Autoimmune Diseases

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.

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

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).

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.

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

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).

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.

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

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).

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 American College of Rheumatology has released a summary of upcoming guidelines on screening, monitoring, and treatment for interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic disease.

The recommendations apply to adults with rheumatic diseases at greater risk for ILD: rheumatoid arthritis, systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM).

“Interstitial lung disease is a major cause of morbidity and mortality across several systemic autoimmune rheumatic diseases,” Sindhu R. Johnson, MD, PhD, lead author of the new guidelines and director of the clinical epidemiology and health care research program at the University of Toronto, said in an ACR press release. “Guidance was needed for which tests to use for screening and monitoring this particular disease.”

The two documents are summaries of part of a larger manuscript currently awaiting peer review, according to the ACR, and the final guidelines are anticipated to be published by early 2024.

The recommendations were developed using “the best available evidence and consensus across a range of expert opinions and incorporated patient values and preferences,” according to the press release.

Highlights of recommendations for screening and monitoring ILD are:

• Providers can screen patients at higher risk for ILD with pulmonary function tests (PFTs) and high-resolution CT of the chest.
• PFTs, chest high-resolution CT, and ambulatory desaturation testing are conditionally recommended for monitoring ILD progression.
• It is conditionally recommended that providers do not use 6-minute walk test distance, chest radiography, or bronchoscopy for screening or monitoring disease.
• It is suggested that patients with IIM-ILD and SSc-ILD receive PFTs for monitoring every 3-6 months during the first year, then less frequently once stable.
• It is suggested that patients with RA-ILD, SjD-ILD, and MCTD-ILD receive PFTs every 3-12 months for the first year, then less frequently once stable.

Suggestions on how often to screen for ILD were not present in the summary documents, but will be made available in the larger manuscript, said Elana Bernstein, MD, director of the Columbia University Medical Center/New York–Presbyterian Hospital scleroderma program, New York. She is co–first author of the guidelines.

Nearly all recommendations are conditional, primarily because the certainty of evidence behind many of these recommendations is low or very low, she said in an interview. More clinical data on ILD in patients with rheumatic disease would help strengthen evidence, she said, particularly for best practices in frequency of testing. “We need more research on how often patients should be screened for ILD and how often they should be monitored for ILD progression,” she said. “That would enable us to provide recommendations, rather than just suggestions.”

Highlights of recommendations for ILD treatment are:

• The guidelines strongly recommend against using glucocorticoids for first-line ILD treatment in patients with SSc-ILD.
• Short-term glucocorticoids are conditionally recommended as a first-line ILD treatment for patients with systemic autoimmune rheumatic disease–related ILD (SARD-ILD), excluding SSc-ILD.
• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all potential first-line ILD treatment options for patients with SARD-ILD.
• It is conditionally recommended that patients with SARD-ILD do not receive leflunomide, methotrexate, tumor necrosis factor inhibitors, or abatacept as first-line ILD treatment.
• If SARD-ILD progresses despite first-line therapy, mycophenolate, rituximab, cyclophosphamide, and nintedanib are potential secondary treatment options.
• If RA-ILD progresses following initial therapy, pirfenidone is a treatment option.
• The guidelines conditionally recommend against pirfenidone as a secondary treatment option for SARD-ILD other than RA-ILD.

These summary guidelines appear “comprehensive,” but there has yet to be information published on the basis of these recommendations, Elizabeth Volkmann, MD, said in an interview.

“It’s important to understand that we don’t know whether most of these recommendations were just driven by expert opinion versus actual evidence from randomized, controlled clinical trials,” said Dr. Volkmann, who codirects the connective tissue disease–related interstitial lung disease program at the University of California, Los Angeles. She was not involved with creating the guidelines.

She expects that many of the recommendations for first- and second-line ILD treatment options were based on expert opinion, as there have been no randomized clinical trials looking at that specific topic, she said. For example, nintedanib is conditionally recommended as a first-line treatment option for SSc-ILD, but as a second-line treatment for SjD-ILD, IIM-ILD, and MCTD-ILD. “There’s no literature to support one or the other – whether nintedanib is first-line or second-line [treatment].”

The decision to publish the summary recommendations online prior to peer review is unusual, she said, as these recommendations could be altered during that process; however, Dr. Bernstein noted that was not likely.

By releasing the summary guideline now, the ACR can “get the needed information to clinicians earlier as the manuscript goes through its remaining stages and is finalized,” an ACR representative explained.

Prior to the expected publication of these guidelines in early 2024, Dr. Volkmann noted that the American Thoracic Society will be publishing guidelines on the treatment of SSc-ILD in the American Journal of Respiratory and Critical Care Medicine in September.

Dr. Bernstein reported grants/contracts with the Department of Defense, the Scleroderma Research Foundation, the National Institutes of Health, Eicos, Boehringer Ingelheim, Kadmon, and Pfizer. Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and GlaxoSmithKline and institutional support for performing studies on systemic sclerosis for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus.

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

The American College of Rheumatology has released a summary of upcoming guidelines on screening, monitoring, and treatment for interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic disease.

The recommendations apply to adults with rheumatic diseases at greater risk for ILD: rheumatoid arthritis, systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM).

“Interstitial lung disease is a major cause of morbidity and mortality across several systemic autoimmune rheumatic diseases,” Sindhu R. Johnson, MD, PhD, lead author of the new guidelines and director of the clinical epidemiology and health care research program at the University of Toronto, said in an ACR press release. “Guidance was needed for which tests to use for screening and monitoring this particular disease.”

The two documents are summaries of part of a larger manuscript currently awaiting peer review, according to the ACR, and the final guidelines are anticipated to be published by early 2024.

The recommendations were developed using “the best available evidence and consensus across a range of expert opinions and incorporated patient values and preferences,” according to the press release.

Highlights of recommendations for screening and monitoring ILD are:

• Providers can screen patients at higher risk for ILD with pulmonary function tests (PFTs) and high-resolution CT of the chest.
• PFTs, chest high-resolution CT, and ambulatory desaturation testing are conditionally recommended for monitoring ILD progression.
• It is conditionally recommended that providers do not use 6-minute walk test distance, chest radiography, or bronchoscopy for screening or monitoring disease.
• It is suggested that patients with IIM-ILD and SSc-ILD receive PFTs for monitoring every 3-6 months during the first year, then less frequently once stable.
• It is suggested that patients with RA-ILD, SjD-ILD, and MCTD-ILD receive PFTs every 3-12 months for the first year, then less frequently once stable.

Suggestions on how often to screen for ILD were not present in the summary documents, but will be made available in the larger manuscript, said Elana Bernstein, MD, director of the Columbia University Medical Center/New York–Presbyterian Hospital scleroderma program, New York. She is co–first author of the guidelines.

Nearly all recommendations are conditional, primarily because the certainty of evidence behind many of these recommendations is low or very low, she said in an interview. More clinical data on ILD in patients with rheumatic disease would help strengthen evidence, she said, particularly for best practices in frequency of testing. “We need more research on how often patients should be screened for ILD and how often they should be monitored for ILD progression,” she said. “That would enable us to provide recommendations, rather than just suggestions.”

Highlights of recommendations for ILD treatment are:

• The guidelines strongly recommend against using glucocorticoids for first-line ILD treatment in patients with SSc-ILD.
• Short-term glucocorticoids are conditionally recommended as a first-line ILD treatment for patients with systemic autoimmune rheumatic disease–related ILD (SARD-ILD), excluding SSc-ILD.
• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all potential first-line ILD treatment options for patients with SARD-ILD.
• It is conditionally recommended that patients with SARD-ILD do not receive leflunomide, methotrexate, tumor necrosis factor inhibitors, or abatacept as first-line ILD treatment.
• If SARD-ILD progresses despite first-line therapy, mycophenolate, rituximab, cyclophosphamide, and nintedanib are potential secondary treatment options.
• If RA-ILD progresses following initial therapy, pirfenidone is a treatment option.
• The guidelines conditionally recommend against pirfenidone as a secondary treatment option for SARD-ILD other than RA-ILD.

These summary guidelines appear “comprehensive,” but there has yet to be information published on the basis of these recommendations, Elizabeth Volkmann, MD, said in an interview.

“It’s important to understand that we don’t know whether most of these recommendations were just driven by expert opinion versus actual evidence from randomized, controlled clinical trials,” said Dr. Volkmann, who codirects the connective tissue disease–related interstitial lung disease program at the University of California, Los Angeles. She was not involved with creating the guidelines.

She expects that many of the recommendations for first- and second-line ILD treatment options were based on expert opinion, as there have been no randomized clinical trials looking at that specific topic, she said. For example, nintedanib is conditionally recommended as a first-line treatment option for SSc-ILD, but as a second-line treatment for SjD-ILD, IIM-ILD, and MCTD-ILD. “There’s no literature to support one or the other – whether nintedanib is first-line or second-line [treatment].”

The decision to publish the summary recommendations online prior to peer review is unusual, she said, as these recommendations could be altered during that process; however, Dr. Bernstein noted that was not likely.

By releasing the summary guideline now, the ACR can “get the needed information to clinicians earlier as the manuscript goes through its remaining stages and is finalized,” an ACR representative explained.

Prior to the expected publication of these guidelines in early 2024, Dr. Volkmann noted that the American Thoracic Society will be publishing guidelines on the treatment of SSc-ILD in the American Journal of Respiratory and Critical Care Medicine in September.

Dr. Bernstein reported grants/contracts with the Department of Defense, the Scleroderma Research Foundation, the National Institutes of Health, Eicos, Boehringer Ingelheim, Kadmon, and Pfizer. Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and GlaxoSmithKline and institutional support for performing studies on systemic sclerosis for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus.

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

The American College of Rheumatology has released a summary of upcoming guidelines on screening, monitoring, and treatment for interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic disease.

The recommendations apply to adults with rheumatic diseases at greater risk for ILD: rheumatoid arthritis, systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren’s disease (SjD), and idiopathic inflammatory myopathies (IIM).

“Interstitial lung disease is a major cause of morbidity and mortality across several systemic autoimmune rheumatic diseases,” Sindhu R. Johnson, MD, PhD, lead author of the new guidelines and director of the clinical epidemiology and health care research program at the University of Toronto, said in an ACR press release. “Guidance was needed for which tests to use for screening and monitoring this particular disease.”

The two documents are summaries of part of a larger manuscript currently awaiting peer review, according to the ACR, and the final guidelines are anticipated to be published by early 2024.

The recommendations were developed using “the best available evidence and consensus across a range of expert opinions and incorporated patient values and preferences,” according to the press release.

Highlights of recommendations for screening and monitoring ILD are:

• Providers can screen patients at higher risk for ILD with pulmonary function tests (PFTs) and high-resolution CT of the chest.
• PFTs, chest high-resolution CT, and ambulatory desaturation testing are conditionally recommended for monitoring ILD progression.
• It is conditionally recommended that providers do not use 6-minute walk test distance, chest radiography, or bronchoscopy for screening or monitoring disease.
• It is suggested that patients with IIM-ILD and SSc-ILD receive PFTs for monitoring every 3-6 months during the first year, then less frequently once stable.
• It is suggested that patients with RA-ILD, SjD-ILD, and MCTD-ILD receive PFTs every 3-12 months for the first year, then less frequently once stable.

Suggestions on how often to screen for ILD were not present in the summary documents, but will be made available in the larger manuscript, said Elana Bernstein, MD, director of the Columbia University Medical Center/New York–Presbyterian Hospital scleroderma program, New York. She is co–first author of the guidelines.

Nearly all recommendations are conditional, primarily because the certainty of evidence behind many of these recommendations is low or very low, she said in an interview. More clinical data on ILD in patients with rheumatic disease would help strengthen evidence, she said, particularly for best practices in frequency of testing. “We need more research on how often patients should be screened for ILD and how often they should be monitored for ILD progression,” she said. “That would enable us to provide recommendations, rather than just suggestions.”

Highlights of recommendations for ILD treatment are:

• The guidelines strongly recommend against using glucocorticoids for first-line ILD treatment in patients with SSc-ILD.
• Short-term glucocorticoids are conditionally recommended as a first-line ILD treatment for patients with systemic autoimmune rheumatic disease–related ILD (SARD-ILD), excluding SSc-ILD.
• Mycophenolate, azathioprine, rituximab, and cyclophosphamide are all potential first-line ILD treatment options for patients with SARD-ILD.
• It is conditionally recommended that patients with SARD-ILD do not receive leflunomide, methotrexate, tumor necrosis factor inhibitors, or abatacept as first-line ILD treatment.
• If SARD-ILD progresses despite first-line therapy, mycophenolate, rituximab, cyclophosphamide, and nintedanib are potential secondary treatment options.
• If RA-ILD progresses following initial therapy, pirfenidone is a treatment option.
• The guidelines conditionally recommend against pirfenidone as a secondary treatment option for SARD-ILD other than RA-ILD.

These summary guidelines appear “comprehensive,” but there has yet to be information published on the basis of these recommendations, Elizabeth Volkmann, MD, said in an interview.

“It’s important to understand that we don’t know whether most of these recommendations were just driven by expert opinion versus actual evidence from randomized, controlled clinical trials,” said Dr. Volkmann, who codirects the connective tissue disease–related interstitial lung disease program at the University of California, Los Angeles. She was not involved with creating the guidelines.

She expects that many of the recommendations for first- and second-line ILD treatment options were based on expert opinion, as there have been no randomized clinical trials looking at that specific topic, she said. For example, nintedanib is conditionally recommended as a first-line treatment option for SSc-ILD, but as a second-line treatment for SjD-ILD, IIM-ILD, and MCTD-ILD. “There’s no literature to support one or the other – whether nintedanib is first-line or second-line [treatment].”

The decision to publish the summary recommendations online prior to peer review is unusual, she said, as these recommendations could be altered during that process; however, Dr. Bernstein noted that was not likely.

By releasing the summary guideline now, the ACR can “get the needed information to clinicians earlier as the manuscript goes through its remaining stages and is finalized,” an ACR representative explained.

Prior to the expected publication of these guidelines in early 2024, Dr. Volkmann noted that the American Thoracic Society will be publishing guidelines on the treatment of SSc-ILD in the American Journal of Respiratory and Critical Care Medicine in September.

Dr. Bernstein reported grants/contracts with the Department of Defense, the Scleroderma Research Foundation, the National Institutes of Health, Eicos, Boehringer Ingelheim, Kadmon, and Pfizer. Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and GlaxoSmithKline and institutional support for performing studies on systemic sclerosis for Kadmon, Boehringer Ingelheim, Horizon, and Prometheus.

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

The Diagnosis: Neonatal Lupus Erythematosus

A review of the medical records of the patient’s mother from her first pregnancy revealed positive anti-Ro/SSA (Sjögren syndrome A) (>8.0 U [reference range <1.0 U]) and anti-La/SSB (Sjögren syndrome B) antibodies (>8.0 U [reference range <1.0 U]), which were reconfirmed during her pregnancy with our patient (the second child). The patient’s older brother was diagnosed with neonatal lupus erythematosus (NLE) 2 years prior at 1 month of age; therefore, the mother took hydroxychloroquine during the pregnancy with the second child to help prevent heart block if the child was diagnosed with NLE. Given the family history, positive antibodies in the mother, and clinical presentation, our patient was diagnosed with NLE. He was referred to a pediatric cardiologist and pediatrician to continue the workup of systemic manifestations of NLE and to rule out the presence of congenital heart block. The rash resolved 6 months after the initial presentation, and he did not develop any systemic manifestations of NLE.

Neonatal lupus erythematosus is a rare acquired autoimmune disorder caused by the placental transfer of anti-Ro/SSA and anti-La/SSB antibodies and less commonly anti-U1 ribonucleoprotein antinuclear autoantibodies.^1,2 Approximately 1% to 2% of mothers with these positive antibodies will have infants affected with NLE.² The annual prevalence of NLE in the United States is approximately 1 in 20,000 live births. Mothers of children with NLE most commonly have clinical Sjögren syndrome; however, anti-Ro/SSA and anti-LA/SSB antibodies may be present in 0.1% to 1.5% of healthy women, and 25% to 60% of women with autoimmune disease may be asymptomatic.¹ As demonstrated in our case, when there is a family history of NLE in an infant from an earlier pregnancy, the risk for NLE increases to 17% to 20% in subsequent pregnancies^1,3 and up to 25% in subsequent pregnancies if the initial child was diagnosed with a congenital heart block in the setting of NLE.¹

Neonatal lupus erythematosus classically presents as annular erythematous macules and plaques with central scaling, telangictasia, atrophy, and pigmentary changes. It may start on the scalp and face and spread caudally.^1,2 Patients may develop these lesions after UV exposure, and 80% of infants may not have dermatologic findings at birth. Importantly, 40% to 60% of mothers may be asymptomatic at the time of presentation of their child’s NLE.¹ The diagnosis can be confirmed via antibody testing in the mother and/or infant. If performed, a punch biopsy shows interface dermatitis, vacuolar degeneration, and possible periadnexal lymphocytic infiltrates on histopathology.^1,2

Management of cutaneous NLE includes sun protection (eg, application of sunscreen) and topical corticosteroids. Most dermatologic manifestations of NLE are transient, resolving after clearance of maternal IgG antibodies in 6 to 9 months; however, some telangiectasia, dyspigmentation, and atrophic scarring may persist.^1-3

Neonatal lupus erythematosus also may have hepatobiliary, cardiac, hematologic, and less commonly neurologic manifestations. Hepatobiliary manifestations usually present as hepatomegaly or asymptomatic elevated transaminases or γ-glutamyl transferase.^1,3 Approximately 10% to 20% of infants with NLE may present with transient anemia and thrombocytopenia.¹ Cardiac manifestations are permanent and may require pacemaker implantation.^1,3 The incidence of a congenital heart block in infants with NLE is 15% to 30%.³ Cardiac NLE most commonly injures the conductive tissue, leading to a congenital atrioventricular block. The development of a congenital heart block develops in the 18th to 24th week of gestation. Manifestations of a more advanced condition can include dilation of the ascending aorta and dilated cardiomyopathy.¹ As such, patients need to be followed by a pediatric cardiologist for monitoring and treatment of any cardiac manifestations.

The overall prognosis of infants affected with NLE varies. Cardiac involvement is associated with a poor prognosis, while isolated cutaneous involvement requires little treatment and portends a favorable prognosis. It is critical for dermatologists to recognize NLE to refer patients to appropriate specialists to investigate and further monitor possible extracutaneous manifestations. With an understanding of the increased risk for a congenital heart block and NLE in subsequent pregnancies, mothers with positive anti-Ro/La antibodies should receive timely counseling and screening. In expectant mothers with suspected autoimmune disease, testing for antinuclear antibodies and SSA and SSB antibodies can be considered, as administration of hydroxychloroquine or prenatal systemic corticosteroids has proven to be effective in preventing a congenital heart block.¹ Our patient was followed by pediatric cardiology and was not found to have a congenital heart block.

The differential diagnosis includes other causes of annular erythema in infants, as NLE can mimic several conditions. Tinea corporis may present as scaly annular plaques with central clearing; however, it rarely is encountered fulminantly in neonates.⁴ Erythema multiforme is a mucocutaneous hypersensitivy reaction distinguished by targetoid morphology.⁵ It is an exceedingly rare diagnosis in neonates; the average pediatric age of onset is 5.6 years.⁶ Erythema multiforme often is associated with an infection, most commonly herpes simplex virus,⁵ and mucosal involvement is common.⁶ Urticaria multiforme (also known as acute annular urticaria) is a benign disease that appears between 2 months to 3 years of age with blanchable urticarial plaques that likely are triggered by viral or bacterial infections, antibiotics, or vaccines.⁶ Specific lesions usually will resolve within 24 hours. Annular erythema of infancy is a benign and asymptomatic gyrate erythema that presents as annular plaques with palpable borders that spread centrifugally in patients younger than 1 year. Notably, lesions should periodically fade and may reappear cyclically for months to years. Evaluation for underlying disease usually is negative.⁶

The Diagnosis: Neonatal Lupus Erythematosus

A review of the medical records of the patient’s mother from her first pregnancy revealed positive anti-Ro/SSA (Sjögren syndrome A) (>8.0 U [reference range <1.0 U]) and anti-La/SSB (Sjögren syndrome B) antibodies (>8.0 U [reference range <1.0 U]), which were reconfirmed during her pregnancy with our patient (the second child). The patient’s older brother was diagnosed with neonatal lupus erythematosus (NLE) 2 years prior at 1 month of age; therefore, the mother took hydroxychloroquine during the pregnancy with the second child to help prevent heart block if the child was diagnosed with NLE. Given the family history, positive antibodies in the mother, and clinical presentation, our patient was diagnosed with NLE. He was referred to a pediatric cardiologist and pediatrician to continue the workup of systemic manifestations of NLE and to rule out the presence of congenital heart block. The rash resolved 6 months after the initial presentation, and he did not develop any systemic manifestations of NLE.

Neonatal lupus erythematosus is a rare acquired autoimmune disorder caused by the placental transfer of anti-Ro/SSA and anti-La/SSB antibodies and less commonly anti-U1 ribonucleoprotein antinuclear autoantibodies.^1,2 Approximately 1% to 2% of mothers with these positive antibodies will have infants affected with NLE.² The annual prevalence of NLE in the United States is approximately 1 in 20,000 live births. Mothers of children with NLE most commonly have clinical Sjögren syndrome; however, anti-Ro/SSA and anti-LA/SSB antibodies may be present in 0.1% to 1.5% of healthy women, and 25% to 60% of women with autoimmune disease may be asymptomatic.¹ As demonstrated in our case, when there is a family history of NLE in an infant from an earlier pregnancy, the risk for NLE increases to 17% to 20% in subsequent pregnancies^1,3 and up to 25% in subsequent pregnancies if the initial child was diagnosed with a congenital heart block in the setting of NLE.¹

Neonatal lupus erythematosus classically presents as annular erythematous macules and plaques with central scaling, telangictasia, atrophy, and pigmentary changes. It may start on the scalp and face and spread caudally.^1,2 Patients may develop these lesions after UV exposure, and 80% of infants may not have dermatologic findings at birth. Importantly, 40% to 60% of mothers may be asymptomatic at the time of presentation of their child’s NLE.¹ The diagnosis can be confirmed via antibody testing in the mother and/or infant. If performed, a punch biopsy shows interface dermatitis, vacuolar degeneration, and possible periadnexal lymphocytic infiltrates on histopathology.^1,2

Management of cutaneous NLE includes sun protection (eg, application of sunscreen) and topical corticosteroids. Most dermatologic manifestations of NLE are transient, resolving after clearance of maternal IgG antibodies in 6 to 9 months; however, some telangiectasia, dyspigmentation, and atrophic scarring may persist.^1-3

Neonatal lupus erythematosus also may have hepatobiliary, cardiac, hematologic, and less commonly neurologic manifestations. Hepatobiliary manifestations usually present as hepatomegaly or asymptomatic elevated transaminases or γ-glutamyl transferase.^1,3 Approximately 10% to 20% of infants with NLE may present with transient anemia and thrombocytopenia.¹ Cardiac manifestations are permanent and may require pacemaker implantation.^1,3 The incidence of a congenital heart block in infants with NLE is 15% to 30%.³ Cardiac NLE most commonly injures the conductive tissue, leading to a congenital atrioventricular block. The development of a congenital heart block develops in the 18th to 24th week of gestation. Manifestations of a more advanced condition can include dilation of the ascending aorta and dilated cardiomyopathy.¹ As such, patients need to be followed by a pediatric cardiologist for monitoring and treatment of any cardiac manifestations.

The overall prognosis of infants affected with NLE varies. Cardiac involvement is associated with a poor prognosis, while isolated cutaneous involvement requires little treatment and portends a favorable prognosis. It is critical for dermatologists to recognize NLE to refer patients to appropriate specialists to investigate and further monitor possible extracutaneous manifestations. With an understanding of the increased risk for a congenital heart block and NLE in subsequent pregnancies, mothers with positive anti-Ro/La antibodies should receive timely counseling and screening. In expectant mothers with suspected autoimmune disease, testing for antinuclear antibodies and SSA and SSB antibodies can be considered, as administration of hydroxychloroquine or prenatal systemic corticosteroids has proven to be effective in preventing a congenital heart block.¹ Our patient was followed by pediatric cardiology and was not found to have a congenital heart block.

The differential diagnosis includes other causes of annular erythema in infants, as NLE can mimic several conditions. Tinea corporis may present as scaly annular plaques with central clearing; however, it rarely is encountered fulminantly in neonates.⁴ Erythema multiforme is a mucocutaneous hypersensitivy reaction distinguished by targetoid morphology.⁵ It is an exceedingly rare diagnosis in neonates; the average pediatric age of onset is 5.6 years.⁶ Erythema multiforme often is associated with an infection, most commonly herpes simplex virus,⁵ and mucosal involvement is common.⁶ Urticaria multiforme (also known as acute annular urticaria) is a benign disease that appears between 2 months to 3 years of age with blanchable urticarial plaques that likely are triggered by viral or bacterial infections, antibiotics, or vaccines.⁶ Specific lesions usually will resolve within 24 hours. Annular erythema of infancy is a benign and asymptomatic gyrate erythema that presents as annular plaques with palpable borders that spread centrifugally in patients younger than 1 year. Notably, lesions should periodically fade and may reappear cyclically for months to years. Evaluation for underlying disease usually is negative.⁶

The Diagnosis: Neonatal Lupus Erythematosus

A review of the medical records of the patient’s mother from her first pregnancy revealed positive anti-Ro/SSA (Sjögren syndrome A) (>8.0 U [reference range <1.0 U]) and anti-La/SSB (Sjögren syndrome B) antibodies (>8.0 U [reference range <1.0 U]), which were reconfirmed during her pregnancy with our patient (the second child). The patient’s older brother was diagnosed with neonatal lupus erythematosus (NLE) 2 years prior at 1 month of age; therefore, the mother took hydroxychloroquine during the pregnancy with the second child to help prevent heart block if the child was diagnosed with NLE. Given the family history, positive antibodies in the mother, and clinical presentation, our patient was diagnosed with NLE. He was referred to a pediatric cardiologist and pediatrician to continue the workup of systemic manifestations of NLE and to rule out the presence of congenital heart block. The rash resolved 6 months after the initial presentation, and he did not develop any systemic manifestations of NLE.

Neonatal lupus erythematosus is a rare acquired autoimmune disorder caused by the placental transfer of anti-Ro/SSA and anti-La/SSB antibodies and less commonly anti-U1 ribonucleoprotein antinuclear autoantibodies.^1,2 Approximately 1% to 2% of mothers with these positive antibodies will have infants affected with NLE.² The annual prevalence of NLE in the United States is approximately 1 in 20,000 live births. Mothers of children with NLE most commonly have clinical Sjögren syndrome; however, anti-Ro/SSA and anti-LA/SSB antibodies may be present in 0.1% to 1.5% of healthy women, and 25% to 60% of women with autoimmune disease may be asymptomatic.¹ As demonstrated in our case, when there is a family history of NLE in an infant from an earlier pregnancy, the risk for NLE increases to 17% to 20% in subsequent pregnancies^1,3 and up to 25% in subsequent pregnancies if the initial child was diagnosed with a congenital heart block in the setting of NLE.¹

Neonatal lupus erythematosus classically presents as annular erythematous macules and plaques with central scaling, telangictasia, atrophy, and pigmentary changes. It may start on the scalp and face and spread caudally.^1,2 Patients may develop these lesions after UV exposure, and 80% of infants may not have dermatologic findings at birth. Importantly, 40% to 60% of mothers may be asymptomatic at the time of presentation of their child’s NLE.¹ The diagnosis can be confirmed via antibody testing in the mother and/or infant. If performed, a punch biopsy shows interface dermatitis, vacuolar degeneration, and possible periadnexal lymphocytic infiltrates on histopathology.^1,2

Management of cutaneous NLE includes sun protection (eg, application of sunscreen) and topical corticosteroids. Most dermatologic manifestations of NLE are transient, resolving after clearance of maternal IgG antibodies in 6 to 9 months; however, some telangiectasia, dyspigmentation, and atrophic scarring may persist.^1-3

Neonatal lupus erythematosus also may have hepatobiliary, cardiac, hematologic, and less commonly neurologic manifestations. Hepatobiliary manifestations usually present as hepatomegaly or asymptomatic elevated transaminases or γ-glutamyl transferase.^1,3 Approximately 10% to 20% of infants with NLE may present with transient anemia and thrombocytopenia.¹ Cardiac manifestations are permanent and may require pacemaker implantation.^1,3 The incidence of a congenital heart block in infants with NLE is 15% to 30%.³ Cardiac NLE most commonly injures the conductive tissue, leading to a congenital atrioventricular block. The development of a congenital heart block develops in the 18th to 24th week of gestation. Manifestations of a more advanced condition can include dilation of the ascending aorta and dilated cardiomyopathy.¹ As such, patients need to be followed by a pediatric cardiologist for monitoring and treatment of any cardiac manifestations.

The overall prognosis of infants affected with NLE varies. Cardiac involvement is associated with a poor prognosis, while isolated cutaneous involvement requires little treatment and portends a favorable prognosis. It is critical for dermatologists to recognize NLE to refer patients to appropriate specialists to investigate and further monitor possible extracutaneous manifestations. With an understanding of the increased risk for a congenital heart block and NLE in subsequent pregnancies, mothers with positive anti-Ro/La antibodies should receive timely counseling and screening. In expectant mothers with suspected autoimmune disease, testing for antinuclear antibodies and SSA and SSB antibodies can be considered, as administration of hydroxychloroquine or prenatal systemic corticosteroids has proven to be effective in preventing a congenital heart block.¹ Our patient was followed by pediatric cardiology and was not found to have a congenital heart block.

The differential diagnosis includes other causes of annular erythema in infants, as NLE can mimic several conditions. Tinea corporis may present as scaly annular plaques with central clearing; however, it rarely is encountered fulminantly in neonates.⁴ Erythema multiforme is a mucocutaneous hypersensitivy reaction distinguished by targetoid morphology.⁵ It is an exceedingly rare diagnosis in neonates; the average pediatric age of onset is 5.6 years.⁶ Erythema multiforme often is associated with an infection, most commonly herpes simplex virus,⁵ and mucosal involvement is common.⁶ Urticaria multiforme (also known as acute annular urticaria) is a benign disease that appears between 2 months to 3 years of age with blanchable urticarial plaques that likely are triggered by viral or bacterial infections, antibiotics, or vaccines.⁶ Specific lesions usually will resolve within 24 hours. Annular erythema of infancy is a benign and asymptomatic gyrate erythema that presents as annular plaques with palpable borders that spread centrifugally in patients younger than 1 year. Notably, lesions should periodically fade and may reappear cyclically for months to years. Evaluation for underlying disease usually is negative.⁶

Dermatomyositis is a rare autoimmune condition characterized by muscle inflammation and weakness, and skin findings. The classical presentation includes symmetric proximal muscle weakness and underlying malignancy and is very common in adult patients. The etiology is unknown, however.

Courtesy Lucas Shapiro and Dr. Natalie Y. Nasser

Some studies suggest people with certain HLA subtypes are at higher risk, and various infectious and pharmacological triggers are suspected to play a role in the pathogenesis of dermatomyositis. Infectious causes include Coxsackie B, enterovirus, and parvovirus. Drugs such as antineoplastic agents, antibiotics, and NSAIDs have been found to be triggers.

The pathogenesis of dermatomyositis involves immune-mediated damage to muscle capillaries and the endothelium of arterioles. In the typical humoral immune response, complement activation occurs. One mechanism of damage in dermatomyositis occurs when the membrane attack complex formed at the end of the complement process deposits in blood vessels, causing inflammation. B cells, autoantibodies, and interferon overexpression may also play a role in damaging the vasculature and muscle fibers. Hypoxia leads to muscular atrophy, resulting in degeneration and death of the fibers. On muscle biopsy, a perivascular and perimysial inflammatory infiltrate, perifascicular atrophy, and microangiopathy may be present. Skin histology reveals vacuolar changes in the basal layer, a lymphocytic infiltrate, and increased mucin production in the dermis.

On clinical examination, patients will have proximal muscle weakness and a skin rash that may include Gottron’s papules, heliotrope erythema, V-sign, shawl sign, holster sign, scalp erythema, midfacial erythema, and photosensitivity. Scalp erythema in dermatomyositis is highly linked to pruritus, alopecia, and telogen effluvium. Patients may experience small fiber neuropathy in dermatomyositis.

Serologies for this patient, who had previously been diagnosed and treated for dermatomyositis, were significant for a positive ANA 1:2560. Anti-Jo-1 antibody was negative. Her liver function tests, aldolase, creatinine kinase, sedimentation rate, C-reactive protein, and serum protein electrophoresis were normal. Imaging revealed mild chronic interstitial lung disease. A malignancy workup was negative.

Treatment of dermatomyositis involves lifestyle changes and pharmacologic therapy. Because of the intense photosensitivity, patients should be diligent with their sun protection. Methotrexate, azathioprine, and mycophenolate mofetil are considered first-line therapies for dermatomyositis. Therapies such as cyclophosphamide, rituximab, IVIg, and plasmapheresis may also be indicated in severe or refractory cases. Additionally, patients with pulmonary involvement should be given systemic steroids. The side effects of these drugs must be considered in the context of the patient’s demographics, comorbidities and lifestyle.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Natalie Y. Nasser, MD, of Kaiser Permanente Riverside Medical Center, Riverside, Calif. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. Qudsiya Z and Waseem M. Dermatomyositis, in “StatPearls.” Treasure Island, Fla.: StatPearls Publishing, 2023 Jan.

2. Kamperman RG et al. Int J Mol Sci. 2022 Apr 13;23(8):4301.

3. Kassamali B et al. Int J WomensDermatol. 2021 Sep 24;7(5Part A):576-82.

4. Vázquez-Herrera NE et al. Skin Appendage Disord. 2018 Aug;4(3):187-99.

Dermatomyositis is a rare autoimmune condition characterized by muscle inflammation and weakness, and skin findings. The classical presentation includes symmetric proximal muscle weakness and underlying malignancy and is very common in adult patients. The etiology is unknown, however.

Courtesy Lucas Shapiro and Dr. Natalie Y. Nasser

Some studies suggest people with certain HLA subtypes are at higher risk, and various infectious and pharmacological triggers are suspected to play a role in the pathogenesis of dermatomyositis. Infectious causes include Coxsackie B, enterovirus, and parvovirus. Drugs such as antineoplastic agents, antibiotics, and NSAIDs have been found to be triggers.

The pathogenesis of dermatomyositis involves immune-mediated damage to muscle capillaries and the endothelium of arterioles. In the typical humoral immune response, complement activation occurs. One mechanism of damage in dermatomyositis occurs when the membrane attack complex formed at the end of the complement process deposits in blood vessels, causing inflammation. B cells, autoantibodies, and interferon overexpression may also play a role in damaging the vasculature and muscle fibers. Hypoxia leads to muscular atrophy, resulting in degeneration and death of the fibers. On muscle biopsy, a perivascular and perimysial inflammatory infiltrate, perifascicular atrophy, and microangiopathy may be present. Skin histology reveals vacuolar changes in the basal layer, a lymphocytic infiltrate, and increased mucin production in the dermis.

On clinical examination, patients will have proximal muscle weakness and a skin rash that may include Gottron’s papules, heliotrope erythema, V-sign, shawl sign, holster sign, scalp erythema, midfacial erythema, and photosensitivity. Scalp erythema in dermatomyositis is highly linked to pruritus, alopecia, and telogen effluvium. Patients may experience small fiber neuropathy in dermatomyositis.

Serologies for this patient, who had previously been diagnosed and treated for dermatomyositis, were significant for a positive ANA 1:2560. Anti-Jo-1 antibody was negative. Her liver function tests, aldolase, creatinine kinase, sedimentation rate, C-reactive protein, and serum protein electrophoresis were normal. Imaging revealed mild chronic interstitial lung disease. A malignancy workup was negative.

Treatment of dermatomyositis involves lifestyle changes and pharmacologic therapy. Because of the intense photosensitivity, patients should be diligent with their sun protection. Methotrexate, azathioprine, and mycophenolate mofetil are considered first-line therapies for dermatomyositis. Therapies such as cyclophosphamide, rituximab, IVIg, and plasmapheresis may also be indicated in severe or refractory cases. Additionally, patients with pulmonary involvement should be given systemic steroids. The side effects of these drugs must be considered in the context of the patient’s demographics, comorbidities and lifestyle.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Natalie Y. Nasser, MD, of Kaiser Permanente Riverside Medical Center, Riverside, Calif. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. Qudsiya Z and Waseem M. Dermatomyositis, in “StatPearls.” Treasure Island, Fla.: StatPearls Publishing, 2023 Jan.

2. Kamperman RG et al. Int J Mol Sci. 2022 Apr 13;23(8):4301.

3. Kassamali B et al. Int J WomensDermatol. 2021 Sep 24;7(5Part A):576-82.

4. Vázquez-Herrera NE et al. Skin Appendage Disord. 2018 Aug;4(3):187-99.

Dermatomyositis is a rare autoimmune condition characterized by muscle inflammation and weakness, and skin findings. The classical presentation includes symmetric proximal muscle weakness and underlying malignancy and is very common in adult patients. The etiology is unknown, however.

Courtesy Lucas Shapiro and Dr. Natalie Y. Nasser

Some studies suggest people with certain HLA subtypes are at higher risk, and various infectious and pharmacological triggers are suspected to play a role in the pathogenesis of dermatomyositis. Infectious causes include Coxsackie B, enterovirus, and parvovirus. Drugs such as antineoplastic agents, antibiotics, and NSAIDs have been found to be triggers.

The pathogenesis of dermatomyositis involves immune-mediated damage to muscle capillaries and the endothelium of arterioles. In the typical humoral immune response, complement activation occurs. One mechanism of damage in dermatomyositis occurs when the membrane attack complex formed at the end of the complement process deposits in blood vessels, causing inflammation. B cells, autoantibodies, and interferon overexpression may also play a role in damaging the vasculature and muscle fibers. Hypoxia leads to muscular atrophy, resulting in degeneration and death of the fibers. On muscle biopsy, a perivascular and perimysial inflammatory infiltrate, perifascicular atrophy, and microangiopathy may be present. Skin histology reveals vacuolar changes in the basal layer, a lymphocytic infiltrate, and increased mucin production in the dermis.

On clinical examination, patients will have proximal muscle weakness and a skin rash that may include Gottron’s papules, heliotrope erythema, V-sign, shawl sign, holster sign, scalp erythema, midfacial erythema, and photosensitivity. Scalp erythema in dermatomyositis is highly linked to pruritus, alopecia, and telogen effluvium. Patients may experience small fiber neuropathy in dermatomyositis.

Serologies for this patient, who had previously been diagnosed and treated for dermatomyositis, were significant for a positive ANA 1:2560. Anti-Jo-1 antibody was negative. Her liver function tests, aldolase, creatinine kinase, sedimentation rate, C-reactive protein, and serum protein electrophoresis were normal. Imaging revealed mild chronic interstitial lung disease. A malignancy workup was negative.

Treatment of dermatomyositis involves lifestyle changes and pharmacologic therapy. Because of the intense photosensitivity, patients should be diligent with their sun protection. Methotrexate, azathioprine, and mycophenolate mofetil are considered first-line therapies for dermatomyositis. Therapies such as cyclophosphamide, rituximab, IVIg, and plasmapheresis may also be indicated in severe or refractory cases. Additionally, patients with pulmonary involvement should be given systemic steroids. The side effects of these drugs must be considered in the context of the patient’s demographics, comorbidities and lifestyle.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Natalie Y. Nasser, MD, of Kaiser Permanente Riverside Medical Center, Riverside, Calif. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

1. Qudsiya Z and Waseem M. Dermatomyositis, in “StatPearls.” Treasure Island, Fla.: StatPearls Publishing, 2023 Jan.

2. Kamperman RG et al. Int J Mol Sci. 2022 Apr 13;23(8):4301.

3. Kassamali B et al. Int J WomensDermatol. 2021 Sep 24;7(5Part A):576-82.

4. Vázquez-Herrera NE et al. Skin Appendage Disord. 2018 Aug;4(3):187-99.

The Diagnosis: Pretibial Myxedema

Histopathology showed superficial and deep mucin deposition with proliferation of fibroblasts and thin wiry collagen bundles that were consistent with a diagnosis of pretibial myxedema. The patient was treated with clobetasol ointment 0.05% twice daily for 3 months, followed by a trial of pentoxifylline 400 mg 3 times daily for 3 months. After this treatment failed, she was started on rituximab infusions of 1 g biweekly for 1 month, followed by 500 mg at 6 months, with marked improvement after the first 2 doses of 1 g.

Pretibial myxedema is an uncommon cutaneous manifestation of autoimmune thyroid disease, occurring in 1% to 5% of patients with Graves disease. It usually occurs in older adult women on the pretibial regions and less commonly on the upper extremities, face, and areas of prior trauma.^1-3 Although typically asymptomatic, it can be painful and ulcerate.³ The clinical presentation consists of bilateral nonpitting edema with overlying indurated skin as well as flesh-colored, yellow-brown, violaceous, or peau d’orange papules and plaques.^2,3 Lesions develop over months and often have been associated with hyperhidrosis and hypertrichosis.² Many variants have been identified including nodular, plaquelike, diffuse swelling (ie, nonpitting edema), tumor, mixture, polypoid, and elephantiasis; severe cases with acral involvement are termed thyroid acropachy.^1-3 Pathogenesis likely involves the activation of thyrotropin receptors on fibroblasts by the circulating thyrotropin autoantibodies found in Graves disease. Activated fibroblasts upregulate glycosaminoglycan production, which osmotically drives the accumulation of dermal and subdermal fluid.^1,3

This diagnosis should be considered in any patient with pretibial edema or edema in areas of trauma. Graves disease most commonly is diagnosed 1 to 2 years prior to the development of pretibial myxedema; other extrathyroidal manifestations, most commonly ophthalmopathies, almost always are found in patients with pretibial myxedema. If a diagnosis of Graves disease has not been established, thyroid studies, including thyrotropin receptor antibody serum levels, should be obtained. Histopathology showing increased mucin in the dermis and increased fibroblasts can aid in diagnosis.^2,3

The differential diagnosis includes inflammatory dermatoses, such as stasis dermatitis and lipodermatosclerosis. Stasis dermatitis is characterized by lichenified yellowbrown plaques that present on the lower extremities; lipodermatosclerosis then can develop and present as atrophic sclerotic plaques with a champagne bottle–like appearance. Necrobiosis lipoidica demonstrates atrophic, shiny, yellow plaques with telangiectases and ulcerations. Hypertrophic lichen planus presents with hyperkeratotic hyperpigmented plaques on the shins.^1,2 Other diseases of cutaneous mucin deposition, namely scleromyxedema, demonstrate similar physical findings but more commonly are located on the trunk, face, and dorsal hands rather than the lower extremities.^1-3

Treatment of pretibial myxedema is difficult; normalization of thyroid function, weight reduction, and compression stockings can help reduce edema. Medical therapies aim to decrease glycosaminoglycan production by fibroblasts. First-line treatment includes topical steroids under occlusion, and second-line therapies include intralesional steroids, systemic corticosteroids, pentoxifylline, and octreotide.^2,3 Therapies for refractory disease include plasmapheresis, surgical excision, radiotherapy, and intravenous immunoglobulin; more recent studies also endorse the use of isotretinoin, intralesional hyaluronidase, and rituximab.^2,4 Success also has been observed with the insulin growth factor 1 receptor inhibitor teprotumumab in active thyroid eye disease, in which insulin growth factor 1 receptor is overexpressed by fibroblasts. Given the similar pathogenesis of thyroid ophthalmopathy with other extrathyroidal manifestations, teprotumumab is a promising option for refractory cases of pretibial myxedema and has led to disease resolution in several patients.⁴

The Diagnosis: Pretibial Myxedema

Histopathology showed superficial and deep mucin deposition with proliferation of fibroblasts and thin wiry collagen bundles that were consistent with a diagnosis of pretibial myxedema. The patient was treated with clobetasol ointment 0.05% twice daily for 3 months, followed by a trial of pentoxifylline 400 mg 3 times daily for 3 months. After this treatment failed, she was started on rituximab infusions of 1 g biweekly for 1 month, followed by 500 mg at 6 months, with marked improvement after the first 2 doses of 1 g.

Pretibial myxedema is an uncommon cutaneous manifestation of autoimmune thyroid disease, occurring in 1% to 5% of patients with Graves disease. It usually occurs in older adult women on the pretibial regions and less commonly on the upper extremities, face, and areas of prior trauma.^1-3 Although typically asymptomatic, it can be painful and ulcerate.³ The clinical presentation consists of bilateral nonpitting edema with overlying indurated skin as well as flesh-colored, yellow-brown, violaceous, or peau d’orange papules and plaques.^2,3 Lesions develop over months and often have been associated with hyperhidrosis and hypertrichosis.² Many variants have been identified including nodular, plaquelike, diffuse swelling (ie, nonpitting edema), tumor, mixture, polypoid, and elephantiasis; severe cases with acral involvement are termed thyroid acropachy.^1-3 Pathogenesis likely involves the activation of thyrotropin receptors on fibroblasts by the circulating thyrotropin autoantibodies found in Graves disease. Activated fibroblasts upregulate glycosaminoglycan production, which osmotically drives the accumulation of dermal and subdermal fluid.^1,3

This diagnosis should be considered in any patient with pretibial edema or edema in areas of trauma. Graves disease most commonly is diagnosed 1 to 2 years prior to the development of pretibial myxedema; other extrathyroidal manifestations, most commonly ophthalmopathies, almost always are found in patients with pretibial myxedema. If a diagnosis of Graves disease has not been established, thyroid studies, including thyrotropin receptor antibody serum levels, should be obtained. Histopathology showing increased mucin in the dermis and increased fibroblasts can aid in diagnosis.^2,3

The differential diagnosis includes inflammatory dermatoses, such as stasis dermatitis and lipodermatosclerosis. Stasis dermatitis is characterized by lichenified yellowbrown plaques that present on the lower extremities; lipodermatosclerosis then can develop and present as atrophic sclerotic plaques with a champagne bottle–like appearance. Necrobiosis lipoidica demonstrates atrophic, shiny, yellow plaques with telangiectases and ulcerations. Hypertrophic lichen planus presents with hyperkeratotic hyperpigmented plaques on the shins.^1,2 Other diseases of cutaneous mucin deposition, namely scleromyxedema, demonstrate similar physical findings but more commonly are located on the trunk, face, and dorsal hands rather than the lower extremities.^1-3

Treatment of pretibial myxedema is difficult; normalization of thyroid function, weight reduction, and compression stockings can help reduce edema. Medical therapies aim to decrease glycosaminoglycan production by fibroblasts. First-line treatment includes topical steroids under occlusion, and second-line therapies include intralesional steroids, systemic corticosteroids, pentoxifylline, and octreotide.^2,3 Therapies for refractory disease include plasmapheresis, surgical excision, radiotherapy, and intravenous immunoglobulin; more recent studies also endorse the use of isotretinoin, intralesional hyaluronidase, and rituximab.^2,4 Success also has been observed with the insulin growth factor 1 receptor inhibitor teprotumumab in active thyroid eye disease, in which insulin growth factor 1 receptor is overexpressed by fibroblasts. Given the similar pathogenesis of thyroid ophthalmopathy with other extrathyroidal manifestations, teprotumumab is a promising option for refractory cases of pretibial myxedema and has led to disease resolution in several patients.⁴

The Diagnosis: Pretibial Myxedema

Histopathology showed superficial and deep mucin deposition with proliferation of fibroblasts and thin wiry collagen bundles that were consistent with a diagnosis of pretibial myxedema. The patient was treated with clobetasol ointment 0.05% twice daily for 3 months, followed by a trial of pentoxifylline 400 mg 3 times daily for 3 months. After this treatment failed, she was started on rituximab infusions of 1 g biweekly for 1 month, followed by 500 mg at 6 months, with marked improvement after the first 2 doses of 1 g.

Pretibial myxedema is an uncommon cutaneous manifestation of autoimmune thyroid disease, occurring in 1% to 5% of patients with Graves disease. It usually occurs in older adult women on the pretibial regions and less commonly on the upper extremities, face, and areas of prior trauma.^1-3 Although typically asymptomatic, it can be painful and ulcerate.³ The clinical presentation consists of bilateral nonpitting edema with overlying indurated skin as well as flesh-colored, yellow-brown, violaceous, or peau d’orange papules and plaques.^2,3 Lesions develop over months and often have been associated with hyperhidrosis and hypertrichosis.² Many variants have been identified including nodular, plaquelike, diffuse swelling (ie, nonpitting edema), tumor, mixture, polypoid, and elephantiasis; severe cases with acral involvement are termed thyroid acropachy.^1-3 Pathogenesis likely involves the activation of thyrotropin receptors on fibroblasts by the circulating thyrotropin autoantibodies found in Graves disease. Activated fibroblasts upregulate glycosaminoglycan production, which osmotically drives the accumulation of dermal and subdermal fluid.^1,3

This diagnosis should be considered in any patient with pretibial edema or edema in areas of trauma. Graves disease most commonly is diagnosed 1 to 2 years prior to the development of pretibial myxedema; other extrathyroidal manifestations, most commonly ophthalmopathies, almost always are found in patients with pretibial myxedema. If a diagnosis of Graves disease has not been established, thyroid studies, including thyrotropin receptor antibody serum levels, should be obtained. Histopathology showing increased mucin in the dermis and increased fibroblasts can aid in diagnosis.^2,3

The differential diagnosis includes inflammatory dermatoses, such as stasis dermatitis and lipodermatosclerosis. Stasis dermatitis is characterized by lichenified yellowbrown plaques that present on the lower extremities; lipodermatosclerosis then can develop and present as atrophic sclerotic plaques with a champagne bottle–like appearance. Necrobiosis lipoidica demonstrates atrophic, shiny, yellow plaques with telangiectases and ulcerations. Hypertrophic lichen planus presents with hyperkeratotic hyperpigmented plaques on the shins.^1,2 Other diseases of cutaneous mucin deposition, namely scleromyxedema, demonstrate similar physical findings but more commonly are located on the trunk, face, and dorsal hands rather than the lower extremities.^1-3

Treatment of pretibial myxedema is difficult; normalization of thyroid function, weight reduction, and compression stockings can help reduce edema. Medical therapies aim to decrease glycosaminoglycan production by fibroblasts. First-line treatment includes topical steroids under occlusion, and second-line therapies include intralesional steroids, systemic corticosteroids, pentoxifylline, and octreotide.^2,3 Therapies for refractory disease include plasmapheresis, surgical excision, radiotherapy, and intravenous immunoglobulin; more recent studies also endorse the use of isotretinoin, intralesional hyaluronidase, and rituximab.^2,4 Success also has been observed with the insulin growth factor 1 receptor inhibitor teprotumumab in active thyroid eye disease, in which insulin growth factor 1 receptor is overexpressed by fibroblasts. Given the similar pathogenesis of thyroid ophthalmopathy with other extrathyroidal manifestations, teprotumumab is a promising option for refractory cases of pretibial myxedema and has led to disease resolution in several patients.⁴

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Cultures for bacteria, varicella zoster virus, herpes simplex virus, and mpox virus were all negative. A biopsy revealed suprabasilar acantholysis with follicular involvement in association with blister formation and inflammation. Direct immunofluorescence was positive for suprabasilar IgG and C₃ deposition, consistent with pemphigus vulgaris (PV).

PV is an autoimmune bullous disease in which antibodies are directed against desmoglein 1 and 3 and less commonly, plakoglobin. There is likely a genetic predisposition. Medications that may induce pemphigus include penicillamine, nifedipine, or captopril.

Clinically, flaccid blistering lesions are present that may be cutaneous and/or mucosal. Bullae can progress to erosions and crusting, which then heal with pigment alteration but not scarring. The most commonly affected sites are the mouth, intertriginous areas, face, and neck. Mucosal lesions may involve the lips, esophagus, conjunctiva, and genitals.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Cultures for bacteria, varicella zoster virus, herpes simplex virus, and mpox virus were all negative. A biopsy revealed suprabasilar acantholysis with follicular involvement in association with blister formation and inflammation. Direct immunofluorescence was positive for suprabasilar IgG and C₃ deposition, consistent with pemphigus vulgaris (PV).

PV is an autoimmune bullous disease in which antibodies are directed against desmoglein 1 and 3 and less commonly, plakoglobin. There is likely a genetic predisposition. Medications that may induce pemphigus include penicillamine, nifedipine, or captopril.

Clinically, flaccid blistering lesions are present that may be cutaneous and/or mucosal. Bullae can progress to erosions and crusting, which then heal with pigment alteration but not scarring. The most commonly affected sites are the mouth, intertriginous areas, face, and neck. Mucosal lesions may involve the lips, esophagus, conjunctiva, and genitals.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

Cultures for bacteria, varicella zoster virus, herpes simplex virus, and mpox virus were all negative. A biopsy revealed suprabasilar acantholysis with follicular involvement in association with blister formation and inflammation. Direct immunofluorescence was positive for suprabasilar IgG and C₃ deposition, consistent with pemphigus vulgaris (PV).

PV is an autoimmune bullous disease in which antibodies are directed against desmoglein 1 and 3 and less commonly, plakoglobin. There is likely a genetic predisposition. Medications that may induce pemphigus include penicillamine, nifedipine, or captopril.

Clinically, flaccid blistering lesions are present that may be cutaneous and/or mucosal. Bullae can progress to erosions and crusting, which then heal with pigment alteration but not scarring. The most commonly affected sites are the mouth, intertriginous areas, face, and neck. Mucosal lesions may involve the lips, esophagus, conjunctiva, and genitals.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

TOPLINE:

Five scleroderma immune responses have associations with cancer risk and could be used to stratify patients, researchers argue.

METHODOLOGY:

• Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
• A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
• Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
• Examined association between autoantibodies and overall cancer risk.

TAKEAWAYS:

• Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
• Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
• These associations remained when looking specifically at cancer-associated scleroderma.
• Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.

IN PRACTICE:

This study is too preliminary to have practice application.

SOURCE:

Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.

DISCLOSURES:

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.

A version of this article appeared on Medscape.com.

TOPLINE:

Five scleroderma immune responses have associations with cancer risk and could be used to stratify patients, researchers argue.

METHODOLOGY:

• Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
• A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
• Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
• Examined association between autoantibodies and overall cancer risk.

TAKEAWAYS:

• Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
• Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
• These associations remained when looking specifically at cancer-associated scleroderma.
• Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.

IN PRACTICE:

This study is too preliminary to have practice application.

SOURCE:

Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.

DISCLOSURES:

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.

A version of this article appeared on Medscape.com.

TOPLINE:

Five scleroderma immune responses have associations with cancer risk and could be used to stratify patients, researchers argue.

METHODOLOGY:

• Included patients from the Johns Hopkins Scleroderma Center Research Registry and the University of Pittsburgh Scleroderma Center, Pittsburgh.
• A total of 676 patients with scleroderma and a history of cancer were compared with 687 control patients with scleroderma but without a history of cancer.
• Serum tested via line blot and enzyme-linked immunosorbent assay for an array of scleroderma autoantibodies.
• Examined association between autoantibodies and overall cancer risk.

TAKEAWAYS:

• Anti-POLR3 and monospecific anti-Ro52 were associated with significantly increased overall cancer risk.
• Anti-centromere and anti-U1RNP were associated with a decreased cancer risk.
• These associations remained when looking specifically at cancer-associated scleroderma.
• Patients positive for anti-Ro52 in combination with either anti-U1RNP or anti-Th/To had a decreased risk of cancer, compared with those who had anti-Ro52 alone.

IN PRACTICE:

This study is too preliminary to have practice application.

SOURCE:

Ji Soo Kim, PhD, of John Hopkins University, Baltimore, was the first author of the study, published in Arthritis & Rheumatology on July 24, 2023. Fellow Johns Hopkins researchers Livia Casciola-Rosen, PhD, and Ami A. Shah, MD, were joint senior authors.

DISCLOSURES:

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Donald B. and Dorothy L. Stabler Foundation, the Jerome L. Greene Foundation, the Chresanthe Staurulakis Memorial Discovery Fund, the Martha McCrory Professorship, and the Johns Hopkins inHealth initiative. The authors disclosed the following patents or patent applications: Autoimmune Antigens and Cancer, Materials and Methods for Assessing Cancer Risk and Treating Cancer.

A version of this article appeared on Medscape.com.

Clinical research in lupus has a mammoth diversity problem: Black individuals are most likely to develop the disease, but they’re the least likely to take part in studies. By the numbers, a 2018 analysis of randomized controlled trials in systemic lupus erythematosus from the years 1997 to 2017 found that 51% of trial participants were White and 14% were Black, even though an estimated 33% of patients with lupus were White and 43% were Black.

Are there ways to fix this disparity? The topic is getting plenty of attention, and speakers at a July 21 online conference touted research projects that aim to boost the numbers of non-White participants in lupus trials.

So far there doesn’t seem to be anything like a magic bullet. Still, the stakes are high. “While race is a social construct, genetic polymorphisms as well as environmental and social differences may influence drugs, safety, and efficacy,” Joy Buie, PhD, MSCR, research director for the Lupus Foundation of America, said at the “Engaging Diverse Participants in Lupus Clinical Trials: The Path Forward” summit held by the American College of Rheumatology (ACR).

As African American patients explained, minority populations often don’t trust the medical system and feel burned by their lengthy struggles to get diagnosed. In some cases, they don’t have full faith in their clinicians and feel unheard.

In a video presentation developed as part of a federal education campaign, Shanelle Gabriel, a poet and musician diagnosed with lupus, described her first reaction when her physician suggested she join a clinical trial. “My first reaction was no. I know my history,” she said, apparently referring to the infamous Tuskegee study that withheld proper treatment from Black men with syphilis for decades. “As an African American woman, I was scared. I didn’t want to be a guinea pig.”

Stacey Kennedy-Conner, a Chicago-area patient and advocate, told the summit audience about how patients can feel that clinical trial information can add “an extra layer of confusion” to their experience. “There’s also the mentality of, ‘If it’s not broke, don’t fix it’: If this medication regimen is working, I don’t want anybody to touch me.”

Monique Gore-Massy, a New York City patient and advocate, added that there can be a perception that patients with lupus “are stuck at home in bed.” In reality, she said, “we have jobs, we have families. Think about that, and consider everything that you’re asking from us: Is this taking me away from my family? Am I going to have to take off work? There may be incentives, but is that worth me taking time off work that I may not get paid for? These are some of the realities that we have to look at in terms of the whole entire clinical trial process.”

It’s also important to keep patients informed of progress being made in trials, she said. “You don’t want to say you just felt like a number and then not get any kind of follow-up.”

In the big picture, “there has to be something that builds up the confidence of individuals so that they are more mindful to participate in these clinical trials,” said Aleta McLean, an Atlanta patient who was diagnosed with lupus 14 years ago.

Several researchers highlighted ongoing projects at the summit. The ACR, for example, has launched a $500,000 initiative called Training to Increase Minority Enrollment in Lupus Clinical Trials with Community Engagement (TIMELY). The federally funded project aims to evaluate whether training of health care professionals can boost clinical trial participation among Black and Hispanic patients.

“We hope to disseminate the results of our project to the scientific community through abstracts, manuscripts, presentations at national meetings,” said rheumatologist Saira Z. Sheikh, MD, of the University of North Carolina at Chapel Hill. “Overall, our goal is to establish new partnerships to support the TIMELY model and advance the education and engagement of providers and community health workers.”

Pamela Payne-Foster, MD, MPH, preventive medicine/public health physician at the University of Alabama College of Community Health Sciences, Tuscaloosa, spoke about the federally funded Deep South Health Equity Project, which is paying patients to take part in an online education program and attend an online regional conference.

Other efforts are underway. The Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have launched two initiatives. One is a program called Project Change (Community-based Health Action Network to Generate Trial Participation and Eliminate Disparities), and the Diversity in Lupus Research Program aims to fund scientists’ work.

Will any of this work boost diversity in clinical trials? As one audience member noted in a Q&A session, health care disparities – and knowledge about them – are nothing new: “Why are we not able to narrow the gap?”

Rear Admiral Richardae Araojo, PharmD, MS, director of the FDA’s Office of Minority Health and Health Equity and associate commissioner for minority health, replied that waves of interest in disparities come and go. “That contributes to why we may not see solutions. But ultimately, there are a lot of people doing a lot of work trying to solve the issues.”

The summit was sponsored by Bristol-Myers Squibb, Genentech, and RemeGen.

A version of this article appeared on Medscape.com.

Clinical research in lupus has a mammoth diversity problem: Black individuals are most likely to develop the disease, but they’re the least likely to take part in studies. By the numbers, a 2018 analysis of randomized controlled trials in systemic lupus erythematosus from the years 1997 to 2017 found that 51% of trial participants were White and 14% were Black, even though an estimated 33% of patients with lupus were White and 43% were Black.

Are there ways to fix this disparity? The topic is getting plenty of attention, and speakers at a July 21 online conference touted research projects that aim to boost the numbers of non-White participants in lupus trials.

So far there doesn’t seem to be anything like a magic bullet. Still, the stakes are high. “While race is a social construct, genetic polymorphisms as well as environmental and social differences may influence drugs, safety, and efficacy,” Joy Buie, PhD, MSCR, research director for the Lupus Foundation of America, said at the “Engaging Diverse Participants in Lupus Clinical Trials: The Path Forward” summit held by the American College of Rheumatology (ACR).

As African American patients explained, minority populations often don’t trust the medical system and feel burned by their lengthy struggles to get diagnosed. In some cases, they don’t have full faith in their clinicians and feel unheard.

In a video presentation developed as part of a federal education campaign, Shanelle Gabriel, a poet and musician diagnosed with lupus, described her first reaction when her physician suggested she join a clinical trial. “My first reaction was no. I know my history,” she said, apparently referring to the infamous Tuskegee study that withheld proper treatment from Black men with syphilis for decades. “As an African American woman, I was scared. I didn’t want to be a guinea pig.”

Stacey Kennedy-Conner, a Chicago-area patient and advocate, told the summit audience about how patients can feel that clinical trial information can add “an extra layer of confusion” to their experience. “There’s also the mentality of, ‘If it’s not broke, don’t fix it’: If this medication regimen is working, I don’t want anybody to touch me.”

Monique Gore-Massy, a New York City patient and advocate, added that there can be a perception that patients with lupus “are stuck at home in bed.” In reality, she said, “we have jobs, we have families. Think about that, and consider everything that you’re asking from us: Is this taking me away from my family? Am I going to have to take off work? There may be incentives, but is that worth me taking time off work that I may not get paid for? These are some of the realities that we have to look at in terms of the whole entire clinical trial process.”

It’s also important to keep patients informed of progress being made in trials, she said. “You don’t want to say you just felt like a number and then not get any kind of follow-up.”

In the big picture, “there has to be something that builds up the confidence of individuals so that they are more mindful to participate in these clinical trials,” said Aleta McLean, an Atlanta patient who was diagnosed with lupus 14 years ago.

Several researchers highlighted ongoing projects at the summit. The ACR, for example, has launched a $500,000 initiative called Training to Increase Minority Enrollment in Lupus Clinical Trials with Community Engagement (TIMELY). The federally funded project aims to evaluate whether training of health care professionals can boost clinical trial participation among Black and Hispanic patients.

“We hope to disseminate the results of our project to the scientific community through abstracts, manuscripts, presentations at national meetings,” said rheumatologist Saira Z. Sheikh, MD, of the University of North Carolina at Chapel Hill. “Overall, our goal is to establish new partnerships to support the TIMELY model and advance the education and engagement of providers and community health workers.”

Pamela Payne-Foster, MD, MPH, preventive medicine/public health physician at the University of Alabama College of Community Health Sciences, Tuscaloosa, spoke about the federally funded Deep South Health Equity Project, which is paying patients to take part in an online education program and attend an online regional conference.

Other efforts are underway. The Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have launched two initiatives. One is a program called Project Change (Community-based Health Action Network to Generate Trial Participation and Eliminate Disparities), and the Diversity in Lupus Research Program aims to fund scientists’ work.

Will any of this work boost diversity in clinical trials? As one audience member noted in a Q&A session, health care disparities – and knowledge about them – are nothing new: “Why are we not able to narrow the gap?”

Rear Admiral Richardae Araojo, PharmD, MS, director of the FDA’s Office of Minority Health and Health Equity and associate commissioner for minority health, replied that waves of interest in disparities come and go. “That contributes to why we may not see solutions. But ultimately, there are a lot of people doing a lot of work trying to solve the issues.”

The summit was sponsored by Bristol-Myers Squibb, Genentech, and RemeGen.

A version of this article appeared on Medscape.com.

Clinical research in lupus has a mammoth diversity problem: Black individuals are most likely to develop the disease, but they’re the least likely to take part in studies. By the numbers, a 2018 analysis of randomized controlled trials in systemic lupus erythematosus from the years 1997 to 2017 found that 51% of trial participants were White and 14% were Black, even though an estimated 33% of patients with lupus were White and 43% were Black.

Are there ways to fix this disparity? The topic is getting plenty of attention, and speakers at a July 21 online conference touted research projects that aim to boost the numbers of non-White participants in lupus trials.

So far there doesn’t seem to be anything like a magic bullet. Still, the stakes are high. “While race is a social construct, genetic polymorphisms as well as environmental and social differences may influence drugs, safety, and efficacy,” Joy Buie, PhD, MSCR, research director for the Lupus Foundation of America, said at the “Engaging Diverse Participants in Lupus Clinical Trials: The Path Forward” summit held by the American College of Rheumatology (ACR).

As African American patients explained, minority populations often don’t trust the medical system and feel burned by their lengthy struggles to get diagnosed. In some cases, they don’t have full faith in their clinicians and feel unheard.

In a video presentation developed as part of a federal education campaign, Shanelle Gabriel, a poet and musician diagnosed with lupus, described her first reaction when her physician suggested she join a clinical trial. “My first reaction was no. I know my history,” she said, apparently referring to the infamous Tuskegee study that withheld proper treatment from Black men with syphilis for decades. “As an African American woman, I was scared. I didn’t want to be a guinea pig.”

Stacey Kennedy-Conner, a Chicago-area patient and advocate, told the summit audience about how patients can feel that clinical trial information can add “an extra layer of confusion” to their experience. “There’s also the mentality of, ‘If it’s not broke, don’t fix it’: If this medication regimen is working, I don’t want anybody to touch me.”

Monique Gore-Massy, a New York City patient and advocate, added that there can be a perception that patients with lupus “are stuck at home in bed.” In reality, she said, “we have jobs, we have families. Think about that, and consider everything that you’re asking from us: Is this taking me away from my family? Am I going to have to take off work? There may be incentives, but is that worth me taking time off work that I may not get paid for? These are some of the realities that we have to look at in terms of the whole entire clinical trial process.”

It’s also important to keep patients informed of progress being made in trials, she said. “You don’t want to say you just felt like a number and then not get any kind of follow-up.”

In the big picture, “there has to be something that builds up the confidence of individuals so that they are more mindful to participate in these clinical trials,” said Aleta McLean, an Atlanta patient who was diagnosed with lupus 14 years ago.

Several researchers highlighted ongoing projects at the summit. The ACR, for example, has launched a $500,000 initiative called Training to Increase Minority Enrollment in Lupus Clinical Trials with Community Engagement (TIMELY). The federally funded project aims to evaluate whether training of health care professionals can boost clinical trial participation among Black and Hispanic patients.

“We hope to disseminate the results of our project to the scientific community through abstracts, manuscripts, presentations at national meetings,” said rheumatologist Saira Z. Sheikh, MD, of the University of North Carolina at Chapel Hill. “Overall, our goal is to establish new partnerships to support the TIMELY model and advance the education and engagement of providers and community health workers.”

Pamela Payne-Foster, MD, MPH, preventive medicine/public health physician at the University of Alabama College of Community Health Sciences, Tuscaloosa, spoke about the federally funded Deep South Health Equity Project, which is paying patients to take part in an online education program and attend an online regional conference.

Other efforts are underway. The Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have launched two initiatives. One is a program called Project Change (Community-based Health Action Network to Generate Trial Participation and Eliminate Disparities), and the Diversity in Lupus Research Program aims to fund scientists’ work.

Will any of this work boost diversity in clinical trials? As one audience member noted in a Q&A session, health care disparities – and knowledge about them – are nothing new: “Why are we not able to narrow the gap?”

Rear Admiral Richardae Araojo, PharmD, MS, director of the FDA’s Office of Minority Health and Health Equity and associate commissioner for minority health, replied that waves of interest in disparities come and go. “That contributes to why we may not see solutions. But ultimately, there are a lot of people doing a lot of work trying to solve the issues.”

The summit was sponsored by Bristol-Myers Squibb, Genentech, and RemeGen.

A version of this article appeared on Medscape.com.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.

The Diagnosis: Extragenital Lichen Sclerosus et Atrophicus

A punch biopsy of the lesion revealed epidermal hyperkeratosis, atrophy, follicular plugs with basal vacuolar degeneration, and homogenous dense fibrosis in the papillary dermis with a dense lymphocytic infiltrate beneath the fibrosis (Figure 1). Dermoscopic examination was remarkable for a distinctive rainbow pattern. Clinical, histopathologic, and dermoscopic findings led to the diagnosis of extragenital lichen sclerosus et atrophicus (LSEA). A potent corticosteroid cream was prescribed twice daily for 2 months, after which the lesions completely resolved. At 2-year follow-up, a relapse was not observed (Figure 2).

Lichen sclerosus et atrophicus is an inflammatory dermatosis that clinically presents as atrophic or hypertrophic plaques that may show pigmentation changes with anogenital and extragenital involvement. It is common among females and predominantly occurs in prepubescent girls and postmenopausal women. The exact etiology is unclear; however, it is hypothesized to occur secondary to autoimmunity with an underlying genetic predisposition. Local trauma, hormonal influences, and infections are other suspected etiologic factors. Genital lesions often lead to itching, pain, and dyspareunia, whereas extragenital lesions predominantly are asymptomatic. When symptomatic, itching usually is the main concern. Unlike genital LSEA, extragenital lesions are not associated with squamous cell carcinoma development. Reported dermoscopic features of LSEA are white structureless areas with scaling, comedolike openings, follicular plugs, white shiny streaks, blue-gray peppering, pigment network, and red-purple globules.¹ In our case, the dermoscopic finding of a rainbow pattern in LSEA is rare.² Although the mechanism behind this appearance unclear, it can be the result of the birefringence effect—local variations in refractive index—influenced by the direction of structures within the dermis such as collagen. In this case, there was diffuse and dense homogenous fibrosis in the superficial dermis that corresponded to dermoscopic white polygonal clods.

Extragenital LSEA commonly is located on the neck, shoulders, wrists, and upper trunk and manifests clinically as whitish papules coalescing into scarlike plaques. Of all patients who have LSEA, 20% have extragenital lesions, and most of these lesions are seen in patients who also have genital LSEA. Approximately 6% of all LSEA patients have extragenital LSEA without genital involvement.³

For experienced dermatologists, clinical symptoms and lesion characteristics usually are sufficient for diagnosis; however, a differential diagnosis of atypical lesions and isolated extragenital presentations such as morphea, lichen simplex chronicus, lichen planus, and vitiligo requires the correlation of clinical findings with histopathology and dermoscopy. Morphea, known as localized scleroderma, is an idiopathic inflammatory skin disease with sclerotic changes. It manifests as inflammatory plaques that vary in color from red to purple. If there is moderate sclerosis in the center of this plaque, the color progressively fades to white, leaving a purplish ring around the edges. Dermoscopic features of morphea are reported as areas of erythema; red-focused vessels of linear, irregular, or dotted morphology; white fibrotic beams; and pigmentary structures.² Lichen simplex chronicus is characterized by single or multiple dry and patchy skin lesions that are intensely pruritic. It commonly occurs on the neck, scalp, extremities, genital areas, and buttocks. Scratching the lesions leads to scarring, thickening of the skin, and increased frequency of itching. Histopathology of lichen simplex chronicus most frequently demonstrates a thickening of the epidermis and papillary dermis, irregularly elongated rete ridges, and fibroplasia with stellate or multinucleated fibroblasts completed by perivascular lymphocytic inflammation.⁴ Lichen planus presents with pruritic, polygonal, purple papules and/or plaques that can present in a variety of clinical forms, including atrophic and hypertrophic lichen planus.⁵ Lichen planus was an unlikely diagnosis for our patient due to the presence of patchy scarlike lesions and dermoscopic features that are well described in patients with LSEA. Lichen sclerosus et atrophicus presents with hypopigmented and/or hyperpigmented patches and plaques, distinguishing itself from vitiligo, which has flat lesions.

Topical steroids are the first-line therapeutic agents in the treatment of LSEA.6 Despite frequent use in this setting, common side effects such as localized scarring and atrophic degenerations have led to debate about their use. In our patient, the lesions resolved almost completely in 2 months, and no relapse was observed in the following 2 years. In the setting of topical steroid resistance, topical calcineurin inhibitors, UVA/UVB phototherapy, and topical tacrolimus can be used for treatment.⁶

The diagnosis of isolated extragenital LSEA may be a clinical challenge and generally requires further workup. When evaluating extragenital lesions, dermatologists should keep in mind extragenital LSEA as a differential diagnosis in the presence of a dermoscopic rainbow pattern arranged over white polygonal clods.