Misha Rosenbach, MD

Sarcoidosis is a chronic inflammatory disease characterized by noncaseating granulomas that can affect many organ systems, most commonly the lungs and skin, with cutaneous involvement in 25% to 30% of patients in the United States.¹ The etiology of sarcoidosis largely is unknown and likely is multifactorial; however, specific environmental, infectious, and pharmaceutical triggers may contribute to its pathogenesis. Sarcoidosis secondary to occupational exposures in US Military veterans historically has been discussed and investigated. Still, it was not considered a service-connected disability until the passing of the Promise to Address Comprehensive Toxics (PACT) Act² in 2022. In this article, we review the risk factors and incidence of sarcoidosis in post–9/11 veterans as well as provide recommendations for managing presumptive service-connected sarcoidosis covered under the recently enacted PACT Act.

The PACT Act and Post–9/11 Military Veterans

Veterans of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) have a history of occupational exposures to open-air burn pits, gun smoke, and recurrent high-intensity sandstorms that may cause chronic disease.³ Burn pits, which were used to dispose of solid waste on forward operating bases, released antigenic particulate matter that was detectable on air sampling.^4,5 Increased respiratory disease rates in veterans that were deployed post–9/11 are well documented, but a causal relationship has not been established.⁶ Although burn pits cannot be directly associated with any disease at this time,⁵ veterans with assumed exposures can now receive a Veterans Affairs (VA) Disability Rating for presumptive conditions under the PACT Act.² The major points of this legislation include expanding and extending eligibility for veterans with toxic exposures, providing access to toxic exposure screening for all veterans receiving VA health care, and increasing research related to toxic exposures in US servicemembers. The PACT Act expands health care benefits, making it easier for veterans exposed post–9/11 to receive coverage for 24 new presumptive diagnoses.² Of these diagnoses, several are relevant to the practicing dermatologist. Patients with metastasis of primary cancers to the skin as well as melanoma or sarcoidosis may be eligible for coverage depending on the location and time of service. The Table lists service locations where the VA has determined servicemembers may have been exposed to burn pits or other toxins. Servicemembers with a presumptive diagnosis who served in these locations may be eligible for care under the PACT Act. Sarcoidosis is of particular concern due to its increased incidence and prevalence in military veterans compared to civilian populations. An analysis of more than 13 million veterans who received health care benefits through the Veterans Health Administration in 2019 found an annual incidence of sarcoidosis of 52 cases per 100,000 person-years and an annual prevalence of 141 cases per 100,000 individuals.⁷ In contrast, the United States has a reported annual incidence of sarcoidosis of 4.9 cases per 100,000 person-years and an annual prevalence of 60 cases per 100,000 individuals.⁸ Although the increased rates of sarcoidosis in veterans have been noted for decades, only recently have investigations provided insights into the etiology of sarcoidosis in this population.

CT112003127_Table.jpg

Sarcoidosis and Environmental Factors

Sarcoidosis is a multisystem granulomatous inflammatory disease that can present in any organ system⁹; however, it most commonly affects the lungs, skin, and eyes—all of which are subjected to direct contact with environmental toxins. The cause of sarcoidosis is unknown, but environmental exposures are theorized to play a role.^9,10 It has been hypothesized that exposure to various immunologically active triggers may invoke the granulomatous inflammatory response that characterizes the disease.¹¹ The World Trade Center disaster on 9/11 has provided insight into the potential environmental component of sarcoidosis. Firefighters who spent extensive amounts of time at the World Trade Center site experienced intense exposure to inorganic particulate matter; it was later found that there was a marked increase in the incidence of sarcoidosis or sarcoidosislike granulomatous pulmonary disease in exposed firefighters. It has been speculated that the elevated exposure to potentially antigenic particulates may have induced granulomatous inflammation, resulting in the manifestation of the disease.¹² Other known occupational exposures associated with an increased risk for sarcoidosis or sarcoidosislike illness include mold, silicates, metal dust, and microbial contaminants.¹¹ Servicemembers commonly are exposed to several of these aerosolized toxins, which theoretically could increase their risk for developing sarcoidosis.

Sarcoidosis in the Military

Servicemembers historically have faced unique environmental hazards that may increase their risk for developing sarcoidosis. Studies of naval veterans have shown relationships between occupational location and increased rates of sarcoidosis. Sailors assigned to aircraft carriers with nonskid coatings containing particulate matter such as aluminum, titanium, and silicates had a higher prevalence of sarcoidosis than those stationed on “clean” ships.^13,14 Although no one trigger was identified, the increased rates of sarcoidosis in populations with extensive exposure to toxins raise concern for the possibility of occupationally induced sarcoidosis in post–9/11 veterans.

Environmental exposures during OIF and OEF may be associated with sarcoidosis. A retrospective review of lung biopsy data collected from Department of Defense military treatment facilities was conducted to identify associations between lung disease and deployment to the Middle East.¹⁵ The study included 391 military patients divided into deployed and nondeployed groups undergoing lung biopsies for various reasons from 2005 to 2012. An analysis of the reported lung histology showed an increased frequency of nonnecrotizing granulomas in those with a history of deployment to the Middle East compared to those who had never been deployed. Development of disease was not associated with confounding factors such as age, ethnicity, sex, or tobacco use, raising suspicion about similar shared toxic exposures among deployed servicemembers.¹⁵ A 2020 study of sarcoidosis in active-duty military personnel reported that the incidence of observed cases was 2-times those seen in civilian Department of Defense employees from 2005 to 2010; however, data collected in this study did not indicate an increased risk for developing sarcoidosis based on deployment to the Middle East. Still, the higher prevalence of sarcoidosis in active-duty military personnel suggests similar shared exposures in this group.¹⁶

Identification of exposures that may potentially trigger sarcoidosis is difficult due to many confounding variables; however, the Airborne Hazards and Open Burn Pit Registry questionnaire has been used to extrapolate prospective hazards of concern. Results from the questionnaire identified that only veterans exposed to convoy activity had a statistically significant (odds ratio, 1.16; 95% CI, 1.00-1.35; P=.046) increased risk for developing sarcoidosis.¹⁷ Interestingly, enlisted personnel had a higher rate of sarcoidosis than officers, comprising upwards of 78% of cases in the Military Health System from 2004 to 2013.⁹ This finding requires further study, but increased exposure to toxins due to occupational specialty may be the cause.

Veterans with sarcoidosis may have a unique pathophysiology, which may point to occupational exposure. Studies show that affected veterans have unique plasma metabolites and metal ions compared to civilians, with lower anti-inflammatory amino acid concentrations and downregulated GABA synthesis. The environmental exposures in OIF and OEF may have primed deployed servicemembers to develop a distinct subtype of sarcoidosis.³ Overall, there is a dearth of literature on post–9/11 veterans with sarcoidosis; therefore, further investigation is necessary to determine the actual risk for developing the disease following exposures related to military service.

Cutaneous sarcoidosis protean morphology is considered an imitator of many other skin diseases. The most common sarcoidosis-specific skin lesions include papules and papulonodules (Figure, A), lupus pernio (Figure, B), plaques (Figure, C), and subcutaneous nodules. Lesions typically present on the face, neck, trunk, and extremities and are associated with a favorable prognosis. Lupus pernio presents as centrofacial, bluish-red or violaceous nodules and can be disfiguring (Figure, B). Subcutaneous nodules occur in the subcutaneous tissue or deep dermis with minimal surface changes. Sarcoidal lesions also can occur at sites of scar tissue or trauma, within tattoos, and around foreign bodies. Other uncommon sarcoidosis-specific skin lesions include ichthyosiform, hypopigmented, atrophic, ulcerative and mucosal lesions; erythroderma; alopecia; and nail sarcoidosis.¹⁸

CT112003127_Fig_ABC.jpg

When cutaneous sarcoidosis is suspected, the skin serves as an easily accessible organ for biopsy to confirm the diagnosis.¹ Sarcoidosis-specific skin lesions are histologically characterized as sarcoidal granulomas with a classic noncaseating naked appearance comprised of epithelioid histocytes with giant cells amidst a mild lymphocytic inflammatory infiltrate. Nonspecific sarcoidosis skin lesions do not contain characteristic noncaseating granulomas. Erythema nodosum is the most common nonspecific lesion and is associated with a favorable prognosis. Other nonspecific sarcoidosis skin findings include calcinosis cutis, clubbing, and vasculitis.¹⁸

Workup

Due to the systemic nature of sarcoidosis, dermatologists should initiate a comprehensive workup upon diagnosis of cutaneous sarcoidosis, which should include the following: a complete in-depth history, including occupational/environmental exposures; a complete review of systems; a military history, including time of service and location of deployments; physical examination; pulmonary function test; high-resolution chest computed tomography¹⁹; pulmonology referral for additional pulmonary function tests, including diffusion capacity for carbon monoxide and 6-minute walk test; ophthalmology referral for full ophthalmologic examination; initial cardiac screening with electrocardiogram; and a review of symptoms including assessment of heart palpitations. Any abnormalities should prompt cardiology referral for evaluation of cardiac involvement with a workup that may include transthoracic echocardiogram, Holter monitor, cardiac magnetic resonance imaging with gadolinium contrast, or cardiac positron emission tomography/computed tomography; a complete blood cell count; comprehensive metabolic panel; urinalysis, with a 24-hour urine calcium if there is a history of a kidney stone; tuberculin skin test or IFN-γ release assay to rule out tuberculosis on a case-by-case basis; thyroid testing; and 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D screening.¹

Treatment

Cutaneous sarcoidosis is treated with topical or intralesional anti-inflammatory medications, immunomodulators, systemic immunosuppressants, and biologic agents. Management of cutaneous sarcoidosis should be done in an escalating approach guided by treatment response, location on the body, and patient preference. Response to therapy can take upwards of 3 months, and appropriate patient counseling is necessary to manage expectations.²⁰ Most cutaneous sarcoidosis treatments are not approved by the US Food and Drug Administration for this purpose, and off-label use is based on available evidence and expert consensus (eTable).

CT112003127_eTable.jpg

An important consideration for treating sarcoidosis in active-duty servicemembers is the use of immunosuppressants or biologics requiring refrigeration or continuous monitoring. According to Department of Defense retention standards, an active-duty servicemember may be disqualified from future service if their condition persists despite appropriate treatment and impairs their ability to perform required military duties. A medical evaluation board typically is initiated on any servicemember who starts a medication while on active duty that requires frequent monitoring by a medical provider, including immunomodulating and immunosuppressant medications.²¹

Final Thoughts

Military servicemembers put themselves at risk for acute bodily harm during deployment and also expose themselves to occupational hazards that may result in chronic health conditions. The VA’s coverage of new presumptive diagnoses means that veterans will receive extended care for conditions presumptively acquired during military service, including sarcoidosis. Although there are no conclusive data on whether exposure while on deployment overseas causes sarcoidosis, environmental exposures should be considered a potential cause. Patients with confirmed cutaneous sarcoidosis should undergo a complete workup for systemic sarcoidosis and be asked about their history of military service to evaluate for coverage under the PACT Act.

Sarcoidosis is a chronic inflammatory disease characterized by noncaseating granulomas that can affect many organ systems, most commonly the lungs and skin, with cutaneous involvement in 25% to 30% of patients in the United States.¹ The etiology of sarcoidosis largely is unknown and likely is multifactorial; however, specific environmental, infectious, and pharmaceutical triggers may contribute to its pathogenesis. Sarcoidosis secondary to occupational exposures in US Military veterans historically has been discussed and investigated. Still, it was not considered a service-connected disability until the passing of the Promise to Address Comprehensive Toxics (PACT) Act² in 2022. In this article, we review the risk factors and incidence of sarcoidosis in post–9/11 veterans as well as provide recommendations for managing presumptive service-connected sarcoidosis covered under the recently enacted PACT Act.

The PACT Act and Post–9/11 Military Veterans

Veterans of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) have a history of occupational exposures to open-air burn pits, gun smoke, and recurrent high-intensity sandstorms that may cause chronic disease.³ Burn pits, which were used to dispose of solid waste on forward operating bases, released antigenic particulate matter that was detectable on air sampling.^4,5 Increased respiratory disease rates in veterans that were deployed post–9/11 are well documented, but a causal relationship has not been established.⁶ Although burn pits cannot be directly associated with any disease at this time,⁵ veterans with assumed exposures can now receive a Veterans Affairs (VA) Disability Rating for presumptive conditions under the PACT Act.² The major points of this legislation include expanding and extending eligibility for veterans with toxic exposures, providing access to toxic exposure screening for all veterans receiving VA health care, and increasing research related to toxic exposures in US servicemembers. The PACT Act expands health care benefits, making it easier for veterans exposed post–9/11 to receive coverage for 24 new presumptive diagnoses.² Of these diagnoses, several are relevant to the practicing dermatologist. Patients with metastasis of primary cancers to the skin as well as melanoma or sarcoidosis may be eligible for coverage depending on the location and time of service. The Table lists service locations where the VA has determined servicemembers may have been exposed to burn pits or other toxins. Servicemembers with a presumptive diagnosis who served in these locations may be eligible for care under the PACT Act. Sarcoidosis is of particular concern due to its increased incidence and prevalence in military veterans compared to civilian populations. An analysis of more than 13 million veterans who received health care benefits through the Veterans Health Administration in 2019 found an annual incidence of sarcoidosis of 52 cases per 100,000 person-years and an annual prevalence of 141 cases per 100,000 individuals.⁷ In contrast, the United States has a reported annual incidence of sarcoidosis of 4.9 cases per 100,000 person-years and an annual prevalence of 60 cases per 100,000 individuals.⁸ Although the increased rates of sarcoidosis in veterans have been noted for decades, only recently have investigations provided insights into the etiology of sarcoidosis in this population.

CT112003127_Table.jpg

Sarcoidosis and Environmental Factors

Sarcoidosis is a multisystem granulomatous inflammatory disease that can present in any organ system⁹; however, it most commonly affects the lungs, skin, and eyes—all of which are subjected to direct contact with environmental toxins. The cause of sarcoidosis is unknown, but environmental exposures are theorized to play a role.^9,10 It has been hypothesized that exposure to various immunologically active triggers may invoke the granulomatous inflammatory response that characterizes the disease.¹¹ The World Trade Center disaster on 9/11 has provided insight into the potential environmental component of sarcoidosis. Firefighters who spent extensive amounts of time at the World Trade Center site experienced intense exposure to inorganic particulate matter; it was later found that there was a marked increase in the incidence of sarcoidosis or sarcoidosislike granulomatous pulmonary disease in exposed firefighters. It has been speculated that the elevated exposure to potentially antigenic particulates may have induced granulomatous inflammation, resulting in the manifestation of the disease.¹² Other known occupational exposures associated with an increased risk for sarcoidosis or sarcoidosislike illness include mold, silicates, metal dust, and microbial contaminants.¹¹ Servicemembers commonly are exposed to several of these aerosolized toxins, which theoretically could increase their risk for developing sarcoidosis.

Sarcoidosis in the Military

Servicemembers historically have faced unique environmental hazards that may increase their risk for developing sarcoidosis. Studies of naval veterans have shown relationships between occupational location and increased rates of sarcoidosis. Sailors assigned to aircraft carriers with nonskid coatings containing particulate matter such as aluminum, titanium, and silicates had a higher prevalence of sarcoidosis than those stationed on “clean” ships.^13,14 Although no one trigger was identified, the increased rates of sarcoidosis in populations with extensive exposure to toxins raise concern for the possibility of occupationally induced sarcoidosis in post–9/11 veterans.

Environmental exposures during OIF and OEF may be associated with sarcoidosis. A retrospective review of lung biopsy data collected from Department of Defense military treatment facilities was conducted to identify associations between lung disease and deployment to the Middle East.¹⁵ The study included 391 military patients divided into deployed and nondeployed groups undergoing lung biopsies for various reasons from 2005 to 2012. An analysis of the reported lung histology showed an increased frequency of nonnecrotizing granulomas in those with a history of deployment to the Middle East compared to those who had never been deployed. Development of disease was not associated with confounding factors such as age, ethnicity, sex, or tobacco use, raising suspicion about similar shared toxic exposures among deployed servicemembers.¹⁵ A 2020 study of sarcoidosis in active-duty military personnel reported that the incidence of observed cases was 2-times those seen in civilian Department of Defense employees from 2005 to 2010; however, data collected in this study did not indicate an increased risk for developing sarcoidosis based on deployment to the Middle East. Still, the higher prevalence of sarcoidosis in active-duty military personnel suggests similar shared exposures in this group.¹⁶

Identification of exposures that may potentially trigger sarcoidosis is difficult due to many confounding variables; however, the Airborne Hazards and Open Burn Pit Registry questionnaire has been used to extrapolate prospective hazards of concern. Results from the questionnaire identified that only veterans exposed to convoy activity had a statistically significant (odds ratio, 1.16; 95% CI, 1.00-1.35; P=.046) increased risk for developing sarcoidosis.¹⁷ Interestingly, enlisted personnel had a higher rate of sarcoidosis than officers, comprising upwards of 78% of cases in the Military Health System from 2004 to 2013.⁹ This finding requires further study, but increased exposure to toxins due to occupational specialty may be the cause.

Veterans with sarcoidosis may have a unique pathophysiology, which may point to occupational exposure. Studies show that affected veterans have unique plasma metabolites and metal ions compared to civilians, with lower anti-inflammatory amino acid concentrations and downregulated GABA synthesis. The environmental exposures in OIF and OEF may have primed deployed servicemembers to develop a distinct subtype of sarcoidosis.³ Overall, there is a dearth of literature on post–9/11 veterans with sarcoidosis; therefore, further investigation is necessary to determine the actual risk for developing the disease following exposures related to military service.

Cutaneous sarcoidosis protean morphology is considered an imitator of many other skin diseases. The most common sarcoidosis-specific skin lesions include papules and papulonodules (Figure, A), lupus pernio (Figure, B), plaques (Figure, C), and subcutaneous nodules. Lesions typically present on the face, neck, trunk, and extremities and are associated with a favorable prognosis. Lupus pernio presents as centrofacial, bluish-red or violaceous nodules and can be disfiguring (Figure, B). Subcutaneous nodules occur in the subcutaneous tissue or deep dermis with minimal surface changes. Sarcoidal lesions also can occur at sites of scar tissue or trauma, within tattoos, and around foreign bodies. Other uncommon sarcoidosis-specific skin lesions include ichthyosiform, hypopigmented, atrophic, ulcerative and mucosal lesions; erythroderma; alopecia; and nail sarcoidosis.¹⁸

CT112003127_Fig_ABC.jpg

When cutaneous sarcoidosis is suspected, the skin serves as an easily accessible organ for biopsy to confirm the diagnosis.¹ Sarcoidosis-specific skin lesions are histologically characterized as sarcoidal granulomas with a classic noncaseating naked appearance comprised of epithelioid histocytes with giant cells amidst a mild lymphocytic inflammatory infiltrate. Nonspecific sarcoidosis skin lesions do not contain characteristic noncaseating granulomas. Erythema nodosum is the most common nonspecific lesion and is associated with a favorable prognosis. Other nonspecific sarcoidosis skin findings include calcinosis cutis, clubbing, and vasculitis.¹⁸

Workup

Due to the systemic nature of sarcoidosis, dermatologists should initiate a comprehensive workup upon diagnosis of cutaneous sarcoidosis, which should include the following: a complete in-depth history, including occupational/environmental exposures; a complete review of systems; a military history, including time of service and location of deployments; physical examination; pulmonary function test; high-resolution chest computed tomography¹⁹; pulmonology referral for additional pulmonary function tests, including diffusion capacity for carbon monoxide and 6-minute walk test; ophthalmology referral for full ophthalmologic examination; initial cardiac screening with electrocardiogram; and a review of symptoms including assessment of heart palpitations. Any abnormalities should prompt cardiology referral for evaluation of cardiac involvement with a workup that may include transthoracic echocardiogram, Holter monitor, cardiac magnetic resonance imaging with gadolinium contrast, or cardiac positron emission tomography/computed tomography; a complete blood cell count; comprehensive metabolic panel; urinalysis, with a 24-hour urine calcium if there is a history of a kidney stone; tuberculin skin test or IFN-γ release assay to rule out tuberculosis on a case-by-case basis; thyroid testing; and 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D screening.¹

Treatment

Cutaneous sarcoidosis is treated with topical or intralesional anti-inflammatory medications, immunomodulators, systemic immunosuppressants, and biologic agents. Management of cutaneous sarcoidosis should be done in an escalating approach guided by treatment response, location on the body, and patient preference. Response to therapy can take upwards of 3 months, and appropriate patient counseling is necessary to manage expectations.²⁰ Most cutaneous sarcoidosis treatments are not approved by the US Food and Drug Administration for this purpose, and off-label use is based on available evidence and expert consensus (eTable).

CT112003127_eTable.jpg

An important consideration for treating sarcoidosis in active-duty servicemembers is the use of immunosuppressants or biologics requiring refrigeration or continuous monitoring. According to Department of Defense retention standards, an active-duty servicemember may be disqualified from future service if their condition persists despite appropriate treatment and impairs their ability to perform required military duties. A medical evaluation board typically is initiated on any servicemember who starts a medication while on active duty that requires frequent monitoring by a medical provider, including immunomodulating and immunosuppressant medications.²¹

Final Thoughts

Military servicemembers put themselves at risk for acute bodily harm during deployment and also expose themselves to occupational hazards that may result in chronic health conditions. The VA’s coverage of new presumptive diagnoses means that veterans will receive extended care for conditions presumptively acquired during military service, including sarcoidosis. Although there are no conclusive data on whether exposure while on deployment overseas causes sarcoidosis, environmental exposures should be considered a potential cause. Patients with confirmed cutaneous sarcoidosis should undergo a complete workup for systemic sarcoidosis and be asked about their history of military service to evaluate for coverage under the PACT Act.

Sarcoidosis is a chronic inflammatory disease characterized by noncaseating granulomas that can affect many organ systems, most commonly the lungs and skin, with cutaneous involvement in 25% to 30% of patients in the United States.¹ The etiology of sarcoidosis largely is unknown and likely is multifactorial; however, specific environmental, infectious, and pharmaceutical triggers may contribute to its pathogenesis. Sarcoidosis secondary to occupational exposures in US Military veterans historically has been discussed and investigated. Still, it was not considered a service-connected disability until the passing of the Promise to Address Comprehensive Toxics (PACT) Act² in 2022. In this article, we review the risk factors and incidence of sarcoidosis in post–9/11 veterans as well as provide recommendations for managing presumptive service-connected sarcoidosis covered under the recently enacted PACT Act.

The PACT Act and Post–9/11 Military Veterans

Veterans of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) have a history of occupational exposures to open-air burn pits, gun smoke, and recurrent high-intensity sandstorms that may cause chronic disease.³ Burn pits, which were used to dispose of solid waste on forward operating bases, released antigenic particulate matter that was detectable on air sampling.^4,5 Increased respiratory disease rates in veterans that were deployed post–9/11 are well documented, but a causal relationship has not been established.⁶ Although burn pits cannot be directly associated with any disease at this time,⁵ veterans with assumed exposures can now receive a Veterans Affairs (VA) Disability Rating for presumptive conditions under the PACT Act.² The major points of this legislation include expanding and extending eligibility for veterans with toxic exposures, providing access to toxic exposure screening for all veterans receiving VA health care, and increasing research related to toxic exposures in US servicemembers. The PACT Act expands health care benefits, making it easier for veterans exposed post–9/11 to receive coverage for 24 new presumptive diagnoses.² Of these diagnoses, several are relevant to the practicing dermatologist. Patients with metastasis of primary cancers to the skin as well as melanoma or sarcoidosis may be eligible for coverage depending on the location and time of service. The Table lists service locations where the VA has determined servicemembers may have been exposed to burn pits or other toxins. Servicemembers with a presumptive diagnosis who served in these locations may be eligible for care under the PACT Act. Sarcoidosis is of particular concern due to its increased incidence and prevalence in military veterans compared to civilian populations. An analysis of more than 13 million veterans who received health care benefits through the Veterans Health Administration in 2019 found an annual incidence of sarcoidosis of 52 cases per 100,000 person-years and an annual prevalence of 141 cases per 100,000 individuals.⁷ In contrast, the United States has a reported annual incidence of sarcoidosis of 4.9 cases per 100,000 person-years and an annual prevalence of 60 cases per 100,000 individuals.⁸ Although the increased rates of sarcoidosis in veterans have been noted for decades, only recently have investigations provided insights into the etiology of sarcoidosis in this population.

CT112003127_Table.jpg

Sarcoidosis and Environmental Factors

Sarcoidosis is a multisystem granulomatous inflammatory disease that can present in any organ system⁹; however, it most commonly affects the lungs, skin, and eyes—all of which are subjected to direct contact with environmental toxins. The cause of sarcoidosis is unknown, but environmental exposures are theorized to play a role.^9,10 It has been hypothesized that exposure to various immunologically active triggers may invoke the granulomatous inflammatory response that characterizes the disease.¹¹ The World Trade Center disaster on 9/11 has provided insight into the potential environmental component of sarcoidosis. Firefighters who spent extensive amounts of time at the World Trade Center site experienced intense exposure to inorganic particulate matter; it was later found that there was a marked increase in the incidence of sarcoidosis or sarcoidosislike granulomatous pulmonary disease in exposed firefighters. It has been speculated that the elevated exposure to potentially antigenic particulates may have induced granulomatous inflammation, resulting in the manifestation of the disease.¹² Other known occupational exposures associated with an increased risk for sarcoidosis or sarcoidosislike illness include mold, silicates, metal dust, and microbial contaminants.¹¹ Servicemembers commonly are exposed to several of these aerosolized toxins, which theoretically could increase their risk for developing sarcoidosis.

Sarcoidosis in the Military

Servicemembers historically have faced unique environmental hazards that may increase their risk for developing sarcoidosis. Studies of naval veterans have shown relationships between occupational location and increased rates of sarcoidosis. Sailors assigned to aircraft carriers with nonskid coatings containing particulate matter such as aluminum, titanium, and silicates had a higher prevalence of sarcoidosis than those stationed on “clean” ships.^13,14 Although no one trigger was identified, the increased rates of sarcoidosis in populations with extensive exposure to toxins raise concern for the possibility of occupationally induced sarcoidosis in post–9/11 veterans.

Environmental exposures during OIF and OEF may be associated with sarcoidosis. A retrospective review of lung biopsy data collected from Department of Defense military treatment facilities was conducted to identify associations between lung disease and deployment to the Middle East.¹⁵ The study included 391 military patients divided into deployed and nondeployed groups undergoing lung biopsies for various reasons from 2005 to 2012. An analysis of the reported lung histology showed an increased frequency of nonnecrotizing granulomas in those with a history of deployment to the Middle East compared to those who had never been deployed. Development of disease was not associated with confounding factors such as age, ethnicity, sex, or tobacco use, raising suspicion about similar shared toxic exposures among deployed servicemembers.¹⁵ A 2020 study of sarcoidosis in active-duty military personnel reported that the incidence of observed cases was 2-times those seen in civilian Department of Defense employees from 2005 to 2010; however, data collected in this study did not indicate an increased risk for developing sarcoidosis based on deployment to the Middle East. Still, the higher prevalence of sarcoidosis in active-duty military personnel suggests similar shared exposures in this group.¹⁶

Identification of exposures that may potentially trigger sarcoidosis is difficult due to many confounding variables; however, the Airborne Hazards and Open Burn Pit Registry questionnaire has been used to extrapolate prospective hazards of concern. Results from the questionnaire identified that only veterans exposed to convoy activity had a statistically significant (odds ratio, 1.16; 95% CI, 1.00-1.35; P=.046) increased risk for developing sarcoidosis.¹⁷ Interestingly, enlisted personnel had a higher rate of sarcoidosis than officers, comprising upwards of 78% of cases in the Military Health System from 2004 to 2013.⁹ This finding requires further study, but increased exposure to toxins due to occupational specialty may be the cause.

Veterans with sarcoidosis may have a unique pathophysiology, which may point to occupational exposure. Studies show that affected veterans have unique plasma metabolites and metal ions compared to civilians, with lower anti-inflammatory amino acid concentrations and downregulated GABA synthesis. The environmental exposures in OIF and OEF may have primed deployed servicemembers to develop a distinct subtype of sarcoidosis.³ Overall, there is a dearth of literature on post–9/11 veterans with sarcoidosis; therefore, further investigation is necessary to determine the actual risk for developing the disease following exposures related to military service.

Cutaneous sarcoidosis protean morphology is considered an imitator of many other skin diseases. The most common sarcoidosis-specific skin lesions include papules and papulonodules (Figure, A), lupus pernio (Figure, B), plaques (Figure, C), and subcutaneous nodules. Lesions typically present on the face, neck, trunk, and extremities and are associated with a favorable prognosis. Lupus pernio presents as centrofacial, bluish-red or violaceous nodules and can be disfiguring (Figure, B). Subcutaneous nodules occur in the subcutaneous tissue or deep dermis with minimal surface changes. Sarcoidal lesions also can occur at sites of scar tissue or trauma, within tattoos, and around foreign bodies. Other uncommon sarcoidosis-specific skin lesions include ichthyosiform, hypopigmented, atrophic, ulcerative and mucosal lesions; erythroderma; alopecia; and nail sarcoidosis.¹⁸

CT112003127_Fig_ABC.jpg

When cutaneous sarcoidosis is suspected, the skin serves as an easily accessible organ for biopsy to confirm the diagnosis.¹ Sarcoidosis-specific skin lesions are histologically characterized as sarcoidal granulomas with a classic noncaseating naked appearance comprised of epithelioid histocytes with giant cells amidst a mild lymphocytic inflammatory infiltrate. Nonspecific sarcoidosis skin lesions do not contain characteristic noncaseating granulomas. Erythema nodosum is the most common nonspecific lesion and is associated with a favorable prognosis. Other nonspecific sarcoidosis skin findings include calcinosis cutis, clubbing, and vasculitis.¹⁸

Workup

Due to the systemic nature of sarcoidosis, dermatologists should initiate a comprehensive workup upon diagnosis of cutaneous sarcoidosis, which should include the following: a complete in-depth history, including occupational/environmental exposures; a complete review of systems; a military history, including time of service and location of deployments; physical examination; pulmonary function test; high-resolution chest computed tomography¹⁹; pulmonology referral for additional pulmonary function tests, including diffusion capacity for carbon monoxide and 6-minute walk test; ophthalmology referral for full ophthalmologic examination; initial cardiac screening with electrocardiogram; and a review of symptoms including assessment of heart palpitations. Any abnormalities should prompt cardiology referral for evaluation of cardiac involvement with a workup that may include transthoracic echocardiogram, Holter monitor, cardiac magnetic resonance imaging with gadolinium contrast, or cardiac positron emission tomography/computed tomography; a complete blood cell count; comprehensive metabolic panel; urinalysis, with a 24-hour urine calcium if there is a history of a kidney stone; tuberculin skin test or IFN-γ release assay to rule out tuberculosis on a case-by-case basis; thyroid testing; and 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D screening.¹

Treatment

Cutaneous sarcoidosis is treated with topical or intralesional anti-inflammatory medications, immunomodulators, systemic immunosuppressants, and biologic agents. Management of cutaneous sarcoidosis should be done in an escalating approach guided by treatment response, location on the body, and patient preference. Response to therapy can take upwards of 3 months, and appropriate patient counseling is necessary to manage expectations.²⁰ Most cutaneous sarcoidosis treatments are not approved by the US Food and Drug Administration for this purpose, and off-label use is based on available evidence and expert consensus (eTable).

CT112003127_eTable.jpg

An important consideration for treating sarcoidosis in active-duty servicemembers is the use of immunosuppressants or biologics requiring refrigeration or continuous monitoring. According to Department of Defense retention standards, an active-duty servicemember may be disqualified from future service if their condition persists despite appropriate treatment and impairs their ability to perform required military duties. A medical evaluation board typically is initiated on any servicemember who starts a medication while on active duty that requires frequent monitoring by a medical provider, including immunomodulating and immunosuppressant medications.²¹

Final Thoughts

Military servicemembers put themselves at risk for acute bodily harm during deployment and also expose themselves to occupational hazards that may result in chronic health conditions. The VA’s coverage of new presumptive diagnoses means that veterans will receive extended care for conditions presumptively acquired during military service, including sarcoidosis. Although there are no conclusive data on whether exposure while on deployment overseas causes sarcoidosis, environmental exposures should be considered a potential cause. Patients with confirmed cutaneous sarcoidosis should undergo a complete workup for systemic sarcoidosis and be asked about their history of military service to evaluate for coverage under the PACT Act.

The impacts of anthropogenic climate change on human health are numerous and growing. The evidence that climate change is occurring due to the burning of fossil fuels is substantial, with a 2019 report elevating the data supporting anthropogenic climate change to a gold standard 5-sigma level of significance.¹ In the peer-reviewed scientific literature, the consensus that humans are causing climate change is greater than 99%.² Both the American Medical Association and the American College of Physicians have acknowledged the health impacts of climate change and importance for action. They encourage physicians to engage in environmentally sustainable practices and to advocate for effective climate change mitigation strategies.^3,4 A survey of dermatologists also found that 99.3% (n=148) recognize climate change is occurring, and similarly high numbers are concerned about its health impacts.⁵

Notably, the health care industry must grapple not only with the health impacts of climate change but with the fact that the health care sector itself is responsible for a large amount of carbon emissions.⁶ The global health care industry as a whole produces enough carbon emissions to be ranked as the fifth largest emitting nation in the world.⁷ A quarter of these emissions are attributed to the US health care system.^8,9 Climate science has shown we must limit CO₂ emissions to avoid catastrophic climate change, with the sixth assessment report of the United Nations’ Intergovernmental Panel on Climate Change and the Paris Agreement targeting large emission reductions within the next decade.¹⁰ In August 2021, the US Department of Health and Human Services created the Office of Climate Change and Health Equity. Assistant Secretary for Health ADM Rachel L. Levine, MD, has committed to reducing the carbon emissions from the health care sector by 25% in the next decade, in line with scientific consensus regarding necessary changes.¹¹

The dermatologic impacts of climate change are myriad. Rising temperatures, increasing air and water pollution, and stratospheric ozone depletion will lead to expanded geographic ranges of vector-borne diseases, worsening of chronic skin conditions such as atopic dermatitis/eczema and pemphigus, and increasing rates of skin cancer.¹² For instance, warmer temperatures have allowed mosquitoes of the Aedes genus to infest new areas, leading to outbreaks of viral illnesses with cutaneous manifestations such as dengue, chikungunya, and Zika virus in previously nonindigenous regions.¹³ Rising temperatures also have been associated with an expanding geographic range of tick- and sandfly-borne illnesses such as Lyme disease, Rocky Mountain spotted fever, and cutaneous leishmaniasis.^13,14 Additionally, short-term exposure to air pollution from wildfire smoke has been associated with an increased use of health care services by patients with atopic dermatitis.¹⁵ Increased levels of air pollutants also have been found to be associated with psoriasis flares as well as hyperpigmentation and wrinkle formation.^16,17 Skin cancer incidence is predicted to rise due to increased UV radiation exposure secondary to stratospheric ozone depletion.¹⁸

Although the effects of climate change are significant and the magnitude of the climate crisis may feel overwhelming, it is essential to avoid doomerism and focus on meaningful impactful actions. Current CO₂ emissions will remain in the atmosphere for hundreds to thousands of years, and the choices we make now commit future generations to live in a world shaped by our decisions. Importantly, there are impactful and low-cost, cost-effective, or cost-saving changes that can be made to mitigate the climate crisis. Herein, we provide 10 practical actionable interventions for dermatologists to help combat climate change.

10 Interventions for Dermatologists to Combat Climate Change

1. Consider switching to renewable sources of energy. Making this switch often is the most impactful decision a dermatologist can make to address climate change. The electricity sector is the largest source of greenhouse gas emissions in the US health care system, and dermatology outpatient practices in particular have been observed to have a higher peak energy consumption than most other specialties studied.^19,20 Many dermatology practices—both privately owned and academic—can switch to renewable energy seamlessly through power purchase agreements (PPAs), which are contracts between power providers and private entities to install renewable energy equipment or source renewable energy from offsite sources at a fixed rate. Using PPAs instead of traditional fossil fuel energy can provide cost savings as well as protect buyers from electrical price volatility. Numerous health care systems utilize PPAs such as Kaiser Permanente, Cleveland Clinic, and Rochester Regional Health. Additionally, dermatologists can directly purchase renewable energy equipment and eventually receive a return on investment from substantially lowered electric bills. It is important to note that the cost of commercial solar energy systems has decreased 69% since 2010 with further cost reductions predicted.^21,22

2. Reduce standby power consumption. This refers to the use of electricity by a device when it appears to be off or is not in use, which can lead to considerable energy consumption and subsequently a larger carbon footprint for your practice. Ensuring electronics such as phone chargers, light fixtures, television screens, and computers are switched off prior to the end of the workday can make a large difference; for instance, a single radiology department at the University of Maryland (College Park, Maryland) found that if clinical workstations were shut down when not in use after an 8-hour workday, it would save 83,866 kWh of energy and $9225.33 per year.²³ Additionally, using power strips with an automatic shutoff feature to shut off power to devices not in use provides a more convenient way to reduce standby power.

3. Optimize thermostat settings. An analysis of energy consumption in 157,000 US health care facilities found that space heating and cooling accounted for 40% of their total energy consumption.²⁴ Thus, ensuring your thermostat and heating/cooling systems are working efficiently can conserve a substantial amount of energy. For maximum efficiency, it is recommended to set air conditioners to 74 °F (24 °C) and heaters to 68 °F (20 °C) or employ smart thermostats to optimally adjust temperatures when the office is not in use.²⁵ In addition, routinely replacing or cleaning air conditioner filters can lower energy consumption by 5% to 15%.²⁶ Similarly, improving insulation and ruggedization of both homes and offices may reduce heating and cooling waste and limit costs and emissions as a result.

4. Offer bicycle racks and charging ports for electric vehicles. In the United States, transportation generates more greenhouse gas emissions than any other source, primarily due to the burning of fossil fuels to power automobiles, trains, and planes. Because bicycles do not consume any fossil fuels and the use of electric vehicles has been found to result in substantial air pollution health benefits, encouraging the use of both can make a considerable positive impact on our climate.²⁷ Providing these resources not only allows those who already travel sustainably to continue to do so but also serves as a reminder to your patients that sustainability is important to you as their health care provider. As electric vehicle sales continue to climb, infrastructure to support their use, including charging stations, will grow in importance. A physician’s office that offers a car-charging station may soon have a competitive advantage over others in the area.

5. Ensure properly regulated medical waste management. Regulated medical waste (also known as infectious medical waste or red bag waste) refers to health care–generated waste unsuitable for disposal in municipal solid waste systems due to concern for the spread of infectious or pathogenic materials. This waste largely is disposed via incineration, which harms the environment in a multitude of ways—both through harmful byproducts and from the CO₂ emissions required to ship the waste to special processing facilities.²⁸ Incineration of regulated medical waste emits potent toxins such as dioxins and furans as well as particulate matter, which contribute to air pollution. Ensuring only materials with infectious potential (as defined by each state’s Environmental Protection Agency) are disposed in regulated medical waste containers can dramatically reduce the harmful effects of incineration. Additionally, limiting regulated medical waste can be very cost-effective, as its disposal is 5- to 10-times more expensive than that of unregulated medical waste.²⁹ Simple nudge measures such as educating staff about what waste goes in which receptacle, placing signage over the red bag waste to prompt staff to pause to consider if use of that bin is required before utilizing, using weights or clasps to make opening red bag waste containers slightly harder, and positioning different trash receptacles in different parts of examination rooms may help reduce inappropriate use of red bag waste.

6. Consider virtual platforms when possible. Due to the COVID-19 pandemic, virtual meeting platforms saw a considerable increase in usage by dermatologists. Teledermatology for patient care became much more widely adopted, and traditionally in-person meetings turned virtual.³⁰ The reduction in emissions from these changes was remarkable. A recent study looking at the environmental impact of 3 months of teledermatology visits early during the COVID-19 pandemic found that 1476 teledermatology appointments saved 55,737 miles of car travel, equivalent to 15.37 metric tons of CO₂.³¹ Whether for patient care when appropriate, academic conferences and continuing medical education credit, or for interviews (eg, medical students, residents, other staff), use of virtual platforms can reduce unnecessary travel and therefore substantially reduce travel-related emissions. When travel is unavoidable, consider exploring validated vetted companies that offer carbon offsets to reduce the harmful environmental impact of high-emission flights.

7. Limit use of single-use disposable items. Although single-use items such as examination gloves or needles are necessary in a dermatology practice, there are many opportunities to incorporate reusable items in your workplace. For instance, you can replace plastic cutlery and single-use plates in kitchen or dining areas with reusable alternatives. Additionally, using reusable isolation gowns instead of their single-use counterparts can help reduce waste; a reusable isolation gown system for providers including laundering services was found to consume 28% less energy and emit 30% fewer greenhouse gases than a single-use isolation gown system.³² Similarly, opting for reusable instruments instead of single-use instruments when possible also can help reduce your practice’s carbon footprint. Carefully evaluating each part of your “dermatology visit supply chain” may offer opportunities to utilize additional cost-saving, environmentally friendly options; for example, an individually plastic-wrapped Dermablade vs a bulk-packaged blade for shave biopsies has a higher cost and worse environmental impact. A single gauze often is sufficient for shave biopsies, but many practices open a plastic container of bulk gauze, much of which results in waste that too often is inappropriately disposed of as regulated medical waste despite not being saturated in blood/body fluids.

8. Educate on the effects of climate change. Dermatologists and other physicians have the unique opportunity to teach members of their community every day through patient care. Physicians are trusted messengers, and appropriately counseling patients regarding the risks of climate change and its effects on their dermatologic health is in line with both American Medical Association and American College of Physicians guidelines.^3,4 For instance, patients with Lyme disease in Canada or Maine were unheard of a few decades ago, but now they are common; flares of atopic dermatitis in regions adjacent to recent wildfires may be attributable to harmful particulate matter resulting from fossil-fueled climate change and record droughts. Educating medical trainees on the impacts of climate change is just as vital, as it is a topic that often is neglected in medical school and residency curricula.³³

9. Install water-efficient toilets and faucets. Anthropogenic climate change has been shown to increase the duration and intensity of droughts throughout the world.³⁴ Much of the western United States also is experiencing record droughts. One way in which dermatology practices can work to combat droughts is through the use of water-conserving toilets, faucets, and urinals. Using water fixtures with the US Environmental Protection Agency’s WaterSense label is a convenient way to do so. The WaterSense label helps identify water fixtures certified to use at least 20% less water as well as save energy and decrease water costs.

10. Advocate through local and national organizations. There are numerous ways in which dermatologists can advocate for action against climate change. Joining professional organizations focused on addressing the climate crisis can help you connect with fellow dermatologists and physicians. The Expert Resource Group on Climate Change and Environmental Issues affiliated with the American Academy of Dermatology (AAD) is one such organization with many opportunities to raise awareness within the field of dermatology. The AAD recently joined the Medical Society Consortium on Climate and Health, an organization providing opportunities for policy and media outreach as well as research on climate change. Advocacy also can mean joining your local chapter of Physicians for Social Responsibility or encouraging divestment from fossil fuel companies within your institution. Voicing support for climate change–focused lectures at events such as grand rounds and society meetings at the local, regional, and state-wide levels can help raise awareness. As the dermatologic effects of climate change grow, being knowledgeable of the views of future leaders in our specialty and country on this issue will become increasingly important.

Final Thoughts

In addition to the climate-friendly decisions one can make as a dermatologist, there are many personal lifestyle choices to consider. Small dietary changes such as limiting consumption of beef and minimizing food waste can have large downstream effects. Opting for transportation via train and limiting air travel are both impactful decisions in reducing CO₂ emissions. Similarly, switching to an electric vehicle or vehicle with minimal emissions can work to reduce greenhouse gas accumulation. For additional resources, note the AAD has partnered with My Green Doctor, a nonprofit service for health care practices that includes practical cost-saving suggestions to support sustainability in physician practices.

A recent joint publication in more than 200 medical journals described climate change as the greatest threat to global public health.³⁵ Climate change is having devastating effects on dermatologic health and will only continue to do so if not addressed now. Dermatologists have the opportunity to join with our colleagues in the house of medicine and to take action to fight climate change and mitigate the health impacts on our patients, the population, and future generations.

The impacts of anthropogenic climate change on human health are numerous and growing. The evidence that climate change is occurring due to the burning of fossil fuels is substantial, with a 2019 report elevating the data supporting anthropogenic climate change to a gold standard 5-sigma level of significance.¹ In the peer-reviewed scientific literature, the consensus that humans are causing climate change is greater than 99%.² Both the American Medical Association and the American College of Physicians have acknowledged the health impacts of climate change and importance for action. They encourage physicians to engage in environmentally sustainable practices and to advocate for effective climate change mitigation strategies.^3,4 A survey of dermatologists also found that 99.3% (n=148) recognize climate change is occurring, and similarly high numbers are concerned about its health impacts.⁵

Notably, the health care industry must grapple not only with the health impacts of climate change but with the fact that the health care sector itself is responsible for a large amount of carbon emissions.⁶ The global health care industry as a whole produces enough carbon emissions to be ranked as the fifth largest emitting nation in the world.⁷ A quarter of these emissions are attributed to the US health care system.^8,9 Climate science has shown we must limit CO₂ emissions to avoid catastrophic climate change, with the sixth assessment report of the United Nations’ Intergovernmental Panel on Climate Change and the Paris Agreement targeting large emission reductions within the next decade.¹⁰ In August 2021, the US Department of Health and Human Services created the Office of Climate Change and Health Equity. Assistant Secretary for Health ADM Rachel L. Levine, MD, has committed to reducing the carbon emissions from the health care sector by 25% in the next decade, in line with scientific consensus regarding necessary changes.¹¹

The dermatologic impacts of climate change are myriad. Rising temperatures, increasing air and water pollution, and stratospheric ozone depletion will lead to expanded geographic ranges of vector-borne diseases, worsening of chronic skin conditions such as atopic dermatitis/eczema and pemphigus, and increasing rates of skin cancer.¹² For instance, warmer temperatures have allowed mosquitoes of the Aedes genus to infest new areas, leading to outbreaks of viral illnesses with cutaneous manifestations such as dengue, chikungunya, and Zika virus in previously nonindigenous regions.¹³ Rising temperatures also have been associated with an expanding geographic range of tick- and sandfly-borne illnesses such as Lyme disease, Rocky Mountain spotted fever, and cutaneous leishmaniasis.^13,14 Additionally, short-term exposure to air pollution from wildfire smoke has been associated with an increased use of health care services by patients with atopic dermatitis.¹⁵ Increased levels of air pollutants also have been found to be associated with psoriasis flares as well as hyperpigmentation and wrinkle formation.^16,17 Skin cancer incidence is predicted to rise due to increased UV radiation exposure secondary to stratospheric ozone depletion.¹⁸

Although the effects of climate change are significant and the magnitude of the climate crisis may feel overwhelming, it is essential to avoid doomerism and focus on meaningful impactful actions. Current CO₂ emissions will remain in the atmosphere for hundreds to thousands of years, and the choices we make now commit future generations to live in a world shaped by our decisions. Importantly, there are impactful and low-cost, cost-effective, or cost-saving changes that can be made to mitigate the climate crisis. Herein, we provide 10 practical actionable interventions for dermatologists to help combat climate change.

10 Interventions for Dermatologists to Combat Climate Change

1. Consider switching to renewable sources of energy. Making this switch often is the most impactful decision a dermatologist can make to address climate change. The electricity sector is the largest source of greenhouse gas emissions in the US health care system, and dermatology outpatient practices in particular have been observed to have a higher peak energy consumption than most other specialties studied.^19,20 Many dermatology practices—both privately owned and academic—can switch to renewable energy seamlessly through power purchase agreements (PPAs), which are contracts between power providers and private entities to install renewable energy equipment or source renewable energy from offsite sources at a fixed rate. Using PPAs instead of traditional fossil fuel energy can provide cost savings as well as protect buyers from electrical price volatility. Numerous health care systems utilize PPAs such as Kaiser Permanente, Cleveland Clinic, and Rochester Regional Health. Additionally, dermatologists can directly purchase renewable energy equipment and eventually receive a return on investment from substantially lowered electric bills. It is important to note that the cost of commercial solar energy systems has decreased 69% since 2010 with further cost reductions predicted.^21,22

2. Reduce standby power consumption. This refers to the use of electricity by a device when it appears to be off or is not in use, which can lead to considerable energy consumption and subsequently a larger carbon footprint for your practice. Ensuring electronics such as phone chargers, light fixtures, television screens, and computers are switched off prior to the end of the workday can make a large difference; for instance, a single radiology department at the University of Maryland (College Park, Maryland) found that if clinical workstations were shut down when not in use after an 8-hour workday, it would save 83,866 kWh of energy and $9225.33 per year.²³ Additionally, using power strips with an automatic shutoff feature to shut off power to devices not in use provides a more convenient way to reduce standby power.

3. Optimize thermostat settings. An analysis of energy consumption in 157,000 US health care facilities found that space heating and cooling accounted for 40% of their total energy consumption.²⁴ Thus, ensuring your thermostat and heating/cooling systems are working efficiently can conserve a substantial amount of energy. For maximum efficiency, it is recommended to set air conditioners to 74 °F (24 °C) and heaters to 68 °F (20 °C) or employ smart thermostats to optimally adjust temperatures when the office is not in use.²⁵ In addition, routinely replacing or cleaning air conditioner filters can lower energy consumption by 5% to 15%.²⁶ Similarly, improving insulation and ruggedization of both homes and offices may reduce heating and cooling waste and limit costs and emissions as a result.

4. Offer bicycle racks and charging ports for electric vehicles. In the United States, transportation generates more greenhouse gas emissions than any other source, primarily due to the burning of fossil fuels to power automobiles, trains, and planes. Because bicycles do not consume any fossil fuels and the use of electric vehicles has been found to result in substantial air pollution health benefits, encouraging the use of both can make a considerable positive impact on our climate.²⁷ Providing these resources not only allows those who already travel sustainably to continue to do so but also serves as a reminder to your patients that sustainability is important to you as their health care provider. As electric vehicle sales continue to climb, infrastructure to support their use, including charging stations, will grow in importance. A physician’s office that offers a car-charging station may soon have a competitive advantage over others in the area.

5. Ensure properly regulated medical waste management. Regulated medical waste (also known as infectious medical waste or red bag waste) refers to health care–generated waste unsuitable for disposal in municipal solid waste systems due to concern for the spread of infectious or pathogenic materials. This waste largely is disposed via incineration, which harms the environment in a multitude of ways—both through harmful byproducts and from the CO₂ emissions required to ship the waste to special processing facilities.²⁸ Incineration of regulated medical waste emits potent toxins such as dioxins and furans as well as particulate matter, which contribute to air pollution. Ensuring only materials with infectious potential (as defined by each state’s Environmental Protection Agency) are disposed in regulated medical waste containers can dramatically reduce the harmful effects of incineration. Additionally, limiting regulated medical waste can be very cost-effective, as its disposal is 5- to 10-times more expensive than that of unregulated medical waste.²⁹ Simple nudge measures such as educating staff about what waste goes in which receptacle, placing signage over the red bag waste to prompt staff to pause to consider if use of that bin is required before utilizing, using weights or clasps to make opening red bag waste containers slightly harder, and positioning different trash receptacles in different parts of examination rooms may help reduce inappropriate use of red bag waste.

6. Consider virtual platforms when possible. Due to the COVID-19 pandemic, virtual meeting platforms saw a considerable increase in usage by dermatologists. Teledermatology for patient care became much more widely adopted, and traditionally in-person meetings turned virtual.³⁰ The reduction in emissions from these changes was remarkable. A recent study looking at the environmental impact of 3 months of teledermatology visits early during the COVID-19 pandemic found that 1476 teledermatology appointments saved 55,737 miles of car travel, equivalent to 15.37 metric tons of CO₂.³¹ Whether for patient care when appropriate, academic conferences and continuing medical education credit, or for interviews (eg, medical students, residents, other staff), use of virtual platforms can reduce unnecessary travel and therefore substantially reduce travel-related emissions. When travel is unavoidable, consider exploring validated vetted companies that offer carbon offsets to reduce the harmful environmental impact of high-emission flights.

7. Limit use of single-use disposable items. Although single-use items such as examination gloves or needles are necessary in a dermatology practice, there are many opportunities to incorporate reusable items in your workplace. For instance, you can replace plastic cutlery and single-use plates in kitchen or dining areas with reusable alternatives. Additionally, using reusable isolation gowns instead of their single-use counterparts can help reduce waste; a reusable isolation gown system for providers including laundering services was found to consume 28% less energy and emit 30% fewer greenhouse gases than a single-use isolation gown system.³² Similarly, opting for reusable instruments instead of single-use instruments when possible also can help reduce your practice’s carbon footprint. Carefully evaluating each part of your “dermatology visit supply chain” may offer opportunities to utilize additional cost-saving, environmentally friendly options; for example, an individually plastic-wrapped Dermablade vs a bulk-packaged blade for shave biopsies has a higher cost and worse environmental impact. A single gauze often is sufficient for shave biopsies, but many practices open a plastic container of bulk gauze, much of which results in waste that too often is inappropriately disposed of as regulated medical waste despite not being saturated in blood/body fluids.

8. Educate on the effects of climate change. Dermatologists and other physicians have the unique opportunity to teach members of their community every day through patient care. Physicians are trusted messengers, and appropriately counseling patients regarding the risks of climate change and its effects on their dermatologic health is in line with both American Medical Association and American College of Physicians guidelines.^3,4 For instance, patients with Lyme disease in Canada or Maine were unheard of a few decades ago, but now they are common; flares of atopic dermatitis in regions adjacent to recent wildfires may be attributable to harmful particulate matter resulting from fossil-fueled climate change and record droughts. Educating medical trainees on the impacts of climate change is just as vital, as it is a topic that often is neglected in medical school and residency curricula.³³

9. Install water-efficient toilets and faucets. Anthropogenic climate change has been shown to increase the duration and intensity of droughts throughout the world.³⁴ Much of the western United States also is experiencing record droughts. One way in which dermatology practices can work to combat droughts is through the use of water-conserving toilets, faucets, and urinals. Using water fixtures with the US Environmental Protection Agency’s WaterSense label is a convenient way to do so. The WaterSense label helps identify water fixtures certified to use at least 20% less water as well as save energy and decrease water costs.

10. Advocate through local and national organizations. There are numerous ways in which dermatologists can advocate for action against climate change. Joining professional organizations focused on addressing the climate crisis can help you connect with fellow dermatologists and physicians. The Expert Resource Group on Climate Change and Environmental Issues affiliated with the American Academy of Dermatology (AAD) is one such organization with many opportunities to raise awareness within the field of dermatology. The AAD recently joined the Medical Society Consortium on Climate and Health, an organization providing opportunities for policy and media outreach as well as research on climate change. Advocacy also can mean joining your local chapter of Physicians for Social Responsibility or encouraging divestment from fossil fuel companies within your institution. Voicing support for climate change–focused lectures at events such as grand rounds and society meetings at the local, regional, and state-wide levels can help raise awareness. As the dermatologic effects of climate change grow, being knowledgeable of the views of future leaders in our specialty and country on this issue will become increasingly important.

Final Thoughts

In addition to the climate-friendly decisions one can make as a dermatologist, there are many personal lifestyle choices to consider. Small dietary changes such as limiting consumption of beef and minimizing food waste can have large downstream effects. Opting for transportation via train and limiting air travel are both impactful decisions in reducing CO₂ emissions. Similarly, switching to an electric vehicle or vehicle with minimal emissions can work to reduce greenhouse gas accumulation. For additional resources, note the AAD has partnered with My Green Doctor, a nonprofit service for health care practices that includes practical cost-saving suggestions to support sustainability in physician practices.

A recent joint publication in more than 200 medical journals described climate change as the greatest threat to global public health.³⁵ Climate change is having devastating effects on dermatologic health and will only continue to do so if not addressed now. Dermatologists have the opportunity to join with our colleagues in the house of medicine and to take action to fight climate change and mitigate the health impacts on our patients, the population, and future generations.

The impacts of anthropogenic climate change on human health are numerous and growing. The evidence that climate change is occurring due to the burning of fossil fuels is substantial, with a 2019 report elevating the data supporting anthropogenic climate change to a gold standard 5-sigma level of significance.¹ In the peer-reviewed scientific literature, the consensus that humans are causing climate change is greater than 99%.² Both the American Medical Association and the American College of Physicians have acknowledged the health impacts of climate change and importance for action. They encourage physicians to engage in environmentally sustainable practices and to advocate for effective climate change mitigation strategies.^3,4 A survey of dermatologists also found that 99.3% (n=148) recognize climate change is occurring, and similarly high numbers are concerned about its health impacts.⁵

Notably, the health care industry must grapple not only with the health impacts of climate change but with the fact that the health care sector itself is responsible for a large amount of carbon emissions.⁶ The global health care industry as a whole produces enough carbon emissions to be ranked as the fifth largest emitting nation in the world.⁷ A quarter of these emissions are attributed to the US health care system.^8,9 Climate science has shown we must limit CO₂ emissions to avoid catastrophic climate change, with the sixth assessment report of the United Nations’ Intergovernmental Panel on Climate Change and the Paris Agreement targeting large emission reductions within the next decade.¹⁰ In August 2021, the US Department of Health and Human Services created the Office of Climate Change and Health Equity. Assistant Secretary for Health ADM Rachel L. Levine, MD, has committed to reducing the carbon emissions from the health care sector by 25% in the next decade, in line with scientific consensus regarding necessary changes.¹¹

The dermatologic impacts of climate change are myriad. Rising temperatures, increasing air and water pollution, and stratospheric ozone depletion will lead to expanded geographic ranges of vector-borne diseases, worsening of chronic skin conditions such as atopic dermatitis/eczema and pemphigus, and increasing rates of skin cancer.¹² For instance, warmer temperatures have allowed mosquitoes of the Aedes genus to infest new areas, leading to outbreaks of viral illnesses with cutaneous manifestations such as dengue, chikungunya, and Zika virus in previously nonindigenous regions.¹³ Rising temperatures also have been associated with an expanding geographic range of tick- and sandfly-borne illnesses such as Lyme disease, Rocky Mountain spotted fever, and cutaneous leishmaniasis.^13,14 Additionally, short-term exposure to air pollution from wildfire smoke has been associated with an increased use of health care services by patients with atopic dermatitis.¹⁵ Increased levels of air pollutants also have been found to be associated with psoriasis flares as well as hyperpigmentation and wrinkle formation.^16,17 Skin cancer incidence is predicted to rise due to increased UV radiation exposure secondary to stratospheric ozone depletion.¹⁸

Although the effects of climate change are significant and the magnitude of the climate crisis may feel overwhelming, it is essential to avoid doomerism and focus on meaningful impactful actions. Current CO₂ emissions will remain in the atmosphere for hundreds to thousands of years, and the choices we make now commit future generations to live in a world shaped by our decisions. Importantly, there are impactful and low-cost, cost-effective, or cost-saving changes that can be made to mitigate the climate crisis. Herein, we provide 10 practical actionable interventions for dermatologists to help combat climate change.

10 Interventions for Dermatologists to Combat Climate Change

1. Consider switching to renewable sources of energy. Making this switch often is the most impactful decision a dermatologist can make to address climate change. The electricity sector is the largest source of greenhouse gas emissions in the US health care system, and dermatology outpatient practices in particular have been observed to have a higher peak energy consumption than most other specialties studied.^19,20 Many dermatology practices—both privately owned and academic—can switch to renewable energy seamlessly through power purchase agreements (PPAs), which are contracts between power providers and private entities to install renewable energy equipment or source renewable energy from offsite sources at a fixed rate. Using PPAs instead of traditional fossil fuel energy can provide cost savings as well as protect buyers from electrical price volatility. Numerous health care systems utilize PPAs such as Kaiser Permanente, Cleveland Clinic, and Rochester Regional Health. Additionally, dermatologists can directly purchase renewable energy equipment and eventually receive a return on investment from substantially lowered electric bills. It is important to note that the cost of commercial solar energy systems has decreased 69% since 2010 with further cost reductions predicted.^21,22

2. Reduce standby power consumption. This refers to the use of electricity by a device when it appears to be off or is not in use, which can lead to considerable energy consumption and subsequently a larger carbon footprint for your practice. Ensuring electronics such as phone chargers, light fixtures, television screens, and computers are switched off prior to the end of the workday can make a large difference; for instance, a single radiology department at the University of Maryland (College Park, Maryland) found that if clinical workstations were shut down when not in use after an 8-hour workday, it would save 83,866 kWh of energy and $9225.33 per year.²³ Additionally, using power strips with an automatic shutoff feature to shut off power to devices not in use provides a more convenient way to reduce standby power.

3. Optimize thermostat settings. An analysis of energy consumption in 157,000 US health care facilities found that space heating and cooling accounted for 40% of their total energy consumption.²⁴ Thus, ensuring your thermostat and heating/cooling systems are working efficiently can conserve a substantial amount of energy. For maximum efficiency, it is recommended to set air conditioners to 74 °F (24 °C) and heaters to 68 °F (20 °C) or employ smart thermostats to optimally adjust temperatures when the office is not in use.²⁵ In addition, routinely replacing or cleaning air conditioner filters can lower energy consumption by 5% to 15%.²⁶ Similarly, improving insulation and ruggedization of both homes and offices may reduce heating and cooling waste and limit costs and emissions as a result.

4. Offer bicycle racks and charging ports for electric vehicles. In the United States, transportation generates more greenhouse gas emissions than any other source, primarily due to the burning of fossil fuels to power automobiles, trains, and planes. Because bicycles do not consume any fossil fuels and the use of electric vehicles has been found to result in substantial air pollution health benefits, encouraging the use of both can make a considerable positive impact on our climate.²⁷ Providing these resources not only allows those who already travel sustainably to continue to do so but also serves as a reminder to your patients that sustainability is important to you as their health care provider. As electric vehicle sales continue to climb, infrastructure to support their use, including charging stations, will grow in importance. A physician’s office that offers a car-charging station may soon have a competitive advantage over others in the area.

5. Ensure properly regulated medical waste management. Regulated medical waste (also known as infectious medical waste or red bag waste) refers to health care–generated waste unsuitable for disposal in municipal solid waste systems due to concern for the spread of infectious or pathogenic materials. This waste largely is disposed via incineration, which harms the environment in a multitude of ways—both through harmful byproducts and from the CO₂ emissions required to ship the waste to special processing facilities.²⁸ Incineration of regulated medical waste emits potent toxins such as dioxins and furans as well as particulate matter, which contribute to air pollution. Ensuring only materials with infectious potential (as defined by each state’s Environmental Protection Agency) are disposed in regulated medical waste containers can dramatically reduce the harmful effects of incineration. Additionally, limiting regulated medical waste can be very cost-effective, as its disposal is 5- to 10-times more expensive than that of unregulated medical waste.²⁹ Simple nudge measures such as educating staff about what waste goes in which receptacle, placing signage over the red bag waste to prompt staff to pause to consider if use of that bin is required before utilizing, using weights or clasps to make opening red bag waste containers slightly harder, and positioning different trash receptacles in different parts of examination rooms may help reduce inappropriate use of red bag waste.

6. Consider virtual platforms when possible. Due to the COVID-19 pandemic, virtual meeting platforms saw a considerable increase in usage by dermatologists. Teledermatology for patient care became much more widely adopted, and traditionally in-person meetings turned virtual.³⁰ The reduction in emissions from these changes was remarkable. A recent study looking at the environmental impact of 3 months of teledermatology visits early during the COVID-19 pandemic found that 1476 teledermatology appointments saved 55,737 miles of car travel, equivalent to 15.37 metric tons of CO₂.³¹ Whether for patient care when appropriate, academic conferences and continuing medical education credit, or for interviews (eg, medical students, residents, other staff), use of virtual platforms can reduce unnecessary travel and therefore substantially reduce travel-related emissions. When travel is unavoidable, consider exploring validated vetted companies that offer carbon offsets to reduce the harmful environmental impact of high-emission flights.

7. Limit use of single-use disposable items. Although single-use items such as examination gloves or needles are necessary in a dermatology practice, there are many opportunities to incorporate reusable items in your workplace. For instance, you can replace plastic cutlery and single-use plates in kitchen or dining areas with reusable alternatives. Additionally, using reusable isolation gowns instead of their single-use counterparts can help reduce waste; a reusable isolation gown system for providers including laundering services was found to consume 28% less energy and emit 30% fewer greenhouse gases than a single-use isolation gown system.³² Similarly, opting for reusable instruments instead of single-use instruments when possible also can help reduce your practice’s carbon footprint. Carefully evaluating each part of your “dermatology visit supply chain” may offer opportunities to utilize additional cost-saving, environmentally friendly options; for example, an individually plastic-wrapped Dermablade vs a bulk-packaged blade for shave biopsies has a higher cost and worse environmental impact. A single gauze often is sufficient for shave biopsies, but many practices open a plastic container of bulk gauze, much of which results in waste that too often is inappropriately disposed of as regulated medical waste despite not being saturated in blood/body fluids.

8. Educate on the effects of climate change. Dermatologists and other physicians have the unique opportunity to teach members of their community every day through patient care. Physicians are trusted messengers, and appropriately counseling patients regarding the risks of climate change and its effects on their dermatologic health is in line with both American Medical Association and American College of Physicians guidelines.^3,4 For instance, patients with Lyme disease in Canada or Maine were unheard of a few decades ago, but now they are common; flares of atopic dermatitis in regions adjacent to recent wildfires may be attributable to harmful particulate matter resulting from fossil-fueled climate change and record droughts. Educating medical trainees on the impacts of climate change is just as vital, as it is a topic that often is neglected in medical school and residency curricula.³³

9. Install water-efficient toilets and faucets. Anthropogenic climate change has been shown to increase the duration and intensity of droughts throughout the world.³⁴ Much of the western United States also is experiencing record droughts. One way in which dermatology practices can work to combat droughts is through the use of water-conserving toilets, faucets, and urinals. Using water fixtures with the US Environmental Protection Agency’s WaterSense label is a convenient way to do so. The WaterSense label helps identify water fixtures certified to use at least 20% less water as well as save energy and decrease water costs.

10. Advocate through local and national organizations. There are numerous ways in which dermatologists can advocate for action against climate change. Joining professional organizations focused on addressing the climate crisis can help you connect with fellow dermatologists and physicians. The Expert Resource Group on Climate Change and Environmental Issues affiliated with the American Academy of Dermatology (AAD) is one such organization with many opportunities to raise awareness within the field of dermatology. The AAD recently joined the Medical Society Consortium on Climate and Health, an organization providing opportunities for policy and media outreach as well as research on climate change. Advocacy also can mean joining your local chapter of Physicians for Social Responsibility or encouraging divestment from fossil fuel companies within your institution. Voicing support for climate change–focused lectures at events such as grand rounds and society meetings at the local, regional, and state-wide levels can help raise awareness. As the dermatologic effects of climate change grow, being knowledgeable of the views of future leaders in our specialty and country on this issue will become increasingly important.

Final Thoughts

In addition to the climate-friendly decisions one can make as a dermatologist, there are many personal lifestyle choices to consider. Small dietary changes such as limiting consumption of beef and minimizing food waste can have large downstream effects. Opting for transportation via train and limiting air travel are both impactful decisions in reducing CO₂ emissions. Similarly, switching to an electric vehicle or vehicle with minimal emissions can work to reduce greenhouse gas accumulation. For additional resources, note the AAD has partnered with My Green Doctor, a nonprofit service for health care practices that includes practical cost-saving suggestions to support sustainability in physician practices.

A recent joint publication in more than 200 medical journals described climate change as the greatest threat to global public health.³⁵ Climate change is having devastating effects on dermatologic health and will only continue to do so if not addressed now. Dermatologists have the opportunity to join with our colleagues in the house of medicine and to take action to fight climate change and mitigate the health impacts on our patients, the population, and future generations.

The recent article on including the impact of climate on health in medical education programs shines an important light on the challenge – and urgent need – of integrating climate change training into medical education. These nascent efforts are just getting underway across the country, with some programs – notably Harvard’s C-CHANGE (Center for Climate, Health, and the Global Environment) program, mentioned in the article, and others, such as the University of Colorado’s Climate Medicine diploma course – leading the way. A number of publications, such as the editorial titled “A planetary health curriculum for medicine” published in 2021 in the BMJ, offer a roadmap to do so.

Rosenbach_Misha_PHILA_web.jpg

Medical schools, residency programs, and other medical specialty programs – including those for advanced practice providers, dentists, nurses, and more – should be incorporating climate change and its myriad of health impacts into their training pathways. The medical student group, Medical Students for a Sustainable Future, has put forth a planetary health report card that evaluates training programs on the strength of their focus on the intersections between climate and health.

While the article did not specifically focus on dermatology, these impacts are true in our field as well. The article notes that “at least one medical journal has recently ramped up its efforts to educate physicians on the links between health issues and climate change.” Notably in dermatology, the International Journal of Women’s Dermatology devoted an entire 124-page themed issue to climate change and dermatology in January, 2021, while JAMA Dermatology editor Kanade Shinkai, MD, PhD, called out climate change as one of the journal’s priorities in her annual editorial, stating, “Another priority for the journal is to better understand the effect of climate change on human health, specifically skin disease.”

The impacts of climate change in dermatology range from heat-related illness (a major cause of climate-associated mortality, with the skin serving as an essential thermoregulatory organ) to changing patterns of vector-borne illnesses to pollution and wildfire smoke flaring inflammatory skin diseases, to an increase in skin cancer, and more. While incorporation of health issues relating to climate change is important at a medical school level, it is also critical at the residency training – and board exam/certification – level as well.

[embed:render:related:node:254524]

Beyond the importance of building climate education into undergraduate and graduate medical education, it is also important that practicing physicians, post-residency training, remain up to date and keep abreast of changing patterns of disease in our rapidly changing climate. Lyme disease now occurs in Canada – and both earlier and later in the year even in places that are geographically used to seeing it. Early recognition is essential, but unprepared physicians may miss the early erythema migrans rash, and patients may suffer more severe sequelae as a result.

Finally, it’s important that medical organizations are aware of not just the health implications of climate change, but also potential policy impacts. Health care is a major emitter of CO₂, and assistant secretary for health for the U.S. Department of Health and Human Services, Admiral Rachel L. Levine, MD, with the National Academy of Medicine, has appropriately pledged to reduce health care carbon emissions as part of the necessary steps that we must all take to avert the worst impacts of a warming world. The field of medicine and individual providers should educate themselves and actively work toward sustainability in health care, to improve the health of their patients, populations, and future generations.


Dr. Rosenbach is associate professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, and is the founder and cochair of the American Academy of Dermatology Expert Resource Group for Climate Change and Environmental Issues. Dr. Rosenbach is speaking on behalf of himself and not the AAD.

The recent article on including the impact of climate on health in medical education programs shines an important light on the challenge – and urgent need – of integrating climate change training into medical education. These nascent efforts are just getting underway across the country, with some programs – notably Harvard’s C-CHANGE (Center for Climate, Health, and the Global Environment) program, mentioned in the article, and others, such as the University of Colorado’s Climate Medicine diploma course – leading the way. A number of publications, such as the editorial titled “A planetary health curriculum for medicine” published in 2021 in the BMJ, offer a roadmap to do so.

Rosenbach_Misha_PHILA_web.jpg

Medical schools, residency programs, and other medical specialty programs – including those for advanced practice providers, dentists, nurses, and more – should be incorporating climate change and its myriad of health impacts into their training pathways. The medical student group, Medical Students for a Sustainable Future, has put forth a planetary health report card that evaluates training programs on the strength of their focus on the intersections between climate and health.

While the article did not specifically focus on dermatology, these impacts are true in our field as well. The article notes that “at least one medical journal has recently ramped up its efforts to educate physicians on the links between health issues and climate change.” Notably in dermatology, the International Journal of Women’s Dermatology devoted an entire 124-page themed issue to climate change and dermatology in January, 2021, while JAMA Dermatology editor Kanade Shinkai, MD, PhD, called out climate change as one of the journal’s priorities in her annual editorial, stating, “Another priority for the journal is to better understand the effect of climate change on human health, specifically skin disease.”

The impacts of climate change in dermatology range from heat-related illness (a major cause of climate-associated mortality, with the skin serving as an essential thermoregulatory organ) to changing patterns of vector-borne illnesses to pollution and wildfire smoke flaring inflammatory skin diseases, to an increase in skin cancer, and more. While incorporation of health issues relating to climate change is important at a medical school level, it is also critical at the residency training – and board exam/certification – level as well.

[embed:render:related:node:254524]

Beyond the importance of building climate education into undergraduate and graduate medical education, it is also important that practicing physicians, post-residency training, remain up to date and keep abreast of changing patterns of disease in our rapidly changing climate. Lyme disease now occurs in Canada – and both earlier and later in the year even in places that are geographically used to seeing it. Early recognition is essential, but unprepared physicians may miss the early erythema migrans rash, and patients may suffer more severe sequelae as a result.

Finally, it’s important that medical organizations are aware of not just the health implications of climate change, but also potential policy impacts. Health care is a major emitter of CO₂, and assistant secretary for health for the U.S. Department of Health and Human Services, Admiral Rachel L. Levine, MD, with the National Academy of Medicine, has appropriately pledged to reduce health care carbon emissions as part of the necessary steps that we must all take to avert the worst impacts of a warming world. The field of medicine and individual providers should educate themselves and actively work toward sustainability in health care, to improve the health of their patients, populations, and future generations.


Dr. Rosenbach is associate professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, and is the founder and cochair of the American Academy of Dermatology Expert Resource Group for Climate Change and Environmental Issues. Dr. Rosenbach is speaking on behalf of himself and not the AAD.

The recent article on including the impact of climate on health in medical education programs shines an important light on the challenge – and urgent need – of integrating climate change training into medical education. These nascent efforts are just getting underway across the country, with some programs – notably Harvard’s C-CHANGE (Center for Climate, Health, and the Global Environment) program, mentioned in the article, and others, such as the University of Colorado’s Climate Medicine diploma course – leading the way. A number of publications, such as the editorial titled “A planetary health curriculum for medicine” published in 2021 in the BMJ, offer a roadmap to do so.

Rosenbach_Misha_PHILA_web.jpg

Medical schools, residency programs, and other medical specialty programs – including those for advanced practice providers, dentists, nurses, and more – should be incorporating climate change and its myriad of health impacts into their training pathways. The medical student group, Medical Students for a Sustainable Future, has put forth a planetary health report card that evaluates training programs on the strength of their focus on the intersections between climate and health.

While the article did not specifically focus on dermatology, these impacts are true in our field as well. The article notes that “at least one medical journal has recently ramped up its efforts to educate physicians on the links between health issues and climate change.” Notably in dermatology, the International Journal of Women’s Dermatology devoted an entire 124-page themed issue to climate change and dermatology in January, 2021, while JAMA Dermatology editor Kanade Shinkai, MD, PhD, called out climate change as one of the journal’s priorities in her annual editorial, stating, “Another priority for the journal is to better understand the effect of climate change on human health, specifically skin disease.”

The impacts of climate change in dermatology range from heat-related illness (a major cause of climate-associated mortality, with the skin serving as an essential thermoregulatory organ) to changing patterns of vector-borne illnesses to pollution and wildfire smoke flaring inflammatory skin diseases, to an increase in skin cancer, and more. While incorporation of health issues relating to climate change is important at a medical school level, it is also critical at the residency training – and board exam/certification – level as well.

[embed:render:related:node:254524]

Beyond the importance of building climate education into undergraduate and graduate medical education, it is also important that practicing physicians, post-residency training, remain up to date and keep abreast of changing patterns of disease in our rapidly changing climate. Lyme disease now occurs in Canada – and both earlier and later in the year even in places that are geographically used to seeing it. Early recognition is essential, but unprepared physicians may miss the early erythema migrans rash, and patients may suffer more severe sequelae as a result.

Finally, it’s important that medical organizations are aware of not just the health implications of climate change, but also potential policy impacts. Health care is a major emitter of CO₂, and assistant secretary for health for the U.S. Department of Health and Human Services, Admiral Rachel L. Levine, MD, with the National Academy of Medicine, has appropriately pledged to reduce health care carbon emissions as part of the necessary steps that we must all take to avert the worst impacts of a warming world. The field of medicine and individual providers should educate themselves and actively work toward sustainability in health care, to improve the health of their patients, populations, and future generations.


Dr. Rosenbach is associate professor of dermatology and medicine at the University of Pennsylvania, Philadelphia, and is the founder and cochair of the American Academy of Dermatology Expert Resource Group for Climate Change and Environmental Issues. Dr. Rosenbach is speaking on behalf of himself and not the AAD.

The virus that causes COVID-19—SARS-CoV-2—has infected more than 128 million individuals, resulting in more than 2.8 million deaths worldwide between December 2019 and April 2021. Disease mortality primarily is driven by hypoxemic respiratory failure and systemic hypercoagulability, resulting in multisystem organ failure.¹ With more than 17 million Americans infected, the virus is estimated to have impacted someone within the social circle of nearly every American.²

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The COVID-19 pandemic has highlighted resource limitations, delayed elective and preventive care, and rapidly increased the adoption of telemedicine, presenting a host of new challenges to providers in every medical specialty, including dermatology. Although COVID-19 primarily is a respiratory disease, clinical manifestations have been observed in nearly every organ, including the skin. The cutaneous manifestations of COVID-19 provide insight into disease diagnosis, prognosis, and pathophysiology. In this article, we review the cutaneous manifestations of COVID-19 and explore the state of knowledge regarding their pathophysiology and clinical significance. Finally, we discuss the role of dermatology consultants in the care of patients with COVID-19, and the impact of the pandemic on the field of dermatology. 

Prevalence of Cutaneous Findings in COVID-19

Early reports characterizing the clinical presentation of patients hospitalized with COVID-19 suggested skin findings associated with the disease were rare. Cohort studies from Europe, China, and New York City in January through March 2020 reported a low prevalence or made no mention of rash.^3-7 However, reports from dermatologists in Italy that emerged in May 2020 indicated a substantially higher proportion of cutaneous disease: 18 of 88 (20.4%) hospitalized patients were found to have cutaneous involvement, primarily consisting of erythematous rash, along with some cases of urticarial and vesicular lesions.⁸ In October 2020, a retrospective cohort study from Spain examining 2761 patients presenting to the emergency department or admitted to the hospital for COVID-19 found that 58 (2.1%) patients had skin lesions attributed to COVID-19.⁹

The wide range in reported prevalence of skin lesions may be due to variable involvement of dermatologic specialists in patient care, particularly in China.¹⁰ Some variation also may be due to variability in the timing of clinical examination, as well as demographic and clinical differences in patient populations. Of note, a multisystem inflammatory disease seen in US children subsequent to infection with COVID-19 has been associated with rash in as many as 74% of cases.¹¹ Although COVID-19 disproportionately impacts people with skin of color, there are few reports of cutaneous manifestations in that population,¹² highlighting the challenges of the dermatologic examination in individuals with darker skin and suggesting the prevalence of dermatologic disease in COVID-19 may be greater than reported. 

Morphologic Patterns of Cutaneous Involvement in COVID-19

Researchers in Europe and the United States have attempted to classify the cutaneous manifestations of COVID-19. A registry established through the American Academy of Dermatology published a compilation of reports from 31 countries, totaling 716 patient profiles.¹³ A prospective Spanish study detailed the cutaneous involvement of 375 patients with suspected or confirmed COVID-19.¹⁴ Together, these efforts have revealed several distinct patterns of cutaneous involvement associated with COVID-19 (Table).^9,15-18 

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Vesicular Rash
Vesicular rash associated with COVID-19 has been described in several studies and case series^8,13,14 and is considered, along with the pseudopernio (or pseudochilblains) morphology, to be one of the more disease-specific patterns in COVID-19.^14,18 Vesicular rash appears to comprise roughly one-tenth of all COVID-19–associated rashes.^13,14 It usually is described as pruritic, with 72% to 83% of patients reporting itch.^13,16 

Small monomorphic or polymorphic vesicles predominantly on the trunk and to a lesser extent the extremities and head have been described by multiple authors.^14,16 Vesicular rash is most common among middle-aged individuals, with studies reporting median and mean ages ranging from 40.5 to 55 years.^9,13,14,16

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Vesicular rash develops concurrent with or after other presenting symptoms of COVID-19; in 2 studies, vesicular rash preceded development of other symptoms in only 15% and 5.6% of cases, respectively.^13,14 Prognostically, vesicular rash is associated with moderate disease severity.^14,16 It may persist for an average of 8 to 10 days.^14,16,18

Histopathologic examination reveals basal layer vacuolar degeneration, hyperchromatic keratinocytes, acantholysis, and dyskeratosis.^9,16,18 

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.^9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.¹⁴ The urticaria, which typically last about 1 week,¹⁴ are seen most frequently in middle-aged patients (mean/median age, 42–48 years)^13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.^13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.¹⁴

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Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.^9,13,14 

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.^9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.^9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.^9,13,14 Onset of morbilliform eruption appears to coincide with¹⁴ or follow^13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.^13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.^9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.¹⁴ A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.²² Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.²³ It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.^9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).¹⁴ The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.^24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.^14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.²⁵

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Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings^9,13,14 and persisted for an average of 12 to 14 days.^13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities⁹ and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.^13,14

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Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.⁹ Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).²⁵ Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.⁹ Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,²⁷ have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.²⁸

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.^13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.¹³ In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.¹⁴

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Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.³¹ This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,¹¹ typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.³¹ Sixty percent³¹ to 74%¹¹ of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.³²

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.³³ Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.³²

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The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.³¹ Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.^11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.³⁴ Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.³⁵

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.^36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3⁺ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.³⁸ This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.³⁶

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease¹⁴ may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome³⁷ and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,³⁹ resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.^14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.^36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.³⁸ Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,¹ both of which are known factors associated with depressed IFN-1 function.^38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.²⁷

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,³⁹ which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,^42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al⁴⁴ found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

 Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.³⁸ It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.¹ In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.⁴⁵

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.^{13,14,29,46-48} In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.^49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,⁵¹ complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.^42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.⁵² In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community. 

Pandemic Dermatology

The pandemic has posed unprecedented challenges for patient care. The use of hydroxychloroquine as a popular but unproven treatment for COVID-19, ⁵³ particularly early in the pandemic, has resulted in drug shortages for patients with lupus and other autoimmune skin diseases. Meanwhile, the need for patients with complex dermatologic conditions to receive systemic immunosuppression has had to be balanced against the associated risks during a global pandemic. To help dermatologists navigate this dilemma, various subspecialty groups have issued guidelines, including the COVID-19 Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists, which recommends a stepwise approach to shared decision-making with the goal of minimizing both the risk for disease flare and that of infection. The use of systemic steroids and rituximab, as well as the dose of immunosuppression—particularly broad-acting immunosuppression—should be limited where permitted. ⁵⁴

Rapid adoption of telemedicine and remote monitoring strategies has enabled dermatologists to provide safe and timely care when in-person visits have not been possible, including for patients with confirmed or suspected COVID-19, as well as for hospitalized patients. ^55-57 Use of telemedicine has facilitated preservation of personal protective equipment at a time when these important resources have been scarce. For patients with transportation or scheduling barriers, telemedicine has even expanded access to care. 

However, this strategy cannot completely replace comprehensive in-person evaluation. Variability in video and photographic quality limits evaluation, while in-person physical examination can reveal subtle morphologic clues necessary for diagnosis. ^{5 8} Additionally, unequal access to technology may disadvantage some patients. For dermatologists to provide optimal care and continue to contribute accurate and insightful observations into COVID-19, it is essential to be physically present in the clinic and in the hospital when necessary, caring for patients in need of dermatologic expertise. Creative management strategies developed during this time will benefit patients and expand the reach of the specialty . ^{5 8}

Final Thoughts

The COVID-19 pandemic has profoundly challenged the medical community and dermatology is no exception. By documenting and characterizing the diverse cutaneous manifestations of this novel disease, dermatologists have furthered understanding of its pathophysiology and management. By adapting quickly and developing creative ways to deliver care, dermatologists have found ways to contribute, both large and small. As we take stock at this juncture of the pandemic, it is clear there remains much to learn. We hope dermatologists will continue to take an active role in meeting the challenges of this time.

The virus that causes COVID-19—SARS-CoV-2—has infected more than 128 million individuals, resulting in more than 2.8 million deaths worldwide between December 2019 and April 2021. Disease mortality primarily is driven by hypoxemic respiratory failure and systemic hypercoagulability, resulting in multisystem organ failure.¹ With more than 17 million Americans infected, the virus is estimated to have impacted someone within the social circle of nearly every American.²

[embed:render:related:node:237479]

The COVID-19 pandemic has highlighted resource limitations, delayed elective and preventive care, and rapidly increased the adoption of telemedicine, presenting a host of new challenges to providers in every medical specialty, including dermatology. Although COVID-19 primarily is a respiratory disease, clinical manifestations have been observed in nearly every organ, including the skin. The cutaneous manifestations of COVID-19 provide insight into disease diagnosis, prognosis, and pathophysiology. In this article, we review the cutaneous manifestations of COVID-19 and explore the state of knowledge regarding their pathophysiology and clinical significance. Finally, we discuss the role of dermatology consultants in the care of patients with COVID-19, and the impact of the pandemic on the field of dermatology. 

Prevalence of Cutaneous Findings in COVID-19

Early reports characterizing the clinical presentation of patients hospitalized with COVID-19 suggested skin findings associated with the disease were rare. Cohort studies from Europe, China, and New York City in January through March 2020 reported a low prevalence or made no mention of rash.^3-7 However, reports from dermatologists in Italy that emerged in May 2020 indicated a substantially higher proportion of cutaneous disease: 18 of 88 (20.4%) hospitalized patients were found to have cutaneous involvement, primarily consisting of erythematous rash, along with some cases of urticarial and vesicular lesions.⁸ In October 2020, a retrospective cohort study from Spain examining 2761 patients presenting to the emergency department or admitted to the hospital for COVID-19 found that 58 (2.1%) patients had skin lesions attributed to COVID-19.⁹

The wide range in reported prevalence of skin lesions may be due to variable involvement of dermatologic specialists in patient care, particularly in China.¹⁰ Some variation also may be due to variability in the timing of clinical examination, as well as demographic and clinical differences in patient populations. Of note, a multisystem inflammatory disease seen in US children subsequent to infection with COVID-19 has been associated with rash in as many as 74% of cases.¹¹ Although COVID-19 disproportionately impacts people with skin of color, there are few reports of cutaneous manifestations in that population,¹² highlighting the challenges of the dermatologic examination in individuals with darker skin and suggesting the prevalence of dermatologic disease in COVID-19 may be greater than reported. 

Morphologic Patterns of Cutaneous Involvement in COVID-19

Researchers in Europe and the United States have attempted to classify the cutaneous manifestations of COVID-19. A registry established through the American Academy of Dermatology published a compilation of reports from 31 countries, totaling 716 patient profiles.¹³ A prospective Spanish study detailed the cutaneous involvement of 375 patients with suspected or confirmed COVID-19.¹⁴ Together, these efforts have revealed several distinct patterns of cutaneous involvement associated with COVID-19 (Table).^9,15-18 

CT107004209_Table.JPG

Vesicular Rash
Vesicular rash associated with COVID-19 has been described in several studies and case series^8,13,14 and is considered, along with the pseudopernio (or pseudochilblains) morphology, to be one of the more disease-specific patterns in COVID-19.^14,18 Vesicular rash appears to comprise roughly one-tenth of all COVID-19–associated rashes.^13,14 It usually is described as pruritic, with 72% to 83% of patients reporting itch.^13,16 

Small monomorphic or polymorphic vesicles predominantly on the trunk and to a lesser extent the extremities and head have been described by multiple authors.^14,16 Vesicular rash is most common among middle-aged individuals, with studies reporting median and mean ages ranging from 40.5 to 55 years.^9,13,14,16

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Vesicular rash develops concurrent with or after other presenting symptoms of COVID-19; in 2 studies, vesicular rash preceded development of other symptoms in only 15% and 5.6% of cases, respectively.^13,14 Prognostically, vesicular rash is associated with moderate disease severity.^14,16 It may persist for an average of 8 to 10 days.^14,16,18

Histopathologic examination reveals basal layer vacuolar degeneration, hyperchromatic keratinocytes, acantholysis, and dyskeratosis.^9,16,18 

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.^9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.¹⁴ The urticaria, which typically last about 1 week,¹⁴ are seen most frequently in middle-aged patients (mean/median age, 42–48 years)^13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.^13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.¹⁴

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Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.^9,13,14 

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.^9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.^9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.^9,13,14 Onset of morbilliform eruption appears to coincide with¹⁴ or follow^13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.^13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.^9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.¹⁴ A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.²² Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.²³ It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.^9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).¹⁴ The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.^24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.^14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.²⁵

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Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings^9,13,14 and persisted for an average of 12 to 14 days.^13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities⁹ and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.^13,14

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Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.⁹ Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).²⁵ Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.⁹ Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,²⁷ have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.²⁸

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.^13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.¹³ In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.¹⁴

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Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.³¹ This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,¹¹ typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.³¹ Sixty percent³¹ to 74%¹¹ of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.³²

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.³³ Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.³²

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The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.³¹ Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.^11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.³⁴ Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.³⁵

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.^36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3⁺ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.³⁸ This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.³⁶

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease¹⁴ may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome³⁷ and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,³⁹ resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.^14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.^36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.³⁸ Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,¹ both of which are known factors associated with depressed IFN-1 function.^38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.²⁷

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,³⁹ which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,^42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al⁴⁴ found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

 Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.³⁸ It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.¹ In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.⁴⁵

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.^{13,14,29,46-48} In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.^49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,⁵¹ complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.^42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.⁵² In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community. 

Pandemic Dermatology

The pandemic has posed unprecedented challenges for patient care. The use of hydroxychloroquine as a popular but unproven treatment for COVID-19, ⁵³ particularly early in the pandemic, has resulted in drug shortages for patients with lupus and other autoimmune skin diseases. Meanwhile, the need for patients with complex dermatologic conditions to receive systemic immunosuppression has had to be balanced against the associated risks during a global pandemic. To help dermatologists navigate this dilemma, various subspecialty groups have issued guidelines, including the COVID-19 Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists, which recommends a stepwise approach to shared decision-making with the goal of minimizing both the risk for disease flare and that of infection. The use of systemic steroids and rituximab, as well as the dose of immunosuppression—particularly broad-acting immunosuppression—should be limited where permitted. ⁵⁴

Rapid adoption of telemedicine and remote monitoring strategies has enabled dermatologists to provide safe and timely care when in-person visits have not been possible, including for patients with confirmed or suspected COVID-19, as well as for hospitalized patients. ^55-57 Use of telemedicine has facilitated preservation of personal protective equipment at a time when these important resources have been scarce. For patients with transportation or scheduling barriers, telemedicine has even expanded access to care. 

However, this strategy cannot completely replace comprehensive in-person evaluation. Variability in video and photographic quality limits evaluation, while in-person physical examination can reveal subtle morphologic clues necessary for diagnosis. ^{5 8} Additionally, unequal access to technology may disadvantage some patients. For dermatologists to provide optimal care and continue to contribute accurate and insightful observations into COVID-19, it is essential to be physically present in the clinic and in the hospital when necessary, caring for patients in need of dermatologic expertise. Creative management strategies developed during this time will benefit patients and expand the reach of the specialty . ^{5 8}

Final Thoughts

The COVID-19 pandemic has profoundly challenged the medical community and dermatology is no exception. By documenting and characterizing the diverse cutaneous manifestations of this novel disease, dermatologists have furthered understanding of its pathophysiology and management. By adapting quickly and developing creative ways to deliver care, dermatologists have found ways to contribute, both large and small. As we take stock at this juncture of the pandemic, it is clear there remains much to learn. We hope dermatologists will continue to take an active role in meeting the challenges of this time.

The virus that causes COVID-19—SARS-CoV-2—has infected more than 128 million individuals, resulting in more than 2.8 million deaths worldwide between December 2019 and April 2021. Disease mortality primarily is driven by hypoxemic respiratory failure and systemic hypercoagulability, resulting in multisystem organ failure.¹ With more than 17 million Americans infected, the virus is estimated to have impacted someone within the social circle of nearly every American.²

[embed:render:related:node:237479]

The COVID-19 pandemic has highlighted resource limitations, delayed elective and preventive care, and rapidly increased the adoption of telemedicine, presenting a host of new challenges to providers in every medical specialty, including dermatology. Although COVID-19 primarily is a respiratory disease, clinical manifestations have been observed in nearly every organ, including the skin. The cutaneous manifestations of COVID-19 provide insight into disease diagnosis, prognosis, and pathophysiology. In this article, we review the cutaneous manifestations of COVID-19 and explore the state of knowledge regarding their pathophysiology and clinical significance. Finally, we discuss the role of dermatology consultants in the care of patients with COVID-19, and the impact of the pandemic on the field of dermatology. 

Prevalence of Cutaneous Findings in COVID-19

Early reports characterizing the clinical presentation of patients hospitalized with COVID-19 suggested skin findings associated with the disease were rare. Cohort studies from Europe, China, and New York City in January through March 2020 reported a low prevalence or made no mention of rash.^3-7 However, reports from dermatologists in Italy that emerged in May 2020 indicated a substantially higher proportion of cutaneous disease: 18 of 88 (20.4%) hospitalized patients were found to have cutaneous involvement, primarily consisting of erythematous rash, along with some cases of urticarial and vesicular lesions.⁸ In October 2020, a retrospective cohort study from Spain examining 2761 patients presenting to the emergency department or admitted to the hospital for COVID-19 found that 58 (2.1%) patients had skin lesions attributed to COVID-19.⁹

The wide range in reported prevalence of skin lesions may be due to variable involvement of dermatologic specialists in patient care, particularly in China.¹⁰ Some variation also may be due to variability in the timing of clinical examination, as well as demographic and clinical differences in patient populations. Of note, a multisystem inflammatory disease seen in US children subsequent to infection with COVID-19 has been associated with rash in as many as 74% of cases.¹¹ Although COVID-19 disproportionately impacts people with skin of color, there are few reports of cutaneous manifestations in that population,¹² highlighting the challenges of the dermatologic examination in individuals with darker skin and suggesting the prevalence of dermatologic disease in COVID-19 may be greater than reported. 

Morphologic Patterns of Cutaneous Involvement in COVID-19

Researchers in Europe and the United States have attempted to classify the cutaneous manifestations of COVID-19. A registry established through the American Academy of Dermatology published a compilation of reports from 31 countries, totaling 716 patient profiles.¹³ A prospective Spanish study detailed the cutaneous involvement of 375 patients with suspected or confirmed COVID-19.¹⁴ Together, these efforts have revealed several distinct patterns of cutaneous involvement associated with COVID-19 (Table).^9,15-18 

CT107004209_Table.JPG

Vesicular Rash
Vesicular rash associated with COVID-19 has been described in several studies and case series^8,13,14 and is considered, along with the pseudopernio (or pseudochilblains) morphology, to be one of the more disease-specific patterns in COVID-19.^14,18 Vesicular rash appears to comprise roughly one-tenth of all COVID-19–associated rashes.^13,14 It usually is described as pruritic, with 72% to 83% of patients reporting itch.^13,16 

Small monomorphic or polymorphic vesicles predominantly on the trunk and to a lesser extent the extremities and head have been described by multiple authors.^14,16 Vesicular rash is most common among middle-aged individuals, with studies reporting median and mean ages ranging from 40.5 to 55 years.^9,13,14,16

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Vesicular rash develops concurrent with or after other presenting symptoms of COVID-19; in 2 studies, vesicular rash preceded development of other symptoms in only 15% and 5.6% of cases, respectively.^13,14 Prognostically, vesicular rash is associated with moderate disease severity.^14,16 It may persist for an average of 8 to 10 days.^14,16,18

Histopathologic examination reveals basal layer vacuolar degeneration, hyperchromatic keratinocytes, acantholysis, and dyskeratosis.^9,16,18 

Urticarial Rash
Urticarial lesions represent approximately 7% to 19% of reported COVID-19–associated rashes.^9,13,14 Urticarial rashes in patients testing positive for SARS-CoV-2 primarily occur on the trunk.¹⁴ The urticaria, which typically last about 1 week,¹⁴ are seen most frequently in middle-aged patients (mean/median age, 42–48 years)^13,14 and are associated with pruritus, which has been reported in 74% to 92% of patients.^13,14 Urticarial lesions typically do not precede other symptoms of COVID-19 and are nonspecific, making them less useful diagnostically.¹⁴

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Urticaria appears to be associated with more severe COVID-19 illness in several studies, but this finding may be confounded by several factors, including older age, increased tobacco use, and polypharmacy. Of 104 patients with reported urticarial rash and suspected or confirmed COVID-19 across 3 studies, only 1 death was reported.^9,13,14 

The histopathologic appearance is that of typical hives, demonstrating a perivascular infiltrate of lymphocytes and eosinophils with edema of the upper dermis.^9,19

Morbilliform Eruption
Morbilliform eruption is a commonly reported morphology associated with COVID-19, accounting for 20% to 47% of rashes.^9,13,14 This categorization may have limited utility from a diagnostic and prognostic perspective, given that morbilliform eruptions are common, nonspecific, and heterogenous and can arise from many causes.^9,13,14 Onset of morbilliform eruption appears to coincide with¹⁴ or follow^13,20,21 the development of other COVID-19–related symptoms, with 5% of patients reporting morbilliform rash as the initial manifestation of infection.^13,14 Morbilliform eruptions have been observed to occur in patients with more severe disease.^9,13,14

Certain morphologic subtypes, such as erythema multiforme–like, erythema elevatum diutinum–like, or pseudovesicular, may be more specific to COVID-19 infection.¹⁴ A small case series highlighted 4 patients with erythema multiforme–like eruptions, 3 of whom also were found to have petechial enanthem occurring after COVID-19 diagnosis; however, the investigators were unable to exclude drug reaction as a potential cause of rash in these patients.²² Another case series of 21 patients with COVID-19 and skin rash described a (primarily) petechial enanthem on the palate in 6 (28.5%) patients.²³ It is unclear to what extent oral enanthem may be underrecognized given that some physicians may be disinclined to remove the masks of known COVID-19–positive patients to examine the oral cavity.

The histologic appearance of morbilliform rash seen in association with COVID-19 has been described as spongiotic with interface dermatitis with perivascular lymphocytic inflammation.^9,21

COVID Toes, Pseudochilblains Rash, Perniolike Rash, and Acral Erythema/Edema
Of all the rashes associated with COVID-19, COVID toes, or pseudochilblains rash, has perhaps attracted the most attention. The characteristic violaceous erythema on the fingers and/or toes may be itchy or painful, presenting similar to idiopathic cases of pernio (Figure 1).¹⁴ The entity has been controversial because of an absence of a clear correlation with a positive SARS-CoV-2 polymerase chain reaction test or antibodies to the virus in a subset of reported cases.^24,25 Onset of the rash late in the disease course, generally after symptom resolution in mild or asymptomatic cases, may explain the absence of viral DNA in the nasopharynx by the time of lesion appearance.^14,26 Seronegative patients may have cleared SARS-CoV-2 infection before humoral immunity could occur via a strong type 1 interferon response.²⁵

Alum_1.JPG

Across 3 studies, perniolike skin lesions constituted 18% to 29% of COVID-19–associated skin findings^9,13,14 and persisted for an average of 12 to 14 days.^13,14 Perniolike lesions portend a favorable outcome; patients with COVID toes rarely present with systemic symptoms or laboratory or imaging abnormalities⁹ and less commonly require hospitalization for severe illness. Perniolike lesions have been reported most frequently in younger patients, with a median or mean age of 32 to 35 years.^13,14

[embed:render:related:node:231153]

Histology demonstrates lichenoid dermatitis with perivascular and periadnexal lymphocytic infiltrates.⁹ Notably, one study observed interface dermatitis of the intraepidermal portion of the acrosyringium, a rare finding in chilblain lupus, in 83% of patients (N=40).²⁵ Direct immunofluorescence demonstrates a vasculopathic pattern, with some patients showing deposition of IgM or IgG, C3, and fibrinogen in dermal blood vessels. Vascular C9 deposits also have been demonstrated on immunohistochemistry.⁹ Biopsies of perniolike lesions in COVID-19 patients have demonstrated the presence of SARS-CoV-2 RNA,²⁷ have identified SARS-CoV-2 spike protein in endothelial cells on immunohistochemistry, and have visualized intracytoplasmic viral particles in vascular endothelium on electron microscopy.²⁸

Livedoid Rash/Retiform Purpura
Netlike purpuric or violaceous patches signifying vessel damage or occlusion have been seen in association with COVID-19, constituting approximately 6% of COVID-19–associated skin findings in 2 studies.^13,14 Livedoid rash (Figure 2) and retiform purpura (Figure 3) are associated with older age and occur primarily in severely ill patients, including those requiring intensive care. In a registry of 716 patients with COVID-19, 100% of patients with retiform purpura were hospitalized, and 82% had acute respiratory distress syndrome.¹³ In another study, 33% (7/21) of patients with livedoid and necrotic lesions required intensive care, and 10% (2/21) died.¹⁴

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Multisystem Inflammatory Disease in Children

A hyperinflammatory syndrome similar to Kawasaki disease and toxic shock syndrome associated with mucocutaneous, cardiac, and gastrointestinal manifestations has been reported following COVID-19 infection.³¹ This syndrome, known as multisystem inflammatory syndrome in children (MIS-C), predominantly affects adolescents and children older than 5 years,¹¹ typically occurs 2 to 4 weeks after infection, and appears to be at least 100-times less common than COVID-19 infection among the same age group.³¹ Sixty percent³¹ to 74%¹¹ of affected patients have mucocutaneous involvement, with the most common clinical findings being conjunctival injection, palmoplantar erythema, lip hyperemia, periorbital erythema and edema, strawberry tongue, and malar erythema, respectively.³²

Because this condition appears to reflect an immune response to the virus, the majority of cases demonstrate negative SARS-CoV-2 polymerase chain reaction and positive antibody testing.³³ Although cutaneous findings are similar to those seen in Kawasaki disease, certain findings have been noted in MIS-C that are not typical of Kawasaki disease, including heliotrope rash–like periorbital edema and erythema as well as erythema infectiosum–like malar erythema and reticulated erythematous eruptions.³²

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The course of MIS-C can be severe; in one case series of patients presenting with MIS-C, 80% (79/99) required intensive care unit admission, with 10% requiring mechanical ventilation and 2% of patients dying during admission.³¹ Cardiac dysfunction, coagulopathy, and gastrointestinal symptoms are common.^11,31 It has been postulated that a superantigenlike region of the SARS-CoV-2 spike protein, similar to that of staphylococcal enterotoxin B, may underlie MIS-C and account for its similarities to toxic shock syndrome.³⁴ Of note, a similar multisystem inflammatory syndrome associated with COVID-19 also has been described in adults, and it too may present with rash as a cardinal feature.³⁵

Pathophysiology of COVID-19: What the Skin May Reveal About the Disease

The diverse range of cutaneous manifestations in COVID-19 reflects a spectrum of host immunologicresponses to SARS-CoV-2 and may inform the pathophysiology of the disease as well as potential treatment modalities.

Host Response to SARS-CoV-2
The body’s response to viral infection is 2-pronged, involving activation of cellular antiviral defenses mediated by type I and III interferons, as well as recruitment of leukocytes, mobilized by cytokines and chemokines.^36,37 Infection with SARS-CoV-2 results in a unique inflammatory response characterized by suppression of interferons, juxtaposed with a rampant proinflammatory cytokine and chemokine response, reminiscent of a cytokine storm. Reflective of this imbalance, a study of 50 COVID-19 patients and 20 healthy controls found decreased natural killer cells and CD3⁺ T cells in COVID-19 patients, particularly severely or critically ill patients, with an increase in B cells and monocytes.³⁸ This distinctive immune imbalance positions SARS-CoV-2 to thrive in the absence of inhibitory interferon activity while submitting the host to the deleterious effects of a cytokine surge.³⁶

Type I Interferons
The perniolike lesions associated with mild COVID-19 disease¹⁴ may represent a robust immune response via effective stimulation of type I interferons (IFN-1). Similar perniolike lesions are observed in Aicardi-Goutières syndrome³⁷ and familial chilblain lupus, hereditary interferonopathies associated with mutations in the TREX1 (three prime repair exonuclease 1) gene and characterized by inappropriate upregulation of IFN-1,³⁹ resulting in chilblains. It has been suggested that perniolike lesions in COVID-19 result from IFN-1 activation—a robust effective immunologic response to the virus.^14,26,40

On the other end of the spectrum, patients with severe COVID-19 may have a blunted IFN-1 response and reduced IFN-1–stimulated gene expression.^36,38 Notably, low IFN-1 response preceded clinical deterioration and was associated with increased risk for evolution to critical illness.³⁸ Severe disease from COVID-19 also is more commonly observed in older patients and those with comorbidities,¹ both of which are known factors associated with depressed IFN-1 function.^38,41 Reflective of this disparate IFN-1 response, biopsies of COVID-19 perniosis have demonstrated striking expression of myxovirus resistance protein A (MXA), a marker for IFN-1 signaling in tissue, whereas its expression is absent in COVID-19 livedo/retiform purpura.²⁷

Familial chilblain lupus may be effectively treated by the Janus kinase inhibitor baricitinib,³⁹ which inhibits IFN-1 signaling. Baricitinib recently received emergency use authorization by the US Food and Drug Administration for treatment of severe COVID-19 pneumonia,^42,43 hinting to disordered IFN-1 signaling in the COVID-19 pathophysiology.

The impaired IFN-1 response in COVID-19 patients may be due to a unique characteristic of SARS-CoV-2: its ORF3b gene is a potent IFN-1 antagonist. In a series of experiments comparing SARS-CoV-2 to the related virus severe acute respiratory disease coronavirus (which was responsible for an epidemic in 2002), Konno et al⁴⁴ found that SARS-CoV-2 is more effectively able to downregulate host IFN-1, likely due to premature stop codons on ORF3b that produce a truncated version of the gene with amplified anti–IFN-1 activity.

 Cytokine Storm and Coagulation Cascade
This dulled interferon response is juxtaposed with a surge of inflammatory chemokines and cytokines, including IL-6, IL-8, IL-10, and tumor necrosis factor α, impairing innate immunity and leading to end-organ damage. This inflammatory response is associated with the influx of innate immune cells, specifically neutrophils and monocytes, which likely contribute to lung injury in COVID-19 acute respiratory distress syndrome.³⁸ It also is thought to lead to downstream activation of coagulation, with a high incidence of thrombotic events observed in patients with severe COVID-19.¹ In a retrospective study of 184 intensive care patients with COVID-19 receiving at least standard doses of thromboprophylaxis, venous thromboembolism occurred in 27% and arterial thrombotic events occurred in 3.7%.⁴⁵

Livedo racemosa and retiform purpura are cutaneous markers of hypercoagulability, which indicate an increased risk for systemic clotting in COVID-19. A positive feedback loop between the complement and coagulation cascades appears to be important.^{13,14,29,46-48} In addition, a few studies have reported antiphospholipid antibody positivity in hospitalized COVID-19 patients.^49,50

The high incidence of coagulopathy in severe COVID-19 has prompted many institutions to develop aggressive prophylactic anticoagulation protocols. Elevation of proinflammatory cytokines and observation of terminal complement activation in the skin and other organs has led to therapeutic trials of IL-6 inhibitors such as tocilizumab,⁵¹ complement inhibitors such as eculizumab, and Janus kinase inhibitors such as ruxolitinib and baricitinib.^42,48

COVID Long-Haulers
The long-term effects of immune dysregulation in COVID-19 patients remain to be seen. Viral triggering of autoimmune disease is a well-established phenomenon, seen in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and other dermatologic diseases, raising the possibility that dermatologists will see a rising incidence of cutaneous autoimmune disease in the aftermath of the pandemic. Disordered interferon stimulation could lead to increased incidence of interferon-mediated disorders, such as sarcoidosis and other granulomatous diseases. Vasculitislike skin lesions could persist beyond the acute infectious period. Recent data from a registry of 990 COVID-19 cases from 39 countries suggest that COVID-19 perniolike lesions may persist as long as 150 days.⁵² In a time of many unknowns, these questions serve as a call to action for rigorous data collection, contribution to existing registries for dermatologic manifestations of COVID-19, and long-term follow-up of COVID-19 patients by the dermatology community. 

Pandemic Dermatology

The pandemic has posed unprecedented challenges for patient care. The use of hydroxychloroquine as a popular but unproven treatment for COVID-19, ⁵³ particularly early in the pandemic, has resulted in drug shortages for patients with lupus and other autoimmune skin diseases. Meanwhile, the need for patients with complex dermatologic conditions to receive systemic immunosuppression has had to be balanced against the associated risks during a global pandemic. To help dermatologists navigate this dilemma, various subspecialty groups have issued guidelines, including the COVID-19 Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists, which recommends a stepwise approach to shared decision-making with the goal of minimizing both the risk for disease flare and that of infection. The use of systemic steroids and rituximab, as well as the dose of immunosuppression—particularly broad-acting immunosuppression—should be limited where permitted. ⁵⁴

Rapid adoption of telemedicine and remote monitoring strategies has enabled dermatologists to provide safe and timely care when in-person visits have not been possible, including for patients with confirmed or suspected COVID-19, as well as for hospitalized patients. ^55-57 Use of telemedicine has facilitated preservation of personal protective equipment at a time when these important resources have been scarce. For patients with transportation or scheduling barriers, telemedicine has even expanded access to care. 

However, this strategy cannot completely replace comprehensive in-person evaluation. Variability in video and photographic quality limits evaluation, while in-person physical examination can reveal subtle morphologic clues necessary for diagnosis. ^{5 8} Additionally, unequal access to technology may disadvantage some patients. For dermatologists to provide optimal care and continue to contribute accurate and insightful observations into COVID-19, it is essential to be physically present in the clinic and in the hospital when necessary, caring for patients in need of dermatologic expertise. Creative management strategies developed during this time will benefit patients and expand the reach of the specialty . ^{5 8}

Final Thoughts

The COVID-19 pandemic has profoundly challenged the medical community and dermatology is no exception. By documenting and characterizing the diverse cutaneous manifestations of this novel disease, dermatologists have furthered understanding of its pathophysiology and management. By adapting quickly and developing creative ways to deliver care, dermatologists have found ways to contribute, both large and small. As we take stock at this juncture of the pandemic, it is clear there remains much to learn. We hope dermatologists will continue to take an active role in meeting the challenges of this time.

Granuloma annulare (GA) is a granulomatous skin disorder of uncertain etiology. A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. Histologically, GA exhibits granulomatous inflammation with either interstitial or palisading lymphocytes and histiocytes with mucin deposition.

Few data exist regarding the epidemiology of GA. Although the pathogenesis of GA is unknown, associations between GA and underlying systemic processes, such as diabetes mellitus, hyperlipidemia, thyroid disease, and human immunodeficiency virus (HIV), have been suggested.

[embed:render:related:node:110198]

The purpose of this retrospective study was to determine the number of cases of GA seen annually at the Department of Dermatology at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. Additionally, we reviewed all cases of biopsy-proven GA from 2010 to 2014 and reported the demographics, underlying medical comorbidities, medications, treatments, and outcomes seen in this patient population.

Methods

We identified the number of outpatients presenting with GA annually using PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs). We queried the EMR database to determine the number of discrete patients seen at the Department of Dermatology at the University of Pennsylvania annually from 2008 (the year the EMR was established) to 2014. We then used PennSeek to determine the number of patients given a diagnosis of GA annually from 2008 to 2014 based on the International Classification of Diseases, Ninth Revision (ICD-9).

[embed:render:related:node:68089]

After using PennSeek to identify all patients given the ICD-9 diagnosis of GA from 2008 to 2014, we reviewed the EMRs of these patients to identify cases that were biopsy proven. For the biopsy-proven cases of GA seen at the University of Pennsylvania from 2010 to 2014, we reviewed the EMRs of these patients for clinical characteristics and treatment outcomes. For each case, we recorded the patient’s age, sex, medical comorbidities, GA subtype, and medications.

This study was approved by the University of Pennsylvania’s institutional review board.

Results

On average, the percentage of patients given a diagnosis of GA annually was 0.22% (95% CI, 0.19%-0.24%). A Pearson χ² test was used to determine if any single annual percentage was significantly different from the others. We found a P value of .321, which suggests that the percentage of patients with GA seen annually has been stable from 2008 to 2014 (Figure).

Rubin1.JPG

There were 133 cases of biopsy-proven GA that were reviewed for clinical characteristics; of them, 86.5% were female. Thyroid disease was noted in 30.1% of patients, hyperlipidemia in 30.1%, and hematologic malignancies in 3.8%. Type 1 diabetes mellitus was noted in 1.5% of patients. None of the patients were HIV-positive, 1.5% were hepatitis B–positive, and 2.3% were hepatitis C–positive. Of the 133 cases, 64.7% had localized GA and 30.8% had generalized GA. Photosensitive and papular GA were rarer (1.5% and 2.3% of cases, respectively). Use of a selective serotonin reuptake inhibitor (SSRI) was noted in 18.1% of patients; use of a calcium channel blocker was noted in 9.0% (Table 1).

CT103002102_Table1.JPG

CT103002102_Table2.JPG

Comment

We attempted to determine the period of prevalence of GA in a tertiary care, university-based referral practice and evaluate disease associations, treatments, and outcomes of patients with biopsy-proven GA. Our calculated period prevalence of GA of 0.22% to 0.27% is consistent with another review, which reported that 0.1% to 0.4% of new patients presenting to a dermatology practice were given a diagnosis of GA.¹ More than 85% of the cases we reviewed were seen in females, a finding that is more heavily skewed compared to prior reports that have suggested a female to male ratio of approximately 1:1 to 2:1.^1-7 Our findings suggest that GA is a female-predominant condition, or women may be more likely to seek evaluation for the condition.

[embed:render:related:node:192305]

More than 95% of the cases we reviewed were localized (64.7%) or generalized (30.8%) GA, making these variants the most common forms of GA, which is consistent with prior reports.^1-3,8,9 Other varieties of GA—drug induced, patch, perforating, photosensitive, palmar, and papular—appear rare. Because this study was conducted at an adult hospital, subcutaneous GA, which often is seen in children, may be underrepresented. As a retrospective chart review, it is possible that documentation is insufficient to capture each rare variant.

[embed:render:related:node:67308]

At 1.5%, the prevalence of type 1 diabetes mellitus in our patients is slightly higher than the national average of 0.3%.²⁵ However, based on a Fisher exact test of analysis of proportions, this difference is not statistically significant (P=.106).

At 1.5% and 2.3%, the prevalence of hepatitis B and hepatitis C, respectively, in our patients is slightly higher than the national average of 0.5% and 1%, respectively.²⁶ However, based on a Fisher exact test of analysis of proportions, these differences are not statistically significant (P=.142 and P=.146, respectively).

Given the high prevalence of hyperlipidemia in the United States (31.7%), this disease is not overrepresented in our sample (30.1%), though others have suggested there may be a connection.^27,28 Based on a Fisher exact test, this difference of proportions is not statistically significant (P=.780).

Selective serotonin reuptake inhibitor use is common in the United States; approximately 11% of Americans older than 12 years use an SSRI.²⁹ At 18.1%, the use of SSRIs in our patient group was statistically significantly higher than the national average (Fisher exact test, P=.017), suggesting a possible association between SSRI use and development of GA, warranting further investigation.

The use of calcium channel blockers, interferon, and tumor necrosis factor inhibitors was not significantly associated with GA in our series.

GA Therapy
The most commonly used treatments for GA in our study were topical steroids and intralesional triamcinolone, followed by hydroxychloroquine; all treatments employed exhibited a widely variable response. Assessing treatment response via retrospective chart review is challenging and response rates may not be accurately captured.

Study Limitations
Our study had several limitations. In calculating the period prevalence of GA, our query was limited by the number of years that the EMR has been in place. The number of cases we reviewed for clinical characteristics was limited to 133, as many cases with the ICD-9 diagnosis of GA were not biopsy proven and therefore were not included in our review. Many of the cases we reviewed were lost to follow-up, which prevented us from determining treatment outcomes.

[embed:render:related:node:192472]

Another weakness of our study was that our query did not provide an estimate of incidence or prevalence of GA overall, as this analysis was not a population-based study. The power of our study was limited by the number of cases of GA seen annually and the number of patients lost to follow-up. Additionally, our study population may only be generalizable to other large academic centers.

Conclusion

This study further solidifies our understanding of the epidemiology of GA and diseases that can be associated with GA. We identified a higher female to male ratio than previous reports, and consistent with prior reports, we noted potential associations with conditions such as thyroid disease and hyperlipidemia. Our population demonstrated higher rates of SSRI use than expected, warranting further investigation. Dermatologists should be aware of potential disease associations with GA, but as a whole we need better data and larger studies to determine the appropriate evaluation and treatment for patients with GA.

Granuloma annulare (GA) is a granulomatous skin disorder of uncertain etiology. A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. Histologically, GA exhibits granulomatous inflammation with either interstitial or palisading lymphocytes and histiocytes with mucin deposition.

Few data exist regarding the epidemiology of GA. Although the pathogenesis of GA is unknown, associations between GA and underlying systemic processes, such as diabetes mellitus, hyperlipidemia, thyroid disease, and human immunodeficiency virus (HIV), have been suggested.

[embed:render:related:node:110198]

The purpose of this retrospective study was to determine the number of cases of GA seen annually at the Department of Dermatology at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. Additionally, we reviewed all cases of biopsy-proven GA from 2010 to 2014 and reported the demographics, underlying medical comorbidities, medications, treatments, and outcomes seen in this patient population.

Methods

We identified the number of outpatients presenting with GA annually using PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs). We queried the EMR database to determine the number of discrete patients seen at the Department of Dermatology at the University of Pennsylvania annually from 2008 (the year the EMR was established) to 2014. We then used PennSeek to determine the number of patients given a diagnosis of GA annually from 2008 to 2014 based on the International Classification of Diseases, Ninth Revision (ICD-9).

[embed:render:related:node:68089]

After using PennSeek to identify all patients given the ICD-9 diagnosis of GA from 2008 to 2014, we reviewed the EMRs of these patients to identify cases that were biopsy proven. For the biopsy-proven cases of GA seen at the University of Pennsylvania from 2010 to 2014, we reviewed the EMRs of these patients for clinical characteristics and treatment outcomes. For each case, we recorded the patient’s age, sex, medical comorbidities, GA subtype, and medications.

This study was approved by the University of Pennsylvania’s institutional review board.

Results

On average, the percentage of patients given a diagnosis of GA annually was 0.22% (95% CI, 0.19%-0.24%). A Pearson χ² test was used to determine if any single annual percentage was significantly different from the others. We found a P value of .321, which suggests that the percentage of patients with GA seen annually has been stable from 2008 to 2014 (Figure).

Rubin1.JPG

There were 133 cases of biopsy-proven GA that were reviewed for clinical characteristics; of them, 86.5% were female. Thyroid disease was noted in 30.1% of patients, hyperlipidemia in 30.1%, and hematologic malignancies in 3.8%. Type 1 diabetes mellitus was noted in 1.5% of patients. None of the patients were HIV-positive, 1.5% were hepatitis B–positive, and 2.3% were hepatitis C–positive. Of the 133 cases, 64.7% had localized GA and 30.8% had generalized GA. Photosensitive and papular GA were rarer (1.5% and 2.3% of cases, respectively). Use of a selective serotonin reuptake inhibitor (SSRI) was noted in 18.1% of patients; use of a calcium channel blocker was noted in 9.0% (Table 1).

CT103002102_Table1.JPG

CT103002102_Table2.JPG

Comment

We attempted to determine the period of prevalence of GA in a tertiary care, university-based referral practice and evaluate disease associations, treatments, and outcomes of patients with biopsy-proven GA. Our calculated period prevalence of GA of 0.22% to 0.27% is consistent with another review, which reported that 0.1% to 0.4% of new patients presenting to a dermatology practice were given a diagnosis of GA.¹ More than 85% of the cases we reviewed were seen in females, a finding that is more heavily skewed compared to prior reports that have suggested a female to male ratio of approximately 1:1 to 2:1.^1-7 Our findings suggest that GA is a female-predominant condition, or women may be more likely to seek evaluation for the condition.

[embed:render:related:node:192305]

More than 95% of the cases we reviewed were localized (64.7%) or generalized (30.8%) GA, making these variants the most common forms of GA, which is consistent with prior reports.^1-3,8,9 Other varieties of GA—drug induced, patch, perforating, photosensitive, palmar, and papular—appear rare. Because this study was conducted at an adult hospital, subcutaneous GA, which often is seen in children, may be underrepresented. As a retrospective chart review, it is possible that documentation is insufficient to capture each rare variant.

[embed:render:related:node:67308]

At 1.5%, the prevalence of type 1 diabetes mellitus in our patients is slightly higher than the national average of 0.3%.²⁵ However, based on a Fisher exact test of analysis of proportions, this difference is not statistically significant (P=.106).

At 1.5% and 2.3%, the prevalence of hepatitis B and hepatitis C, respectively, in our patients is slightly higher than the national average of 0.5% and 1%, respectively.²⁶ However, based on a Fisher exact test of analysis of proportions, these differences are not statistically significant (P=.142 and P=.146, respectively).

Given the high prevalence of hyperlipidemia in the United States (31.7%), this disease is not overrepresented in our sample (30.1%), though others have suggested there may be a connection.^27,28 Based on a Fisher exact test, this difference of proportions is not statistically significant (P=.780).

Selective serotonin reuptake inhibitor use is common in the United States; approximately 11% of Americans older than 12 years use an SSRI.²⁹ At 18.1%, the use of SSRIs in our patient group was statistically significantly higher than the national average (Fisher exact test, P=.017), suggesting a possible association between SSRI use and development of GA, warranting further investigation.

The use of calcium channel blockers, interferon, and tumor necrosis factor inhibitors was not significantly associated with GA in our series.

GA Therapy
The most commonly used treatments for GA in our study were topical steroids and intralesional triamcinolone, followed by hydroxychloroquine; all treatments employed exhibited a widely variable response. Assessing treatment response via retrospective chart review is challenging and response rates may not be accurately captured.

Study Limitations
Our study had several limitations. In calculating the period prevalence of GA, our query was limited by the number of years that the EMR has been in place. The number of cases we reviewed for clinical characteristics was limited to 133, as many cases with the ICD-9 diagnosis of GA were not biopsy proven and therefore were not included in our review. Many of the cases we reviewed were lost to follow-up, which prevented us from determining treatment outcomes.

[embed:render:related:node:192472]

Another weakness of our study was that our query did not provide an estimate of incidence or prevalence of GA overall, as this analysis was not a population-based study. The power of our study was limited by the number of cases of GA seen annually and the number of patients lost to follow-up. Additionally, our study population may only be generalizable to other large academic centers.

Conclusion

This study further solidifies our understanding of the epidemiology of GA and diseases that can be associated with GA. We identified a higher female to male ratio than previous reports, and consistent with prior reports, we noted potential associations with conditions such as thyroid disease and hyperlipidemia. Our population demonstrated higher rates of SSRI use than expected, warranting further investigation. Dermatologists should be aware of potential disease associations with GA, but as a whole we need better data and larger studies to determine the appropriate evaluation and treatment for patients with GA.

Granuloma annulare (GA) is a granulomatous skin disorder of uncertain etiology. A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. Histologically, GA exhibits granulomatous inflammation with either interstitial or palisading lymphocytes and histiocytes with mucin deposition.

Few data exist regarding the epidemiology of GA. Although the pathogenesis of GA is unknown, associations between GA and underlying systemic processes, such as diabetes mellitus, hyperlipidemia, thyroid disease, and human immunodeficiency virus (HIV), have been suggested.

[embed:render:related:node:110198]

The purpose of this retrospective study was to determine the number of cases of GA seen annually at the Department of Dermatology at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. Additionally, we reviewed all cases of biopsy-proven GA from 2010 to 2014 and reported the demographics, underlying medical comorbidities, medications, treatments, and outcomes seen in this patient population.

Methods

We identified the number of outpatients presenting with GA annually using PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs). We queried the EMR database to determine the number of discrete patients seen at the Department of Dermatology at the University of Pennsylvania annually from 2008 (the year the EMR was established) to 2014. We then used PennSeek to determine the number of patients given a diagnosis of GA annually from 2008 to 2014 based on the International Classification of Diseases, Ninth Revision (ICD-9).

[embed:render:related:node:68089]

After using PennSeek to identify all patients given the ICD-9 diagnosis of GA from 2008 to 2014, we reviewed the EMRs of these patients to identify cases that were biopsy proven. For the biopsy-proven cases of GA seen at the University of Pennsylvania from 2010 to 2014, we reviewed the EMRs of these patients for clinical characteristics and treatment outcomes. For each case, we recorded the patient’s age, sex, medical comorbidities, GA subtype, and medications.

This study was approved by the University of Pennsylvania’s institutional review board.

Results

On average, the percentage of patients given a diagnosis of GA annually was 0.22% (95% CI, 0.19%-0.24%). A Pearson χ² test was used to determine if any single annual percentage was significantly different from the others. We found a P value of .321, which suggests that the percentage of patients with GA seen annually has been stable from 2008 to 2014 (Figure).

Rubin1.JPG

There were 133 cases of biopsy-proven GA that were reviewed for clinical characteristics; of them, 86.5% were female. Thyroid disease was noted in 30.1% of patients, hyperlipidemia in 30.1%, and hematologic malignancies in 3.8%. Type 1 diabetes mellitus was noted in 1.5% of patients. None of the patients were HIV-positive, 1.5% were hepatitis B–positive, and 2.3% were hepatitis C–positive. Of the 133 cases, 64.7% had localized GA and 30.8% had generalized GA. Photosensitive and papular GA were rarer (1.5% and 2.3% of cases, respectively). Use of a selective serotonin reuptake inhibitor (SSRI) was noted in 18.1% of patients; use of a calcium channel blocker was noted in 9.0% (Table 1).

CT103002102_Table1.JPG

CT103002102_Table2.JPG

Comment

We attempted to determine the period of prevalence of GA in a tertiary care, university-based referral practice and evaluate disease associations, treatments, and outcomes of patients with biopsy-proven GA. Our calculated period prevalence of GA of 0.22% to 0.27% is consistent with another review, which reported that 0.1% to 0.4% of new patients presenting to a dermatology practice were given a diagnosis of GA.¹ More than 85% of the cases we reviewed were seen in females, a finding that is more heavily skewed compared to prior reports that have suggested a female to male ratio of approximately 1:1 to 2:1.^1-7 Our findings suggest that GA is a female-predominant condition, or women may be more likely to seek evaluation for the condition.

[embed:render:related:node:192305]

More than 95% of the cases we reviewed were localized (64.7%) or generalized (30.8%) GA, making these variants the most common forms of GA, which is consistent with prior reports.^1-3,8,9 Other varieties of GA—drug induced, patch, perforating, photosensitive, palmar, and papular—appear rare. Because this study was conducted at an adult hospital, subcutaneous GA, which often is seen in children, may be underrepresented. As a retrospective chart review, it is possible that documentation is insufficient to capture each rare variant.

[embed:render:related:node:67308]

At 1.5%, the prevalence of type 1 diabetes mellitus in our patients is slightly higher than the national average of 0.3%.²⁵ However, based on a Fisher exact test of analysis of proportions, this difference is not statistically significant (P=.106).

At 1.5% and 2.3%, the prevalence of hepatitis B and hepatitis C, respectively, in our patients is slightly higher than the national average of 0.5% and 1%, respectively.²⁶ However, based on a Fisher exact test of analysis of proportions, these differences are not statistically significant (P=.142 and P=.146, respectively).

Given the high prevalence of hyperlipidemia in the United States (31.7%), this disease is not overrepresented in our sample (30.1%), though others have suggested there may be a connection.^27,28 Based on a Fisher exact test, this difference of proportions is not statistically significant (P=.780).

Selective serotonin reuptake inhibitor use is common in the United States; approximately 11% of Americans older than 12 years use an SSRI.²⁹ At 18.1%, the use of SSRIs in our patient group was statistically significantly higher than the national average (Fisher exact test, P=.017), suggesting a possible association between SSRI use and development of GA, warranting further investigation.

The use of calcium channel blockers, interferon, and tumor necrosis factor inhibitors was not significantly associated with GA in our series.

GA Therapy
The most commonly used treatments for GA in our study were topical steroids and intralesional triamcinolone, followed by hydroxychloroquine; all treatments employed exhibited a widely variable response. Assessing treatment response via retrospective chart review is challenging and response rates may not be accurately captured.

Study Limitations
Our study had several limitations. In calculating the period prevalence of GA, our query was limited by the number of years that the EMR has been in place. The number of cases we reviewed for clinical characteristics was limited to 133, as many cases with the ICD-9 diagnosis of GA were not biopsy proven and therefore were not included in our review. Many of the cases we reviewed were lost to follow-up, which prevented us from determining treatment outcomes.

[embed:render:related:node:192472]

Another weakness of our study was that our query did not provide an estimate of incidence or prevalence of GA overall, as this analysis was not a population-based study. The power of our study was limited by the number of cases of GA seen annually and the number of patients lost to follow-up. Additionally, our study population may only be generalizable to other large academic centers.

Conclusion

This study further solidifies our understanding of the epidemiology of GA and diseases that can be associated with GA. We identified a higher female to male ratio than previous reports, and consistent with prior reports, we noted potential associations with conditions such as thyroid disease and hyperlipidemia. Our population demonstrated higher rates of SSRI use than expected, warranting further investigation. Dermatologists should be aware of potential disease associations with GA, but as a whole we need better data and larger studies to determine the appropriate evaluation and treatment for patients with GA.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

CT102005e20_f1.JPG

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

CT102005e20_t1A.JPG

CT102005e20_t1B.JPG

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

CT102005e20_f1.JPG

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

CT102005e20_t1A.JPG

CT102005e20_t1B.JPG

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

To the Editor:

Gemcitabine is a nucleoside analogue used to treat a variety of solid and hematologic malignancies. Cutaneous toxicities include radiation recall dermatitis and erysipelaslike reactions that occur in areas not previously treated with radiation. Often referred to as pseudocellulitis, these reactions generally have been reported in areas of lymphedema in patients with solid malignancies.^1-6 Herein, we report a rare case of gemcitabine-induced pseudocellulitis on the legs in a patient with a history of hematologic malignancy and total body irradiation (TBI).

A 61-year-old woman with history of peripheral T-cell lymphoma presented to the emergency department at our institution with acute-onset redness, tenderness, and swelling of the legs that was concerning for cellulitis. The patient’s history was notable for receiving gemcitabine 1000 mg/m² for treatment of refractory lymphoma (12 and 4 days prior to presentation) as well as lymphedema of the legs. Her complete treatment course included multiple rounds of chemotherapy and matched unrelated donor nonmyeloablative allogeneic stem cell transplantation with a single dose of TBI at 200 cGy at our institution. Her transplant was complicated only by mild cutaneous graft-versus-host disease, which resolved with prednisone and tacrolimus.

On physical examination, the patient was afebrile with symmetric erythema and induration extending from the bilateral knees to the dorsal feet. A complete blood cell count was notable for a white blood cell count of 5400/µL (reference range, 4500–11,000/µL) and a platelet count of 96,000/µL (reference range, 150,000–400,000/µL). Plain film radiographs of the bilateral ankles were remarkable only for moderate subcutaneous edema. She received vancomycin in the emergency department and was admitted to the oncology service. Blood cultures drawn on admission were negative. Dermatology was consulted on admission, and a diagnosis of pseudocellulitis was made in conjunction with oncology (Figure). Antibiotics were held, and the patient was treated symptomatically with ibuprofen and was discharged 1 day after admission. The reaction resolved after 1 week with the use of diphenhydramine, nonsteroidal anti-inflammatory drugs, and compression. The patient was not rechallenged with gemcitabine.

CT102005e20_f1.JPG

Gemcitabine-induced pseudocellulitis is a rare cutaneous side effect of gemcitabine therapy. Reported cases have suggested key characteristics of pseudocellulitis (Table). The reaction is characterized by localized erythema, edema, and tenderness of the skin, with onset generally 48 hours to 1 week after receiving gemcitabine.^1-6 Lymphedema appears to be a risk factor.^1,3-5 Six cases (including the current case) demonstrated confinement of these findings to areas of prior lymphedema.^1,4,6 Infectious workup is negative, and rechallenging with gemcitabine likely will reproduce the reaction. Unlike radiation recall dermatitis, there is no prior localized radiation exposure.

CT102005e20_t1A.JPG

CT102005e20_t1B.JPG

Our patient had a history of hematologic malignancy and a one-time low-dose TBI of 200 cGy, unlike the other reported cases described in the Table. It is difficult to attribute our patient’s localized eruption to radiation recall given the history of TBI. The clinical examination, laboratory findings, and time frame of the reaction were consistent with gemcitabine-induced pseudocellulitis.

It is important to be aware of pseudocellulitis as a possible complication of gemcitabine therapy in patients without history of localized radiation. Early recognition of pseudocellulitis may prevent unnecessary exposure to broad-spectrum antibiotics. Patients’ temperature, white blood cell count, clinical examination, and potentially ancillary studies (eg, vascular studies, inflammatory markers) should be reviewed carefully to determine whether there is an infectious or alternate etiology. In patients with known prior lymphedema, it may be beneficial to educate clinicians and patients alike about this potential adverse effect of gemcitabine and the high likelihood of recurrence on re-exposure.

Serum sickness was first described by von Pirquet and Schick¹ as a constellation of signs and symptoms displayed in patients receiving equine serum as an antitoxin for the treatment of scarlet fever and diphtheria. Serum sickness is an immune complex–mediated hypersensitivity reaction that can be clinically diagnosed in patients who present with fever, rash, and polyarthralgia or polyarthritis following exposure to heterologous serum proteins.^2,3 Symptom onset typically occurs within 1 to 2 weeks of first exposure to the serum, and resolution frequently occurs with discontinuation of the offending agent. Other symptoms may include malaise, gastrointestinal tract concerns, headache, blurred vision, or lymphadenopathy.⁴ Proteinuria, hematuria, and a transient decrease in creatinine clearance also have been reported in serum sickness.⁴

Serum sickness is caused by a type III immune complex–mediated hypersensitivity reaction to heterologous rabbit or equine serum proteins. Nonhuman proteins present in antithymocyte globulin (ATG) stimulate the production of IgG, IgM, IgA, and IgE antibodies.^2-4 If the resultant immune complexes overwhelm the mononuclear phagocyte system, these complexes are deposited in blood vessels and tissues, which leads to complement activation and the production of complement fragments such as C3a and C5a.⁵ C3a is an anaphylatoxin that causes mast cell degranulation and the consequent formation of urticarial lesions. C5a is a neutrophil chemoattractant that promotes inflammation at the site of complement deposition.

Serum sickness–like reactions may occur days to weeks following administration of certain drugs, such as cefaclor or penicillin. Although the symptoms and timing of serum sickness–like reactions are similar to serum sickness, they are not caused by an immune complex–mediated mechanism and are believed to be secondary to an idiosyncratic delayed drug reaction.⁶

Thymoglobulin, a type of ATG, is a polyclonal antibody generated in rabbits that targets numerous human epitopes, including cell surface markers on T cells (CD2, CD3, CD4, CD8), B cells (CD21, CD19, CD40), and adhesion molecules (CD6, CD25, CD44, CD45, and the integrin LFA-1 [lymphocyte function-associated antigen-1]).^7,8 Thymoglobulin has proven efficacy in the setting of cardiac transplantation.^9-11 Although calcineurin inhibitors form the foundation in the armamentarium of immunosuppressive agents in cardiac transplantation, their nephrotoxicity has limited their unrestrained use in patients.⁹ By delaying the need for calcineurin inhibitors, thymoglobulin preserves greater renal function without increasing the risk for acute rejection.^9,10 Akin to its use in the patient presented in this case report, thymoglobulin also is used in the treatment of acute cellular rejection in heart transplant recipients with signs of heart failure.¹¹

Case Report

A 35-year-old man with a history of familial cardiomyopathy who underwent orthotopic heart transplantation presented with grade 3R acute cellular rejection. The patient’s immunosuppressive regimen consisted of thymoglobulin 150 mg once daily, tacrolimus 2.5 mg twice daily, hydrocortisone 100 mg once daily, and mycophenolate mofetil 1000 mg twice daily. On day 7 of thymoglobulin treatment, the dermatology department was consulted to evaluate a pruritic eruption. The patient reported that he noticed redness of the palms and soles, as well as redness accentuated in the axilla, groin, and other skin creases 2 days prior. The patient also reported symmetric bilateral hand pain that had started 1 day following rash onset. He denied fever and remained afebrile throughout his hospitalization.

On physical examination, the patient displayed a blanching, erythematous, edematous, evanescent macular rash with some areas of wheal formation symmetrically distributed in the bilateral axillae, inframammary folds, and groin (Figure, A and B). The palms and soles were tender with diffuse blanching erythema. The eruption was accentuated at the lateral and medial borders of both feet (Figure, C). There was concern that the patient may have a form of serum sickness with a blunted incomplete response due to his concomitant use of immunosuppressive agents. Shortly after evaluation, the patient left the hospital against medical advice before the recommended evaluation and systemic workup could be implemented.

The patient returned for an outpatient appointment approximately 1 week later. Medical records indicated that the patient’s skin eruption had resolved. Tests for antithymoglobulin antibodies at this visit were negative. The antithymoglobulin antibody enzyme-linked immunosorbent assay has a diagnostic sensitivity of 86%¹² and large interlaboratory variability.¹³ Given the presence of other features of serum sickness, a false-negative result was considered by dermatology. Nonetheless, one must consider other differential diagnoses, including a simple cutaneous adverse drug eruption or viral exanthem that might have in fact been causative.

ct100003186_fig.png

Comment

We present an atypical case of possible serum sickness in a heart transplant recipient following thymoglobulin treatment of acute cellular rejection of the cardiac allograft. Serum sickness is a clinical diagnosis supported by laboratory data. Some authors have suggested major and minor diagnostic criteria to aid with the diagnosis.⁷ Major diagnostic criteria include onset more than 7 days after the initial thymoglobulin administration, persistent high fevers (temperature, >38.4°C), persistent arthritis/arthralgia, and positive heterologous antibodies on enzyme-linked immunosorbent assay. Minor diagnostic criteria include rash, acute renal failure, trismus, and low serum complement (C3 and C4).

The variable cutaneous presentations of serum sickness are important to recognize in the process of making the correct diagnosis. Rash is frequently reported in serum sickness, with some studies displaying rates of up to 93%.^4,14 The skin findings are most frequently described as urticarial or serpiginous macular lesions.³ Other variations of the eruption exist, and morbilliform eruptions or a combination of morbilliform and urticarial eruptions have been reported.³ It is important to judge cutaneous eruptions of serum sickness within the context of the potential cytopenia in a patient being treated with ATG. As such, purpuric eruptions have been attributed to serum sickness in thrombocytopenic patients receiving ATG for bone marrow failure.¹⁴

Usually, cutaneous eruptions of serum sickness initially are identified in the groin, axilla, and periumbilical region, and then they proceed to include the trunk and extremities. Erythema of the palms and soles frequently is described as well as a linear accentuation of the rash along the lateral and medial borders of the feet and hands at the margin of the plantar or palmar skin, respectively.¹⁴ The mucous membranes frequently are spared in serum sickness.

Despite the lack of evidence-based guidelines, case series and literature reviews have suggested a treatment regimen for serum sickness,^7,15-18 calling for immediate withdrawal of the offending agent. Antihistamines may be added to control pruritus and rash. Patients with high fever, a progressive rash, or severe arthralgia have benefited from short courses of oral^16,18 or intravenous^7,17 glucocorticoids. The extent of the eruption in our patient was concerning, particularly because he was already receiving systemic corticosteroids in conjunction with other immunosuppressives, which may have explained his lack of fever.

Because our patient satisfied some diagnostic criteria for serum sickness and failed to satisfy others, our team was faced with the challenge of balancing the risks of possible serum sickness with the risks of the potential for progressive cardiac rejection from the withdrawal of thymoglobulin.⁷ There is some evidence in the literature for the use of therapeutic plasma exchange (TPE) for the treatment of serum sickness if the offending agent could not be discontinued. Tanriover et al¹⁹ presented a case series of 5 renal transplant recipients treated with thymoglobulin who developed serum sickness. The diagnosis of serum sickness was made clinically and augmented by the presence of antiheterologous antibodies. All 5 patients had persistent symptoms of serum sickness despite 2 days of glucocorticoid treatment. Interestingly, 3 patients had complete resolution of all symptoms after a single TPE treatment, and 2 patients achieved resolution of fever and arthritis after 2 consecutive days of TPE treatments.¹⁹ Because plasmapheresis is used to treat cardiac allograft rejection in patients showing signs of heart failure,¹¹ the employment of TPE in these patients may have dual beneficial effects of concurrently treating serum sickness and allograft rejection.

Given the patient’s noncompliance and leaving the hospital against medical advice, a full workup was not able to be pursued in this case, though fortunately the eruption and his other symptoms had resolved by the time he was seen for outpatient follow-up 1 week later. Noncompliance with immunosuppressive therapy is a considerable risk factor for morbidity and mortality following heart transplantation. These patients have more transplant coronary artery disease and substantially shorter clinical event-free time.²⁰ Our patient demonstrates the need for proactive compliance-enhancing interventions in heart transplant patients who experience allograft rejection.

Serum sickness was first described by von Pirquet and Schick¹ as a constellation of signs and symptoms displayed in patients receiving equine serum as an antitoxin for the treatment of scarlet fever and diphtheria. Serum sickness is an immune complex–mediated hypersensitivity reaction that can be clinically diagnosed in patients who present with fever, rash, and polyarthralgia or polyarthritis following exposure to heterologous serum proteins.^2,3 Symptom onset typically occurs within 1 to 2 weeks of first exposure to the serum, and resolution frequently occurs with discontinuation of the offending agent. Other symptoms may include malaise, gastrointestinal tract concerns, headache, blurred vision, or lymphadenopathy.⁴ Proteinuria, hematuria, and a transient decrease in creatinine clearance also have been reported in serum sickness.⁴

Serum sickness is caused by a type III immune complex–mediated hypersensitivity reaction to heterologous rabbit or equine serum proteins. Nonhuman proteins present in antithymocyte globulin (ATG) stimulate the production of IgG, IgM, IgA, and IgE antibodies.^2-4 If the resultant immune complexes overwhelm the mononuclear phagocyte system, these complexes are deposited in blood vessels and tissues, which leads to complement activation and the production of complement fragments such as C3a and C5a.⁵ C3a is an anaphylatoxin that causes mast cell degranulation and the consequent formation of urticarial lesions. C5a is a neutrophil chemoattractant that promotes inflammation at the site of complement deposition.

Serum sickness–like reactions may occur days to weeks following administration of certain drugs, such as cefaclor or penicillin. Although the symptoms and timing of serum sickness–like reactions are similar to serum sickness, they are not caused by an immune complex–mediated mechanism and are believed to be secondary to an idiosyncratic delayed drug reaction.⁶

Thymoglobulin, a type of ATG, is a polyclonal antibody generated in rabbits that targets numerous human epitopes, including cell surface markers on T cells (CD2, CD3, CD4, CD8), B cells (CD21, CD19, CD40), and adhesion molecules (CD6, CD25, CD44, CD45, and the integrin LFA-1 [lymphocyte function-associated antigen-1]).^7,8 Thymoglobulin has proven efficacy in the setting of cardiac transplantation.^9-11 Although calcineurin inhibitors form the foundation in the armamentarium of immunosuppressive agents in cardiac transplantation, their nephrotoxicity has limited their unrestrained use in patients.⁹ By delaying the need for calcineurin inhibitors, thymoglobulin preserves greater renal function without increasing the risk for acute rejection.^9,10 Akin to its use in the patient presented in this case report, thymoglobulin also is used in the treatment of acute cellular rejection in heart transplant recipients with signs of heart failure.¹¹

Case Report

A 35-year-old man with a history of familial cardiomyopathy who underwent orthotopic heart transplantation presented with grade 3R acute cellular rejection. The patient’s immunosuppressive regimen consisted of thymoglobulin 150 mg once daily, tacrolimus 2.5 mg twice daily, hydrocortisone 100 mg once daily, and mycophenolate mofetil 1000 mg twice daily. On day 7 of thymoglobulin treatment, the dermatology department was consulted to evaluate a pruritic eruption. The patient reported that he noticed redness of the palms and soles, as well as redness accentuated in the axilla, groin, and other skin creases 2 days prior. The patient also reported symmetric bilateral hand pain that had started 1 day following rash onset. He denied fever and remained afebrile throughout his hospitalization.

On physical examination, the patient displayed a blanching, erythematous, edematous, evanescent macular rash with some areas of wheal formation symmetrically distributed in the bilateral axillae, inframammary folds, and groin (Figure, A and B). The palms and soles were tender with diffuse blanching erythema. The eruption was accentuated at the lateral and medial borders of both feet (Figure, C). There was concern that the patient may have a form of serum sickness with a blunted incomplete response due to his concomitant use of immunosuppressive agents. Shortly after evaluation, the patient left the hospital against medical advice before the recommended evaluation and systemic workup could be implemented.

The patient returned for an outpatient appointment approximately 1 week later. Medical records indicated that the patient’s skin eruption had resolved. Tests for antithymoglobulin antibodies at this visit were negative. The antithymoglobulin antibody enzyme-linked immunosorbent assay has a diagnostic sensitivity of 86%¹² and large interlaboratory variability.¹³ Given the presence of other features of serum sickness, a false-negative result was considered by dermatology. Nonetheless, one must consider other differential diagnoses, including a simple cutaneous adverse drug eruption or viral exanthem that might have in fact been causative.

ct100003186_fig.png

Comment

We present an atypical case of possible serum sickness in a heart transplant recipient following thymoglobulin treatment of acute cellular rejection of the cardiac allograft. Serum sickness is a clinical diagnosis supported by laboratory data. Some authors have suggested major and minor diagnostic criteria to aid with the diagnosis.⁷ Major diagnostic criteria include onset more than 7 days after the initial thymoglobulin administration, persistent high fevers (temperature, >38.4°C), persistent arthritis/arthralgia, and positive heterologous antibodies on enzyme-linked immunosorbent assay. Minor diagnostic criteria include rash, acute renal failure, trismus, and low serum complement (C3 and C4).

The variable cutaneous presentations of serum sickness are important to recognize in the process of making the correct diagnosis. Rash is frequently reported in serum sickness, with some studies displaying rates of up to 93%.^4,14 The skin findings are most frequently described as urticarial or serpiginous macular lesions.³ Other variations of the eruption exist, and morbilliform eruptions or a combination of morbilliform and urticarial eruptions have been reported.³ It is important to judge cutaneous eruptions of serum sickness within the context of the potential cytopenia in a patient being treated with ATG. As such, purpuric eruptions have been attributed to serum sickness in thrombocytopenic patients receiving ATG for bone marrow failure.¹⁴

Usually, cutaneous eruptions of serum sickness initially are identified in the groin, axilla, and periumbilical region, and then they proceed to include the trunk and extremities. Erythema of the palms and soles frequently is described as well as a linear accentuation of the rash along the lateral and medial borders of the feet and hands at the margin of the plantar or palmar skin, respectively.¹⁴ The mucous membranes frequently are spared in serum sickness.

Despite the lack of evidence-based guidelines, case series and literature reviews have suggested a treatment regimen for serum sickness,^7,15-18 calling for immediate withdrawal of the offending agent. Antihistamines may be added to control pruritus and rash. Patients with high fever, a progressive rash, or severe arthralgia have benefited from short courses of oral^16,18 or intravenous^7,17 glucocorticoids. The extent of the eruption in our patient was concerning, particularly because he was already receiving systemic corticosteroids in conjunction with other immunosuppressives, which may have explained his lack of fever.

Because our patient satisfied some diagnostic criteria for serum sickness and failed to satisfy others, our team was faced with the challenge of balancing the risks of possible serum sickness with the risks of the potential for progressive cardiac rejection from the withdrawal of thymoglobulin.⁷ There is some evidence in the literature for the use of therapeutic plasma exchange (TPE) for the treatment of serum sickness if the offending agent could not be discontinued. Tanriover et al¹⁹ presented a case series of 5 renal transplant recipients treated with thymoglobulin who developed serum sickness. The diagnosis of serum sickness was made clinically and augmented by the presence of antiheterologous antibodies. All 5 patients had persistent symptoms of serum sickness despite 2 days of glucocorticoid treatment. Interestingly, 3 patients had complete resolution of all symptoms after a single TPE treatment, and 2 patients achieved resolution of fever and arthritis after 2 consecutive days of TPE treatments.¹⁹ Because plasmapheresis is used to treat cardiac allograft rejection in patients showing signs of heart failure,¹¹ the employment of TPE in these patients may have dual beneficial effects of concurrently treating serum sickness and allograft rejection.

Given the patient’s noncompliance and leaving the hospital against medical advice, a full workup was not able to be pursued in this case, though fortunately the eruption and his other symptoms had resolved by the time he was seen for outpatient follow-up 1 week later. Noncompliance with immunosuppressive therapy is a considerable risk factor for morbidity and mortality following heart transplantation. These patients have more transplant coronary artery disease and substantially shorter clinical event-free time.²⁰ Our patient demonstrates the need for proactive compliance-enhancing interventions in heart transplant patients who experience allograft rejection.

Serum sickness was first described by von Pirquet and Schick¹ as a constellation of signs and symptoms displayed in patients receiving equine serum as an antitoxin for the treatment of scarlet fever and diphtheria. Serum sickness is an immune complex–mediated hypersensitivity reaction that can be clinically diagnosed in patients who present with fever, rash, and polyarthralgia or polyarthritis following exposure to heterologous serum proteins.^2,3 Symptom onset typically occurs within 1 to 2 weeks of first exposure to the serum, and resolution frequently occurs with discontinuation of the offending agent. Other symptoms may include malaise, gastrointestinal tract concerns, headache, blurred vision, or lymphadenopathy.⁴ Proteinuria, hematuria, and a transient decrease in creatinine clearance also have been reported in serum sickness.⁴

Serum sickness is caused by a type III immune complex–mediated hypersensitivity reaction to heterologous rabbit or equine serum proteins. Nonhuman proteins present in antithymocyte globulin (ATG) stimulate the production of IgG, IgM, IgA, and IgE antibodies.^2-4 If the resultant immune complexes overwhelm the mononuclear phagocyte system, these complexes are deposited in blood vessels and tissues, which leads to complement activation and the production of complement fragments such as C3a and C5a.⁵ C3a is an anaphylatoxin that causes mast cell degranulation and the consequent formation of urticarial lesions. C5a is a neutrophil chemoattractant that promotes inflammation at the site of complement deposition.

Serum sickness–like reactions may occur days to weeks following administration of certain drugs, such as cefaclor or penicillin. Although the symptoms and timing of serum sickness–like reactions are similar to serum sickness, they are not caused by an immune complex–mediated mechanism and are believed to be secondary to an idiosyncratic delayed drug reaction.⁶

Thymoglobulin, a type of ATG, is a polyclonal antibody generated in rabbits that targets numerous human epitopes, including cell surface markers on T cells (CD2, CD3, CD4, CD8), B cells (CD21, CD19, CD40), and adhesion molecules (CD6, CD25, CD44, CD45, and the integrin LFA-1 [lymphocyte function-associated antigen-1]).^7,8 Thymoglobulin has proven efficacy in the setting of cardiac transplantation.^9-11 Although calcineurin inhibitors form the foundation in the armamentarium of immunosuppressive agents in cardiac transplantation, their nephrotoxicity has limited their unrestrained use in patients.⁹ By delaying the need for calcineurin inhibitors, thymoglobulin preserves greater renal function without increasing the risk for acute rejection.^9,10 Akin to its use in the patient presented in this case report, thymoglobulin also is used in the treatment of acute cellular rejection in heart transplant recipients with signs of heart failure.¹¹

Case Report

A 35-year-old man with a history of familial cardiomyopathy who underwent orthotopic heart transplantation presented with grade 3R acute cellular rejection. The patient’s immunosuppressive regimen consisted of thymoglobulin 150 mg once daily, tacrolimus 2.5 mg twice daily, hydrocortisone 100 mg once daily, and mycophenolate mofetil 1000 mg twice daily. On day 7 of thymoglobulin treatment, the dermatology department was consulted to evaluate a pruritic eruption. The patient reported that he noticed redness of the palms and soles, as well as redness accentuated in the axilla, groin, and other skin creases 2 days prior. The patient also reported symmetric bilateral hand pain that had started 1 day following rash onset. He denied fever and remained afebrile throughout his hospitalization.

On physical examination, the patient displayed a blanching, erythematous, edematous, evanescent macular rash with some areas of wheal formation symmetrically distributed in the bilateral axillae, inframammary folds, and groin (Figure, A and B). The palms and soles were tender with diffuse blanching erythema. The eruption was accentuated at the lateral and medial borders of both feet (Figure, C). There was concern that the patient may have a form of serum sickness with a blunted incomplete response due to his concomitant use of immunosuppressive agents. Shortly after evaluation, the patient left the hospital against medical advice before the recommended evaluation and systemic workup could be implemented.

The patient returned for an outpatient appointment approximately 1 week later. Medical records indicated that the patient’s skin eruption had resolved. Tests for antithymoglobulin antibodies at this visit were negative. The antithymoglobulin antibody enzyme-linked immunosorbent assay has a diagnostic sensitivity of 86%¹² and large interlaboratory variability.¹³ Given the presence of other features of serum sickness, a false-negative result was considered by dermatology. Nonetheless, one must consider other differential diagnoses, including a simple cutaneous adverse drug eruption or viral exanthem that might have in fact been causative.

ct100003186_fig.png

Comment

We present an atypical case of possible serum sickness in a heart transplant recipient following thymoglobulin treatment of acute cellular rejection of the cardiac allograft. Serum sickness is a clinical diagnosis supported by laboratory data. Some authors have suggested major and minor diagnostic criteria to aid with the diagnosis.⁷ Major diagnostic criteria include onset more than 7 days after the initial thymoglobulin administration, persistent high fevers (temperature, >38.4°C), persistent arthritis/arthralgia, and positive heterologous antibodies on enzyme-linked immunosorbent assay. Minor diagnostic criteria include rash, acute renal failure, trismus, and low serum complement (C3 and C4).

The variable cutaneous presentations of serum sickness are important to recognize in the process of making the correct diagnosis. Rash is frequently reported in serum sickness, with some studies displaying rates of up to 93%.^4,14 The skin findings are most frequently described as urticarial or serpiginous macular lesions.³ Other variations of the eruption exist, and morbilliform eruptions or a combination of morbilliform and urticarial eruptions have been reported.³ It is important to judge cutaneous eruptions of serum sickness within the context of the potential cytopenia in a patient being treated with ATG. As such, purpuric eruptions have been attributed to serum sickness in thrombocytopenic patients receiving ATG for bone marrow failure.¹⁴

Usually, cutaneous eruptions of serum sickness initially are identified in the groin, axilla, and periumbilical region, and then they proceed to include the trunk and extremities. Erythema of the palms and soles frequently is described as well as a linear accentuation of the rash along the lateral and medial borders of the feet and hands at the margin of the plantar or palmar skin, respectively.¹⁴ The mucous membranes frequently are spared in serum sickness.

Despite the lack of evidence-based guidelines, case series and literature reviews have suggested a treatment regimen for serum sickness,^7,15-18 calling for immediate withdrawal of the offending agent. Antihistamines may be added to control pruritus and rash. Patients with high fever, a progressive rash, or severe arthralgia have benefited from short courses of oral^16,18 or intravenous^7,17 glucocorticoids. The extent of the eruption in our patient was concerning, particularly because he was already receiving systemic corticosteroids in conjunction with other immunosuppressives, which may have explained his lack of fever.

Because our patient satisfied some diagnostic criteria for serum sickness and failed to satisfy others, our team was faced with the challenge of balancing the risks of possible serum sickness with the risks of the potential for progressive cardiac rejection from the withdrawal of thymoglobulin.⁷ There is some evidence in the literature for the use of therapeutic plasma exchange (TPE) for the treatment of serum sickness if the offending agent could not be discontinued. Tanriover et al¹⁹ presented a case series of 5 renal transplant recipients treated with thymoglobulin who developed serum sickness. The diagnosis of serum sickness was made clinically and augmented by the presence of antiheterologous antibodies. All 5 patients had persistent symptoms of serum sickness despite 2 days of glucocorticoid treatment. Interestingly, 3 patients had complete resolution of all symptoms after a single TPE treatment, and 2 patients achieved resolution of fever and arthritis after 2 consecutive days of TPE treatments.¹⁹ Because plasmapheresis is used to treat cardiac allograft rejection in patients showing signs of heart failure,¹¹ the employment of TPE in these patients may have dual beneficial effects of concurrently treating serum sickness and allograft rejection.

Given the patient’s noncompliance and leaving the hospital against medical advice, a full workup was not able to be pursued in this case, though fortunately the eruption and his other symptoms had resolved by the time he was seen for outpatient follow-up 1 week later. Noncompliance with immunosuppressive therapy is a considerable risk factor for morbidity and mortality following heart transplantation. These patients have more transplant coronary artery disease and substantially shorter clinical event-free time.²⁰ Our patient demonstrates the need for proactive compliance-enhancing interventions in heart transplant patients who experience allograft rejection.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

ct098012377_fig1.png

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

ct098012377_fig2.png

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

ct098012377_fig1.png

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

ct098012377_fig2.png

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

Sarcoidosis is a multisystem granulomatous disease of unknown etiology that most commonly affects the lungs, eyes, and skin. Cutaneous involvement is reported in 25% to 35% of patients with sarcoidosis and may occur in a variety of forms including macules, papules, plaques, and lupus pernio.^1,2 Dermatologists commonly are confronted with the diagnosis and management of sarcoidosis because of its high incidence of cutaneous involvement. Due to the protean nature of the disease, skin biopsy plays a key role in confirming the diagnosis. Histological evidence of noncaseating granulomas in combination with an appropriate clinical and radiographic picture is necessary for the diagnosis of sarcoidosis.^1,2 Brincker and Wilbek³ first described the link between pulmonary sarcoidosis and an increased incidence of malignancy in 1974. Since then, a number of studies have suggested that sarcoidosis may be associated with an increased risk for hematologic malignancy as well as an increased risk for cancers of the lungs, stomach, colon, liver, and skin.^4,5 To date, few studies exist that examine the relationship between cutaneous sarcoidosis and malignancy.⁶

We describe 3 patients with sarcoidosis who developed squamous cell carcinoma (SCC) of the skin, including 2 black patients, which highlights the potential for SCC development.

Case Reports

Patient 1

A black woman in her 60s with a history of sarcoidosis affecting the lungs and skin that was well controlled with biweekly adalimumab 40 mg subcutaneous injections presented with a new dark painful lesion on the right third finger. She reported the lesion had been present for 1 to 2 years prior to the current presentation and was increasing in size. She had no history of prior skin cancers.

Physical examination revealed a waxy, brown-pigmented papule with overlying scale on the ulnar aspect of the right third digit near the web space (Figure 1A). A shave biopsy revealed atypical keratinocytes involving all layers of the epidermis along with associated parakeratotic scale consistent with a diagnosis of SCC in situ (Figure 1B). Human papillomavirus staining was negative. Due to the location of the lesion, the patient underwent Mohs micrographic surgery and the lesion was completely excised.

ct098012377_fig1.png

Patient 2

A black woman in her 60s with a history of cutaneous sarcoidosis that was maintained on minocycline 100 mg twice daily, chloroquine 250 mg daily, tacrolimus ointment 0.1%, tretinoin cream 0.025%, and intermittent intralesional triamcinolone acetonide injections to the nose, as well as quiescent pulmonary sarcoidosis, developed a new, growing, asymptomatic, hyperpigmented lesion on the left side of the submandibular neck over a period of a few months. A biopsy was performed and the lesion was found to be an SCC, which subsequently was completely excised.

Patient 3

A white man in his 60s with a history of prior quiescent pulmonary sarcoidosis, remote melanoma, and multiple nonmelanoma skin cancers developed scaly papules on the scalp for months, one that was interpreted by an outside pathologist as an invasive SCC (Figure 2A). He was referred to our institution for Mohs micrographic surgery. On presentation when his scalp was shaved for surgery, he was noted to have several violaceous, annular, thin plaques on the scalp (Figure 2B). A biopsy of an annular plaque demonstrated several areas of granulomatous dermatitis consistent with a diagnosis of cutaneous sarcoidosis (Figure 2C). The patient had clinical lymphadenopathy of the neck and supraclavicular region. Given the patient’s history, the differential diagnosis for these lesions included metastatic SCC, lymphoma, and sarcoidosis. The patient underwent a positron emission tomography scan, which demonstrated fluorodeoxyglucose-positive regions in both lungs and the right side of the neck. After evaluation by the pulmonary and otorhinolaryngology departments, including a lymph node biopsy, the positron emission tomography–enhancing lesions were ultimately determined to be consistent with sarcoidosis.

The patient underwent Mohs micrographic surgery for treatment of the scalp SCC and was started on triamcinolone cream 0.1% for the body, clobetasol propionate foam 0.05% for the scalp, and hydroxychloroquine sulfate 400 mg daily for the cutaneous sarcoidosis. His annular scalp lesions resolved, but over the following 12 months the patient had numerous clinically suspicious skin lesions that were biopsied and were consistent with multiple basal cell carcinomas, actinic keratoses, and SCC in situ. They were treated with surgery, cryosurgical destruction with liquid nitrogen, and 5-fluorouracil cream.

ct098012377_fig2.png

Comment

The potential increased risk for malignancy in patients with sarcoidosis has been well documented.^3-6 Brincker and Wilbek³ first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.³ In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al⁵ noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.⁵ In a retrospective cohort study examining more than 9000 patients, Askling et al⁴ also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.⁴ Reich et al⁷ cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.⁷

Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.⁸ Alexandrescu et al⁶ evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.⁶

We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.

Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.

The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.^1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4⁺ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.^1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.^1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.^6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.⁶

Conclusion

An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.

To the Editor:

Dermatofibromas, the most common fibrohistiocytic tumors of the skin, are typically solitary lesions. Clustering of and multiple dermatofibromas (multiple eruptive dermatofibromas [MEDFs]) are relatively less common. The association between MEDF and systemic immunoaltered disease states such as systemic lupus erythematosus (SLE) or human immunodeficiency virus infection has been described and led to speculation that MEDF might be a result of an abnormal immune response. We report a patient with sarcoidosis who developed multiple large dermatofibromas, some clustered, on the neck, left shoulder, and back.

ct098008001_e_goldbach_fig1.png

A 61-year-old woman with a history of mild pulmonary sarcoidosis confirmed by transbronchial biopsies presented to our clinic with a 2-year history of hyperpigmented papules on the trunk and extremities with subjective enlargement and increased erythema of a papule on the left shoulder over the last 6 months. She had associated pain and pruritus in the area. She was not on any systemic medications for sarcoidosis at the time. Physical examination revealed 2 large, firm, hyperpigmented nodules on the left shoulder, one with overlying erythema and mild scale (Figure 1). There also were multiple scattered hyperpigmented papules on the back, chest, and right arm that dimpled when compressed. A biopsy was obtained because of clinical concern for cutaneous sarcoidosis. Histopathologic evaluation of the largest nodule demonstrated epidermal hyperplasia with effacement of the rete ridges and a proliferation of spindle cells that wrapped around collagen fibers in the dermis, consistent with a dermatofibroma (Figure 2).

ct098008001_e_goldbach_fig2.jpg

Dermatofibromas are common fibrohistiocytic neoplasms in the skin that typically present as a solitary lesion. A clustering of dermatofibromas, MEDFs, is relatively less common, representing only 0.3% of all dermatofibromas.^1,2 Histopathologically, similar to solitary dermatofibromas,³ MEDF has classically been defined as more than 15 lesions, though another definition includes the appearance of several dermatofibromas over a relatively short period of time.²

Multiple eruptive dermatofibromas have been described in association with several underlying diseases. A strong association between MEDFs and immune dysregulation appears to exist, with 69% of reported cases of MEDF associated with an underlying disease, 83% of which were related to dysregulated immunity. Systemic lupus erythematosus was the most common underlying disease associated with MEDF, representing 25% of published cases.³ Multiple eruptive dermatofibromas also have been linked to other autoimmune disorders such as myasthenia gravis,^4,5 Hashimoto thyroiditis,⁴ diabetes mellitus,⁶ Sjögren syndrome,^7,8 dermatomyositis,⁹ and Graves-Basedow disease.¹⁰

Multiple eruptive dermatofibromas also have been linked to immunosuppression, including human immunodeficiency virus¹¹; malignancy^12,13; and immunosuppressive or immunomodulatory drugs such as corticosteroids,¹⁴ cyclophosphamide,⁵ methotrexate,⁹ efalizumab,¹⁵ and interferon alfa.¹² The degree of immunosuppression, however, does not seem to correlate to the number of MEDFs.³ In addition, MEDFs have been reported in pregnancy and a variety of other systemic disorders including atopic dermatitis,^1,16,17 hypertriglyceridemia,⁸ and pulmonary hypertension.¹⁸ We report a case of MEDF in a patient with sarcoidosis who was not treated with immunosuppressive medication. A report of sarcoidosis and MEDF was previously published, but the patient had been treated for many years with prednisone.¹⁹ Most reports of SLE-associated MEDF occurred in the setting of steroid use.

Although the etiology of dermatofibromas is unclear, the link between MEDFs and altered immunity has led to speculation that dermatofibromas could be a manifestation of defective autoimmune inflammatory regulation. This hypothesis has been supported by the observation that the lesions are often associated with cells that express class II MHC molecules and also bear morphologic similarity to dermal antigen-presenting cells.²⁰ Reports of familial cases of MEDF suggest that there could be a genetic predisposition.¹

The association of MEDFs and underlying immune disorders is important for clinicians to know for appropriate evaluation of potential systemic associations, including sarcoidosis. In addition, biopsy should be considered to confirm the diagnosis with large or atypical lesions to exclude other potential diagnoses. Given the protean nature of sarcoidosis, skin biopsy often is indicated to identify whether cutaneous findings are granulomatous sarcoid-related manifestations. The association of MEDFs with sarcoidosis requires further evaluation but might provide keys to understanding the pathophysiology of these lesions.

To the Editor:

Dermatofibromas, the most common fibrohistiocytic tumors of the skin, are typically solitary lesions. Clustering of and multiple dermatofibromas (multiple eruptive dermatofibromas [MEDFs]) are relatively less common. The association between MEDF and systemic immunoaltered disease states such as systemic lupus erythematosus (SLE) or human immunodeficiency virus infection has been described and led to speculation that MEDF might be a result of an abnormal immune response. We report a patient with sarcoidosis who developed multiple large dermatofibromas, some clustered, on the neck, left shoulder, and back.

ct098008001_e_goldbach_fig1.png

A 61-year-old woman with a history of mild pulmonary sarcoidosis confirmed by transbronchial biopsies presented to our clinic with a 2-year history of hyperpigmented papules on the trunk and extremities with subjective enlargement and increased erythema of a papule on the left shoulder over the last 6 months. She had associated pain and pruritus in the area. She was not on any systemic medications for sarcoidosis at the time. Physical examination revealed 2 large, firm, hyperpigmented nodules on the left shoulder, one with overlying erythema and mild scale (Figure 1). There also were multiple scattered hyperpigmented papules on the back, chest, and right arm that dimpled when compressed. A biopsy was obtained because of clinical concern for cutaneous sarcoidosis. Histopathologic evaluation of the largest nodule demonstrated epidermal hyperplasia with effacement of the rete ridges and a proliferation of spindle cells that wrapped around collagen fibers in the dermis, consistent with a dermatofibroma (Figure 2).

ct098008001_e_goldbach_fig2.jpg

Dermatofibromas are common fibrohistiocytic neoplasms in the skin that typically present as a solitary lesion. A clustering of dermatofibromas, MEDFs, is relatively less common, representing only 0.3% of all dermatofibromas.^1,2 Histopathologically, similar to solitary dermatofibromas,³ MEDF has classically been defined as more than 15 lesions, though another definition includes the appearance of several dermatofibromas over a relatively short period of time.²

Multiple eruptive dermatofibromas have been described in association with several underlying diseases. A strong association between MEDFs and immune dysregulation appears to exist, with 69% of reported cases of MEDF associated with an underlying disease, 83% of which were related to dysregulated immunity. Systemic lupus erythematosus was the most common underlying disease associated with MEDF, representing 25% of published cases.³ Multiple eruptive dermatofibromas also have been linked to other autoimmune disorders such as myasthenia gravis,^4,5 Hashimoto thyroiditis,⁴ diabetes mellitus,⁶ Sjögren syndrome,^7,8 dermatomyositis,⁹ and Graves-Basedow disease.¹⁰

Multiple eruptive dermatofibromas also have been linked to immunosuppression, including human immunodeficiency virus¹¹; malignancy^12,13; and immunosuppressive or immunomodulatory drugs such as corticosteroids,¹⁴ cyclophosphamide,⁵ methotrexate,⁹ efalizumab,¹⁵ and interferon alfa.¹² The degree of immunosuppression, however, does not seem to correlate to the number of MEDFs.³ In addition, MEDFs have been reported in pregnancy and a variety of other systemic disorders including atopic dermatitis,^1,16,17 hypertriglyceridemia,⁸ and pulmonary hypertension.¹⁸ We report a case of MEDF in a patient with sarcoidosis who was not treated with immunosuppressive medication. A report of sarcoidosis and MEDF was previously published, but the patient had been treated for many years with prednisone.¹⁹ Most reports of SLE-associated MEDF occurred in the setting of steroid use.

Although the etiology of dermatofibromas is unclear, the link between MEDFs and altered immunity has led to speculation that dermatofibromas could be a manifestation of defective autoimmune inflammatory regulation. This hypothesis has been supported by the observation that the lesions are often associated with cells that express class II MHC molecules and also bear morphologic similarity to dermal antigen-presenting cells.²⁰ Reports of familial cases of MEDF suggest that there could be a genetic predisposition.¹

The association of MEDFs and underlying immune disorders is important for clinicians to know for appropriate evaluation of potential systemic associations, including sarcoidosis. In addition, biopsy should be considered to confirm the diagnosis with large or atypical lesions to exclude other potential diagnoses. Given the protean nature of sarcoidosis, skin biopsy often is indicated to identify whether cutaneous findings are granulomatous sarcoid-related manifestations. The association of MEDFs with sarcoidosis requires further evaluation but might provide keys to understanding the pathophysiology of these lesions.

To the Editor:

Dermatofibromas, the most common fibrohistiocytic tumors of the skin, are typically solitary lesions. Clustering of and multiple dermatofibromas (multiple eruptive dermatofibromas [MEDFs]) are relatively less common. The association between MEDF and systemic immunoaltered disease states such as systemic lupus erythematosus (SLE) or human immunodeficiency virus infection has been described and led to speculation that MEDF might be a result of an abnormal immune response. We report a patient with sarcoidosis who developed multiple large dermatofibromas, some clustered, on the neck, left shoulder, and back.

ct098008001_e_goldbach_fig1.png

A 61-year-old woman with a history of mild pulmonary sarcoidosis confirmed by transbronchial biopsies presented to our clinic with a 2-year history of hyperpigmented papules on the trunk and extremities with subjective enlargement and increased erythema of a papule on the left shoulder over the last 6 months. She had associated pain and pruritus in the area. She was not on any systemic medications for sarcoidosis at the time. Physical examination revealed 2 large, firm, hyperpigmented nodules on the left shoulder, one with overlying erythema and mild scale (Figure 1). There also were multiple scattered hyperpigmented papules on the back, chest, and right arm that dimpled when compressed. A biopsy was obtained because of clinical concern for cutaneous sarcoidosis. Histopathologic evaluation of the largest nodule demonstrated epidermal hyperplasia with effacement of the rete ridges and a proliferation of spindle cells that wrapped around collagen fibers in the dermis, consistent with a dermatofibroma (Figure 2).

ct098008001_e_goldbach_fig2.jpg

Dermatofibromas are common fibrohistiocytic neoplasms in the skin that typically present as a solitary lesion. A clustering of dermatofibromas, MEDFs, is relatively less common, representing only 0.3% of all dermatofibromas.^1,2 Histopathologically, similar to solitary dermatofibromas,³ MEDF has classically been defined as more than 15 lesions, though another definition includes the appearance of several dermatofibromas over a relatively short period of time.²

Multiple eruptive dermatofibromas have been described in association with several underlying diseases. A strong association between MEDFs and immune dysregulation appears to exist, with 69% of reported cases of MEDF associated with an underlying disease, 83% of which were related to dysregulated immunity. Systemic lupus erythematosus was the most common underlying disease associated with MEDF, representing 25% of published cases.³ Multiple eruptive dermatofibromas also have been linked to other autoimmune disorders such as myasthenia gravis,^4,5 Hashimoto thyroiditis,⁴ diabetes mellitus,⁶ Sjögren syndrome,^7,8 dermatomyositis,⁹ and Graves-Basedow disease.¹⁰

Multiple eruptive dermatofibromas also have been linked to immunosuppression, including human immunodeficiency virus¹¹; malignancy^12,13; and immunosuppressive or immunomodulatory drugs such as corticosteroids,¹⁴ cyclophosphamide,⁵ methotrexate,⁹ efalizumab,¹⁵ and interferon alfa.¹² The degree of immunosuppression, however, does not seem to correlate to the number of MEDFs.³ In addition, MEDFs have been reported in pregnancy and a variety of other systemic disorders including atopic dermatitis,^1,16,17 hypertriglyceridemia,⁸ and pulmonary hypertension.¹⁸ We report a case of MEDF in a patient with sarcoidosis who was not treated with immunosuppressive medication. A report of sarcoidosis and MEDF was previously published, but the patient had been treated for many years with prednisone.¹⁹ Most reports of SLE-associated MEDF occurred in the setting of steroid use.

Although the etiology of dermatofibromas is unclear, the link between MEDFs and altered immunity has led to speculation that dermatofibromas could be a manifestation of defective autoimmune inflammatory regulation. This hypothesis has been supported by the observation that the lesions are often associated with cells that express class II MHC molecules and also bear morphologic similarity to dermal antigen-presenting cells.²⁰ Reports of familial cases of MEDF suggest that there could be a genetic predisposition.¹

The association of MEDFs and underlying immune disorders is important for clinicians to know for appropriate evaluation of potential systemic associations, including sarcoidosis. In addition, biopsy should be considered to confirm the diagnosis with large or atypical lesions to exclude other potential diagnoses. Given the protean nature of sarcoidosis, skin biopsy often is indicated to identify whether cutaneous findings are granulomatous sarcoid-related manifestations. The association of MEDFs with sarcoidosis requires further evaluation but might provide keys to understanding the pathophysiology of these lesions.

The Diagnosis: Atypical Mycobacterial Infection

Punch biopsy specimens demonstrated necrotizing granulomatous inflammation in the dermis and subcutis (Figure). Special staining for microorganisms was negative. Tissue culture grew Mycobacterium avium-intracellulare (MAI). The patient began treatment with azithromycin, ethambutol, and rifabutin. Tissue susceptibilities later showed resistance to rifabutin and sensitivity to clarithromycin, moxifloxacin, and clofazimine. She subsequently was switched to azithromycin, clofazimine, and moxifloxacin with good response.

ct098008082_fig.png

Mycobacterium avium-intracellulare is a slow-growing, nonchromogenic, atypical mycobacteria. Although ubiquitous, it tends to only cause serious infection in the setting of immunosuppression. Transmission usually is through the respiratory or gastrointestinal tract.¹ Skin infections with MAI are uncommon and usually are secondary to seeding from disseminated infection or from direct inoculation.²

The clinical presentations of primary cutaneous MAI are myriad, including an isolated red nodule, multiple ulcers, abscesses, draining sinuses, facial nodules, granulomatous plaques, and panniculitis.^2,3 Of 3 reported cases of primary cutaneous MAI in the form of sporotrichoid lesions, 2 involved patients with AIDS² and 1 involved a cardiac transplant recipient.⁴

Cutaneous MAI is typically diagnosed with skin biopsy and tissue culture. Tissue culture is critical for determining the specific mycobacterial species and antibiotic susceptibilities. Polymerase chain reaction has been utilized to rapidly diagnose cutaneous MAI infection from an acid-fast bacilli–positive tissue sample in which the tissue culture was negative.⁵

Recommended treatment protocols for MAI involve multidrug regimens because of the intrinsic resistance of MAI and the concern for development of resistance with monotherapy.² No definitive guidelines exist for treatment of primary cutaneous MAI infections. However, regimens for the treatment of pulmonary infection that also have been successfully utilized for cutaneous infection include a macrolide, ethambutol, and a rifamycin.⁶ Clinicians should be aware of MAI as a cause of primary cutaneous infections presenting as lymphocutaneous suppurative nodules and ulcerations.

The Diagnosis: Atypical Mycobacterial Infection

Punch biopsy specimens demonstrated necrotizing granulomatous inflammation in the dermis and subcutis (Figure). Special staining for microorganisms was negative. Tissue culture grew Mycobacterium avium-intracellulare (MAI). The patient began treatment with azithromycin, ethambutol, and rifabutin. Tissue susceptibilities later showed resistance to rifabutin and sensitivity to clarithromycin, moxifloxacin, and clofazimine. She subsequently was switched to azithromycin, clofazimine, and moxifloxacin with good response.

ct098008082_fig.png

Mycobacterium avium-intracellulare is a slow-growing, nonchromogenic, atypical mycobacteria. Although ubiquitous, it tends to only cause serious infection in the setting of immunosuppression. Transmission usually is through the respiratory or gastrointestinal tract.¹ Skin infections with MAI are uncommon and usually are secondary to seeding from disseminated infection or from direct inoculation.²

The clinical presentations of primary cutaneous MAI are myriad, including an isolated red nodule, multiple ulcers, abscesses, draining sinuses, facial nodules, granulomatous plaques, and panniculitis.^2,3 Of 3 reported cases of primary cutaneous MAI in the form of sporotrichoid lesions, 2 involved patients with AIDS² and 1 involved a cardiac transplant recipient.⁴

Cutaneous MAI is typically diagnosed with skin biopsy and tissue culture. Tissue culture is critical for determining the specific mycobacterial species and antibiotic susceptibilities. Polymerase chain reaction has been utilized to rapidly diagnose cutaneous MAI infection from an acid-fast bacilli–positive tissue sample in which the tissue culture was negative.⁵

Recommended treatment protocols for MAI involve multidrug regimens because of the intrinsic resistance of MAI and the concern for development of resistance with monotherapy.² No definitive guidelines exist for treatment of primary cutaneous MAI infections. However, regimens for the treatment of pulmonary infection that also have been successfully utilized for cutaneous infection include a macrolide, ethambutol, and a rifamycin.⁶ Clinicians should be aware of MAI as a cause of primary cutaneous infections presenting as lymphocutaneous suppurative nodules and ulcerations.

The Diagnosis: Atypical Mycobacterial Infection

Punch biopsy specimens demonstrated necrotizing granulomatous inflammation in the dermis and subcutis (Figure). Special staining for microorganisms was negative. Tissue culture grew Mycobacterium avium-intracellulare (MAI). The patient began treatment with azithromycin, ethambutol, and rifabutin. Tissue susceptibilities later showed resistance to rifabutin and sensitivity to clarithromycin, moxifloxacin, and clofazimine. She subsequently was switched to azithromycin, clofazimine, and moxifloxacin with good response.

ct098008082_fig.png

Mycobacterium avium-intracellulare is a slow-growing, nonchromogenic, atypical mycobacteria. Although ubiquitous, it tends to only cause serious infection in the setting of immunosuppression. Transmission usually is through the respiratory or gastrointestinal tract.¹ Skin infections with MAI are uncommon and usually are secondary to seeding from disseminated infection or from direct inoculation.²

The clinical presentations of primary cutaneous MAI are myriad, including an isolated red nodule, multiple ulcers, abscesses, draining sinuses, facial nodules, granulomatous plaques, and panniculitis.^2,3 Of 3 reported cases of primary cutaneous MAI in the form of sporotrichoid lesions, 2 involved patients with AIDS² and 1 involved a cardiac transplant recipient.⁴

Cutaneous MAI is typically diagnosed with skin biopsy and tissue culture. Tissue culture is critical for determining the specific mycobacterial species and antibiotic susceptibilities. Polymerase chain reaction has been utilized to rapidly diagnose cutaneous MAI infection from an acid-fast bacilli–positive tissue sample in which the tissue culture was negative.⁵

Recommended treatment protocols for MAI involve multidrug regimens because of the intrinsic resistance of MAI and the concern for development of resistance with monotherapy.² No definitive guidelines exist for treatment of primary cutaneous MAI infections. However, regimens for the treatment of pulmonary infection that also have been successfully utilized for cutaneous infection include a macrolide, ethambutol, and a rifamycin.⁶ Clinicians should be aware of MAI as a cause of primary cutaneous infections presenting as lymphocutaneous suppurative nodules and ulcerations.