody, myositis panel, ribonucleoprotein antibody, Smith antibody, Sjögren syndrome–related antigens A and B antibodies, rheumatoid factor, and RNA polymerase III antibody all were within reference range. Our patient was treated with monthly intravenous immunoglobulin (IVIG), and he noted substantial improvement in skin findings after 3 months of IVIG.

Localized lichen myxedematosus is a rare idiopathic cutaneous disease that clinically is characterized by waxy indurated papules and histologically is characterized by diffuse mucin deposition and fibroblast proliferation in the upper dermis.¹ Scleromyxedema is a diffuse variant of LM in which the papules and plaques of LM are associated with skin thickening involving almost the entire body and associated systemic disease. The exact mechanism of this disease is unknown, but the most widely accepted hypothesis is that immunoglobulins and cytokines contribute to the synthesis of glycosaminoglycans and thereby the deposition of mucin in the dermis.² Scleromyxedema has a chronic course and generally responds poorly to existing treatments.¹ Partial improvement has been demonstrated in treatment with topical calcineurin inhibitors and topical steroids.²

The differential diagnosis in our patient included scleromyxedema, scleredema, scleroderma, LM, and reticular erythematosus mucinosis. He was diagnosed with scleromyxedema with kappa monoclonal gammopathy. Scleromyxedema is a rare disorder involving the deposition of mucinous material in the papillary dermis that causes the formation of infiltrative skin lesions.³ The etiology is unknown, but the presence of a monoclonal protein is an important characteristic of this disorder. It is important to rule out thyroid disease as a possible etiology before concluding that the disease process is driven by the monoclonal gammopathy; this will help determine appropriate therapies.^4,5 Usually the monoclonal protein is associated with the IgG lambda subtype. Intravenous immunoglobulin often is considered as a first-line treatment of scleromyxedema and usually is administered at a dosage of 2 g/kg divided over 2 to 5 consecutive days per month.³ Previously, our patient had been treated with IVIG for 3 years for chronic inflammatory demyelinating polyneuropathy and had stopped 1 to 2 years before his cutaneous symptoms started. Generally, scleromyxedema patients must stay on IVIG long-term to prevent relapse, typically every 6 to 8 weeks. Second-line treatments for scleromyxedema include systemic corticosteroids and thalidomide.⁶ Scleromyxedema and LM have several clinical and histopathologic features in common. Our patient’s biopsy revealed increased mucin deposition associated with fibroblast proliferation confined to the superficial dermis. These histologic changes can be seen in the setting of either LM or scleromyxedema. Our patient’s diffuse skin thickening and monoclonal gammopathy were more characteristic of scleromyxedema. In contrast, LM is a localized eruption with no internal organ manifestations and no associated systemic disease, such as monoclonal gammopathy and thyroid disease.

Scleredema adultorum of Buschke (also referred to as scleredema) is a rare idiopathic dermatologic condition characterized by thickening and tightening of the skin that leads to firm, nonpitting, woody edema that initially involves the upper back and neck but can spread to the face, scalp, and shoulders; importantly, scleredema spares the hands and feet.⁷ Scleredema has been associated with type 2 diabetes mellitus, streptococcal upper respiratory tract infections, and monoclonal gammopathy.⁸ Although our patient did have a monoclonal gammopathy, he also experienced prominent hand involvement with diffuse skin thickening, which is not typical of scleredema. Additionally, biopsy of scleredema would show increased mucin but would not show the proliferation of fibroblasts that was seen in our patient’s biopsy. Furthermore, scleredema has more profound diffuse superficial and deep mucin deposition compared to scleromyxedema. Scleroderma is an autoimmune cutaneous condition that is divided into 2 categories: localized scleroderma and systemic sclerosis (SSc).⁹ Localized scleroderma (also called morphea) often is characterized by indurated hyperpigmented or hypopigmented lesions. There is an absence of Raynaud phenomenon, telangiectasia, and systemic disease.⁹ Systemic sclerosis is further divided into 2 categories—limited cutaneous and diffuse cutaneous—which are differentiated by the extent of organ system involvement. Limited cutaneous SSc involves calcinosis, Raynaud phenomenon, esophageal dysmotility, skin sclerosis distal to the elbows and knees, and telangiectasia.⁹ Diffuse cutaneous SSc is characterized by Raynaud phenomenon; cutaneous sclerosis proximal to the elbows and knees; and fibrosis of the gastrointestinal, pulmonary, renal, and cardiac systems.9 Scl-70 antibodies are specific for diffuse cutaneous SSc, and centromere antibodies are specific for limited cutaneous SSc. Scleromyxedema shares many of the same clinical symptoms as scleroderma; therefore, histopathologic examination is important for differentiating these disorders. Histologically, scleroderma is characterized by thickened collagen bundles associated with a variable degree of perivascular and interstitial lymphoplasmacytic inflammation. No increased dermal mucin is present.⁹ Our patient did not have the clinical cutaneous features of localized scleroderma and lacked the signs of internal organ involvement that typically are found in SSc. He did have Raynaud phenomenon but did not have matlike telangiectases or Scl-70 or centromere antibodies.

Reticular erythematosus mucinosis (REM) is a rare inflammatory cutaneous disease that is characterized by diffuse reticular erythematous macules or papules that may be asymptomatic or associated with pruritus.¹⁰ Reticular erythematosus mucinosis most frequently affects middle-aged women and appears on the trunk.⁹ Our patient was not part of the demographic group most frequently affected by REM. More importantly, our patient’s lesions were not erythematous or reticular in appearance, making the diagnosis of REM unlikely. Furthermore, REM has no associated cutaneous sclerosis or induration.

Men have a significantly increased risk of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” said lead author Sarah S. Jackson, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggested.

In an interview, Dr. Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told this news organization. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”
 

Comprehensive analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” said the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University in St. Louis.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they said.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wondered if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggested.

Nevertheless, they pointed out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic variable should be enforced along the whole cancer continuum, from risk prediction and cancer primary prevention, cancer screening, and secondary prevention to cancer treatment and patient management,” Dr. Luo and Dr. Colditz concluded.
 

Details of the analysis 

In their paper, Dr. Jackson and colleagues pointed out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs. 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of health care, and cancer screening between men and women, to explain the sex disparity, the researchers noted, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health–AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six U.S. states. At the time, 617,119 returned the baseline questionnaire (a 17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow-up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8,742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio versus women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team said that, overall, the increased relative risk among men was retained after adjustment for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters-Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

There were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Dr. Jackson told this news organization that sex differences in cancer outcomes “represents a very promising area of research” and the researchers “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Dr. Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the division of cancer epidemiology and genetics, National Cancer Institute. Dr. Marks reports relationships with Merck outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Dr. Luo reports grants from the National Institutes of Health outside the submitted work. Dr. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships were declared.

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

Men have a significantly increased risk of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” said lead author Sarah S. Jackson, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggested.

In an interview, Dr. Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told this news organization. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”
 

Comprehensive analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” said the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University in St. Louis.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they said.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wondered if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggested.

Nevertheless, they pointed out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic variable should be enforced along the whole cancer continuum, from risk prediction and cancer primary prevention, cancer screening, and secondary prevention to cancer treatment and patient management,” Dr. Luo and Dr. Colditz concluded.
 

Details of the analysis 

In their paper, Dr. Jackson and colleagues pointed out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs. 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of health care, and cancer screening between men and women, to explain the sex disparity, the researchers noted, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health–AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six U.S. states. At the time, 617,119 returned the baseline questionnaire (a 17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow-up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8,742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio versus women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team said that, overall, the increased relative risk among men was retained after adjustment for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters-Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

There were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Dr. Jackson told this news organization that sex differences in cancer outcomes “represents a very promising area of research” and the researchers “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Dr. Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the division of cancer epidemiology and genetics, National Cancer Institute. Dr. Marks reports relationships with Merck outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Dr. Luo reports grants from the National Institutes of Health outside the submitted work. Dr. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships were declared.

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

Men have a significantly increased risk of developing 11 different cancers, and the risk is three times greater for men for certain cancers, including those of the esophagus, larynx, gastric cardia, and bladder.

But why? A new analysis finds that the difference can only partly be explained by risky behaviors and carcinogenic exposure.

“There are differences in cancer incidence that are not explained by environmental exposures alone,” said lead author Sarah S. Jackson, PhD, of the division of cancer epidemiology and genetics at the National Cancer Institute in Bethesda, Md.

“This suggests that there are intrinsic biological differences between men and women that affect susceptibility to cancer,” she added in a statement.

The study was published online in the journal Cancer.

“Understanding the sex-related biologic mechanisms that lead to the male predominance of cancer at shared anatomic sites could have important implications for etiology and prevention,” the researchers suggested.

In an interview, Dr. Jackson said that the results “do not support changes to existing cancer prevention protocol” to address the disparities in cancer rates between men and women.

“More research is needed before any recommendations can be made,” she told this news organization. “For example, we need more research on the female immune response. If we can discover the mechanisms by which females have an immune advantage, we may be able to develop therapeutics to bolster the immune system to prevent and treat cancer.

“We also should start reporting our findings on cancer incidence, screening, and survival by sex to ensure that we are not missing important sex-specific associations.”
 

Comprehensive analyses

The researchers “should be applauded” for their “thorough and comprehensive analyses,” said the authors of an accompanying editorial, Jingqin R. Luo, PhD, and Graham A. Colditz, MD, DrPH, both from Washington University in St. Louis.

This study “has furthered our understanding on sex disparities in cancer, particularly in terms of the contributions of risk factors.”

However, as it included a largely elderly population and omitted comorbidities such as hypertension, hypercholesterolemia, and cardiovascular disease, the study has some “pertinent” limitations, they said.

The contribution of risk factors to sex disparities is “likely by means of complex interactions,” and the editorialists wondered if the statistical modeling used in the study was “over-stringent.” Other aspects that need to be considered include race as well as socioeconomic determinants of health, they suggested.

Nevertheless, they pointed out that sex disparities have been “observed in nearly every aspect of the cancer continuum,” and a “multifaceted approach” is needed to address them.

“Strategically including sex as a biologic variable should be enforced along the whole cancer continuum, from risk prediction and cancer primary prevention, cancer screening, and secondary prevention to cancer treatment and patient management,” Dr. Luo and Dr. Colditz concluded.
 

Details of the analysis 

In their paper, Dr. Jackson and colleagues pointed out that the lifetime probability of developing cancer is “approximately equal” in men and women, at 40% vs. 39%.

However, the burden of cancer at shared anatomic sites is “significantly higher” in men, with the relative risk more than twofold higher than in women.

Some previous studies have pointed to differences in smoking, alcohol use, diet, access to and use of health care, and cancer screening between men and women, to explain the sex disparity, the researchers noted, but few have used individual-level data.

They therefore examined records from the prospective National Institutes of Health–AARP Diet and Health Study. This was launched in 1995 with a baseline questionnaire sent to 3.5 million members of AARP aged 50-71 years and living in six U.S. states. At the time, 617,119 returned the baseline questionnaire (a 17.6% response rate).

The current study focused on 334,905 participants who also completed a follow-up questionnaire between 1996 and 1997, which included more detailed information on diet and other lifestyle factors.

After excluding those who had already had a cancer diagnosis, self-reported poor health, extremely high or low caloric intake, or conflicting gender information, the researchers focused on 294,100 individuals (58% men, 42% women, median age 63.5 years).

After more than a decade of follow-up (mean of 11.5 person-years for men and 12.4 person-years for women), the team found 26,693 incident cancers at 21 shared anatomical cancer sites. Of those, 17,951 were in men and 8,742 in women.

The five most common cancers were nearly the same: the top three were lung, colon, and skin cancer in both men and women, and the fifth most common was kidney cancer in both. No. 4 for men was bladder cancer and for women it was pancreatic cancer.

After adjusting for demographic, lifestyle, and dietary covariates, the researchers found that the cancers with the highest male-to-female hazard ratios were esophageal adenocarcinoma, at 10.80, larynx cancer, at 3.53, gastric cardia cancer, at 3.49, and bladder cancer, at 3.33.

In contrast, men had a reduced risk of thyroid cancer, at a hazard ratio versus women of 0.55, and gallbladder cancer, at a hazard ratio of 0.33.

The team said that, overall, the increased relative risk among men was retained after adjustment for covariates for 11 cancers, but the relationship was no longer significant for many others, including lung, pancreas, small intestine, colon, oral cavity, esophagus-squamous cell carcinoma, and other head and neck cancers.

Cox proportional hazards regression modeling using the Peters-Belson method indicated that sex differences in risk factors explained at least some of the observed differences between men and women for seven cancer sites.

These were lung, colon, rectum, other biliary tract, skin, bladder, and esophageal adenocarcinoma, with 11.2% of the variance explained by risk factor differences for esophageal adenocarcinoma, rising to 49.4% for lung cancer.

There were no significant interactions between cancer rates at any of the anatomic sites and alcohol use, smoking status, body mass index, and age group.

Dr. Jackson told this news organization that sex differences in cancer outcomes “represents a very promising area of research” and the researchers “absolutely want to examine these associations further.”

“The dataset we used consists largely of non-Hispanic White adults. We’d like to see if the same sex bias is present in other ethnic groups, which would provide more evidence for a biological basis for these differences.

“We’d also like to explore the contribution of sex hormones and genetics to cancer incidence in future research,” Dr. Jackson added.

The study was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. Morgan A. Marks, PhD, performed this work as a postdoctoral fellow at the division of cancer epidemiology and genetics, National Cancer Institute. Dr. Marks reports relationships with Merck outside the submitted work.

The editorial was supported in part by a National Cancer Institute Cancer Center Support Grant. Dr. Luo reports grants from the National Institutes of Health outside the submitted work. Dr. Colditz reports grants from the Breast Cancer Research Foundation and the National Cancer Institute outside the submitted work.

No other relevant financial relationships were declared.

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

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

PORTLAND, ORE. – In his nearly 2 decades of dermatology practice, Keith L. Duffy, MD, has seen his share of cases where Mohs surgery was misused or misappropriated.

“Appropriate use criteria in Mohs are near and dear to my heart,” Dr. Duffy, associate professor of dermatology at the University of Utah, Salt Lake City, said at the annual meeting of the Pacific Dermatologic Association. “I want to protect our specialty. I see patients who have dozens of skin cancers. I want to emphasize the long game of management in those patients. You have to think about the tumors in terms of decades.”

In 2012, an ad hoc task force from the American Academy of Dermatology (AAD), the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery developed appropriate use criteria (AUC) for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered. The task force used a 9-point scale to rate each indication, as follows:

• A score of 7 to 9: The use of MMS is appropriate for the specific indication and is generally considered acceptable.
• A score of 4 to 6: The use of MMS is uncertain for the specific indication, although its use may be appropriate and acceptable.
• A score of 1 to 3: The use of MMS is inappropriate for the specific indication and is generally not considered acceptable.

These ratings were translated into a free Mohs Surgery Appropriate Use Criteria App developed by the AAD.

Subsequently, Dr. Duffy and colleagues retrospectively examined the University of Utah’s adherence to the Mohs AUC over the course of 3 months. Their analysis, published in 2015, included 1,026 nonmelanoma skin cancers in 724 patients. Of the 1,026 cancers, 350 (34.1%) were treated with MMS. Of these, 339 (96.9%) were deemed appropriate based on the AUC guidelines, 4 (1.1%) were deemed uncertain, and 7 (2%) were deemed inappropriate.

There were also 611 skin cancers that were not treated with Mohs but met criteria for treatment with Mohs. “Most of these were AUC 7 tumors,” Dr. Duffy said. “When I see an AUC 7 tumor, I give high consideration for certain anatomic locations, especially the lower leg, scalp, eyelid, genitalia, ear, hands, and feet. I also think about the patient’s age, the number of skin cancers, and histological characteristics. Consider the long game in management and remember that skin cancer patients can make a near infinite amount of skin cancers, so be conservative when excising skin cancers to preserve precious skin.”

In his opinion, full thickness wounds requiring sutures should be avoided on the scalp and lower leg, if possible. “Most carcinomas in these locations are superficial and not aggressive in immunocompetent patients,” said Dr. Duffy, who said he has had one patient in 12 years who was not a transplant patient who had a metastatic squamous cell carcinoma on the lower leg. “Postop complications can be totally avoided. I don’t worry about these patients bleeding or [about] dehiscence. They can go back and play golf the next day, so you save valuable skin where the real estate is precious. This underscores a practice pearl: Incorporate the Mohs AUC and consideration of anatomic location when considering the most appropriate treatment of skin cancers.”

He also advises dermatologists to consider the histopathologic characteristics of the tumor when treating skin cancers to reduce complications and save tissue, so that patients can resume their lifestyle. “When you read the pathology report, really think about what the dermatopathologist saw under the microscope,” said Dr. Duffy, who is an investigator at the University of Utah’s Huntsman Cancer Institute. He said that he is able to review the slides for 90% of his own cases before surgery. “I’m lucky that way, but if you have any questions, your dermatopathologist should be on speed dial.”

Ultimately, he concluded, proper selection of a treatment modality for a specific tumor and patient rules the day. “Tumors should be thought about in the context of the patient and not as a single or isolated cancer,” he said.

Dr. Duffy reported having no relevant disclosures.

PORTLAND, ORE. – In his nearly 2 decades of dermatology practice, Keith L. Duffy, MD, has seen his share of cases where Mohs surgery was misused or misappropriated.

“Appropriate use criteria in Mohs are near and dear to my heart,” Dr. Duffy, associate professor of dermatology at the University of Utah, Salt Lake City, said at the annual meeting of the Pacific Dermatologic Association. “I want to protect our specialty. I see patients who have dozens of skin cancers. I want to emphasize the long game of management in those patients. You have to think about the tumors in terms of decades.”

In 2012, an ad hoc task force from the American Academy of Dermatology (AAD), the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery developed appropriate use criteria (AUC) for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered. The task force used a 9-point scale to rate each indication, as follows:

• A score of 7 to 9: The use of MMS is appropriate for the specific indication and is generally considered acceptable.
• A score of 4 to 6: The use of MMS is uncertain for the specific indication, although its use may be appropriate and acceptable.
• A score of 1 to 3: The use of MMS is inappropriate for the specific indication and is generally not considered acceptable.

These ratings were translated into a free Mohs Surgery Appropriate Use Criteria App developed by the AAD.

Subsequently, Dr. Duffy and colleagues retrospectively examined the University of Utah’s adherence to the Mohs AUC over the course of 3 months. Their analysis, published in 2015, included 1,026 nonmelanoma skin cancers in 724 patients. Of the 1,026 cancers, 350 (34.1%) were treated with MMS. Of these, 339 (96.9%) were deemed appropriate based on the AUC guidelines, 4 (1.1%) were deemed uncertain, and 7 (2%) were deemed inappropriate.

There were also 611 skin cancers that were not treated with Mohs but met criteria for treatment with Mohs. “Most of these were AUC 7 tumors,” Dr. Duffy said. “When I see an AUC 7 tumor, I give high consideration for certain anatomic locations, especially the lower leg, scalp, eyelid, genitalia, ear, hands, and feet. I also think about the patient’s age, the number of skin cancers, and histological characteristics. Consider the long game in management and remember that skin cancer patients can make a near infinite amount of skin cancers, so be conservative when excising skin cancers to preserve precious skin.”

In his opinion, full thickness wounds requiring sutures should be avoided on the scalp and lower leg, if possible. “Most carcinomas in these locations are superficial and not aggressive in immunocompetent patients,” said Dr. Duffy, who said he has had one patient in 12 years who was not a transplant patient who had a metastatic squamous cell carcinoma on the lower leg. “Postop complications can be totally avoided. I don’t worry about these patients bleeding or [about] dehiscence. They can go back and play golf the next day, so you save valuable skin where the real estate is precious. This underscores a practice pearl: Incorporate the Mohs AUC and consideration of anatomic location when considering the most appropriate treatment of skin cancers.”

He also advises dermatologists to consider the histopathologic characteristics of the tumor when treating skin cancers to reduce complications and save tissue, so that patients can resume their lifestyle. “When you read the pathology report, really think about what the dermatopathologist saw under the microscope,” said Dr. Duffy, who is an investigator at the University of Utah’s Huntsman Cancer Institute. He said that he is able to review the slides for 90% of his own cases before surgery. “I’m lucky that way, but if you have any questions, your dermatopathologist should be on speed dial.”

Ultimately, he concluded, proper selection of a treatment modality for a specific tumor and patient rules the day. “Tumors should be thought about in the context of the patient and not as a single or isolated cancer,” he said.

Dr. Duffy reported having no relevant disclosures.

PORTLAND, ORE. – In his nearly 2 decades of dermatology practice, Keith L. Duffy, MD, has seen his share of cases where Mohs surgery was misused or misappropriated.

“Appropriate use criteria in Mohs are near and dear to my heart,” Dr. Duffy, associate professor of dermatology at the University of Utah, Salt Lake City, said at the annual meeting of the Pacific Dermatologic Association. “I want to protect our specialty. I see patients who have dozens of skin cancers. I want to emphasize the long game of management in those patients. You have to think about the tumors in terms of decades.”

In 2012, an ad hoc task force from the American Academy of Dermatology (AAD), the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery developed appropriate use criteria (AUC) for 270 scenarios for which Mohs micrographic surgery (MMS) is frequently considered. The task force used a 9-point scale to rate each indication, as follows:

• A score of 7 to 9: The use of MMS is appropriate for the specific indication and is generally considered acceptable.
• A score of 4 to 6: The use of MMS is uncertain for the specific indication, although its use may be appropriate and acceptable.
• A score of 1 to 3: The use of MMS is inappropriate for the specific indication and is generally not considered acceptable.

These ratings were translated into a free Mohs Surgery Appropriate Use Criteria App developed by the AAD.

Subsequently, Dr. Duffy and colleagues retrospectively examined the University of Utah’s adherence to the Mohs AUC over the course of 3 months. Their analysis, published in 2015, included 1,026 nonmelanoma skin cancers in 724 patients. Of the 1,026 cancers, 350 (34.1%) were treated with MMS. Of these, 339 (96.9%) were deemed appropriate based on the AUC guidelines, 4 (1.1%) were deemed uncertain, and 7 (2%) were deemed inappropriate.

There were also 611 skin cancers that were not treated with Mohs but met criteria for treatment with Mohs. “Most of these were AUC 7 tumors,” Dr. Duffy said. “When I see an AUC 7 tumor, I give high consideration for certain anatomic locations, especially the lower leg, scalp, eyelid, genitalia, ear, hands, and feet. I also think about the patient’s age, the number of skin cancers, and histological characteristics. Consider the long game in management and remember that skin cancer patients can make a near infinite amount of skin cancers, so be conservative when excising skin cancers to preserve precious skin.”

In his opinion, full thickness wounds requiring sutures should be avoided on the scalp and lower leg, if possible. “Most carcinomas in these locations are superficial and not aggressive in immunocompetent patients,” said Dr. Duffy, who said he has had one patient in 12 years who was not a transplant patient who had a metastatic squamous cell carcinoma on the lower leg. “Postop complications can be totally avoided. I don’t worry about these patients bleeding or [about] dehiscence. They can go back and play golf the next day, so you save valuable skin where the real estate is precious. This underscores a practice pearl: Incorporate the Mohs AUC and consideration of anatomic location when considering the most appropriate treatment of skin cancers.”

He also advises dermatologists to consider the histopathologic characteristics of the tumor when treating skin cancers to reduce complications and save tissue, so that patients can resume their lifestyle. “When you read the pathology report, really think about what the dermatopathologist saw under the microscope,” said Dr. Duffy, who is an investigator at the University of Utah’s Huntsman Cancer Institute. He said that he is able to review the slides for 90% of his own cases before surgery. “I’m lucky that way, but if you have any questions, your dermatopathologist should be on speed dial.”

Ultimately, he concluded, proper selection of a treatment modality for a specific tumor and patient rules the day. “Tumors should be thought about in the context of the patient and not as a single or isolated cancer,” he said.

Dr. Duffy reported having no relevant disclosures.

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

Long-term lipid lowering with evolocumab (Repatha) further reduces cardiovascular events, including CV death, without a safety signal, according to results from the FOURIER open-label extension (OLE) study.

In the parent FOURIER trial, treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor over a median of 2.2 years reduced the primary efficacy endpoint by 15% but showed no CV mortality signal, compared with placebo, in patients with atherosclerotic disease on background statin therapy.

Now with follow-up out to 8.4 years – the longest to date in any PCSK9 study – cardiovascular mortality was cut by 23% in patients who remained on evolocumab, compared with those originally assigned to placebo (3.32% vs. 4.45%; hazard ratio, 0.77; 95% confidence interval, 0.60-0.99).

The Kaplan-Meier curves during FOURIER were “essentially superimposed and it was not until the open-label extension period had begun with longer-term follow up that the benefit in terms of cardiovascular mortality reduction became apparent,” said principal investigator Michelle O’Donoghue, MD, MPH, of Brigham and Women’s Hospital, Boston.

The results were reported at the annual congress of the European Society of Cardiology and published simultaneously in Circulation.

Pivotal statin trials have median follow-up times of 4-5 years and demonstrated both a lag effect, meaning clinical benefit grew over time, and a legacy effect, where clinical benefit persisted in extended follow-up after the parent study, Dr. O’Donoghue observed.

With shorter follow-up in the parent FOURIER trial, there was evidence of a lag effect with the risk reduction in CV death, MI, and stroke increasing from 16% in the first year to 25% over time with evolocumab.

FOURIER-OLE enrolled 6,635 patients (3355 randomly assigned to evolocumab and 3280 to placebo), who completed the parent study and self-injected evolocumab subcutaneously with the choice of 140 mg every 2 weeks or 420 mg monthly. Study visits were at week 12 and then every 24 weeks. Median follow-up was 5 years.

Their mean age was 62 years, three-fourths were men, a third had diabetes. Three-fourths were on a high-intensity statin at the time of enrollment in FOURIER, and median LDL cholesterol at randomization was 91 mg/dL (2.4 mmol/L).

At week 12, the median LDL cholesterol was 30 mg/dL (0.78 mmol/L), and this was sustained throughout follow-up, Dr. O’Donoghue reported. Most patients achieved very low LDL cholesterol levels, with 63.2% achieving levels less than 40 mg/dL (1.04 mmol/L) and 26.6% less than 20 mg/dL (0.52 mmol/L).

Patients randomly assigned in the parent trial to evolocumab versus placebo had a 15% lower risk of the primary outcome of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization (15.4% vs. 17.5%; HR, 0.85; 95% CI, 0.75-0.96).

Their risk of CV death, MI, or stroke was 20% lower (9.7% vs. 11.9%; HR, 0.80; 95% CI, 0.68-0.93), and, as noted previously, 23% lower for CV death.

When major adverse cardiovascular events data were parsed out by year, the largest LDL cholesterol reduction was in years 1 and 2 of the parent study (delta, 62 mg/dL between treatment arms), “highlighting that lag of benefit that continued to accrue with time,” Dr. O’Donoghue said.

“There was then carryover into the extension period, such that there was legacy effect from the LDL [cholesterol] delta that was seen during the parent study,” she said. “This benefit was most apparent early on during open-label extension and then, as one might expect when all patients were being treated with the same therapy, it began to attenuate somewhat with time.”

Although early studies raised concerns that very low LDL cholesterol may be associated with an increased risk of hemorrhagic stroke and neurocognitive effects, the frequency of adverse events did not increase over time with evolocumab exposure.

Annualized incidence rates for patients initially randomized to evolocumab did not exceed those for placebo-treated patients for any of the following events of interest: serious safety events (10% vs. 13%), hemorrhagic stroke (0.04% vs. 0.05%), new-onset diabetes (1.2% vs. 2.3%), muscle-related events (1.2% vs. 1.9%), injection-site reactions (0.4% vs. 0.7%), and drug-related allergic reactions (0.6% vs. 1.1%).

“Long-term use of evolocumab with a median follow-up of more than 7 years appears both safe and well tolerated,” Dr. O’Donoghue said.

Taken together with the continued accrual of cardiovascular benefit, including CV mortality, “these findings argue for early initiation of a marked and sustained LDL cholesterol reduction to maximize benefit,” she concluded.
 

Translating the benefits

Ulrich Laufs, MD, Leipzig (Germany) University Hospital, Germany, and invited commentator for the session, said the trial addresses two key issues: the long-term safety of low LDL cholesterol lowering and the long-term safety of inhibiting PCSK9, which is highly expressed not only in the liver but also in the brain, small intestine, and kidneys. Indeed, an LDL cholesterol level below 30 mg/dL is lower than the ESC treatment recommendation for very-high-risk patients and is, in fact, lower than most assays are reliable to interpret.

“So it is very important that we have these very clear data showing us that there were no adverse events, also including cataracts and hemorrhagic stroke, and these were on the level of placebo and did not increase over time,” he said.

The question of efficacy is triggered by observations of another PCSK9, the humanized monoclonal antibody bococizumab, which was associated in the SPIRE trial with an increase in LDL cholesterol over time because of neutralizing antibodies. Reassuringly, there was “completely sustained LDL [cholesterol] reduction” with no neutralizing antibodies with the fully human antibody evolocumab in FOURIER-OLE and in recent data from the OSLER-1 study, Dr. Laufs observed.

Acknowledging the potential for selection bias with an OLE program, Dr. Laufs said there are two important open questions: “Can the safety data observed for extracellular PCSK9 inhibition using an antibody be transferred to other mechanisms of PCSK9 inhibition? And obviously, from the perspective of patient care, how can we implement these important data into patient care and improve access to PCSK9 inhibitors?”

With regard to the latter point, he said physicians should be cautious in using the term “plaque regression,” opting instead for prevention and stabilization of atherosclerosis, and when using the term “legacy,” which may be misinterpreted by patients to imply there was cessation of therapy.

“From my perspective, [what] the open-label extension really shows is that earlier treatment is better,” Dr. Laufs said. “This should be our message.”

In a press conference prior to the presentation, ESC commentator Johann Bauersachs, MD, Hannover (Germany) Medical School, said “this is extremely important data because it confirms that it’s safe, and the criticism of the FOURIER study that mortality, cardiovascular mortality, was not reduced is now also reduced.”

Dr. Bauersachs said it would have been unethical to wait 7 years for a placebo-controlled trial and questioned whether data are available and suggestive of a legacy effect among patients who did not participate in the open-label extension.

Dr. O’Donoghue said unfortunately those data aren’t available but that Kaplan-Meier curves for the primary endpoint in the parent trial continued to diverge over time and that there was somewhat of a lag in terms of that divergence. “So, a median follow-up of 2 years may have been insufficient, especially for the emerging cardiovascular mortality that took longer to appear.”

The study was funded by Amgen. Dr. O’Donoghue reported receiving research grants from Amgen, AstraZeneca, Janssen, Intarcia, and Novartis, and consulting fees from Amgen, Novartis, AstraZeneca, and Janssen. Dr. Laufs reported receiving honoraria/reimbursement for lecture, study participation, and scientific cooperation with Saarland or Leipzig University, as well as relationships with multiple pharmaceutical and device makers.

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

A baby’s weight and neurodevelopment in the first 2 years of life could be influenced by maternal fat metabolism in the early stages of pregnancy, according to a study.

Patterns of fetal abdominal growth were associated with maternal lipid metabolites that tracked newborn growth, adiposity, and development into childhood and could be identified as early as the 5th month of pregnancy, according to researchers at the University of Oxford, working with colleagues at the University of California.

These fetal growth patterns were also associated with blood flow and nutrient transfer by the placenta, demonstrating a complex interaction between maternal and fetal nutrition early in pregnancy, with implications for postnatal weight and health in later life, they suggested.

Stephen Kennedy, MD, professor of reproductive medicine at the University of Oxford, who co-led the investigation, said it had “provided valuable new insights into the biological origins of childhood obesity, which is one of the most pressing public health issues facing governments around the world.”
 

International study

The prospective observational study, published in The Lancet Diabetes and Endocrinology, involved 3,598 pregnant women from six countries – Brazil, Kenya, Pakistan, South Africa, Thailand, and the United Kingdom – aged 18 and older and with a BMI of less than 35 kg/m². The women were monitored using regular fetal ultrasound scans and metabolomic analysis of early pregnancy maternal blood and umbilical cord venous blood at the time of birth.

Their infants, who were singletons, and conceived naturally, were then followed for 2 years to assess their growth and development.

Fetal abdominal circumference growth was found to accelerate or decelerate within “a crucial 20-25 week gestational age window” that followed 4 trajectories of faltering growth, early accelerating growth, late accelerating growth, or median growth. These traits were matched by fetus-placenta blood flow patterns throughout pregnancy and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood, researchers said.

Overall, 709 maternal metabolites had a positive effect for the faltering growth phenotype, and 54 for the early accelerating growth phenotype, whilst 31 had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype.

The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was “highly abundant” in the early accelerating growth phenotype group.
 

‘A unique insight’

Aris Papageorghiou, professor of Fetal Medicine at the University of Oxford, who co-led the research, said: “This study provides evidence of distinct patterns of fetal abdominal growth and placental transfer and how they relate to longer term health. The finding of an association with maternal lipid metabolism early in pregnancy also provides unique insights into how the mother’s health and diet influence her child’s adiposity.”

First author José Villar, MD, professor of perinatal medicine at Oxford, said: “The study complements our previous work that identified fetal head growth trajectories associated with different developmental, behavioral, visual, and growth outcomes at 2 years of age.” Taken together, “the growth of babies’ bodies and brain[s] track separately and early – while still within the womb,” he said.

According to Dr. Kennedy, the latest results “could contribute to earlier identification of infants at risk of obesity” and urged policymakers to “take notice of these findings in their efforts to prevent the oncoming epidemic of obesity, with all its likely adverse social and economic consequences.”

Funding for the study was provided by the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape UK.

A baby’s weight and neurodevelopment in the first 2 years of life could be influenced by maternal fat metabolism in the early stages of pregnancy, according to a study.

Patterns of fetal abdominal growth were associated with maternal lipid metabolites that tracked newborn growth, adiposity, and development into childhood and could be identified as early as the 5th month of pregnancy, according to researchers at the University of Oxford, working with colleagues at the University of California.

These fetal growth patterns were also associated with blood flow and nutrient transfer by the placenta, demonstrating a complex interaction between maternal and fetal nutrition early in pregnancy, with implications for postnatal weight and health in later life, they suggested.

Stephen Kennedy, MD, professor of reproductive medicine at the University of Oxford, who co-led the investigation, said it had “provided valuable new insights into the biological origins of childhood obesity, which is one of the most pressing public health issues facing governments around the world.”
 

International study

The prospective observational study, published in The Lancet Diabetes and Endocrinology, involved 3,598 pregnant women from six countries – Brazil, Kenya, Pakistan, South Africa, Thailand, and the United Kingdom – aged 18 and older and with a BMI of less than 35 kg/m². The women were monitored using regular fetal ultrasound scans and metabolomic analysis of early pregnancy maternal blood and umbilical cord venous blood at the time of birth.

Their infants, who were singletons, and conceived naturally, were then followed for 2 years to assess their growth and development.

Fetal abdominal circumference growth was found to accelerate or decelerate within “a crucial 20-25 week gestational age window” that followed 4 trajectories of faltering growth, early accelerating growth, late accelerating growth, or median growth. These traits were matched by fetus-placenta blood flow patterns throughout pregnancy and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood, researchers said.

Overall, 709 maternal metabolites had a positive effect for the faltering growth phenotype, and 54 for the early accelerating growth phenotype, whilst 31 had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype.

The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was “highly abundant” in the early accelerating growth phenotype group.
 

‘A unique insight’

Aris Papageorghiou, professor of Fetal Medicine at the University of Oxford, who co-led the research, said: “This study provides evidence of distinct patterns of fetal abdominal growth and placental transfer and how they relate to longer term health. The finding of an association with maternal lipid metabolism early in pregnancy also provides unique insights into how the mother’s health and diet influence her child’s adiposity.”

First author José Villar, MD, professor of perinatal medicine at Oxford, said: “The study complements our previous work that identified fetal head growth trajectories associated with different developmental, behavioral, visual, and growth outcomes at 2 years of age.” Taken together, “the growth of babies’ bodies and brain[s] track separately and early – while still within the womb,” he said.

According to Dr. Kennedy, the latest results “could contribute to earlier identification of infants at risk of obesity” and urged policymakers to “take notice of these findings in their efforts to prevent the oncoming epidemic of obesity, with all its likely adverse social and economic consequences.”

Funding for the study was provided by the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape UK.

A baby’s weight and neurodevelopment in the first 2 years of life could be influenced by maternal fat metabolism in the early stages of pregnancy, according to a study.

Patterns of fetal abdominal growth were associated with maternal lipid metabolites that tracked newborn growth, adiposity, and development into childhood and could be identified as early as the 5th month of pregnancy, according to researchers at the University of Oxford, working with colleagues at the University of California.

These fetal growth patterns were also associated with blood flow and nutrient transfer by the placenta, demonstrating a complex interaction between maternal and fetal nutrition early in pregnancy, with implications for postnatal weight and health in later life, they suggested.

Stephen Kennedy, MD, professor of reproductive medicine at the University of Oxford, who co-led the investigation, said it had “provided valuable new insights into the biological origins of childhood obesity, which is one of the most pressing public health issues facing governments around the world.”
 

International study

The prospective observational study, published in The Lancet Diabetes and Endocrinology, involved 3,598 pregnant women from six countries – Brazil, Kenya, Pakistan, South Africa, Thailand, and the United Kingdom – aged 18 and older and with a BMI of less than 35 kg/m². The women were monitored using regular fetal ultrasound scans and metabolomic analysis of early pregnancy maternal blood and umbilical cord venous blood at the time of birth.

Their infants, who were singletons, and conceived naturally, were then followed for 2 years to assess their growth and development.

Fetal abdominal circumference growth was found to accelerate or decelerate within “a crucial 20-25 week gestational age window” that followed 4 trajectories of faltering growth, early accelerating growth, late accelerating growth, or median growth. These traits were matched by fetus-placenta blood flow patterns throughout pregnancy and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood, researchers said.

Overall, 709 maternal metabolites had a positive effect for the faltering growth phenotype, and 54 for the early accelerating growth phenotype, whilst 31 had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype.

The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was “highly abundant” in the early accelerating growth phenotype group.
 

‘A unique insight’

Aris Papageorghiou, professor of Fetal Medicine at the University of Oxford, who co-led the research, said: “This study provides evidence of distinct patterns of fetal abdominal growth and placental transfer and how they relate to longer term health. The finding of an association with maternal lipid metabolism early in pregnancy also provides unique insights into how the mother’s health and diet influence her child’s adiposity.”

First author José Villar, MD, professor of perinatal medicine at Oxford, said: “The study complements our previous work that identified fetal head growth trajectories associated with different developmental, behavioral, visual, and growth outcomes at 2 years of age.” Taken together, “the growth of babies’ bodies and brain[s] track separately and early – while still within the womb,” he said.

According to Dr. Kennedy, the latest results “could contribute to earlier identification of infants at risk of obesity” and urged policymakers to “take notice of these findings in their efforts to prevent the oncoming epidemic of obesity, with all its likely adverse social and economic consequences.”

Funding for the study was provided by the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape UK.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

Beta-blockers have long been recommended to prevent aortic dissection associated with Marfan syndrome despite limited evidence, but a new analysis also supports a benefit from angiotensin receptors blockers (ARBs) and further suggests that beta-blockers and ARBs exert independent effects.

For the endpoint of inhibition of growth of the aortic root, “there is no evidence of any interaction between the effects of ARBs with beta-blockers, and so we think that the treatment effects are likely to be additive,” reported Alex Pitcher, BMBCh, DPhil, Oxford (England) University Hospitals, NHS Trust.

Based on these data, Dr. Pitcher recommended considering ARBs and beta-blockers together soon after the diagnosis of Marfan syndrome. This includes young children.

“We think that medical treatments can delay surgery and dissection substantially if given for a number of years,” he added.

In this study, undertaken by the Marfan Treatment Trialists (MTT) collaboration, data were available from 1,442 Marfan syndrome patients participating in seven treatment trials. The primary outcome was aortic root enlargement, a predictor of life-threatening aortic dissection and rupture. Rather than a meta-analysis of the pooled data, the meta-analysis was conducted with individual patient data that involved collaboration with the original trialists.

Four of the studies with 746 patients compared ARBs to placebo or a control medication. A second group of three trials with 766 patients compared ARBs to beta-blockers.

From the two sets of data, a calculation of the effect of beta-blockers was indirectly estimated.
 

ARBs slow annualized aortic growth rate significantly

In the first set of trials, the analysis showed a significantly slower annualized aortic root growth rate for those treated with ARBs relative to controls (0.07 vs. 0.13), producing a statistically significant absolute difference (0.7%; P = .01) in favor of the ARB.

“In other words, the rate of growth was nearly double in the control arm,” Dr. Pitcher said.

In the three trials comparing ARBs to beta-blockers, the annualized growth rate among those taking an ARB was similar (0.8%) to that seen in the previous set of controlled trials. This rate of annualized growth was not significantly different from the 0.11% annualized rate of growth in patients receiving beta-blockers. When an analysis of the impact of beta-blockers was conducted by indirectly evaluating the change in growth relative to controls, the estimated impact was an annualized growth rate of 0.9% (P = .042).

A second set of data provided the basis for suggesting that the effects of beta ARBs and beta-blockers are independent and potentially additive.

“We were able to look at subgroups of patients in the ARB trials that were broken down by whether they were or were not on beta-blockers at baseline, and so by doing able to estimate independent effects,” Dr. Pitcher said. The lack of any interactions led Dr. Pitcher to conclude that benefits are likely additive.

Of patients genotyped in the ARB studies, more than 80% had the FBN1 pathogenic variant of Marfan syndrome. When the data were analyzed by subgroups, including age or blood pressure, there were no differences in treatment effect except for those with the FBN1 mutation in whom the benefit of ARB therapy was greater relative to those without.

As FBN1 is one of the most common genetic signatures of Marfan syndrome, the “greater effect of ARBs in this group makes it more plausible that the effect is real,” Dr. Pitcher said.
 

Results could change treatment guidelines

Current guidelines recommend beta-blockers in Marfan syndrome prior to a dilatation size of 4.5 to 5 cm when surgery is indicated, according to Dr. Pitcher, but he said these data might change guidelines. While reinforcing the benefit of beta-blockers, this analysis suggests ARBs should also be considered, possibly in combination with beta-blockers.

“What I hope this meta-analysis does is add substantially to the certainty with which physicians can discuss treatments with patients.”

As for the mechanism, it is reasonable to speculate the antihypertensive effect of both medications is relevant, but each has plausible independent activities that might contribute to modifying aortic growth, according to Roland R.J. van Kimmenade, MD, PhD, a specialist in aortic diseases and heart failure at Raboud University Medical Center, Nijmegan, the Netherlands.

Citing several studies, he suggested that the benefit of beta-blockers could also stem from their ability to reduce heart rate and aortic stiffness while ARBs are likely to inhibit the interaction between the renin-angiotensin system (RAS) and TGF-beta pathway. Each of these might participate in risk of aortic root growth, according to Dr. van Kimmenade, who was invited by ESC to discuss this study.

On the basis of these data as well as past studies, he agreed that the combination of beta-blockers and ARBs might not just be additive but “even a little bit synergistic.”

While Dr. Pitcher suggested that the evidence supports starting both beta-blockers and ARBs soon after the diagnosis, Dr. van Kimmenade said, “I don’t like using beta-blockers in young patients, but ARBs are now shown to be an excellent alternative.”

Ultimately, “the prescription pencil will not replace the surgical knife” in a disease that is likely to eventually require surgery to prevent life-threatening events, according to Dr. van Kimmenade, but he agreed that these data provide more certainty about the value of beta-blockers and ARBs for slowing progression.

Dr. Pitcher reports no potential conflicts of interest. Dr. van Kimmenade has financial relationships with Bayer and Novartis.

At the risk of losing a digit or two I am going to dip my toes into the murky waters of gender-affirming care, sometimes referred to as trans care. Recently, Moira Szilagyi, MD, PhD, president of the American Academy of Pediatrics, released two statements, one in the Aug. 22, 2022, Wall Street Journal, the other summarized in the Aug. 25, 2022, AAP Daily Briefing, in which she attempts to clarify the academy’s position on gender-affirming care. They were well-worded and heroic attempts to clear the air. I fear these explanations will do little to encourage informed and courteous discussions between those entrenched on either side of a disagreement that is unfortunately being played out on media outlets and state legislatures instead of the offices of primary care physicians and specialists where it belongs.

The current mess is an example of what can happen when there is a paucity of reliable data, a superabundance of emotion, and a system that feeds on instant news and sound bites with little understanding of how science should work.

Some of the turmoil is a response to the notion that in certain situations gender dysphoria may be a condition that can be learned or mimicked from exposure to other gender-dysphoric individuals. Two papers anchor either side of the debate. The first paper was published in 2018 by a then–Brown University health expert who hypothesized the existence of a condition which she labeled “rapid-onset gender dysphoria [ROGD]”. One can imagine that “social contagion” might be considered as one of the potential contributors to this hypothesized condition. Unfortunately, the publication of the paper ignited a firestorm of criticism from a segment of the population that advocates for the transgender community, prompting the university and the online publisher to backpedal and reevaluate the quality of the research on which the paper was based.

One of the concerns voiced at the time of publication was that the research could be used to support the transphobic agenda by some state legislatures hoping to ban gender-affirming care. How large a role the paper played in the current spate of legislation in is unclear. I suspect it has been small. But, one can’t deny the potential exists.

Leaping forward to 2022, the second paper was published in the August issue of Pediatrics, in which the authors attempted to test the ROGD hypothesis and question the inference of social contagion.

The investigators found that in 2017 and 2019 the birth ratios of transgender-diverse (TGD) individuals did not favor assigned female-sex-at-birth (AFAB) individuals. They also discovered that in their sample overall there was a decrease in the percentage of adolescents who self-identified as TGD. Not surprisingly, “bullying victimization and suicidality were higher among TGD youth when compared with their cisgender peers.” The authors concluded that their findings were “incongruent with an ROGD hypothesis that posits social contagion” nor should it be used to restrict access to gender-affirming care.

There you have it. Are we any closer to understanding gender dysphoria and its origins? I don’t think so. The media is somewhat less confused. The NBC News online presence headline on Aug. 3, 2022, reads “‘Social contagion’ isn’t causing more youths to be transgender, study finds.”

My sense is that the general population perceives an increase in the prevalence of gender dysphoria. It is very likely that this perception is primarily a reflection of a more compassionate and educated attitude in a significant portion of the population making it less challenging for gender-dysphoric youth to surface. However, it should not surprise us that some parents and observers are concerned that a percentage of this increased prevalence is the result of social contagion. Nor should it surprise us that some advocates for the trans population feel threatened by this hypothesis.

Neither of these studies really answers the question of whether some cases of gender dysphoria are the result of social contagion. Both were small samples using methodology that has been called into question. The bottom line is that we need more studies and must remain open to considering their results. That’s how science should work.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

At the risk of losing a digit or two I am going to dip my toes into the murky waters of gender-affirming care, sometimes referred to as trans care. Recently, Moira Szilagyi, MD, PhD, president of the American Academy of Pediatrics, released two statements, one in the Aug. 22, 2022, Wall Street Journal, the other summarized in the Aug. 25, 2022, AAP Daily Briefing, in which she attempts to clarify the academy’s position on gender-affirming care. They were well-worded and heroic attempts to clear the air. I fear these explanations will do little to encourage informed and courteous discussions between those entrenched on either side of a disagreement that is unfortunately being played out on media outlets and state legislatures instead of the offices of primary care physicians and specialists where it belongs.

The current mess is an example of what can happen when there is a paucity of reliable data, a superabundance of emotion, and a system that feeds on instant news and sound bites with little understanding of how science should work.

Some of the turmoil is a response to the notion that in certain situations gender dysphoria may be a condition that can be learned or mimicked from exposure to other gender-dysphoric individuals. Two papers anchor either side of the debate. The first paper was published in 2018 by a then–Brown University health expert who hypothesized the existence of a condition which she labeled “rapid-onset gender dysphoria [ROGD]”. One can imagine that “social contagion” might be considered as one of the potential contributors to this hypothesized condition. Unfortunately, the publication of the paper ignited a firestorm of criticism from a segment of the population that advocates for the transgender community, prompting the university and the online publisher to backpedal and reevaluate the quality of the research on which the paper was based.

One of the concerns voiced at the time of publication was that the research could be used to support the transphobic agenda by some state legislatures hoping to ban gender-affirming care. How large a role the paper played in the current spate of legislation in is unclear. I suspect it has been small. But, one can’t deny the potential exists.

Leaping forward to 2022, the second paper was published in the August issue of Pediatrics, in which the authors attempted to test the ROGD hypothesis and question the inference of social contagion.

The investigators found that in 2017 and 2019 the birth ratios of transgender-diverse (TGD) individuals did not favor assigned female-sex-at-birth (AFAB) individuals. They also discovered that in their sample overall there was a decrease in the percentage of adolescents who self-identified as TGD. Not surprisingly, “bullying victimization and suicidality were higher among TGD youth when compared with their cisgender peers.” The authors concluded that their findings were “incongruent with an ROGD hypothesis that posits social contagion” nor should it be used to restrict access to gender-affirming care.

There you have it. Are we any closer to understanding gender dysphoria and its origins? I don’t think so. The media is somewhat less confused. The NBC News online presence headline on Aug. 3, 2022, reads “‘Social contagion’ isn’t causing more youths to be transgender, study finds.”

My sense is that the general population perceives an increase in the prevalence of gender dysphoria. It is very likely that this perception is primarily a reflection of a more compassionate and educated attitude in a significant portion of the population making it less challenging for gender-dysphoric youth to surface. However, it should not surprise us that some parents and observers are concerned that a percentage of this increased prevalence is the result of social contagion. Nor should it surprise us that some advocates for the trans population feel threatened by this hypothesis.

Neither of these studies really answers the question of whether some cases of gender dysphoria are the result of social contagion. Both were small samples using methodology that has been called into question. The bottom line is that we need more studies and must remain open to considering their results. That’s how science should work.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

At the risk of losing a digit or two I am going to dip my toes into the murky waters of gender-affirming care, sometimes referred to as trans care. Recently, Moira Szilagyi, MD, PhD, president of the American Academy of Pediatrics, released two statements, one in the Aug. 22, 2022, Wall Street Journal, the other summarized in the Aug. 25, 2022, AAP Daily Briefing, in which she attempts to clarify the academy’s position on gender-affirming care. They were well-worded and heroic attempts to clear the air. I fear these explanations will do little to encourage informed and courteous discussions between those entrenched on either side of a disagreement that is unfortunately being played out on media outlets and state legislatures instead of the offices of primary care physicians and specialists where it belongs.

The current mess is an example of what can happen when there is a paucity of reliable data, a superabundance of emotion, and a system that feeds on instant news and sound bites with little understanding of how science should work.

Some of the turmoil is a response to the notion that in certain situations gender dysphoria may be a condition that can be learned or mimicked from exposure to other gender-dysphoric individuals. Two papers anchor either side of the debate. The first paper was published in 2018 by a then–Brown University health expert who hypothesized the existence of a condition which she labeled “rapid-onset gender dysphoria [ROGD]”. One can imagine that “social contagion” might be considered as one of the potential contributors to this hypothesized condition. Unfortunately, the publication of the paper ignited a firestorm of criticism from a segment of the population that advocates for the transgender community, prompting the university and the online publisher to backpedal and reevaluate the quality of the research on which the paper was based.

One of the concerns voiced at the time of publication was that the research could be used to support the transphobic agenda by some state legislatures hoping to ban gender-affirming care. How large a role the paper played in the current spate of legislation in is unclear. I suspect it has been small. But, one can’t deny the potential exists.

Leaping forward to 2022, the second paper was published in the August issue of Pediatrics, in which the authors attempted to test the ROGD hypothesis and question the inference of social contagion.

The investigators found that in 2017 and 2019 the birth ratios of transgender-diverse (TGD) individuals did not favor assigned female-sex-at-birth (AFAB) individuals. They also discovered that in their sample overall there was a decrease in the percentage of adolescents who self-identified as TGD. Not surprisingly, “bullying victimization and suicidality were higher among TGD youth when compared with their cisgender peers.” The authors concluded that their findings were “incongruent with an ROGD hypothesis that posits social contagion” nor should it be used to restrict access to gender-affirming care.

There you have it. Are we any closer to understanding gender dysphoria and its origins? I don’t think so. The media is somewhat less confused. The NBC News online presence headline on Aug. 3, 2022, reads “‘Social contagion’ isn’t causing more youths to be transgender, study finds.”

My sense is that the general population perceives an increase in the prevalence of gender dysphoria. It is very likely that this perception is primarily a reflection of a more compassionate and educated attitude in a significant portion of the population making it less challenging for gender-dysphoric youth to surface. However, it should not surprise us that some parents and observers are concerned that a percentage of this increased prevalence is the result of social contagion. Nor should it surprise us that some advocates for the trans population feel threatened by this hypothesis.

Neither of these studies really answers the question of whether some cases of gender dysphoria are the result of social contagion. Both were small samples using methodology that has been called into question. The bottom line is that we need more studies and must remain open to considering their results. That’s how science should work.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].