Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Epic tweets

Need a little break from seeing all your patients? Hop on Twitter for a few minutes – specifically, the Epic parody account.

A frustrated but hilarious physician somewhere on the East Coast created the account a month ago to brighten busy days and help other physicians connect through a shared hatred of Epic, the electronic health records system.

The account’s bio states: “My goal is to create confusion for doctors. I will not rest until doctors do nothing but click buttons. Eye contact is evil.” In continuing with this theme, the account dedicates many Tweets to decrying patient-doctor interaction and encouraging computer-doctor interaction instead. And it rails against the “shaming of data-entry clerks.”

If you, too, are frustrated with Epic or your own EHR system, submit them to @EPICEMRparody with the hashtag #EPICfail. Join the club.
 

Pour me another, bartender

All the beauty of alcohol without the soul-crushing hangover the next day? I’ll take two on the rocks, please.

For the last decade, visionary, scientist, and soon-to-be hero David Nutt, DM, has been working on a formula for synthetic alcohol that gets you nice and tipsy, but spares you the hangover. Dr. Nutt has created a compound he calls “alcosynth” that triggers a buzz but doesn’t activate the brain receptors that cause the symptoms of hangover.

Dr. Nutt is confident that his alcohol will hit liquor stores in just 5 years. As the director of neuropsychopharmacology at the Imperial College London and a wine bar owner, he knows a bit more than the average person about alcohol and brain receptors. He realized that the brain’s GABA receptors can be stimulated by alcohol and developed his product, Alcarelle, to simulate that stimulation without causing headaches, nausea, dizziness, and other hangover symptoms.

Dr. Nutt guards his process pretty tightly, however – the secret to hangover-free booze is as precious as a golden ticket to the Wonka factory. Everyone’s going to want to get their hands on it!
 

Don’t just do something, lie there

As the Trump administration tries to implement work requirements for food stamps and Medicaid, the Artificial Gravity Bed Rest Study offers another way to get paid for doing nothing.

DLR (CC-BY 3.0)

This joint effort between NASA, the European Space Agency, and the German Space Agency will recreate outer space conditions right here on earth – in Cologne, Germany, to be exact – by having participants lie down for 60 days with their heads 6 degrees below their feet, causing fluids in the body to shift toward their heads and reproducing conditions experienced by astronauts in the absence of gravity.

Unsurprisingly, not just anyone will be considered: Participants have to be women aged 24-55 years with body mass indexes of 19-30 kg/m² who speak German and don’t smoke. Test subjects have to bathe, eat (the project’s website mentions pancakes), and go to the toilet while lying down, and they will spend 30 minutes a day in the human centrifuge – that’s the artificial gravity part of the study – to counteract the effects of weightlessness. They also will receive an expense allowance of about $18,500.

So, you can earn almost 20 grand as you get waited on, stuffed with pancakes, and massaged while catching up on your reading and relaxing for 2 months. Hmm, we may have gotten this backwards with that work requirement remark. Sounds more like a trial membership into the “1%,” so be sure to keep track of your portfolios.

That’s why mosquitoes don’t go to clubs

There’s not a whole lot of positive things that can be said about mosquitoes, spreaders of such wonderful diseases such as malaria and Zika. But we’ll give them this: They have good taste in music.

Those musical standards were the subject of a study published in Acta Tropica, in which female mosquitoes were starved for 12 hours, introduced to a fresh hamster for an all-you-can-eat buffet and a single male mosquito for reproductive purposes, then subjected to either silence or some extremely loud dubstep music, courtesy of the artist Skrillex. The researchers’ goal was simple: Is loud music an “environmentally friendly” repellent alternative?

In a blow to the egos of dubstep fans everywhere, not only did the mosquitoes forced to listen to Skrillex take longer to start sucking blood from the hamster, they sucked out less blood and made fewer attempts to reproduce with the lone male mosquito. According to the researchers, the so-called music’s aggressive vibrations disrupts the mosquito’s ability to fly and synchronize wing beats.

This is really a good news/bad news situation here. Good news, we’ve found an easy way to drive off a very annoying insect. Bad news, we have to suffer through loud dubstep music. Personally, we’ll take the mosquitoes.

[email protected]

Epic tweets

Need a little break from seeing all your patients? Hop on Twitter for a few minutes – specifically, the Epic parody account.

A frustrated but hilarious physician somewhere on the East Coast created the account a month ago to brighten busy days and help other physicians connect through a shared hatred of Epic, the electronic health records system.

The account’s bio states: “My goal is to create confusion for doctors. I will not rest until doctors do nothing but click buttons. Eye contact is evil.” In continuing with this theme, the account dedicates many Tweets to decrying patient-doctor interaction and encouraging computer-doctor interaction instead. And it rails against the “shaming of data-entry clerks.”

If you, too, are frustrated with Epic or your own EHR system, submit them to @EPICEMRparody with the hashtag #EPICfail. Join the club.
 

Pour me another, bartender

All the beauty of alcohol without the soul-crushing hangover the next day? I’ll take two on the rocks, please.

For the last decade, visionary, scientist, and soon-to-be hero David Nutt, DM, has been working on a formula for synthetic alcohol that gets you nice and tipsy, but spares you the hangover. Dr. Nutt has created a compound he calls “alcosynth” that triggers a buzz but doesn’t activate the brain receptors that cause the symptoms of hangover.

Dr. Nutt is confident that his alcohol will hit liquor stores in just 5 years. As the director of neuropsychopharmacology at the Imperial College London and a wine bar owner, he knows a bit more than the average person about alcohol and brain receptors. He realized that the brain’s GABA receptors can be stimulated by alcohol and developed his product, Alcarelle, to simulate that stimulation without causing headaches, nausea, dizziness, and other hangover symptoms.

Dr. Nutt guards his process pretty tightly, however – the secret to hangover-free booze is as precious as a golden ticket to the Wonka factory. Everyone’s going to want to get their hands on it!
 

Don’t just do something, lie there

As the Trump administration tries to implement work requirements for food stamps and Medicaid, the Artificial Gravity Bed Rest Study offers another way to get paid for doing nothing.

DLR (CC-BY 3.0)

This joint effort between NASA, the European Space Agency, and the German Space Agency will recreate outer space conditions right here on earth – in Cologne, Germany, to be exact – by having participants lie down for 60 days with their heads 6 degrees below their feet, causing fluids in the body to shift toward their heads and reproducing conditions experienced by astronauts in the absence of gravity.

Unsurprisingly, not just anyone will be considered: Participants have to be women aged 24-55 years with body mass indexes of 19-30 kg/m² who speak German and don’t smoke. Test subjects have to bathe, eat (the project’s website mentions pancakes), and go to the toilet while lying down, and they will spend 30 minutes a day in the human centrifuge – that’s the artificial gravity part of the study – to counteract the effects of weightlessness. They also will receive an expense allowance of about $18,500.

So, you can earn almost 20 grand as you get waited on, stuffed with pancakes, and massaged while catching up on your reading and relaxing for 2 months. Hmm, we may have gotten this backwards with that work requirement remark. Sounds more like a trial membership into the “1%,” so be sure to keep track of your portfolios.

That’s why mosquitoes don’t go to clubs

There’s not a whole lot of positive things that can be said about mosquitoes, spreaders of such wonderful diseases such as malaria and Zika. But we’ll give them this: They have good taste in music.

Those musical standards were the subject of a study published in Acta Tropica, in which female mosquitoes were starved for 12 hours, introduced to a fresh hamster for an all-you-can-eat buffet and a single male mosquito for reproductive purposes, then subjected to either silence or some extremely loud dubstep music, courtesy of the artist Skrillex. The researchers’ goal was simple: Is loud music an “environmentally friendly” repellent alternative?

In a blow to the egos of dubstep fans everywhere, not only did the mosquitoes forced to listen to Skrillex take longer to start sucking blood from the hamster, they sucked out less blood and made fewer attempts to reproduce with the lone male mosquito. According to the researchers, the so-called music’s aggressive vibrations disrupts the mosquito’s ability to fly and synchronize wing beats.

This is really a good news/bad news situation here. Good news, we’ve found an easy way to drive off a very annoying insect. Bad news, we have to suffer through loud dubstep music. Personally, we’ll take the mosquitoes.

[email protected]

Epic tweets

Need a little break from seeing all your patients? Hop on Twitter for a few minutes – specifically, the Epic parody account.

A frustrated but hilarious physician somewhere on the East Coast created the account a month ago to brighten busy days and help other physicians connect through a shared hatred of Epic, the electronic health records system.

The account’s bio states: “My goal is to create confusion for doctors. I will not rest until doctors do nothing but click buttons. Eye contact is evil.” In continuing with this theme, the account dedicates many Tweets to decrying patient-doctor interaction and encouraging computer-doctor interaction instead. And it rails against the “shaming of data-entry clerks.”

If you, too, are frustrated with Epic or your own EHR system, submit them to @EPICEMRparody with the hashtag #EPICfail. Join the club.
 

Pour me another, bartender

All the beauty of alcohol without the soul-crushing hangover the next day? I’ll take two on the rocks, please.

For the last decade, visionary, scientist, and soon-to-be hero David Nutt, DM, has been working on a formula for synthetic alcohol that gets you nice and tipsy, but spares you the hangover. Dr. Nutt has created a compound he calls “alcosynth” that triggers a buzz but doesn’t activate the brain receptors that cause the symptoms of hangover.

Dr. Nutt is confident that his alcohol will hit liquor stores in just 5 years. As the director of neuropsychopharmacology at the Imperial College London and a wine bar owner, he knows a bit more than the average person about alcohol and brain receptors. He realized that the brain’s GABA receptors can be stimulated by alcohol and developed his product, Alcarelle, to simulate that stimulation without causing headaches, nausea, dizziness, and other hangover symptoms.

Dr. Nutt guards his process pretty tightly, however – the secret to hangover-free booze is as precious as a golden ticket to the Wonka factory. Everyone’s going to want to get their hands on it!
 

Don’t just do something, lie there

As the Trump administration tries to implement work requirements for food stamps and Medicaid, the Artificial Gravity Bed Rest Study offers another way to get paid for doing nothing.

DLR (CC-BY 3.0)

This joint effort between NASA, the European Space Agency, and the German Space Agency will recreate outer space conditions right here on earth – in Cologne, Germany, to be exact – by having participants lie down for 60 days with their heads 6 degrees below their feet, causing fluids in the body to shift toward their heads and reproducing conditions experienced by astronauts in the absence of gravity.

Unsurprisingly, not just anyone will be considered: Participants have to be women aged 24-55 years with body mass indexes of 19-30 kg/m² who speak German and don’t smoke. Test subjects have to bathe, eat (the project’s website mentions pancakes), and go to the toilet while lying down, and they will spend 30 minutes a day in the human centrifuge – that’s the artificial gravity part of the study – to counteract the effects of weightlessness. They also will receive an expense allowance of about $18,500.

So, you can earn almost 20 grand as you get waited on, stuffed with pancakes, and massaged while catching up on your reading and relaxing for 2 months. Hmm, we may have gotten this backwards with that work requirement remark. Sounds more like a trial membership into the “1%,” so be sure to keep track of your portfolios.

That’s why mosquitoes don’t go to clubs

There’s not a whole lot of positive things that can be said about mosquitoes, spreaders of such wonderful diseases such as malaria and Zika. But we’ll give them this: They have good taste in music.

Those musical standards were the subject of a study published in Acta Tropica, in which female mosquitoes were starved for 12 hours, introduced to a fresh hamster for an all-you-can-eat buffet and a single male mosquito for reproductive purposes, then subjected to either silence or some extremely loud dubstep music, courtesy of the artist Skrillex. The researchers’ goal was simple: Is loud music an “environmentally friendly” repellent alternative?

In a blow to the egos of dubstep fans everywhere, not only did the mosquitoes forced to listen to Skrillex take longer to start sucking blood from the hamster, they sucked out less blood and made fewer attempts to reproduce with the lone male mosquito. According to the researchers, the so-called music’s aggressive vibrations disrupts the mosquito’s ability to fly and synchronize wing beats.

This is really a good news/bad news situation here. Good news, we’ve found an easy way to drive off a very annoying insect. Bad news, we have to suffer through loud dubstep music. Personally, we’ll take the mosquitoes.

[email protected]

Patients seek healthy skin that conveys overall health and well-being. Cosmeceuticals claim to therapeutically affect the structure and function of the skin, and it is rational to hold them to scientific standards that substantiate efficacy claims.¹ Notably, it is increasingly important to consider nature-based products in helping patients and consumers to achieve healthier skin. Despite the availability of sophisticated efficacy testing, explanations of the underlying physiologic and pharmacologic principles of nature-based products lag behind those of conventional formulations. In many instances, simple form and function information cannot adequately support their desired use and expected benefits. In addition, cosmetic regulations do not even permit structure-function claims that are allowed for dietary supplements.

Physicians whose patients want recommendations for nature-based products often do not know where to turn for definitive product and use information. Unlike prescription medications or even beauty-from-within dietary supplement products, natural cosmetics and cosmeceuticals are barred from communicating scientific evidence and experience of use to form proper opinions for recommendations. Without the benefit of full product labeling, physicians are left to mine sparse, confusing, and often contradictory literature in an effort to self-educate. Here, we share our experiences with patients, our operating knowledge base, and our recommendations for investigation to improve the available information and ensure practicing physicians have the information they need to appropriately recommend nature-based products.

General Observations Pertaining to Patients and Nature-Based Products

Ethnic and cultural customs and traditions have accepted and employed nature-based products for skin health for millennia (eTables 1–3).^2-20 African and the derived Caribbean cultures frequently use shea butter, black soap, or coconut oil. East Asian ethnobotanical practices include the use of ginseng, green tea, almond, and angelica root in skin care. Indian culture employs Ayurvedic medicine principles that include herbal remedies comprised of ground chickpeas, rice, turmeric, neem, ashwagandha, moringa, and kutki. These cultural traditions continue into modern times, and patients regularly use these products. Modern social trends that focus on a healthy lifestyle also create demand for nature-based products for skin health. In our opinion, the current growing interest in nature-based products implies continued growth in their use as patients become more familiar and comfortable with them.

For beauty and skin health, a new trend has evolved in which the first source of advice is rarely a dermatologist. Social media, nonphysician influencers, and pseudoscience have created an authority previously reserved for dermatologists among patients and consumers. Bloggers and social media influencers, posting their individual real-world experiences, shape the perceptions of consumers and patients.^21,22 Nonphysician influencers leverage their celebrity to provide guidance and advice on beauty and cosmetic tips.²³ Much of the evidence supporting cosmetic and especially nature-based products for skin care and health often is believed to be less rigorous and of lower quality than that typically supporting physician recommendations.^24-26

Nature-Based Products in Skin Health and Dermatologic Conditions

Patients turn to nature-based products for skin care and health for many reasons. The simplest reason is that they grew up with such products and continue their use. Many patients find nature-based products themselves, have favorable experiences, and seek advice on their efficacy and safety for continued use. Patients also use these products as part of a holistic approach to health in which diet and exercise coincide with the idea of ministering to the whole self instead of preventing or treating an illness. These nature-based treatment options fit their natural lifestyles. Patients sometimes express concerns about synthetic products that lead them to seek out nature-based products. Chemicals and preservatives (eg, parabens, sunscreens, nanoparticles) may evoke concerns about negative health consequences, which can be a cause of great anxiety to patients.

Nature-based products, when recommended by physicians, can fulfill important roles. As healthier alternatives, they can address health concerns in the belief that plant-based ingredients may be more compatible with overall health than synthetic ingredients. This compatibility may have resulted from the human species coevolving with plant species containing therapeutic utility, leading to the development of specific receptors for many natural products, such as digoxin from foxglove (Digitalis purpurea), opioids from poppies (Papaver somniferum), and cannabinoids (Cannabis sativa and hybrids). Natural products can become alternatives to synthetic products or adjuncts to prescription medications. Often, inclusion of nature-based products into a treatment plan enables patients to feel that they are a more integral part of the care team treating their conditions. By virtue of physician recommendations, patients may have expectations on product efficacy being as robust as prescription products with the safety profile of plant-based products. Patients should be advised to accept a realistic view of the efficacy and tolerability profiles. In the end, patients consider physician recommendations based on the assumption that they are credible and derived from experience and knowledge.

Physician Perceptions of Nature-Based Products

Physicians recommend nature-based products based on several factors. Central to the recommendation is an understanding, through appropriate documentation, that the product will be reasonably efficacious. Critical to this point, physicians must understand what ingredients are in nature-based products, their concentrations or amounts, and why they are present. However, our experience with nature-based products suggests that many of these factors are not met. Limited or unclear information on the efficacy of nature-based products fails to satisfy a physician’s need for adequate information to support recommendations. Although natural ingredients are listed on product labels, their intended benefit and efficacy characteristics often are unclear or poorly stated, in some cases resulting from improper labeling and in other cases due to claim restrictions imposed on cosmetics. In addition, insufficient details on formulation, such as type and percentages of oils, antioxidants, and vitamins, hinder the physician’s ability to identify and explain mechanisms that bring benefit to the patient. Universal benchmarks do not exist for amounts or concentrations of ingredients that are required for a stated benefit.²⁷ Currently, no standards exist for assurances that product quality, control, and efficacy are consistently reproducible. For example, angel dusting is a practice that discloses that an active ingredient is present, yet these ingredients may be present in quantities that are insufficient to provide measurable benefit. Sourcing of ingredients also can be concerning, as they may not always meet manufacturer, physician, or patient expectations for characterization or efficacy.^28,29 Dry testing, which is when a manufacturer contracts a laboratory to certify their ingredients without performing assays, has been increasingly reported in lay and botanical literature over the last few years.³⁰

It is unknown if many nature-based products clinically exhibit their stated efficacy. Empirical evidence or well-conducted clinical studies on which to base recommendations of these products are limited. Individual natural ingredients, however, do have some supporting evidence of efficacy: shea butter moisturizes³¹; coconut oil exhibits anti-inflammatory properties^32,33; and vinegar, yogurt, and diluted tea tree oil exhibit antibacterial properties in postprocedure care and fungal infections, and as adjuvants to prescription antibiotics in atopic dermatitis, acne, and rosacea.^34-41 Honey also has been shown to improve wound healing and is even available as a medical device for wounds.^42,43 Although nature-based products are an interesting alternative to synthetic products, they require a fulsome understanding of characteristics and efficacy properties to support physician recommendations.

Physician Recommendations

Physicians must be educated to understand when and how to recommend nature-based products. Although we recommend increased product information to guide physicians, current laws, including the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act, are satisfactory from a regulatory standpoint.⁴⁴ Here, we discuss the information physicians could use to support an informed recommendation of nature-based products.

A clear specific explanation of natural ingredient sources, their intended efficacy, and rigorous scientific clinical evidence supporting their use should be given. Manufacturers are needed to document and report the structure and function of natural ingredients, leading to a common understanding by practicing dermatologists.⁴⁵ For this reason, manufacturers must provide nonambiguous and standardized methods and measures to demonstrate the mechanism of ingredient efficacy and the limits of safety and tolerability.

We recommend that manufacturers provide standardized transparency into the composition of nature-based formulations, including amounts and concentrations of ingredients; geographic sources; parts of plants used; and if extracted, what agent(s) this standard is based on (eg, hypericin in Saint-John’s-wort or kavalactones in kava kava). Most natural products contain an aqueous phase and therefore will likely require preservatives such as synthetic parabens or alcohols to avoid degradation. Unnecessary ingredients, including fragrances, fillers, and support chemicals, should be absent since inert agents may exhibit biologic effects, obscuring the boundary between active and inert. A clear explanation of the origins of these nature-based ingredients and the concentration, purity, and activity assessment should be provided. In the context of an authoritative review with standardized measures, labels that provide the common name, plant name, part used, how it was obtained, concentrations and/or amounts, and standardized activity measures can be helpful to the recommending physician, who will then know the efficacy patients should expect from the ingredients. They also can assess the expected tolerability based on the concentrations and their own experience managing a particular disorder, tempered by the patient’s experiences with prior therapies. Transparent and standardized labeling describing the formulation, quantities of ingredients, and intended activity will help inform expectations of efficacy.

We recommend clear preclinical and clinical demonstrations of the efficacy and benefits that are claimed by nature-based formulations. Properly designed placebo- or active-controlled, blinded, randomized studies with standardized measures and end points are recommended to determine efficacy and safety. These demonstrations of efficacy can provide physicians with credible evidence on which to base their recommendations and guide the use of products for the patient’s best experience. Given sufficient involvement from manufacturers and publication of the information in peer-reviewed journals, the relative benefits for each nature-based product can be cataloged as a resource for physicians.

Conclusion

Patients turn to nature-based products for many reasons. They have high expectations but also harbor concerns as to the efficacy of these products for skin and health care. Physicians seek to recommend nature-based products for these patients but often find themselves disadvantaged by limited published evidence and insufficient labeling information on composition and efficacy, which should support recommendations for use. To remedy this situation, we suggest research to allow a clear explanation of the activity of natural ingredients, clear demonstrations of the efficacy of nature-based formulas using clinical standardized measures and end points, and clear education and disclosure of ingredients contained within nature-based products.



Acknowledgments—Burt’s Bees (Durham, North Carolina) provided funding for editorial support by Medical Dynamics, Inc (New York, New York).

Patients seek healthy skin that conveys overall health and well-being. Cosmeceuticals claim to therapeutically affect the structure and function of the skin, and it is rational to hold them to scientific standards that substantiate efficacy claims.¹ Notably, it is increasingly important to consider nature-based products in helping patients and consumers to achieve healthier skin. Despite the availability of sophisticated efficacy testing, explanations of the underlying physiologic and pharmacologic principles of nature-based products lag behind those of conventional formulations. In many instances, simple form and function information cannot adequately support their desired use and expected benefits. In addition, cosmetic regulations do not even permit structure-function claims that are allowed for dietary supplements.

Physicians whose patients want recommendations for nature-based products often do not know where to turn for definitive product and use information. Unlike prescription medications or even beauty-from-within dietary supplement products, natural cosmetics and cosmeceuticals are barred from communicating scientific evidence and experience of use to form proper opinions for recommendations. Without the benefit of full product labeling, physicians are left to mine sparse, confusing, and often contradictory literature in an effort to self-educate. Here, we share our experiences with patients, our operating knowledge base, and our recommendations for investigation to improve the available information and ensure practicing physicians have the information they need to appropriately recommend nature-based products.

General Observations Pertaining to Patients and Nature-Based Products

Ethnic and cultural customs and traditions have accepted and employed nature-based products for skin health for millennia (eTables 1–3).^2-20 African and the derived Caribbean cultures frequently use shea butter, black soap, or coconut oil. East Asian ethnobotanical practices include the use of ginseng, green tea, almond, and angelica root in skin care. Indian culture employs Ayurvedic medicine principles that include herbal remedies comprised of ground chickpeas, rice, turmeric, neem, ashwagandha, moringa, and kutki. These cultural traditions continue into modern times, and patients regularly use these products. Modern social trends that focus on a healthy lifestyle also create demand for nature-based products for skin health. In our opinion, the current growing interest in nature-based products implies continued growth in their use as patients become more familiar and comfortable with them.

For beauty and skin health, a new trend has evolved in which the first source of advice is rarely a dermatologist. Social media, nonphysician influencers, and pseudoscience have created an authority previously reserved for dermatologists among patients and consumers. Bloggers and social media influencers, posting their individual real-world experiences, shape the perceptions of consumers and patients.^21,22 Nonphysician influencers leverage their celebrity to provide guidance and advice on beauty and cosmetic tips.²³ Much of the evidence supporting cosmetic and especially nature-based products for skin care and health often is believed to be less rigorous and of lower quality than that typically supporting physician recommendations.^24-26

Nature-Based Products in Skin Health and Dermatologic Conditions

Patients turn to nature-based products for skin care and health for many reasons. The simplest reason is that they grew up with such products and continue their use. Many patients find nature-based products themselves, have favorable experiences, and seek advice on their efficacy and safety for continued use. Patients also use these products as part of a holistic approach to health in which diet and exercise coincide with the idea of ministering to the whole self instead of preventing or treating an illness. These nature-based treatment options fit their natural lifestyles. Patients sometimes express concerns about synthetic products that lead them to seek out nature-based products. Chemicals and preservatives (eg, parabens, sunscreens, nanoparticles) may evoke concerns about negative health consequences, which can be a cause of great anxiety to patients.

Nature-based products, when recommended by physicians, can fulfill important roles. As healthier alternatives, they can address health concerns in the belief that plant-based ingredients may be more compatible with overall health than synthetic ingredients. This compatibility may have resulted from the human species coevolving with plant species containing therapeutic utility, leading to the development of specific receptors for many natural products, such as digoxin from foxglove (Digitalis purpurea), opioids from poppies (Papaver somniferum), and cannabinoids (Cannabis sativa and hybrids). Natural products can become alternatives to synthetic products or adjuncts to prescription medications. Often, inclusion of nature-based products into a treatment plan enables patients to feel that they are a more integral part of the care team treating their conditions. By virtue of physician recommendations, patients may have expectations on product efficacy being as robust as prescription products with the safety profile of plant-based products. Patients should be advised to accept a realistic view of the efficacy and tolerability profiles. In the end, patients consider physician recommendations based on the assumption that they are credible and derived from experience and knowledge.

Physician Perceptions of Nature-Based Products

Physicians recommend nature-based products based on several factors. Central to the recommendation is an understanding, through appropriate documentation, that the product will be reasonably efficacious. Critical to this point, physicians must understand what ingredients are in nature-based products, their concentrations or amounts, and why they are present. However, our experience with nature-based products suggests that many of these factors are not met. Limited or unclear information on the efficacy of nature-based products fails to satisfy a physician’s need for adequate information to support recommendations. Although natural ingredients are listed on product labels, their intended benefit and efficacy characteristics often are unclear or poorly stated, in some cases resulting from improper labeling and in other cases due to claim restrictions imposed on cosmetics. In addition, insufficient details on formulation, such as type and percentages of oils, antioxidants, and vitamins, hinder the physician’s ability to identify and explain mechanisms that bring benefit to the patient. Universal benchmarks do not exist for amounts or concentrations of ingredients that are required for a stated benefit.²⁷ Currently, no standards exist for assurances that product quality, control, and efficacy are consistently reproducible. For example, angel dusting is a practice that discloses that an active ingredient is present, yet these ingredients may be present in quantities that are insufficient to provide measurable benefit. Sourcing of ingredients also can be concerning, as they may not always meet manufacturer, physician, or patient expectations for characterization or efficacy.^28,29 Dry testing, which is when a manufacturer contracts a laboratory to certify their ingredients without performing assays, has been increasingly reported in lay and botanical literature over the last few years.³⁰

It is unknown if many nature-based products clinically exhibit their stated efficacy. Empirical evidence or well-conducted clinical studies on which to base recommendations of these products are limited. Individual natural ingredients, however, do have some supporting evidence of efficacy: shea butter moisturizes³¹; coconut oil exhibits anti-inflammatory properties^32,33; and vinegar, yogurt, and diluted tea tree oil exhibit antibacterial properties in postprocedure care and fungal infections, and as adjuvants to prescription antibiotics in atopic dermatitis, acne, and rosacea.^34-41 Honey also has been shown to improve wound healing and is even available as a medical device for wounds.^42,43 Although nature-based products are an interesting alternative to synthetic products, they require a fulsome understanding of characteristics and efficacy properties to support physician recommendations.

Physician Recommendations

Physicians must be educated to understand when and how to recommend nature-based products. Although we recommend increased product information to guide physicians, current laws, including the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act, are satisfactory from a regulatory standpoint.⁴⁴ Here, we discuss the information physicians could use to support an informed recommendation of nature-based products.

A clear specific explanation of natural ingredient sources, their intended efficacy, and rigorous scientific clinical evidence supporting their use should be given. Manufacturers are needed to document and report the structure and function of natural ingredients, leading to a common understanding by practicing dermatologists.⁴⁵ For this reason, manufacturers must provide nonambiguous and standardized methods and measures to demonstrate the mechanism of ingredient efficacy and the limits of safety and tolerability.

We recommend that manufacturers provide standardized transparency into the composition of nature-based formulations, including amounts and concentrations of ingredients; geographic sources; parts of plants used; and if extracted, what agent(s) this standard is based on (eg, hypericin in Saint-John’s-wort or kavalactones in kava kava). Most natural products contain an aqueous phase and therefore will likely require preservatives such as synthetic parabens or alcohols to avoid degradation. Unnecessary ingredients, including fragrances, fillers, and support chemicals, should be absent since inert agents may exhibit biologic effects, obscuring the boundary between active and inert. A clear explanation of the origins of these nature-based ingredients and the concentration, purity, and activity assessment should be provided. In the context of an authoritative review with standardized measures, labels that provide the common name, plant name, part used, how it was obtained, concentrations and/or amounts, and standardized activity measures can be helpful to the recommending physician, who will then know the efficacy patients should expect from the ingredients. They also can assess the expected tolerability based on the concentrations and their own experience managing a particular disorder, tempered by the patient’s experiences with prior therapies. Transparent and standardized labeling describing the formulation, quantities of ingredients, and intended activity will help inform expectations of efficacy.

We recommend clear preclinical and clinical demonstrations of the efficacy and benefits that are claimed by nature-based formulations. Properly designed placebo- or active-controlled, blinded, randomized studies with standardized measures and end points are recommended to determine efficacy and safety. These demonstrations of efficacy can provide physicians with credible evidence on which to base their recommendations and guide the use of products for the patient’s best experience. Given sufficient involvement from manufacturers and publication of the information in peer-reviewed journals, the relative benefits for each nature-based product can be cataloged as a resource for physicians.

Conclusion

Patients turn to nature-based products for many reasons. They have high expectations but also harbor concerns as to the efficacy of these products for skin and health care. Physicians seek to recommend nature-based products for these patients but often find themselves disadvantaged by limited published evidence and insufficient labeling information on composition and efficacy, which should support recommendations for use. To remedy this situation, we suggest research to allow a clear explanation of the activity of natural ingredients, clear demonstrations of the efficacy of nature-based formulas using clinical standardized measures and end points, and clear education and disclosure of ingredients contained within nature-based products.



Acknowledgments—Burt’s Bees (Durham, North Carolina) provided funding for editorial support by Medical Dynamics, Inc (New York, New York).

Patients seek healthy skin that conveys overall health and well-being. Cosmeceuticals claim to therapeutically affect the structure and function of the skin, and it is rational to hold them to scientific standards that substantiate efficacy claims.¹ Notably, it is increasingly important to consider nature-based products in helping patients and consumers to achieve healthier skin. Despite the availability of sophisticated efficacy testing, explanations of the underlying physiologic and pharmacologic principles of nature-based products lag behind those of conventional formulations. In many instances, simple form and function information cannot adequately support their desired use and expected benefits. In addition, cosmetic regulations do not even permit structure-function claims that are allowed for dietary supplements.

Physicians whose patients want recommendations for nature-based products often do not know where to turn for definitive product and use information. Unlike prescription medications or even beauty-from-within dietary supplement products, natural cosmetics and cosmeceuticals are barred from communicating scientific evidence and experience of use to form proper opinions for recommendations. Without the benefit of full product labeling, physicians are left to mine sparse, confusing, and often contradictory literature in an effort to self-educate. Here, we share our experiences with patients, our operating knowledge base, and our recommendations for investigation to improve the available information and ensure practicing physicians have the information they need to appropriately recommend nature-based products.

General Observations Pertaining to Patients and Nature-Based Products

Ethnic and cultural customs and traditions have accepted and employed nature-based products for skin health for millennia (eTables 1–3).^2-20 African and the derived Caribbean cultures frequently use shea butter, black soap, or coconut oil. East Asian ethnobotanical practices include the use of ginseng, green tea, almond, and angelica root in skin care. Indian culture employs Ayurvedic medicine principles that include herbal remedies comprised of ground chickpeas, rice, turmeric, neem, ashwagandha, moringa, and kutki. These cultural traditions continue into modern times, and patients regularly use these products. Modern social trends that focus on a healthy lifestyle also create demand for nature-based products for skin health. In our opinion, the current growing interest in nature-based products implies continued growth in their use as patients become more familiar and comfortable with them.

For beauty and skin health, a new trend has evolved in which the first source of advice is rarely a dermatologist. Social media, nonphysician influencers, and pseudoscience have created an authority previously reserved for dermatologists among patients and consumers. Bloggers and social media influencers, posting their individual real-world experiences, shape the perceptions of consumers and patients.^21,22 Nonphysician influencers leverage their celebrity to provide guidance and advice on beauty and cosmetic tips.²³ Much of the evidence supporting cosmetic and especially nature-based products for skin care and health often is believed to be less rigorous and of lower quality than that typically supporting physician recommendations.^24-26

Nature-Based Products in Skin Health and Dermatologic Conditions

Patients turn to nature-based products for skin care and health for many reasons. The simplest reason is that they grew up with such products and continue their use. Many patients find nature-based products themselves, have favorable experiences, and seek advice on their efficacy and safety for continued use. Patients also use these products as part of a holistic approach to health in which diet and exercise coincide with the idea of ministering to the whole self instead of preventing or treating an illness. These nature-based treatment options fit their natural lifestyles. Patients sometimes express concerns about synthetic products that lead them to seek out nature-based products. Chemicals and preservatives (eg, parabens, sunscreens, nanoparticles) may evoke concerns about negative health consequences, which can be a cause of great anxiety to patients.

Nature-based products, when recommended by physicians, can fulfill important roles. As healthier alternatives, they can address health concerns in the belief that plant-based ingredients may be more compatible with overall health than synthetic ingredients. This compatibility may have resulted from the human species coevolving with plant species containing therapeutic utility, leading to the development of specific receptors for many natural products, such as digoxin from foxglove (Digitalis purpurea), opioids from poppies (Papaver somniferum), and cannabinoids (Cannabis sativa and hybrids). Natural products can become alternatives to synthetic products or adjuncts to prescription medications. Often, inclusion of nature-based products into a treatment plan enables patients to feel that they are a more integral part of the care team treating their conditions. By virtue of physician recommendations, patients may have expectations on product efficacy being as robust as prescription products with the safety profile of plant-based products. Patients should be advised to accept a realistic view of the efficacy and tolerability profiles. In the end, patients consider physician recommendations based on the assumption that they are credible and derived from experience and knowledge.

Physician Perceptions of Nature-Based Products

Physicians recommend nature-based products based on several factors. Central to the recommendation is an understanding, through appropriate documentation, that the product will be reasonably efficacious. Critical to this point, physicians must understand what ingredients are in nature-based products, their concentrations or amounts, and why they are present. However, our experience with nature-based products suggests that many of these factors are not met. Limited or unclear information on the efficacy of nature-based products fails to satisfy a physician’s need for adequate information to support recommendations. Although natural ingredients are listed on product labels, their intended benefit and efficacy characteristics often are unclear or poorly stated, in some cases resulting from improper labeling and in other cases due to claim restrictions imposed on cosmetics. In addition, insufficient details on formulation, such as type and percentages of oils, antioxidants, and vitamins, hinder the physician’s ability to identify and explain mechanisms that bring benefit to the patient. Universal benchmarks do not exist for amounts or concentrations of ingredients that are required for a stated benefit.²⁷ Currently, no standards exist for assurances that product quality, control, and efficacy are consistently reproducible. For example, angel dusting is a practice that discloses that an active ingredient is present, yet these ingredients may be present in quantities that are insufficient to provide measurable benefit. Sourcing of ingredients also can be concerning, as they may not always meet manufacturer, physician, or patient expectations for characterization or efficacy.^28,29 Dry testing, which is when a manufacturer contracts a laboratory to certify their ingredients without performing assays, has been increasingly reported in lay and botanical literature over the last few years.³⁰

It is unknown if many nature-based products clinically exhibit their stated efficacy. Empirical evidence or well-conducted clinical studies on which to base recommendations of these products are limited. Individual natural ingredients, however, do have some supporting evidence of efficacy: shea butter moisturizes³¹; coconut oil exhibits anti-inflammatory properties^32,33; and vinegar, yogurt, and diluted tea tree oil exhibit antibacterial properties in postprocedure care and fungal infections, and as adjuvants to prescription antibiotics in atopic dermatitis, acne, and rosacea.^34-41 Honey also has been shown to improve wound healing and is even available as a medical device for wounds.^42,43 Although nature-based products are an interesting alternative to synthetic products, they require a fulsome understanding of characteristics and efficacy properties to support physician recommendations.

Physician Recommendations

Physicians must be educated to understand when and how to recommend nature-based products. Although we recommend increased product information to guide physicians, current laws, including the Federal Food, Drug, and Cosmetic Act and the Fair Packaging and Labeling Act, are satisfactory from a regulatory standpoint.⁴⁴ Here, we discuss the information physicians could use to support an informed recommendation of nature-based products.

A clear specific explanation of natural ingredient sources, their intended efficacy, and rigorous scientific clinical evidence supporting their use should be given. Manufacturers are needed to document and report the structure and function of natural ingredients, leading to a common understanding by practicing dermatologists.⁴⁵ For this reason, manufacturers must provide nonambiguous and standardized methods and measures to demonstrate the mechanism of ingredient efficacy and the limits of safety and tolerability.

We recommend that manufacturers provide standardized transparency into the composition of nature-based formulations, including amounts and concentrations of ingredients; geographic sources; parts of plants used; and if extracted, what agent(s) this standard is based on (eg, hypericin in Saint-John’s-wort or kavalactones in kava kava). Most natural products contain an aqueous phase and therefore will likely require preservatives such as synthetic parabens or alcohols to avoid degradation. Unnecessary ingredients, including fragrances, fillers, and support chemicals, should be absent since inert agents may exhibit biologic effects, obscuring the boundary between active and inert. A clear explanation of the origins of these nature-based ingredients and the concentration, purity, and activity assessment should be provided. In the context of an authoritative review with standardized measures, labels that provide the common name, plant name, part used, how it was obtained, concentrations and/or amounts, and standardized activity measures can be helpful to the recommending physician, who will then know the efficacy patients should expect from the ingredients. They also can assess the expected tolerability based on the concentrations and their own experience managing a particular disorder, tempered by the patient’s experiences with prior therapies. Transparent and standardized labeling describing the formulation, quantities of ingredients, and intended activity will help inform expectations of efficacy.

We recommend clear preclinical and clinical demonstrations of the efficacy and benefits that are claimed by nature-based formulations. Properly designed placebo- or active-controlled, blinded, randomized studies with standardized measures and end points are recommended to determine efficacy and safety. These demonstrations of efficacy can provide physicians with credible evidence on which to base their recommendations and guide the use of products for the patient’s best experience. Given sufficient involvement from manufacturers and publication of the information in peer-reviewed journals, the relative benefits for each nature-based product can be cataloged as a resource for physicians.

Conclusion

Patients turn to nature-based products for many reasons. They have high expectations but also harbor concerns as to the efficacy of these products for skin and health care. Physicians seek to recommend nature-based products for these patients but often find themselves disadvantaged by limited published evidence and insufficient labeling information on composition and efficacy, which should support recommendations for use. To remedy this situation, we suggest research to allow a clear explanation of the activity of natural ingredients, clear demonstrations of the efficacy of nature-based formulas using clinical standardized measures and end points, and clear education and disclosure of ingredients contained within nature-based products.



Acknowledgments—Burt’s Bees (Durham, North Carolina) provided funding for editorial support by Medical Dynamics, Inc (New York, New York).

Case Report

A 62-year-old woman presented with multiple large friable tumors of the abdominal panniculus. The patient also reported an unintentional 75-lb weight loss over the last 9 months as well as vaginal bleeding and fecal discharge from the vagina of 2 weeks’ duration. The patient had a surgical and medical history of a robotic-assisted hysterectomy and bilateral salpingo-oophorectomy performed 4 years prior to presentation. Final surgical pathology showed complex atypical endometrial hyperplasia with no adenocarcinoma identified.

Physical examination revealed multiple large, friable, exophytic tumors of the left side of the lower abdominal panniculus within close vicinity of the patient’s abdominal hysterectomy scars (Figure 1). The largest lesion measured approximately 6 cm in length. Laboratory values were elevated for carcinoembryonic antigen (5.9 ng/mL [reference range, <3.0 ng/mL]) and cancer antigen 125 (202 U/mL [reference range, <35 U/mL]). Computed tomography of the abdomen and pelvis revealed diffuse metastatic disease.

Comment

Incidence and Pathogenesis
Endometrial carcinoma is the most common gynecologic malignancy in the United States, but it rarely progresses to disseminated disease because of routine gynecologic examinations and the low threshold for surgical intervention. Cutaneous metastases represent one of the rarest presentations of disseminated disease, occurring in only 0.8% of those diagnosed with endometrial carcinoma.¹ Cutaneous metastases occur almost exclusively in women older than 50 years and typically appear several months to years after hysterectomy. Although the exact pathogenesis is unknown, it is theorized that small foci of malignant cells may be seeded during surgery, leading to visceral and cutaneous involvement.

Clinical Presentation
Lesions vary morphologically, most commonly presenting as nonspecific, painless, hemorrhagic nodules. Lesions typically present in areas of direct local extension; prior radiotherapy; or areas of initial surgery, as was the case with our patient.² Approximately 20 cases of umbilical involvement (Sister Mary Joseph nodule) have been reported in the literature. These cases are thought to occur from direct local spread of disease from the peritoneum.³ Hematogenous and lymphatic spread to distant sites such as the scalp and mandible also have been reported. More than 50% of patients will have underlying visceral metastatic disease at the time of diagnosis.³

Histopathologic Findings
Histopathology varies with the morphology of the underlying primary tumor, with endometrioid adenocarcinoma being the most common form associated with cutaneous metastasis, as was the case with our patient.⁴ Histology is characterized by dermal proliferation of atypical glandular epithelium with diffuse hemorrhage. Staining typically is positive for CK7 and negative for CK20 and CDX2.⁵ Histopathology and immunohistochemical staining are not specific for diagnosis and must be correlated with clinical history.

Management and Prognosis
Similar to cutaneous metastasis in other internal malignancies, prognosis is poor, as widespread dissemination of the underlying malignancy typically is present. Mean life expectancy is 4 to 12 months.⁶ Treatment is primarily palliative, as chemotherapy and radiotherapy are largely ineffective.

Conclusion

Our patient represents a dramatic form of cutaneous extension of a common disease. Dermatologists often are consulted because of the nonspecific nature of the lesions and must be conscious of this entity. As with other cutaneous metastases, a thorough medical and surgical history in conjunction with histopathology are necessary for an accurate diagnosis.

Case Report

A 62-year-old woman presented with multiple large friable tumors of the abdominal panniculus. The patient also reported an unintentional 75-lb weight loss over the last 9 months as well as vaginal bleeding and fecal discharge from the vagina of 2 weeks’ duration. The patient had a surgical and medical history of a robotic-assisted hysterectomy and bilateral salpingo-oophorectomy performed 4 years prior to presentation. Final surgical pathology showed complex atypical endometrial hyperplasia with no adenocarcinoma identified.

Physical examination revealed multiple large, friable, exophytic tumors of the left side of the lower abdominal panniculus within close vicinity of the patient’s abdominal hysterectomy scars (Figure 1). The largest lesion measured approximately 6 cm in length. Laboratory values were elevated for carcinoembryonic antigen (5.9 ng/mL [reference range, <3.0 ng/mL]) and cancer antigen 125 (202 U/mL [reference range, <35 U/mL]). Computed tomography of the abdomen and pelvis revealed diffuse metastatic disease.

Comment

Incidence and Pathogenesis
Endometrial carcinoma is the most common gynecologic malignancy in the United States, but it rarely progresses to disseminated disease because of routine gynecologic examinations and the low threshold for surgical intervention. Cutaneous metastases represent one of the rarest presentations of disseminated disease, occurring in only 0.8% of those diagnosed with endometrial carcinoma.¹ Cutaneous metastases occur almost exclusively in women older than 50 years and typically appear several months to years after hysterectomy. Although the exact pathogenesis is unknown, it is theorized that small foci of malignant cells may be seeded during surgery, leading to visceral and cutaneous involvement.

Clinical Presentation
Lesions vary morphologically, most commonly presenting as nonspecific, painless, hemorrhagic nodules. Lesions typically present in areas of direct local extension; prior radiotherapy; or areas of initial surgery, as was the case with our patient.² Approximately 20 cases of umbilical involvement (Sister Mary Joseph nodule) have been reported in the literature. These cases are thought to occur from direct local spread of disease from the peritoneum.³ Hematogenous and lymphatic spread to distant sites such as the scalp and mandible also have been reported. More than 50% of patients will have underlying visceral metastatic disease at the time of diagnosis.³

Histopathologic Findings
Histopathology varies with the morphology of the underlying primary tumor, with endometrioid adenocarcinoma being the most common form associated with cutaneous metastasis, as was the case with our patient.⁴ Histology is characterized by dermal proliferation of atypical glandular epithelium with diffuse hemorrhage. Staining typically is positive for CK7 and negative for CK20 and CDX2.⁵ Histopathology and immunohistochemical staining are not specific for diagnosis and must be correlated with clinical history.

Management and Prognosis
Similar to cutaneous metastasis in other internal malignancies, prognosis is poor, as widespread dissemination of the underlying malignancy typically is present. Mean life expectancy is 4 to 12 months.⁶ Treatment is primarily palliative, as chemotherapy and radiotherapy are largely ineffective.

Conclusion

Our patient represents a dramatic form of cutaneous extension of a common disease. Dermatologists often are consulted because of the nonspecific nature of the lesions and must be conscious of this entity. As with other cutaneous metastases, a thorough medical and surgical history in conjunction with histopathology are necessary for an accurate diagnosis.

Case Report

A 62-year-old woman presented with multiple large friable tumors of the abdominal panniculus. The patient also reported an unintentional 75-lb weight loss over the last 9 months as well as vaginal bleeding and fecal discharge from the vagina of 2 weeks’ duration. The patient had a surgical and medical history of a robotic-assisted hysterectomy and bilateral salpingo-oophorectomy performed 4 years prior to presentation. Final surgical pathology showed complex atypical endometrial hyperplasia with no adenocarcinoma identified.

Physical examination revealed multiple large, friable, exophytic tumors of the left side of the lower abdominal panniculus within close vicinity of the patient’s abdominal hysterectomy scars (Figure 1). The largest lesion measured approximately 6 cm in length. Laboratory values were elevated for carcinoembryonic antigen (5.9 ng/mL [reference range, <3.0 ng/mL]) and cancer antigen 125 (202 U/mL [reference range, <35 U/mL]). Computed tomography of the abdomen and pelvis revealed diffuse metastatic disease.

Comment

Incidence and Pathogenesis
Endometrial carcinoma is the most common gynecologic malignancy in the United States, but it rarely progresses to disseminated disease because of routine gynecologic examinations and the low threshold for surgical intervention. Cutaneous metastases represent one of the rarest presentations of disseminated disease, occurring in only 0.8% of those diagnosed with endometrial carcinoma.¹ Cutaneous metastases occur almost exclusively in women older than 50 years and typically appear several months to years after hysterectomy. Although the exact pathogenesis is unknown, it is theorized that small foci of malignant cells may be seeded during surgery, leading to visceral and cutaneous involvement.

Clinical Presentation
Lesions vary morphologically, most commonly presenting as nonspecific, painless, hemorrhagic nodules. Lesions typically present in areas of direct local extension; prior radiotherapy; or areas of initial surgery, as was the case with our patient.² Approximately 20 cases of umbilical involvement (Sister Mary Joseph nodule) have been reported in the literature. These cases are thought to occur from direct local spread of disease from the peritoneum.³ Hematogenous and lymphatic spread to distant sites such as the scalp and mandible also have been reported. More than 50% of patients will have underlying visceral metastatic disease at the time of diagnosis.³

Histopathologic Findings
Histopathology varies with the morphology of the underlying primary tumor, with endometrioid adenocarcinoma being the most common form associated with cutaneous metastasis, as was the case with our patient.⁴ Histology is characterized by dermal proliferation of atypical glandular epithelium with diffuse hemorrhage. Staining typically is positive for CK7 and negative for CK20 and CDX2.⁵ Histopathology and immunohistochemical staining are not specific for diagnosis and must be correlated with clinical history.

Management and Prognosis
Similar to cutaneous metastasis in other internal malignancies, prognosis is poor, as widespread dissemination of the underlying malignancy typically is present. Mean life expectancy is 4 to 12 months.⁶ Treatment is primarily palliative, as chemotherapy and radiotherapy are largely ineffective.

Conclusion

Our patient represents a dramatic form of cutaneous extension of a common disease. Dermatologists often are consulted because of the nonspecific nature of the lesions and must be conscious of this entity. As with other cutaneous metastases, a thorough medical and surgical history in conjunction with histopathology are necessary for an accurate diagnosis.

Patients frequently present to dermatologists with nail disorders as their chief concern. Alternatively, nail conditions may be encountered by the examining physician as an incidental finding that may be a clue to underlying systemic disease. Competence in the diagnosis and treatment of nail diseases can drastically improve patient quality of life and can be lifesaving,¹ but many dermatologists find management of nail diseases challenging.² Bridging this educational gap begins with dermatology resident and medical student education. In a collaboration with dermatology educators, the American Academy of Dermatology (AAD) prepared a free online core curriculum for medical students that covers the essential concepts of dermatology. We sought to determine the integration of nail education in the AAD Basic Dermatology Curriculum.

Methods

A cross-sectional study of the AAD Basic Dermatology Curriculum was conducted to determine nail disease content. The curriculum modules were downloaded in June 2018,³ and mentions of nails were recorded and evaluated for overall quantities and relevant content. References to nail procedures and diagnostic techniques including nail biopsies, fungal cultures, microscopy on nail scrapings, nail clippings, and nail-related cancers also were assessed in the analysis.

Results

Of 342 patients discussed in cases and quizzes, nails were mentioned for 19 patients (89 times total)(Table 1). Additionally, there were 2 mentions each of nail clippings and nail tumors, 0 mentions of nail biopsies, and 1 mention each of fungal cultures and microscopy on nail scrapings (Table 1). Of the 40 modules, nails were mentioned in 12 modules (Table 2) and 6 introductions to the modules (Table 1). There were no mentions of the terms nails, subungual, or onychomycosis in the learning objectives.³

Comment

Our study demonstrates a paucity of content relevant to nails in the AAD Basic Dermatology Curriculum. Medical students are missing an important opportunity to learn about diagnosis and management of nail conditions and may incorrectly conclude that nail expertise is not essential to becoming a competent board-certified dermatologist.

Particularly concerning is the exclusion of nail examinations in the skin exam module addressing full-body skin examinations (0 mentions in 31 slides). This curriculum may negatively influence medical students and may then follow at the resident level, with a study reporting that 50.3% (69/137) of residents examine nails only when the patient brings it to their attention.⁴

Most concerning was the inadequate coverage of nail unit melanoma in the melanoma module (1 mention in 53 slides). Furthermore, the ABCDE—asymmetry, border, color, diameter, and evolving—mnemonic for cutaneous melanoma was covered in 6 slides in this module, and the ABCDEF—family history added—mnemonic for nail unit melanoma was completely excluded. Not surprisingly, resident knowledge of melanonychia diagnosis is deficient, with a prior study demonstrating that 62% (88/142) of residents were not confident diagnosing and managing patients with melanonychia, and only 88% (125/142) of residents were aware of the nail melanoma mnemonic.⁴

Similarly, nail biopsy for melanonychia diagnosis was excluded from the curriculum, whereas skin biopsy was thoroughly discussed in the context of a cutaneous melanoma diagnosis. This deficient teaching may track to the dermatology resident curriculum, as a survey of third-year dermatology residents (N=240) showed that 58% performed 10 or fewer nail procedures, and one-third of residents felt incompetent in nail surgery.⁵

We acknowledge that the AAD Basic Dermatology Curriculum is simply an introduction to dermatology. However, given that dermatologists are among the major specialists who care for nail patients, we advocate for more content on nail diseases in this curriculum. Nails can easily be incorporated into existing modules, and a new module specifically dedicated to nail disease should be added. Moreover, we envision that our findings will positively reflect on competence in treating nail disease for dermatology residents.

Patients frequently present to dermatologists with nail disorders as their chief concern. Alternatively, nail conditions may be encountered by the examining physician as an incidental finding that may be a clue to underlying systemic disease. Competence in the diagnosis and treatment of nail diseases can drastically improve patient quality of life and can be lifesaving,¹ but many dermatologists find management of nail diseases challenging.² Bridging this educational gap begins with dermatology resident and medical student education. In a collaboration with dermatology educators, the American Academy of Dermatology (AAD) prepared a free online core curriculum for medical students that covers the essential concepts of dermatology. We sought to determine the integration of nail education in the AAD Basic Dermatology Curriculum.

Methods

A cross-sectional study of the AAD Basic Dermatology Curriculum was conducted to determine nail disease content. The curriculum modules were downloaded in June 2018,³ and mentions of nails were recorded and evaluated for overall quantities and relevant content. References to nail procedures and diagnostic techniques including nail biopsies, fungal cultures, microscopy on nail scrapings, nail clippings, and nail-related cancers also were assessed in the analysis.

Results

Of 342 patients discussed in cases and quizzes, nails were mentioned for 19 patients (89 times total)(Table 1). Additionally, there were 2 mentions each of nail clippings and nail tumors, 0 mentions of nail biopsies, and 1 mention each of fungal cultures and microscopy on nail scrapings (Table 1). Of the 40 modules, nails were mentioned in 12 modules (Table 2) and 6 introductions to the modules (Table 1). There were no mentions of the terms nails, subungual, or onychomycosis in the learning objectives.³

Comment

Our study demonstrates a paucity of content relevant to nails in the AAD Basic Dermatology Curriculum. Medical students are missing an important opportunity to learn about diagnosis and management of nail conditions and may incorrectly conclude that nail expertise is not essential to becoming a competent board-certified dermatologist.

Particularly concerning is the exclusion of nail examinations in the skin exam module addressing full-body skin examinations (0 mentions in 31 slides). This curriculum may negatively influence medical students and may then follow at the resident level, with a study reporting that 50.3% (69/137) of residents examine nails only when the patient brings it to their attention.⁴

Most concerning was the inadequate coverage of nail unit melanoma in the melanoma module (1 mention in 53 slides). Furthermore, the ABCDE—asymmetry, border, color, diameter, and evolving—mnemonic for cutaneous melanoma was covered in 6 slides in this module, and the ABCDEF—family history added—mnemonic for nail unit melanoma was completely excluded. Not surprisingly, resident knowledge of melanonychia diagnosis is deficient, with a prior study demonstrating that 62% (88/142) of residents were not confident diagnosing and managing patients with melanonychia, and only 88% (125/142) of residents were aware of the nail melanoma mnemonic.⁴

Similarly, nail biopsy for melanonychia diagnosis was excluded from the curriculum, whereas skin biopsy was thoroughly discussed in the context of a cutaneous melanoma diagnosis. This deficient teaching may track to the dermatology resident curriculum, as a survey of third-year dermatology residents (N=240) showed that 58% performed 10 or fewer nail procedures, and one-third of residents felt incompetent in nail surgery.⁵

We acknowledge that the AAD Basic Dermatology Curriculum is simply an introduction to dermatology. However, given that dermatologists are among the major specialists who care for nail patients, we advocate for more content on nail diseases in this curriculum. Nails can easily be incorporated into existing modules, and a new module specifically dedicated to nail disease should be added. Moreover, we envision that our findings will positively reflect on competence in treating nail disease for dermatology residents.

Patients frequently present to dermatologists with nail disorders as their chief concern. Alternatively, nail conditions may be encountered by the examining physician as an incidental finding that may be a clue to underlying systemic disease. Competence in the diagnosis and treatment of nail diseases can drastically improve patient quality of life and can be lifesaving,¹ but many dermatologists find management of nail diseases challenging.² Bridging this educational gap begins with dermatology resident and medical student education. In a collaboration with dermatology educators, the American Academy of Dermatology (AAD) prepared a free online core curriculum for medical students that covers the essential concepts of dermatology. We sought to determine the integration of nail education in the AAD Basic Dermatology Curriculum.

Methods

A cross-sectional study of the AAD Basic Dermatology Curriculum was conducted to determine nail disease content. The curriculum modules were downloaded in June 2018,³ and mentions of nails were recorded and evaluated for overall quantities and relevant content. References to nail procedures and diagnostic techniques including nail biopsies, fungal cultures, microscopy on nail scrapings, nail clippings, and nail-related cancers also were assessed in the analysis.

Results

Of 342 patients discussed in cases and quizzes, nails were mentioned for 19 patients (89 times total)(Table 1). Additionally, there were 2 mentions each of nail clippings and nail tumors, 0 mentions of nail biopsies, and 1 mention each of fungal cultures and microscopy on nail scrapings (Table 1). Of the 40 modules, nails were mentioned in 12 modules (Table 2) and 6 introductions to the modules (Table 1). There were no mentions of the terms nails, subungual, or onychomycosis in the learning objectives.³

Comment

Our study demonstrates a paucity of content relevant to nails in the AAD Basic Dermatology Curriculum. Medical students are missing an important opportunity to learn about diagnosis and management of nail conditions and may incorrectly conclude that nail expertise is not essential to becoming a competent board-certified dermatologist.

Particularly concerning is the exclusion of nail examinations in the skin exam module addressing full-body skin examinations (0 mentions in 31 slides). This curriculum may negatively influence medical students and may then follow at the resident level, with a study reporting that 50.3% (69/137) of residents examine nails only when the patient brings it to their attention.⁴

Most concerning was the inadequate coverage of nail unit melanoma in the melanoma module (1 mention in 53 slides). Furthermore, the ABCDE—asymmetry, border, color, diameter, and evolving—mnemonic for cutaneous melanoma was covered in 6 slides in this module, and the ABCDEF—family history added—mnemonic for nail unit melanoma was completely excluded. Not surprisingly, resident knowledge of melanonychia diagnosis is deficient, with a prior study demonstrating that 62% (88/142) of residents were not confident diagnosing and managing patients with melanonychia, and only 88% (125/142) of residents were aware of the nail melanoma mnemonic.⁴

Similarly, nail biopsy for melanonychia diagnosis was excluded from the curriculum, whereas skin biopsy was thoroughly discussed in the context of a cutaneous melanoma diagnosis. This deficient teaching may track to the dermatology resident curriculum, as a survey of third-year dermatology residents (N=240) showed that 58% performed 10 or fewer nail procedures, and one-third of residents felt incompetent in nail surgery.⁵

We acknowledge that the AAD Basic Dermatology Curriculum is simply an introduction to dermatology. However, given that dermatologists are among the major specialists who care for nail patients, we advocate for more content on nail diseases in this curriculum. Nails can easily be incorporated into existing modules, and a new module specifically dedicated to nail disease should be added. Moreover, we envision that our findings will positively reflect on competence in treating nail disease for dermatology residents.

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, is launching the first in-human trial of a universal influenza vaccine candidate.

Copyright National Institutes of Health

The experimental vaccine, H1ssF_3928, is derived from the stem of an H1N1 virus and has a surface made from hemagglutinin and ferritin. By including only the stem of the virus, which changes less than the head, the vaccine should require fewer updates. A similar vaccine made from the same materials was shown to be safe and well tolerated in humans.

The clinical trial (NCT03814720) will be conducted at the NIH Clinical Center in Bethesda, Md., and will gradually enroll at least 53 healthy adults aged 18-70 years. The first 5 participants will receive one 20-mcg intramuscular injection of the vaccine; the other 48 participants will receive two 60-mcg vaccinations 16 weeks apart. Patients will return for 9-11 follow-ups over a 12- to 15-month period, and will provide blood samples for analysis of anti-influenza antibodies.

copyright itsmejust/Thinkstock

“Seasonal influenza is a perpetual public health challenge, and we continually face the possibility of an influenza pandemic resulting from the emergence and spread of novel influenza viruses. This phase 1 clinical trial is a step forward in our efforts to develop a durable and broadly protective universal influenza vaccine,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in the press release.

Find the full press release on the NIH website.

[email protected]

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, is launching the first in-human trial of a universal influenza vaccine candidate.

Copyright National Institutes of Health

The experimental vaccine, H1ssF_3928, is derived from the stem of an H1N1 virus and has a surface made from hemagglutinin and ferritin. By including only the stem of the virus, which changes less than the head, the vaccine should require fewer updates. A similar vaccine made from the same materials was shown to be safe and well tolerated in humans.

The clinical trial (NCT03814720) will be conducted at the NIH Clinical Center in Bethesda, Md., and will gradually enroll at least 53 healthy adults aged 18-70 years. The first 5 participants will receive one 20-mcg intramuscular injection of the vaccine; the other 48 participants will receive two 60-mcg vaccinations 16 weeks apart. Patients will return for 9-11 follow-ups over a 12- to 15-month period, and will provide blood samples for analysis of anti-influenza antibodies.

copyright itsmejust/Thinkstock

“Seasonal influenza is a perpetual public health challenge, and we continually face the possibility of an influenza pandemic resulting from the emergence and spread of novel influenza viruses. This phase 1 clinical trial is a step forward in our efforts to develop a durable and broadly protective universal influenza vaccine,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in the press release.

Find the full press release on the NIH website.

[email protected]

The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, is launching the first in-human trial of a universal influenza vaccine candidate.

Copyright National Institutes of Health

The experimental vaccine, H1ssF_3928, is derived from the stem of an H1N1 virus and has a surface made from hemagglutinin and ferritin. By including only the stem of the virus, which changes less than the head, the vaccine should require fewer updates. A similar vaccine made from the same materials was shown to be safe and well tolerated in humans.

The clinical trial (NCT03814720) will be conducted at the NIH Clinical Center in Bethesda, Md., and will gradually enroll at least 53 healthy adults aged 18-70 years. The first 5 participants will receive one 20-mcg intramuscular injection of the vaccine; the other 48 participants will receive two 60-mcg vaccinations 16 weeks apart. Patients will return for 9-11 follow-ups over a 12- to 15-month period, and will provide blood samples for analysis of anti-influenza antibodies.

copyright itsmejust/Thinkstock

“Seasonal influenza is a perpetual public health challenge, and we continually face the possibility of an influenza pandemic resulting from the emergence and spread of novel influenza viruses. This phase 1 clinical trial is a step forward in our efforts to develop a durable and broadly protective universal influenza vaccine,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in the press release.

Find the full press release on the NIH website.

[email protected]

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Practice Gap

Onychocryptosis, or ingrown toenail, is a highly prevalent nail condition characterized by penetration of the periungual skin by the nail plate (Figure, A). Patients may report pain either while at rest or walking, which may be debilitating in severe cases and may adversely affect daily living. Treatment may be approached using conservative or surgical therapies. Conservative methods are noninvasive and appropriate for mild cases but require excellent compliance. Although nail trimming is the simplest method, it may necessitate cutting soft tissue, particularly when the nail is anchored deep within the periungual skin. Another conservative method is taping, which aims to separate the nail fold from the offending nail edge by using an adhesive. In common practice, the adhesive often detaches within a few hours, which is further exacerbated by moisture from sweating or bathing.¹ Therefore, for effective treatment of onychocryptosis, the tape typically must be reapplied multiple times per day, limiting compliance.

Tools

We propose using kinesiology tape to treat onychocryptosis. Kinesiology tape is a highly elastic adhesive that was originally employed by athletes to relieve pain while supporting muscles, tendons, and ligaments during strenuous activity. We hypothesized that its stronger adherent properties and greater elasticity would be advantageous for treatment of onychocryptosis compared to standard tape.

The Technique

A strip of tape is cut to approximately 10 to 15 mm×5 cm and is applied once daily to the lateral nail fold, pulling it away from the nail plate in oblique and proximal directions and then wrapping it around the plantar surface dorsally (Figure, B). Kinesiology tape properties allow for less frequent application and greater tension to be applied to the nail fold while reducing the risk for vasoconstriction, as the tape does not need to be fully wrapped around the digit for reliable adherence.

Practice Implications

Kinesiology tape adheres more firmly than other tapes and requires less frequent applications. Use of kinesiology tape for onychocryptosis therapy often is effective and may negate the need for more invasive procedures and improve quality of life during and after treatment.

Which patients are likely to benefit from using aspirin for primary prevention? In this article, we review the evidence to date, summarized for primary care settings in guidelines issued by the US Preventive Services Task Force (USPSTF). We supplement this summary with a rundown of the risks associated with aspirin use. And then we wrap up by identifying a clinical decision tool that is available to help make personalized decisions in a busy clinic setting, where determining an individual’s potential cardiovascular benefits and bleeding risk can be challenging.

The “roadmap” from the guidelines. In 2014, after performing a review of the literature, the US Food and Drug Administration recommended against the routine use of aspirin for primary prevention of cardiovascular disease (CVD).¹ In 2016, the USPSTF published 4 separate systematic reviews along with a decision analysis using a microsimulation model, which informed their position statement on aspirin for primary prevention.^2-6 These USPSTF reviews and recommendations incorporated both CVD and colorectal cancer (CRC) benefits with the bleeding risks from aspirin. Generally, for individuals 50 to 59 years old, the benefits are deemed to outweigh the harms; shared decision making is advised with those 60 to 69 years of age. For patients younger than 50 or 70 and older, evidence is inconclusive.

The benefits of primary prevention with aspirin

Cardiovascular disease

The Antithrombotic Trialists’ (ATT) Collaboration was one of the first meta-analyses that addressed the benefit-to-harm balance and called into question the routine use of aspirin for primary prevention.⁷ The USPSTF systematic review included the studies from the ATT Collaboration as well as trials performed after its publication, bringing the total number of eligible randomized controlled trials reviewed to 11.²

The benefit of aspirin for primary prevention of nonfatal myocardial infarction (MI) has been shown in multiple randomized controlled trials. The USPSTF systematic review showed a statistically significant relative risk reduction of 17% in patients taking low-dose aspirin (≤ 100 mg; relative risk [RR] = 0.83; confidence interval [95% CI], 0.74-0.94), although the heterogeneity of the studies was high. The same low dose of aspirin showed a statistically significant reduction in nonfatal stroke (RR = 0.86; 95% CI, 0.76-0.98), although the same benefit was not observed when all doses of aspirin were included. Cardiovascular disease mortality and all-cause mortality were not statistically different for patients taking low-dose aspirin when compared with placebo (RR = 0.97; 95% CI, 0.85-1.10 for CVD mortality; RR = 0.95; 95% CI, 0.89-1.01 for all-cause mortality).²

One study of more than 14,000 older (≥ 60 years) Japanese patients showed a statistically significant reduction in nonfatal MI (hazard ratio [HR] = 0.53; 95% CI, 0.31-0.91, P = .02) and nonfatal strokes (HR = 0.57; 95% CI, 0.32-0.99; P = .04). The study was stopped early because at 5 years of follow-up there was no statistically significant difference in a composite primary outcome, which included death from cardiovascular causes, nonfatal MI, and nonfatal stroke (HR = 0.94; 95% CI, 0.77-1.15; P = .54).⁸

Preventive benefits of aspirin outweigh risks for those 50-59 years of age who have a 10-year cardiovascular disease risk of ≥ 10%.

Several recent landmark studies have called into question the benefit of aspirin for cardiovascular primary prevention, especially in obese individuals, patients with diabetes, and the elderly. A meta-analysis of 10 trials showed that the effectiveness of aspirin doses between 75 mg and 100 mg for primary prevention decreased as weight increased; patients weighing 70 kg or more received no benefit.⁹ The ASCEND (A Study of Cardiovascular Events in Diabetes) trial included more than 15,000 patients with diabetes but no cardiovascular disease. Patients randomized to receive the low-dose aspirin did have fewer serious vascular events (incidence rate ratio [IRR] = 0.88; 95% CI, 0.79-0.97; P = .01), but they also had high risk of major bleeding events (IRR = 1.29; 95% CI, 1.09-1.52; P = .003).¹⁰ The ASPREE (Aspirin in Reducing Events in the Elderly) trial included more than 19,000 patients ages 70 years and older with no cardiovascular disease and compared low-dose aspirin to placebo. There was no statistically significant cardiovascular benefit, although there was an increase of major hemorrhage (HR = 1.38; 95% CI, 1.18-1.62; P < .001).¹¹ The ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial included 12,546 moderate atherosclerotic CVD (ASCVD) risk patients. Although a per-protocol analysis showed a decrease in rates of fatal and nonfatal MI (HR = 0.53; 95% CI, 0.36-0.79; P = .0014), the more reliable intention-to-treat analysis showed no improvement for any outcomes.¹²

[polldaddy:10286821]

Colorectal cancer

The literature base on prevention of cancer has been growing rapidly. However, the deluge of findings over the past 2 decades of trials and analyses has also introduced ambiguity and, often, conflicting results. The first journal article suggesting aspirin for primary prevention of cancer, published in 1988, was a case-control study wherein a population with CRC was matched to controls to look for potential protective factors.¹³ The most notable finding was the CRC risk reduction for those taking aspirin or aspirin-containing medications. Since then numerous studies and analyses have explored aspirin’s potential in primary prevention of many types of cancer, with overall unclear findings as denoted in the 2016 USPSTF systemic reviews and recommendations.

Continue to: One major limiting factor...

One major limiting factor is that most data come from CVD prevention trials, and only a limited number of trials have focused specifically on cancer prevention. For the USPSTF, these data showed no statistically significant risk reduction in overall cancer mortality (RR = 0.96; 95% CI, 0.87-1.06) or in total cancer incidence (RR = 0.98; 95% CI, 0.93-1.04).⁴ Other ongoing trials may yield more definitive data.¹⁴

The particular interest in CRC was due to it being the first cancer found to be preventable with aspirin therapy. The USPSTF, while acknowledging the homogeneous nature of supporting studies, noted that their significant number and resulting evidence made CRC the only cancer warranting evaluation. Population studies have now shown more benefit than the few randomized control trials. The Women’s Health Study and the Physicians’ Health Study were both limited by their duration. But such studies conducted over a longer period revealed notable benefits in the second decade of use, with a statistically significant lower CRC incidence (RR = 0.60; 95% CI, 0.47-0.76). Additionally, CRC mortality at 20 years was decreased in patients taking aspirin regularly (RR = 0.67; 95% CI, 0.52-0.86).⁴ Multiple studies are in progress to better establish aspirin’s CRC benefit.

While not directly applicable to the general population, use of aspirin for patients with Lynch syndrome to prevent CRC has strong supporting evidence.¹⁵ Beyond CRC, there is nascent evidence from limited observational studies that aspirin may have a preventive effect on melanoma and ovarian and pancreatic cancers.^16-18 Further studies or compilations of data would be needed to draw more significant conclusions on other types of cancers. Larger studies would prove more difficult to do, given the smaller incidences of these cancers.

Interestingly, a recent study showed that for individuals 70 years and older, aspirin might increase the risk for all-cause mortality, primarily due to increased cancer mortality across all types.¹⁹ Although this result was unexpected, caution should be used when prescribing aspirin particularly for patients 70 or older with active cancer.

A look at the harms associated with aspirin use

Aspirin has long been known to cause clinically significant bleeding. Aspirin inhibits platelet-derived cyclooxygenase-1 (COX-1), a potent vasoconstrictor, and thereby decreases platelet aggregation, reducing thromboembolic potential and prolonging bleeding time. These effects can confer health benefits but also carry the potential for risks. A decision to initiate aspirin therapy for primary prevention relies on an understanding of the benefit-to-harm balance.

Continue to: Initial aspirin studies...

Initial aspirin studies did not show a statistically significant increase in bleeding, likely due to too few events and inadequate powering. Subsequent meta-analyses from multiple evaluations have consistently shown bleeding to be a risk.^3,7 The risk for bleeding with aspirin has also been examined in multiple cohort studies, which has helped elucidate the risk in greater detail.

Gastrointestinal bleeding

Epidemiologic data show that among patients who do not use nonsteroidal anti-inflammatory drugs (NSAIDs), the rate of upper gastrointestinal (GI) complications is 1 case per 1000 patient-years.²⁰ Multiple studies have consistently shown that aspirin use increases the rate of significant upper GI bleeding over baseline risk (odds ratio [OR] = 1.54-1.58).^3,21,22 Interestingly, these increases seem not to be influenced by other factors, such as comorbidities that increase the risk for ASCVD. Analysis of cancer prevention studies showed similar epidemiologic trends, with aspirin use exceeding a baseline bleeding risk of 0.7 cases of upper GI complications per 1000 patient-years (OR = 1.31-1.73).²³

Other risk factors. Evaluation of risk factors for bleeding primarily comes from 2 studies.^3,7 Most data concern the impact of individual factors on significant GI bleeding, with fewer data available for evaluating risk for intracerebral hemorrhage (ICH). Initial analysis of individual prospective studies showed little or no correlation between risk for bleeding and such factors as gender, age, or history of hypertension or ASCVD.²¹ Subsequent analysis of meta-data and large cohorts did show statistically significant impact on rates of bleeding across several factors (TABLE 1^3,7).

Enteric coating on aspirin does appear to lower the rates of gastric mucosal injury.

Of note is a large heterogeneous cohort study conducted in Spain. Data showed significant increases in baseline risk for GI bleeding in older men with a history of GI bleeding and NSAID use. The absolute risk for GI bleed in this group was potentially as high as 150 cases per 1000 patient-years, well above the risk level assumed for the average patient.²⁴ A seemingly small OR of 1.5 could dramatically increase the absolute risk for bleeding in such patients, and it suggests that a generalized risk for bleeding probably shouldn’t be applied to all patients. Individuals may be better served by a baseline risk calculation reflecting multiple factors.

Intracerebral hemorrhage

Due to the comparatively uncommon nature of ICH, fewer data are available to support definitive conclusions about its increased risk with aspirin use. Aspirin use appeared to increase the risk for ICH with ratios between 1.27 and 1.32 in meta-analyses (measured as an OR or as an RR),^3,7,21 with an IRR of 1.54 in a cohort study.²² The only statistically significant factors suspected to increase the risk of ICH at baseline were smoking (RR = 2.18) and mean BP > 20 mm Hg over normal (OR = 2.18). Age, gender, and diabetes all showed a nonsignificant trend toward risk increase.⁷

Continue to: Risk based on dose and formulation

The effect of aspirin dose and formulation on bleeding risk is uncertain. Some studies have shown an increased risk for bleeding with daily doses of aspirin ≥ 300 mg, while others have shown no significant increase in rates for bleeding with differing doses.^21,25 Enteric coating does appear to lower the rates of gastric mucosal injury, although there are few data on the effect toward reducing clinically significant bleeding.²⁶ Currently, several prospective studies are underway to help clarify the evidence.²⁷

Putting it all together

For the general population, the evidence shows that the benefits and harms of aspirin for primary prevention are relatively even. The USPSTF guidelines are the first to recommend aspirin for both CVD and cancer prevention while taking into account the bleeding risk. According to the findings of the USPSTF, the balance of benefits and harms of aspirin use is contingent on 4 factors: age, baseline CVD risk, risk for bleeding, and preferences about taking aspirin.⁶ The complete recommendations from the USPSTF, along with other leading organizations, are outlined in TABLE 2.^6,28-31

Applying the evidence and varying guidelines in practice can feel daunting. Some practical tools have been developed to help clinicians understand patients’ bleeding risk and potential benefits with aspirin use. One such tool is highlighted below. Others are also available, and each has its own strengths and weaknesses.

Aspirin-Guide (www.aspiringuide.com) is a Web-based clinical decision support tool with an associated mobile application. It uses internal calculators (including the pooled cohort calculator prepared jointly by the American College of Cardiology and the American Heart Association) to assess CVD risk as well as bleeding risk. This tool gives clinicians patient-specific numbers-needed-to-treat and numbers-needed-to-harm when considering starting aspirin for primary prevention. It gives specific recommendations for aspirin use based on the data entered, and it also gives providers information to help guide shared decision-making with patients.³² Unfortunately, this decision support tool and others do not take into account the data from the most recent trials, so they should be used with caution.

CORRESPONDENCE
LCDR Dustin K. Smith, DO, Naval Branch Clinic Diego Garcia, PSC 466, Box 301, FPO, AP 96595; [email protected].

Which patients are likely to benefit from using aspirin for primary prevention? In this article, we review the evidence to date, summarized for primary care settings in guidelines issued by the US Preventive Services Task Force (USPSTF). We supplement this summary with a rundown of the risks associated with aspirin use. And then we wrap up by identifying a clinical decision tool that is available to help make personalized decisions in a busy clinic setting, where determining an individual’s potential cardiovascular benefits and bleeding risk can be challenging.

The “roadmap” from the guidelines. In 2014, after performing a review of the literature, the US Food and Drug Administration recommended against the routine use of aspirin for primary prevention of cardiovascular disease (CVD).¹ In 2016, the USPSTF published 4 separate systematic reviews along with a decision analysis using a microsimulation model, which informed their position statement on aspirin for primary prevention.^2-6 These USPSTF reviews and recommendations incorporated both CVD and colorectal cancer (CRC) benefits with the bleeding risks from aspirin. Generally, for individuals 50 to 59 years old, the benefits are deemed to outweigh the harms; shared decision making is advised with those 60 to 69 years of age. For patients younger than 50 or 70 and older, evidence is inconclusive.

The benefits of primary prevention with aspirin

Cardiovascular disease

The Antithrombotic Trialists’ (ATT) Collaboration was one of the first meta-analyses that addressed the benefit-to-harm balance and called into question the routine use of aspirin for primary prevention.⁷ The USPSTF systematic review included the studies from the ATT Collaboration as well as trials performed after its publication, bringing the total number of eligible randomized controlled trials reviewed to 11.²

The benefit of aspirin for primary prevention of nonfatal myocardial infarction (MI) has been shown in multiple randomized controlled trials. The USPSTF systematic review showed a statistically significant relative risk reduction of 17% in patients taking low-dose aspirin (≤ 100 mg; relative risk [RR] = 0.83; confidence interval [95% CI], 0.74-0.94), although the heterogeneity of the studies was high. The same low dose of aspirin showed a statistically significant reduction in nonfatal stroke (RR = 0.86; 95% CI, 0.76-0.98), although the same benefit was not observed when all doses of aspirin were included. Cardiovascular disease mortality and all-cause mortality were not statistically different for patients taking low-dose aspirin when compared with placebo (RR = 0.97; 95% CI, 0.85-1.10 for CVD mortality; RR = 0.95; 95% CI, 0.89-1.01 for all-cause mortality).²

One study of more than 14,000 older (≥ 60 years) Japanese patients showed a statistically significant reduction in nonfatal MI (hazard ratio [HR] = 0.53; 95% CI, 0.31-0.91, P = .02) and nonfatal strokes (HR = 0.57; 95% CI, 0.32-0.99; P = .04). The study was stopped early because at 5 years of follow-up there was no statistically significant difference in a composite primary outcome, which included death from cardiovascular causes, nonfatal MI, and nonfatal stroke (HR = 0.94; 95% CI, 0.77-1.15; P = .54).⁸

Preventive benefits of aspirin outweigh risks for those 50-59 years of age who have a 10-year cardiovascular disease risk of ≥ 10%.

Several recent landmark studies have called into question the benefit of aspirin for cardiovascular primary prevention, especially in obese individuals, patients with diabetes, and the elderly. A meta-analysis of 10 trials showed that the effectiveness of aspirin doses between 75 mg and 100 mg for primary prevention decreased as weight increased; patients weighing 70 kg or more received no benefit.⁹ The ASCEND (A Study of Cardiovascular Events in Diabetes) trial included more than 15,000 patients with diabetes but no cardiovascular disease. Patients randomized to receive the low-dose aspirin did have fewer serious vascular events (incidence rate ratio [IRR] = 0.88; 95% CI, 0.79-0.97; P = .01), but they also had high risk of major bleeding events (IRR = 1.29; 95% CI, 1.09-1.52; P = .003).¹⁰ The ASPREE (Aspirin in Reducing Events in the Elderly) trial included more than 19,000 patients ages 70 years and older with no cardiovascular disease and compared low-dose aspirin to placebo. There was no statistically significant cardiovascular benefit, although there was an increase of major hemorrhage (HR = 1.38; 95% CI, 1.18-1.62; P < .001).¹¹ The ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial included 12,546 moderate atherosclerotic CVD (ASCVD) risk patients. Although a per-protocol analysis showed a decrease in rates of fatal and nonfatal MI (HR = 0.53; 95% CI, 0.36-0.79; P = .0014), the more reliable intention-to-treat analysis showed no improvement for any outcomes.¹²

[polldaddy:10286821]

Colorectal cancer

The literature base on prevention of cancer has been growing rapidly. However, the deluge of findings over the past 2 decades of trials and analyses has also introduced ambiguity and, often, conflicting results. The first journal article suggesting aspirin for primary prevention of cancer, published in 1988, was a case-control study wherein a population with CRC was matched to controls to look for potential protective factors.¹³ The most notable finding was the CRC risk reduction for those taking aspirin or aspirin-containing medications. Since then numerous studies and analyses have explored aspirin’s potential in primary prevention of many types of cancer, with overall unclear findings as denoted in the 2016 USPSTF systemic reviews and recommendations.

Continue to: One major limiting factor...

One major limiting factor is that most data come from CVD prevention trials, and only a limited number of trials have focused specifically on cancer prevention. For the USPSTF, these data showed no statistically significant risk reduction in overall cancer mortality (RR = 0.96; 95% CI, 0.87-1.06) or in total cancer incidence (RR = 0.98; 95% CI, 0.93-1.04).⁴ Other ongoing trials may yield more definitive data.¹⁴

The particular interest in CRC was due to it being the first cancer found to be preventable with aspirin therapy. The USPSTF, while acknowledging the homogeneous nature of supporting studies, noted that their significant number and resulting evidence made CRC the only cancer warranting evaluation. Population studies have now shown more benefit than the few randomized control trials. The Women’s Health Study and the Physicians’ Health Study were both limited by their duration. But such studies conducted over a longer period revealed notable benefits in the second decade of use, with a statistically significant lower CRC incidence (RR = 0.60; 95% CI, 0.47-0.76). Additionally, CRC mortality at 20 years was decreased in patients taking aspirin regularly (RR = 0.67; 95% CI, 0.52-0.86).⁴ Multiple studies are in progress to better establish aspirin’s CRC benefit.

While not directly applicable to the general population, use of aspirin for patients with Lynch syndrome to prevent CRC has strong supporting evidence.¹⁵ Beyond CRC, there is nascent evidence from limited observational studies that aspirin may have a preventive effect on melanoma and ovarian and pancreatic cancers.^16-18 Further studies or compilations of data would be needed to draw more significant conclusions on other types of cancers. Larger studies would prove more difficult to do, given the smaller incidences of these cancers.

Interestingly, a recent study showed that for individuals 70 years and older, aspirin might increase the risk for all-cause mortality, primarily due to increased cancer mortality across all types.¹⁹ Although this result was unexpected, caution should be used when prescribing aspirin particularly for patients 70 or older with active cancer.

A look at the harms associated with aspirin use

Aspirin has long been known to cause clinically significant bleeding. Aspirin inhibits platelet-derived cyclooxygenase-1 (COX-1), a potent vasoconstrictor, and thereby decreases platelet aggregation, reducing thromboembolic potential and prolonging bleeding time. These effects can confer health benefits but also carry the potential for risks. A decision to initiate aspirin therapy for primary prevention relies on an understanding of the benefit-to-harm balance.

Continue to: Initial aspirin studies...

Initial aspirin studies did not show a statistically significant increase in bleeding, likely due to too few events and inadequate powering. Subsequent meta-analyses from multiple evaluations have consistently shown bleeding to be a risk.^3,7 The risk for bleeding with aspirin has also been examined in multiple cohort studies, which has helped elucidate the risk in greater detail.

Gastrointestinal bleeding

Epidemiologic data show that among patients who do not use nonsteroidal anti-inflammatory drugs (NSAIDs), the rate of upper gastrointestinal (GI) complications is 1 case per 1000 patient-years.²⁰ Multiple studies have consistently shown that aspirin use increases the rate of significant upper GI bleeding over baseline risk (odds ratio [OR] = 1.54-1.58).^3,21,22 Interestingly, these increases seem not to be influenced by other factors, such as comorbidities that increase the risk for ASCVD. Analysis of cancer prevention studies showed similar epidemiologic trends, with aspirin use exceeding a baseline bleeding risk of 0.7 cases of upper GI complications per 1000 patient-years (OR = 1.31-1.73).²³

Other risk factors. Evaluation of risk factors for bleeding primarily comes from 2 studies.^3,7 Most data concern the impact of individual factors on significant GI bleeding, with fewer data available for evaluating risk for intracerebral hemorrhage (ICH). Initial analysis of individual prospective studies showed little or no correlation between risk for bleeding and such factors as gender, age, or history of hypertension or ASCVD.²¹ Subsequent analysis of meta-data and large cohorts did show statistically significant impact on rates of bleeding across several factors (TABLE 1^3,7).

Enteric coating on aspirin does appear to lower the rates of gastric mucosal injury.

Of note is a large heterogeneous cohort study conducted in Spain. Data showed significant increases in baseline risk for GI bleeding in older men with a history of GI bleeding and NSAID use. The absolute risk for GI bleed in this group was potentially as high as 150 cases per 1000 patient-years, well above the risk level assumed for the average patient.²⁴ A seemingly small OR of 1.5 could dramatically increase the absolute risk for bleeding in such patients, and it suggests that a generalized risk for bleeding probably shouldn’t be applied to all patients. Individuals may be better served by a baseline risk calculation reflecting multiple factors.

Intracerebral hemorrhage

Due to the comparatively uncommon nature of ICH, fewer data are available to support definitive conclusions about its increased risk with aspirin use. Aspirin use appeared to increase the risk for ICH with ratios between 1.27 and 1.32 in meta-analyses (measured as an OR or as an RR),^3,7,21 with an IRR of 1.54 in a cohort study.²² The only statistically significant factors suspected to increase the risk of ICH at baseline were smoking (RR = 2.18) and mean BP > 20 mm Hg over normal (OR = 2.18). Age, gender, and diabetes all showed a nonsignificant trend toward risk increase.⁷

Continue to: Risk based on dose and formulation

The effect of aspirin dose and formulation on bleeding risk is uncertain. Some studies have shown an increased risk for bleeding with daily doses of aspirin ≥ 300 mg, while others have shown no significant increase in rates for bleeding with differing doses.^21,25 Enteric coating does appear to lower the rates of gastric mucosal injury, although there are few data on the effect toward reducing clinically significant bleeding.²⁶ Currently, several prospective studies are underway to help clarify the evidence.²⁷

Putting it all together

For the general population, the evidence shows that the benefits and harms of aspirin for primary prevention are relatively even. The USPSTF guidelines are the first to recommend aspirin for both CVD and cancer prevention while taking into account the bleeding risk. According to the findings of the USPSTF, the balance of benefits and harms of aspirin use is contingent on 4 factors: age, baseline CVD risk, risk for bleeding, and preferences about taking aspirin.⁶ The complete recommendations from the USPSTF, along with other leading organizations, are outlined in TABLE 2.^6,28-31

Applying the evidence and varying guidelines in practice can feel daunting. Some practical tools have been developed to help clinicians understand patients’ bleeding risk and potential benefits with aspirin use. One such tool is highlighted below. Others are also available, and each has its own strengths and weaknesses.

Aspirin-Guide (www.aspiringuide.com) is a Web-based clinical decision support tool with an associated mobile application. It uses internal calculators (including the pooled cohort calculator prepared jointly by the American College of Cardiology and the American Heart Association) to assess CVD risk as well as bleeding risk. This tool gives clinicians patient-specific numbers-needed-to-treat and numbers-needed-to-harm when considering starting aspirin for primary prevention. It gives specific recommendations for aspirin use based on the data entered, and it also gives providers information to help guide shared decision-making with patients.³² Unfortunately, this decision support tool and others do not take into account the data from the most recent trials, so they should be used with caution.

CORRESPONDENCE
LCDR Dustin K. Smith, DO, Naval Branch Clinic Diego Garcia, PSC 466, Box 301, FPO, AP 96595; [email protected].

Which patients are likely to benefit from using aspirin for primary prevention? In this article, we review the evidence to date, summarized for primary care settings in guidelines issued by the US Preventive Services Task Force (USPSTF). We supplement this summary with a rundown of the risks associated with aspirin use. And then we wrap up by identifying a clinical decision tool that is available to help make personalized decisions in a busy clinic setting, where determining an individual’s potential cardiovascular benefits and bleeding risk can be challenging.

The “roadmap” from the guidelines. In 2014, after performing a review of the literature, the US Food and Drug Administration recommended against the routine use of aspirin for primary prevention of cardiovascular disease (CVD).¹ In 2016, the USPSTF published 4 separate systematic reviews along with a decision analysis using a microsimulation model, which informed their position statement on aspirin for primary prevention.^2-6 These USPSTF reviews and recommendations incorporated both CVD and colorectal cancer (CRC) benefits with the bleeding risks from aspirin. Generally, for individuals 50 to 59 years old, the benefits are deemed to outweigh the harms; shared decision making is advised with those 60 to 69 years of age. For patients younger than 50 or 70 and older, evidence is inconclusive.

The benefits of primary prevention with aspirin

Cardiovascular disease

The Antithrombotic Trialists’ (ATT) Collaboration was one of the first meta-analyses that addressed the benefit-to-harm balance and called into question the routine use of aspirin for primary prevention.⁷ The USPSTF systematic review included the studies from the ATT Collaboration as well as trials performed after its publication, bringing the total number of eligible randomized controlled trials reviewed to 11.²

The benefit of aspirin for primary prevention of nonfatal myocardial infarction (MI) has been shown in multiple randomized controlled trials. The USPSTF systematic review showed a statistically significant relative risk reduction of 17% in patients taking low-dose aspirin (≤ 100 mg; relative risk [RR] = 0.83; confidence interval [95% CI], 0.74-0.94), although the heterogeneity of the studies was high. The same low dose of aspirin showed a statistically significant reduction in nonfatal stroke (RR = 0.86; 95% CI, 0.76-0.98), although the same benefit was not observed when all doses of aspirin were included. Cardiovascular disease mortality and all-cause mortality were not statistically different for patients taking low-dose aspirin when compared with placebo (RR = 0.97; 95% CI, 0.85-1.10 for CVD mortality; RR = 0.95; 95% CI, 0.89-1.01 for all-cause mortality).²

One study of more than 14,000 older (≥ 60 years) Japanese patients showed a statistically significant reduction in nonfatal MI (hazard ratio [HR] = 0.53; 95% CI, 0.31-0.91, P = .02) and nonfatal strokes (HR = 0.57; 95% CI, 0.32-0.99; P = .04). The study was stopped early because at 5 years of follow-up there was no statistically significant difference in a composite primary outcome, which included death from cardiovascular causes, nonfatal MI, and nonfatal stroke (HR = 0.94; 95% CI, 0.77-1.15; P = .54).⁸

Preventive benefits of aspirin outweigh risks for those 50-59 years of age who have a 10-year cardiovascular disease risk of ≥ 10%.

Several recent landmark studies have called into question the benefit of aspirin for cardiovascular primary prevention, especially in obese individuals, patients with diabetes, and the elderly. A meta-analysis of 10 trials showed that the effectiveness of aspirin doses between 75 mg and 100 mg for primary prevention decreased as weight increased; patients weighing 70 kg or more received no benefit.⁹ The ASCEND (A Study of Cardiovascular Events in Diabetes) trial included more than 15,000 patients with diabetes but no cardiovascular disease. Patients randomized to receive the low-dose aspirin did have fewer serious vascular events (incidence rate ratio [IRR] = 0.88; 95% CI, 0.79-0.97; P = .01), but they also had high risk of major bleeding events (IRR = 1.29; 95% CI, 1.09-1.52; P = .003).¹⁰ The ASPREE (Aspirin in Reducing Events in the Elderly) trial included more than 19,000 patients ages 70 years and older with no cardiovascular disease and compared low-dose aspirin to placebo. There was no statistically significant cardiovascular benefit, although there was an increase of major hemorrhage (HR = 1.38; 95% CI, 1.18-1.62; P < .001).¹¹ The ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial included 12,546 moderate atherosclerotic CVD (ASCVD) risk patients. Although a per-protocol analysis showed a decrease in rates of fatal and nonfatal MI (HR = 0.53; 95% CI, 0.36-0.79; P = .0014), the more reliable intention-to-treat analysis showed no improvement for any outcomes.¹²

[polldaddy:10286821]

Colorectal cancer

The literature base on prevention of cancer has been growing rapidly. However, the deluge of findings over the past 2 decades of trials and analyses has also introduced ambiguity and, often, conflicting results. The first journal article suggesting aspirin for primary prevention of cancer, published in 1988, was a case-control study wherein a population with CRC was matched to controls to look for potential protective factors.¹³ The most notable finding was the CRC risk reduction for those taking aspirin or aspirin-containing medications. Since then numerous studies and analyses have explored aspirin’s potential in primary prevention of many types of cancer, with overall unclear findings as denoted in the 2016 USPSTF systemic reviews and recommendations.

Continue to: One major limiting factor...

One major limiting factor is that most data come from CVD prevention trials, and only a limited number of trials have focused specifically on cancer prevention. For the USPSTF, these data showed no statistically significant risk reduction in overall cancer mortality (RR = 0.96; 95% CI, 0.87-1.06) or in total cancer incidence (RR = 0.98; 95% CI, 0.93-1.04).⁴ Other ongoing trials may yield more definitive data.¹⁴

The particular interest in CRC was due to it being the first cancer found to be preventable with aspirin therapy. The USPSTF, while acknowledging the homogeneous nature of supporting studies, noted that their significant number and resulting evidence made CRC the only cancer warranting evaluation. Population studies have now shown more benefit than the few randomized control trials. The Women’s Health Study and the Physicians’ Health Study were both limited by their duration. But such studies conducted over a longer period revealed notable benefits in the second decade of use, with a statistically significant lower CRC incidence (RR = 0.60; 95% CI, 0.47-0.76). Additionally, CRC mortality at 20 years was decreased in patients taking aspirin regularly (RR = 0.67; 95% CI, 0.52-0.86).⁴ Multiple studies are in progress to better establish aspirin’s CRC benefit.

While not directly applicable to the general population, use of aspirin for patients with Lynch syndrome to prevent CRC has strong supporting evidence.¹⁵ Beyond CRC, there is nascent evidence from limited observational studies that aspirin may have a preventive effect on melanoma and ovarian and pancreatic cancers.^16-18 Further studies or compilations of data would be needed to draw more significant conclusions on other types of cancers. Larger studies would prove more difficult to do, given the smaller incidences of these cancers.

Interestingly, a recent study showed that for individuals 70 years and older, aspirin might increase the risk for all-cause mortality, primarily due to increased cancer mortality across all types.¹⁹ Although this result was unexpected, caution should be used when prescribing aspirin particularly for patients 70 or older with active cancer.

A look at the harms associated with aspirin use

Aspirin has long been known to cause clinically significant bleeding. Aspirin inhibits platelet-derived cyclooxygenase-1 (COX-1), a potent vasoconstrictor, and thereby decreases platelet aggregation, reducing thromboembolic potential and prolonging bleeding time. These effects can confer health benefits but also carry the potential for risks. A decision to initiate aspirin therapy for primary prevention relies on an understanding of the benefit-to-harm balance.

Continue to: Initial aspirin studies...

Initial aspirin studies did not show a statistically significant increase in bleeding, likely due to too few events and inadequate powering. Subsequent meta-analyses from multiple evaluations have consistently shown bleeding to be a risk.^3,7 The risk for bleeding with aspirin has also been examined in multiple cohort studies, which has helped elucidate the risk in greater detail.

Gastrointestinal bleeding

Epidemiologic data show that among patients who do not use nonsteroidal anti-inflammatory drugs (NSAIDs), the rate of upper gastrointestinal (GI) complications is 1 case per 1000 patient-years.²⁰ Multiple studies have consistently shown that aspirin use increases the rate of significant upper GI bleeding over baseline risk (odds ratio [OR] = 1.54-1.58).^3,21,22 Interestingly, these increases seem not to be influenced by other factors, such as comorbidities that increase the risk for ASCVD. Analysis of cancer prevention studies showed similar epidemiologic trends, with aspirin use exceeding a baseline bleeding risk of 0.7 cases of upper GI complications per 1000 patient-years (OR = 1.31-1.73).²³

Other risk factors. Evaluation of risk factors for bleeding primarily comes from 2 studies.^3,7 Most data concern the impact of individual factors on significant GI bleeding, with fewer data available for evaluating risk for intracerebral hemorrhage (ICH). Initial analysis of individual prospective studies showed little or no correlation between risk for bleeding and such factors as gender, age, or history of hypertension or ASCVD.²¹ Subsequent analysis of meta-data and large cohorts did show statistically significant impact on rates of bleeding across several factors (TABLE 1^3,7).

Enteric coating on aspirin does appear to lower the rates of gastric mucosal injury.

Of note is a large heterogeneous cohort study conducted in Spain. Data showed significant increases in baseline risk for GI bleeding in older men with a history of GI bleeding and NSAID use. The absolute risk for GI bleed in this group was potentially as high as 150 cases per 1000 patient-years, well above the risk level assumed for the average patient.²⁴ A seemingly small OR of 1.5 could dramatically increase the absolute risk for bleeding in such patients, and it suggests that a generalized risk for bleeding probably shouldn’t be applied to all patients. Individuals may be better served by a baseline risk calculation reflecting multiple factors.

Intracerebral hemorrhage

Due to the comparatively uncommon nature of ICH, fewer data are available to support definitive conclusions about its increased risk with aspirin use. Aspirin use appeared to increase the risk for ICH with ratios between 1.27 and 1.32 in meta-analyses (measured as an OR or as an RR),^3,7,21 with an IRR of 1.54 in a cohort study.²² The only statistically significant factors suspected to increase the risk of ICH at baseline were smoking (RR = 2.18) and mean BP > 20 mm Hg over normal (OR = 2.18). Age, gender, and diabetes all showed a nonsignificant trend toward risk increase.⁷

Continue to: Risk based on dose and formulation

The effect of aspirin dose and formulation on bleeding risk is uncertain. Some studies have shown an increased risk for bleeding with daily doses of aspirin ≥ 300 mg, while others have shown no significant increase in rates for bleeding with differing doses.^21,25 Enteric coating does appear to lower the rates of gastric mucosal injury, although there are few data on the effect toward reducing clinically significant bleeding.²⁶ Currently, several prospective studies are underway to help clarify the evidence.²⁷

Putting it all together

For the general population, the evidence shows that the benefits and harms of aspirin for primary prevention are relatively even. The USPSTF guidelines are the first to recommend aspirin for both CVD and cancer prevention while taking into account the bleeding risk. According to the findings of the USPSTF, the balance of benefits and harms of aspirin use is contingent on 4 factors: age, baseline CVD risk, risk for bleeding, and preferences about taking aspirin.⁶ The complete recommendations from the USPSTF, along with other leading organizations, are outlined in TABLE 2.^6,28-31

Applying the evidence and varying guidelines in practice can feel daunting. Some practical tools have been developed to help clinicians understand patients’ bleeding risk and potential benefits with aspirin use. One such tool is highlighted below. Others are also available, and each has its own strengths and weaknesses.

Aspirin-Guide (www.aspiringuide.com) is a Web-based clinical decision support tool with an associated mobile application. It uses internal calculators (including the pooled cohort calculator prepared jointly by the American College of Cardiology and the American Heart Association) to assess CVD risk as well as bleeding risk. This tool gives clinicians patient-specific numbers-needed-to-treat and numbers-needed-to-harm when considering starting aspirin for primary prevention. It gives specific recommendations for aspirin use based on the data entered, and it also gives providers information to help guide shared decision-making with patients.³² Unfortunately, this decision support tool and others do not take into account the data from the most recent trials, so they should be used with caution.

CORRESPONDENCE
LCDR Dustin K. Smith, DO, Naval Branch Clinic Diego Garcia, PSC 466, Box 301, FPO, AP 96595; [email protected].

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.

Clinical Presentation

Millipedes secrete a noxious toxin implicated in millipede burns. The toxic substance is benzoquinone, a strong irritant secreted from the repugnatorial glands contained in each segment of the arthropod (Figure 1). This compound serves as a natural insect repellant, acting as the millipede’s defense mechanism from potential predators.¹ On human skin, benzoquinone causes localized pigmentary changes most commonly presenting on the feet and toes. Local lesions may be associated with pain or burning, but there are no known reports of adverse systemic effects.² Affected patients experience cutaneous pigmentary changes, which may be dark red, blue, or black, and spontaneously resolve over time.² The degree of pigment change may be associated with duration of skin contact with the toxin. The affected areas may resemble burns, dermatitis, or skin necrosis. More distal lesions may present similarly to blue toe syndrome or acute arterial occlusion but can be differentiated by the presence of intact peripheral pulses and lack of temperature discrepancy between the feet.^3,4 Histologic evaluation of the lesions generally reveals nonspecific full-thickness epidermal necrosis, making clinical suspicion and physical examination paramount to the diagnosis of millipede burns.⁵

Diagnostic Difficulties

Accurate diagnosis of millipede burns is more difficult when the burn involves an unusual site. The most common site of involvement is the foot (Figure 2), followed by other commonly exposed areas such as the arms, face, and eyes.^2,3,6,7 Covered parts of the body are much less commonly affected, requiring the arthropod to gain access via infiltration of clothing, often when hanging on a clothesline. In these cases, burns may be mistaken for child abuse, especially if certain areas of the body are involved, such as the groin and genitals.² The well-defined arcuate lesions of the burns may resemble injuries from a wire or belt to the unsuspecting observer.

Conclusion

Although millipedes often are regarded as harmless, they are capable of causing adverse reactions through the secretion of toxic chemicals. Millipede burns cause localized pigmentary changes that may be associated with pain or burning in some patients. Because these burns may resemble child abuse in pediatric patients, physicians should be aware of this diagnosis when unusual parts of the body are involved.