Cutis

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

North American venomous snakes traditionally are classified as members of either the Viperidae (eg, rattlesnakes, copperheads, cottonmouths) or Elapidae (eg, coral snakes) families and account for roughly 5000 to 10,000 reported envenomations annually.^1,2 In 2021, America’s Poison Centers reported 2287 calls related to copperheads, 71 related to coral snakes, 229 related to cottonmouths, 1184 related to rattlesnakes, and 524 related to unknown snakes.³ The majority of calls related to snake bites were for adult patients, resulting in absent to minor outcomes. Only 1 death due to a rattlesnake bite was reported.³ Death by envenomation from a North American snake species is considered rare and typically is attributed to a lapse in medical attention; however, rattlesnakes are the most common reported cause of death by snake envenomation (Figure 1).^1,3 A study comparing snake bites and hospital stays in the southeast vs southwest United States found that the southeast had the highest incidence of copperhead bites (37%), while the southwest had a higher incidence of rattlesnake bites (70%); those who were bitten by a rattlesnake were reported to have more severe symptoms and greater need for medical attention and antivenin.⁴ Some reports have linked pediatric and elderly patients to worse outcomes.⁵ However, one study examining 24,388 emergency department visits for snake bites from 2006 through 2014 found that the majority of pediatric cases were handled by non– trauma centers in the southern United States,⁶ supporting evidence found by Campbell et al⁷ indicating that most snake bites in children can be managed with conservative care. Though reported complications—including weakness, paralysis, hypovolemic shock, thrombocytopenia, and death—from North American venomous snake bites are low, they are still considered a medical emergency.⁸ It is essential for physicians to understand the clinical manifestations and treatment of North American venomous snake bites and to educate patients on how to protect themselves against and avoid provoking snakes, particularly in rural areas.² In this article, we review the characteristics of common North American venomous snakes and the clinical manifestations of their bites. We also discuss the appropriate measures for staging, evaluating, and treating snake envenomation to improve patient management and care.

Features of North American Venomous Snakes

Individual snakes within the Viperidae family vary in size, markings and coloration, activity, and region, and physicians should consult their local health departments regarding snakes that are common in their area.² Cottonmouth snakes are semiaquatic and traditionally are found within the southern and central United States. With a spade-shaped head and distinct two-tone coloration, cottonmouths may be mistaken for other nonvenomous water snakes in these regions (Figure 2).² Copperheads, true to their name, are red in color; they inhabit a large portion of the southeastern United States and eastern Texas regions and are the cause of the majority of venomous snake bites in North America (Figure 3). Both cottonmouths and copperheads are believed to bite and envenomate as a defensive mechanism when provoked.

Coral snakes, found in the eastern United States and Texas regions, are the only subspecies of the Elapidae family (Figure 4).^2,9 They can be distinguished from the nonvenomous milk snake by their characteristic banding, as coral snakes are patterned in a red-yellow-black band sequence and milk snakes are patterned in a red-black-yellow or white sequence. The differences in appearance of these snakes often is remembered by the phrase “red on yellow kills a fellow.”

Anatomic differences between the Viperidae and Elapidae families, including fang size, placement, and type, as well as venom composition, are directly linked to clinical manifestations of the bites. Viperidae fangs extend from the maxillary bones and are mobile, long, and hollow, making it easy for the snake to control fang movement and envenomation.⁹ Viperidae snakes are uniquely capable of inflicting puncture wounds without the injection of venom, known as dry bites. In contrast, Elapidae snakes have short, hollow, and fixed fangs, and thus patients can protect themselves by wearing appropriate clothing and covered footwear.⁹ Currently, identifying the type of snake responsible for the bite relies on visualization of the snake and/or the identification of clinical symptoms of envenomation by a dermatologist.

Clinical Manifestations of Venomous Snake Bites

Clinical manifestations and cutaneous findings often are used to grade the severity of venomous snake bites as well as to dictate treatment procedures. Grade 0 indicates a bite has occurred without envenomation, while grades I to V describe the progression and severity of envenomation.¹⁰ Grade I describes minimal erythema and edema around the site (fang marks may or may not be present) and no systemic symptoms. Grade II describes erythema and edema extending up the extremity to the first joint (eg, hand to wrist), pain, some systemic symptoms if there is rapid progression, and potential bleeding at the site. Grade III describes erythema and edema spreading to the second joint in the extremity, pain, and systemic symptoms, including coagulation defects. Grade IV describes erythema and edema of the whole extremity, a rapid reaction and progression following the bite, and risk for compartment syndrome. Grade V includes erythema and edema beyond the extremity and increasing systemic symptoms.¹⁰

Local pain and edema, usually on easily accessible or exposed extremities, are the most common clinical symptoms reported following a Viperidae snake bite.¹¹ Due to their capability of producing a dry bite, puncture markings alone do not indicate envenomation. Patients will need to be monitored for several hours for signs of envenomation, which may include swelling, pain, ecchymosis, and indications of systemic manifestation (eg, weakness, dizziness, nausea, severe hypotension, thrombocytopenia).¹¹ Viperidae venom hemorrhagic metalloproteinases act on capillary blood vessels by cleaving basement membrane proteins and allowing for extravasation of fluid into local tissue.¹² The inflammatory response produced at the site of envenomation likely is due to the release of tumor necrosis factor á and endogenous matrix metalloprotein.¹² There is a higher risk for death associated with bites from rattlesnakes within the Viperidae family because their venom contains a unique neurotoxin that works by blocking presynaptic junctions and causing a range of paralytic symptoms from ptosis to respiratory failure.¹³

The severity of Elapidae bites is thought to be related to the amount of venom injected, the size of the victim, and the length of the snake. Though clothing may offer protection, envenomation occurs in 75% of coral snake bites and can produce devastating consequences due to the venom content.¹⁴ In a retrospective study between 2002 and 2004, 90% of Elapidae snake bite patients (n=82) reported local pain, redness, and paresthesia, while around 7% developed systemic symptoms.¹⁵ Elapidae venom primarily is neurotoxic and is thought to spread via lymphatics.¹⁶ Delayed reactions are common and may take up to 12 hours to develop. Patients should be monitored, as local reactions may progress to weakness, fasciculations, extremity paralysis, and lastly, respiratory paralysis. Due to the risk for progression, all patients with likely coral snake bites should be given antivenin.^8,15,17

Much like the North American coral snake, the venomous snake species Gloydius blomhoffii—referred to as the salmosa or mamushi snake depending on the region of origin (ie, Korea or Japan)—is a frequent source of devastating rural snake bites due to neurotoxins (Figure 5). The species’ slender fangs are thought to directly inject the snake’s potent venom, which contains hemorrhagic toxins and α-neurotoxins and Β-neurotoxins, into the bloodstream; however, the salmosa is considered a viper like the North American cottonmouth and copperhead because of its triangular head shape and hollow fangs, which allow for the accommodation of venom-containing glands and mechanism of venom injection. Salmosa venom shares both Viperidae and Elapidae characteristics. Cutaneous findings such as progressive edema, erythema, and bleeding frequently are reported and are attributed to the proteases and hemorrhagic toxins characteristic of vipers (Figure 6). α-Neurotoxins and Β-neurotoxins, similar to the proteolytic venom of the Elapidae family, are responsible for the unique visual disturbances (binocular diplopia) caused by the salmosa.^12,18,19

Treatment

Treating snake bites begins with assessing the patient’s airway, breathing, and circulation, followed by a thorough medical and encounter history (including description of how the bite occurred). Due to the range of Viperidae symptoms, it generally is recommended that patients remove any restrictive clothing or jewelry near the bite and/or over the affected limb or body part, place the affected body part at the level of the heart, and go to the nearest medical facility for prompt care. Historically, empiric antibiotics often were used to prevent wound infections; however, studies have since demonstrated that antibiotics are not necessary and lack efficacy in uncomplicated snake bites.^16,20 In a study of 114 pediatric cases from 1995 to 2005, it was determined that most patients could be managed with conservative treatment directed at pain management and swelling reduction via elevation of the affected extremity.⁶ While conservative management may be all that is needed to care for the majority of cases, one retrospective study from Texas indicated that 70% of pediatric venomous snake bites were treated with either intravenous antibiotics and/or antivenin, highlighting the variability in management and opportunity for improvement.²¹

Antivenin, specifically antivenin (Crotalidae) polyvalent, is the indicated treatment for Viperidae hemorrhagic or coagulopathic envenomation.^13,22 Per guidelines from the World Health Organization, physical examination will yield a grading of the snake bite based on cutaneous findings. Grades III to V are considered moderate to severe and should be given antivenin.²³ Physicians should look for signs of progressive injury and coagulopathy, such as increased swelling, bruising, hypotension, or altered mental status.²² Due to the major neurotoxic risks associated with Elapidae venom, all coral snake bites should be treated with antivenin; early intubation and ventilation may be considered.¹³ Similarly, patients who report a salmosa snake bite require prompt treatment with antivenin and/or cepharanthine, an additive agent to reduce swelling and pain.¹⁸ Due to the nature of the neurotoxins contained in the salmosa venom (α-neurotoxin causing postsynaptic inhibition of the neuromuscular junction and Β-neurotoxin inhibiting neurotransmitter release from the presynaptic terminal), anticholinesterases, which work by blocking the enzymatic breakdown of the neurotransmitter acetylcholine, should not be used.¹⁹ While bleeding and skin and systemic changes may be reversed by antivenin, visual changes are unlikely to resolve with antivenin administration due to the presynaptic binding of Β-neurotoxin and the blockade of neuromuscular signaling.¹⁹

Antivenin should be administered intravenously for the fastest onset of action in a setting suitable for the management of anaphylaxis.²⁴ In situations when the benefits may outweigh the risks (eg, if the patient has had a prior allergic reaction or is not in an environment where they can be watched for at least 8 hours for progression of envenomation or adverse reactions), premedication with an antihistamine or epinephrine may be considered.17 Per the World Allergy Organization and World Health Organization, adverse reactions should be treated with crystalloid solutions and antihistamines, corticosteroids, or epinephrine as indicated.²⁵ In a qualitative analysis of emergency physicians’ attitudes toward antivenin, most expressed treatment hesitancy due to lack of knowledge and experience using the medication.²⁶ When possible, snake bites should thus be managed in consultation with a toxicologist.²

Conclusion

Snake bites and envenomation occur commonly in the United States due to exposure to a variety of venomous snakes in the North American Viperidae and Elapidae families. Appropriate and successful management of snake bites by physicians requires general knowledge of regional snakes, the cutaneous and systemic manifestations of snake bites and envenomation, and current treatment methods.

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

Patients often ask dermatologists how to best care for their specific hair type; however, there are no formal recommendations that apply to the many different hair care practices utilized by Black patients, as hair types in this community can range from wavy to tightly coiled.¹ Understanding the the history of hair care in those of African ancestry and various styling practices in this population is necessary to adequately counsel patients and gain trust in the doctor-patient relationship. In this article, we provide an overview of hair care recommendations based on common styling practices in Black women.

A PubMed search of articles indexed for MEDLINE using the terms Black hair care, African American hair management, hair loss prevention, hair care practices, natural hair, natural-hair styles, alopecia, hairdressing, hair breakage, hair fragility, heat-stressed hair, traction alopecia, and natural hair care yielded 305 results; 107 duplicates were identified and removed, leaving 198 articles to be screened for eligibility (ie, English-language studies created in the past 15 years). Sixty-eight full-text articles were screened against the exclusion criteria, which included case reports and case series, articles not focused on Afro-textured hair, and cancer-related hair loss. Three additional fulltext articles were identified via resources from Wayne State University library (Detroit, Michigan) that were not available on PubMed. A total of 29 full-text articles were included in our review.

Background on Hair Care and Styling in African Populations

It is difficult to understand the history of hair in those of African ancestry in the United States.² Prior to slavery, hair styling was considered a way of identification, classification, and communication as well as a medium through which to connect with the spiritual world in many parts of Africa. Hair-styling practices in Africa included elaborate cornrows, threading, and braiding with many accessories. Notable hair-styling products included natural butters, herbs, and powders to assist with moisture retention. Scarves also were used during this time for ceremonies or protection.³ During the mass enslavement of African populations and their transportation to the Americas by Europeans, slaveholders routinely cut off all the hair of both men and women in order to objectify and erase the culture of African hair styling passed down through generations.^4,5 Hair texture then was weaponized to create a caste system in plantation life, in which Black slaves with straight hair textures were granted the “privilege” of domestic work, while those with kinky hair were relegated to arduous manual labor in the fields.⁴ Years later, during the 1800s, laws were enacted in the United States to prohibit Black women from wearing tightly coiled natural hair in public places.⁵ Over the next few centuries from the 1800s to the early 2000s, various hair-styling trends such as the use of hot combs, perms, afros, and Jheri curls developed as a means for Black individuals to conform to societal pressure to adopt more European features; however, as time progressed, afros, braids, locs, and natural hair would become more dominant as statements against these same societal pressures.⁵

The natural hair movement, which emerged in the United States in the 2000s, encouraged Black women to abandon the use of toxic chemical hair straighteners, cultivate healthier hair care practices, disrupt Eurocentric standards of wearing straightened hair, and facilitate self-definition of beauty ideals from the Civil Rights Movement of the 1960s.^4,5 It is estimated that between 30% and 70% of all Black women in the United States wear natural hair, including 79% of millennial Black women younger than 30 years⁶; however, several new trends such as wigs and weaves have grown in popularity since the early 2000s due to mainstream pop culture and improvements in creating natural hairlines.^7,8

Key Features of Afro-Textured Hair

Individuals of African descent have the most diverse hair texture phenotypes, ranging from straight to tightly coiled.⁹ Although hair is chemically similar across various racial groups, differences are noted mainly in the shape of the hair shaft, with elliptical and curved shapes seen in Afrotextured hair. These differences yield more tightly curled strands than in other hair types; however, these features also contribute to fragility, as it creates points of weakness and decreases the tensile strength of the hair shaft.¹⁰ This inherent fragility leads to higher rates of hair breakage as well as lower moisture content and slower growth rates, which is why Afro-textured hair requires special care.⁹

Afro-textured hair generally falls into 2 main categories of the Andre Walker hair typing system: 4A-4C and 3A-3C.¹¹ In the 4A-4C category, hair is described as coily or kinky. Common concerns related to this hair type include dryness and brittleness with increased susceptibility to breakage. The 3A-3C category is described as loose to corkscrew curls, with a common concern of dryness.^11,12 Additionally, Loussouarn et al¹³ established a method to further define natural hair curliness using curve diameter and curl meters on glass plates to measure the curvature of hair strands. This method allows for assessing diversity and range of curliness within various races without relying on ethnic origin.¹³

Common Hair Care Practices

A description of each hair type and recommended styling practices with their levels of evidence can be found in the eTable.

Natural Hair—Natural hair is classified as hair that has not been chemically changed by perms, heat, or other straightening treatments.^12,14 For natural hair, retaining the moisture of the hair shaft should be the main focus, as moisture loss leads to considerable dryness.¹⁴ Generally, it is recommended to wash natural hair once per week or every other week; however, this can change based on hair length and oil production on the scalp. Washing daily may be ideal for shorter hair and monthly for longer hair to help prevent product build-up that can have a drying effect.¹⁵ Avoid shampoos that are drying (eg, sulfate and silicone products). The co-washing method also can be utilized, which entails washing the hair with a conditioning cleanser instead of shampoo and conditioner. However, this technique is not meant to completely replace shampoo.¹⁶ In fact, a clarifying shampoo is recommended after co-washing 3 or 4 times.¹⁶ The use of a hot oil treatment twice per month can promote moisture retention and reduce split-end formation.¹⁷ For maintenance between washes, many utilize the liquid, oil, cream (LOC) or liquid, cream, oil (LCO) methods, which describe regimens that utilize water, an oil of choice, and cream such as shea butter to lock in moisture.¹⁸ This method can be used as often as needed for dry hair.

Due to the susceptibility of Afro-textured hair to tangle and knot, using a wide-tooth comb, detangling brush, or detangling conditioners is a grade B recommendation for care (eTable). Though not widely documented in the literature, many of our patients have had anecdotal success detangling their hair simply by pulling hair strands apart by hand or “finger detangling” as well as using wide-tooth combs. Although both hair types are healthier in their natural states, kinky hair (type 4A-4C) is extremely fragile and more difficult to manage than less kinky hair (type 3A-3C).¹⁸

Special care is needed when detangling due to strands being weaker when wet.¹⁹ Detangling should be performed in a retrograde fashion. Deep conditioning can aid in moisture retention and should be performed weekly or biweekly.^17-20 Depending on the health of the hair, protein treatments can be considered on a monthly basis to help preserve the cuticle. Styling with braids, twists, or other protective styles can then be completed on an individual basis.

Thermal Straightening—A blowout involves straightening the hair after a wash with the use of a hair dryer.²¹ This common hair-styling method does not employ the use of chemicals beyond light hair oils and heat-protectant creams or sprays, typically resulting in a less kinky afro or semi-straight hair. Thermal straightening utilizes heat to temporarily straighten hair strands. Flat irons with heated metal plates then can be used after blow-drying the hair to fully straighten and smooth the strands. These processes combined commonly are known as a silk press.^21-22

For thermally straightened hair, it is recommended to either wrap the hair around the scalp to keep it flat or pin curl the hair and cover with a bonnet to sleep. Safe straightening techniques with the use of a flat iron include setting the temperature no higher than 175 °F or a low/medium setting while also limiting use to once per week if possible.²³ The number of passes of the flat iron also should be limited to 1 to 2 to reduce breakage. A heat-protectant cream or spray also can be applied to the hair before flat ironing to minimize damage. Applying heat protectant to the hair prior to styling will help minimize heat damage by distributing the heat along the hair fiber surface, avoiding water boiling in the hair shaft and the development of bubble hair leading to damage.²⁴

Chemical Straightening—Similar to how relaxers, perms, and Jheri curl treatments chemically modify hair texture using distinct chemicals yielding different curl patterns, the Brazilian blowout similarly straightens hair using a hair dryer and chemicals applied to hair strands after washing.^21-24 Relaxers utilize sodium or guanidine hydroxide for straightening, perms use ammonium thioglycolate for curling, and Jheri curl treatments employ thioglycolates or mercaptans for defined curls. However, these treatments generally are cautioned against due to potential hair damage and recent associations with uterine and breast cancer in Black women. Research has suggested that endocrine disrupters in these products, especially those marketed to Black women, contribute to hormone-related disease processes.^25,26 One study found higher concentrations of alkylphenols, the fragrance marker diethyl phthalate, and parabens in relaxers²⁷; however, more research is needed to determine specific chemicals associated with these cancers.

Braids and Locs—Braiding is a technique that involves interlocking 3 or more sections of hair that may or may not be fixated to the scalp like a cornrow,¹¹ and one can utilize extensions or natural hair depending on the desired outcome. Intended for long-term wear (ie, weeks to months), braids minimize breakage and reduce daily styling needs. Two popular styles—cornrows and individual braids—differ in preparation and weaving techniques. Cornrows are an Afro-centric style involving uniform, tightly woven braids that are close to the scalp, creating distinct patterns. Conversely, individual braids weave separate hair sections, offering diverse styling possibilities. Braiding practices should exclude hairline edges—often termed baby hairs—to prevent traction alopecia. Minimal use of edge gel, which helps to tame the vellus hairs at the frontotemporal scalp, as well as mindful weave volume, weight, and length are recommended to avert breakage. Braids that cause pain are too tight, can damage hair, and may cause traction alopecia.¹¹ Braids should not be worn for longer than 3 months at a time and require biweekly washing with diluted shampoo and conditioner. Proper drying by wringing the hair with a microfiber towel is essential to avoid frizz and mold formation.

Locs are a low-maintenance hairstyle considered permanent until cut.²⁸ This style involves twisting, palm rolling, or using tools such as crochet hooks to “lock” the hair. Regular maintenance with retwisting and cleaning is vital for loc health. Increased weight and tight twisting of locs can cause damage to the scalp and hair strands; however, locs are known to increase hair volume over time, often due to the accumulation of hairs that would otherwise have been shed in the telogen phase.²⁸

Wigs and Weaves—Wigs consist of synthetic or human hair that can be strapped to the head with an adjustable band or glued to the scalp depending on the desired style.²⁹ Wigs are removed daily, which allows for quick access to hair for cleansing and moisturizing. In contrast, weaves typically are sewn into the natural hair, which may make it difficult to reach the scalp for cleansing, leading to dryness and product build-up.²⁹ Notably, there is evidence of a relationship between long-term use of weaves and traction alopecia.³⁰

Wigs can have a fully synthetic hair line or lace hair line and can range from very affordable to expensive. When applied correctly, both styles offer an easy way to cover and protect the natural hair by reducing the amount of physical trauma related to daily hair styling. A lace-front wig contains a frontal thin mesh or lace that camouflages the natural frontal hairline.^29,30 A risk of lace-front wigs is that they can cause friction alopecia secondary to repeated use of adhesives and repeated friction against the hairline. Generally, wigs and weaves should be cared for as one would care for one’s own hair.

Hair Care in Black Children—Children’s hair care begins with washing the hair and scalp with shampoo, applying conditioner, and detangling as needed.³¹ After rinsing out the conditioner, a leave-in conditioner can assist with moisture retention and further detangling. The hair is then styled, either wet or dry. Recommendations for hair care practices in Black children include loose hairstyles that do not strain hair roots and nightly removal of root-securing accessories (eg, barrettes, elastic hairbeads). Frequent cornrow styling and friction on chemically straightened hair were identified by a survey as considerable traction alopecia risk factors.³² Thus, educating caregivers on appropriate hair-grooming practices for children is important.

Hair Protection—Proactive steps to reduce hair loss include wearing satin bonnets and/or using satin pillowcases while sleeping regardless of hairstyle. Although evidence is limited, it is thought that satin and silk allow the hair to retain its moisture and natural oils, preventing breakage and friction.^33,34 Frequent hair trimming every 2 to 4 months can reduce breakage when doing thermal treatments.^35,36 When prolonged or repetitive styles are used, it is encouraged to give the hair a break between styles to recover from the repeated stress. Wearing an intermittent updo or high bun—a hairstyle in which the hair is pulled upward—can prevent breakage by reducing heavy strain on the hair; however, it is important to avoid the use of rubber bands due to friction and risk for tangling of hair strands. Instead, the use of covered elastic ties and/or those without metal is preferred.¹¹ Alternatively, if a polished and neat appearance with slicked-back hair is desired, the practice of tautly pulling the hair is not recommended. Instead, use of an alcohol-free gel is suggested along with a satin scarf wrapped around the hairline to facilitate the setting of the hair in place.¹¹

A common practice to preserve curly hairstyles while sleeping is known as the pineapple method, which protects the hair and aids in preserving the freshness and style of the curls.³⁷ It consists of a loosely tied high ponytail at the top of the head allowing the curls to fall forward. This minimizes frizz and prevents the curls from forming knots.

Conclusion

Hair care recommendations in Black women can be complex due to a wide range of personal care preferences and styling techniques in this population. While evidence in the literature is limited, it still is important for dermatologists to be familiar with the different hair care practices utilized by Black women so they can effectively counsel patients and improve hair health. Knowledge of optimal hair care practices can aid in the prevention of common hair disorders that disproportionately affect this patient population, such as traction alopecia and trichorrhexis nodosa or breakage.

Patients often ask dermatologists how to best care for their specific hair type; however, there are no formal recommendations that apply to the many different hair care practices utilized by Black patients, as hair types in this community can range from wavy to tightly coiled.¹ Understanding the the history of hair care in those of African ancestry and various styling practices in this population is necessary to adequately counsel patients and gain trust in the doctor-patient relationship. In this article, we provide an overview of hair care recommendations based on common styling practices in Black women.

A PubMed search of articles indexed for MEDLINE using the terms Black hair care, African American hair management, hair loss prevention, hair care practices, natural hair, natural-hair styles, alopecia, hairdressing, hair breakage, hair fragility, heat-stressed hair, traction alopecia, and natural hair care yielded 305 results; 107 duplicates were identified and removed, leaving 198 articles to be screened for eligibility (ie, English-language studies created in the past 15 years). Sixty-eight full-text articles were screened against the exclusion criteria, which included case reports and case series, articles not focused on Afro-textured hair, and cancer-related hair loss. Three additional fulltext articles were identified via resources from Wayne State University library (Detroit, Michigan) that were not available on PubMed. A total of 29 full-text articles were included in our review.

Background on Hair Care and Styling in African Populations

It is difficult to understand the history of hair in those of African ancestry in the United States.² Prior to slavery, hair styling was considered a way of identification, classification, and communication as well as a medium through which to connect with the spiritual world in many parts of Africa. Hair-styling practices in Africa included elaborate cornrows, threading, and braiding with many accessories. Notable hair-styling products included natural butters, herbs, and powders to assist with moisture retention. Scarves also were used during this time for ceremonies or protection.³ During the mass enslavement of African populations and their transportation to the Americas by Europeans, slaveholders routinely cut off all the hair of both men and women in order to objectify and erase the culture of African hair styling passed down through generations.^4,5 Hair texture then was weaponized to create a caste system in plantation life, in which Black slaves with straight hair textures were granted the “privilege” of domestic work, while those with kinky hair were relegated to arduous manual labor in the fields.⁴ Years later, during the 1800s, laws were enacted in the United States to prohibit Black women from wearing tightly coiled natural hair in public places.⁵ Over the next few centuries from the 1800s to the early 2000s, various hair-styling trends such as the use of hot combs, perms, afros, and Jheri curls developed as a means for Black individuals to conform to societal pressure to adopt more European features; however, as time progressed, afros, braids, locs, and natural hair would become more dominant as statements against these same societal pressures.⁵

The natural hair movement, which emerged in the United States in the 2000s, encouraged Black women to abandon the use of toxic chemical hair straighteners, cultivate healthier hair care practices, disrupt Eurocentric standards of wearing straightened hair, and facilitate self-definition of beauty ideals from the Civil Rights Movement of the 1960s.^4,5 It is estimated that between 30% and 70% of all Black women in the United States wear natural hair, including 79% of millennial Black women younger than 30 years⁶; however, several new trends such as wigs and weaves have grown in popularity since the early 2000s due to mainstream pop culture and improvements in creating natural hairlines.^7,8

Key Features of Afro-Textured Hair

Individuals of African descent have the most diverse hair texture phenotypes, ranging from straight to tightly coiled.⁹ Although hair is chemically similar across various racial groups, differences are noted mainly in the shape of the hair shaft, with elliptical and curved shapes seen in Afrotextured hair. These differences yield more tightly curled strands than in other hair types; however, these features also contribute to fragility, as it creates points of weakness and decreases the tensile strength of the hair shaft.¹⁰ This inherent fragility leads to higher rates of hair breakage as well as lower moisture content and slower growth rates, which is why Afro-textured hair requires special care.⁹

Afro-textured hair generally falls into 2 main categories of the Andre Walker hair typing system: 4A-4C and 3A-3C.¹¹ In the 4A-4C category, hair is described as coily or kinky. Common concerns related to this hair type include dryness and brittleness with increased susceptibility to breakage. The 3A-3C category is described as loose to corkscrew curls, with a common concern of dryness.^11,12 Additionally, Loussouarn et al¹³ established a method to further define natural hair curliness using curve diameter and curl meters on glass plates to measure the curvature of hair strands. This method allows for assessing diversity and range of curliness within various races without relying on ethnic origin.¹³

Common Hair Care Practices

A description of each hair type and recommended styling practices with their levels of evidence can be found in the eTable.

Natural Hair—Natural hair is classified as hair that has not been chemically changed by perms, heat, or other straightening treatments.^12,14 For natural hair, retaining the moisture of the hair shaft should be the main focus, as moisture loss leads to considerable dryness.¹⁴ Generally, it is recommended to wash natural hair once per week or every other week; however, this can change based on hair length and oil production on the scalp. Washing daily may be ideal for shorter hair and monthly for longer hair to help prevent product build-up that can have a drying effect.¹⁵ Avoid shampoos that are drying (eg, sulfate and silicone products). The co-washing method also can be utilized, which entails washing the hair with a conditioning cleanser instead of shampoo and conditioner. However, this technique is not meant to completely replace shampoo.¹⁶ In fact, a clarifying shampoo is recommended after co-washing 3 or 4 times.¹⁶ The use of a hot oil treatment twice per month can promote moisture retention and reduce split-end formation.¹⁷ For maintenance between washes, many utilize the liquid, oil, cream (LOC) or liquid, cream, oil (LCO) methods, which describe regimens that utilize water, an oil of choice, and cream such as shea butter to lock in moisture.¹⁸ This method can be used as often as needed for dry hair.

Due to the susceptibility of Afro-textured hair to tangle and knot, using a wide-tooth comb, detangling brush, or detangling conditioners is a grade B recommendation for care (eTable). Though not widely documented in the literature, many of our patients have had anecdotal success detangling their hair simply by pulling hair strands apart by hand or “finger detangling” as well as using wide-tooth combs. Although both hair types are healthier in their natural states, kinky hair (type 4A-4C) is extremely fragile and more difficult to manage than less kinky hair (type 3A-3C).¹⁸

Special care is needed when detangling due to strands being weaker when wet.¹⁹ Detangling should be performed in a retrograde fashion. Deep conditioning can aid in moisture retention and should be performed weekly or biweekly.^17-20 Depending on the health of the hair, protein treatments can be considered on a monthly basis to help preserve the cuticle. Styling with braids, twists, or other protective styles can then be completed on an individual basis.

Thermal Straightening—A blowout involves straightening the hair after a wash with the use of a hair dryer.²¹ This common hair-styling method does not employ the use of chemicals beyond light hair oils and heat-protectant creams or sprays, typically resulting in a less kinky afro or semi-straight hair. Thermal straightening utilizes heat to temporarily straighten hair strands. Flat irons with heated metal plates then can be used after blow-drying the hair to fully straighten and smooth the strands. These processes combined commonly are known as a silk press.^21-22

For thermally straightened hair, it is recommended to either wrap the hair around the scalp to keep it flat or pin curl the hair and cover with a bonnet to sleep. Safe straightening techniques with the use of a flat iron include setting the temperature no higher than 175 °F or a low/medium setting while also limiting use to once per week if possible.²³ The number of passes of the flat iron also should be limited to 1 to 2 to reduce breakage. A heat-protectant cream or spray also can be applied to the hair before flat ironing to minimize damage. Applying heat protectant to the hair prior to styling will help minimize heat damage by distributing the heat along the hair fiber surface, avoiding water boiling in the hair shaft and the development of bubble hair leading to damage.²⁴

Chemical Straightening—Similar to how relaxers, perms, and Jheri curl treatments chemically modify hair texture using distinct chemicals yielding different curl patterns, the Brazilian blowout similarly straightens hair using a hair dryer and chemicals applied to hair strands after washing.^21-24 Relaxers utilize sodium or guanidine hydroxide for straightening, perms use ammonium thioglycolate for curling, and Jheri curl treatments employ thioglycolates or mercaptans for defined curls. However, these treatments generally are cautioned against due to potential hair damage and recent associations with uterine and breast cancer in Black women. Research has suggested that endocrine disrupters in these products, especially those marketed to Black women, contribute to hormone-related disease processes.^25,26 One study found higher concentrations of alkylphenols, the fragrance marker diethyl phthalate, and parabens in relaxers²⁷; however, more research is needed to determine specific chemicals associated with these cancers.

Braids and Locs—Braiding is a technique that involves interlocking 3 or more sections of hair that may or may not be fixated to the scalp like a cornrow,¹¹ and one can utilize extensions or natural hair depending on the desired outcome. Intended for long-term wear (ie, weeks to months), braids minimize breakage and reduce daily styling needs. Two popular styles—cornrows and individual braids—differ in preparation and weaving techniques. Cornrows are an Afro-centric style involving uniform, tightly woven braids that are close to the scalp, creating distinct patterns. Conversely, individual braids weave separate hair sections, offering diverse styling possibilities. Braiding practices should exclude hairline edges—often termed baby hairs—to prevent traction alopecia. Minimal use of edge gel, which helps to tame the vellus hairs at the frontotemporal scalp, as well as mindful weave volume, weight, and length are recommended to avert breakage. Braids that cause pain are too tight, can damage hair, and may cause traction alopecia.¹¹ Braids should not be worn for longer than 3 months at a time and require biweekly washing with diluted shampoo and conditioner. Proper drying by wringing the hair with a microfiber towel is essential to avoid frizz and mold formation.

Locs are a low-maintenance hairstyle considered permanent until cut.²⁸ This style involves twisting, palm rolling, or using tools such as crochet hooks to “lock” the hair. Regular maintenance with retwisting and cleaning is vital for loc health. Increased weight and tight twisting of locs can cause damage to the scalp and hair strands; however, locs are known to increase hair volume over time, often due to the accumulation of hairs that would otherwise have been shed in the telogen phase.²⁸

Wigs and Weaves—Wigs consist of synthetic or human hair that can be strapped to the head with an adjustable band or glued to the scalp depending on the desired style.²⁹ Wigs are removed daily, which allows for quick access to hair for cleansing and moisturizing. In contrast, weaves typically are sewn into the natural hair, which may make it difficult to reach the scalp for cleansing, leading to dryness and product build-up.²⁹ Notably, there is evidence of a relationship between long-term use of weaves and traction alopecia.³⁰

Wigs can have a fully synthetic hair line or lace hair line and can range from very affordable to expensive. When applied correctly, both styles offer an easy way to cover and protect the natural hair by reducing the amount of physical trauma related to daily hair styling. A lace-front wig contains a frontal thin mesh or lace that camouflages the natural frontal hairline.^29,30 A risk of lace-front wigs is that they can cause friction alopecia secondary to repeated use of adhesives and repeated friction against the hairline. Generally, wigs and weaves should be cared for as one would care for one’s own hair.

Hair Care in Black Children—Children’s hair care begins with washing the hair and scalp with shampoo, applying conditioner, and detangling as needed.³¹ After rinsing out the conditioner, a leave-in conditioner can assist with moisture retention and further detangling. The hair is then styled, either wet or dry. Recommendations for hair care practices in Black children include loose hairstyles that do not strain hair roots and nightly removal of root-securing accessories (eg, barrettes, elastic hairbeads). Frequent cornrow styling and friction on chemically straightened hair were identified by a survey as considerable traction alopecia risk factors.³² Thus, educating caregivers on appropriate hair-grooming practices for children is important.

Hair Protection—Proactive steps to reduce hair loss include wearing satin bonnets and/or using satin pillowcases while sleeping regardless of hairstyle. Although evidence is limited, it is thought that satin and silk allow the hair to retain its moisture and natural oils, preventing breakage and friction.^33,34 Frequent hair trimming every 2 to 4 months can reduce breakage when doing thermal treatments.^35,36 When prolonged or repetitive styles are used, it is encouraged to give the hair a break between styles to recover from the repeated stress. Wearing an intermittent updo or high bun—a hairstyle in which the hair is pulled upward—can prevent breakage by reducing heavy strain on the hair; however, it is important to avoid the use of rubber bands due to friction and risk for tangling of hair strands. Instead, the use of covered elastic ties and/or those without metal is preferred.¹¹ Alternatively, if a polished and neat appearance with slicked-back hair is desired, the practice of tautly pulling the hair is not recommended. Instead, use of an alcohol-free gel is suggested along with a satin scarf wrapped around the hairline to facilitate the setting of the hair in place.¹¹

A common practice to preserve curly hairstyles while sleeping is known as the pineapple method, which protects the hair and aids in preserving the freshness and style of the curls.³⁷ It consists of a loosely tied high ponytail at the top of the head allowing the curls to fall forward. This minimizes frizz and prevents the curls from forming knots.

Conclusion

Hair care recommendations in Black women can be complex due to a wide range of personal care preferences and styling techniques in this population. While evidence in the literature is limited, it still is important for dermatologists to be familiar with the different hair care practices utilized by Black women so they can effectively counsel patients and improve hair health. Knowledge of optimal hair care practices can aid in the prevention of common hair disorders that disproportionately affect this patient population, such as traction alopecia and trichorrhexis nodosa or breakage.

Patients often ask dermatologists how to best care for their specific hair type; however, there are no formal recommendations that apply to the many different hair care practices utilized by Black patients, as hair types in this community can range from wavy to tightly coiled.¹ Understanding the the history of hair care in those of African ancestry and various styling practices in this population is necessary to adequately counsel patients and gain trust in the doctor-patient relationship. In this article, we provide an overview of hair care recommendations based on common styling practices in Black women.

A PubMed search of articles indexed for MEDLINE using the terms Black hair care, African American hair management, hair loss prevention, hair care practices, natural hair, natural-hair styles, alopecia, hairdressing, hair breakage, hair fragility, heat-stressed hair, traction alopecia, and natural hair care yielded 305 results; 107 duplicates were identified and removed, leaving 198 articles to be screened for eligibility (ie, English-language studies created in the past 15 years). Sixty-eight full-text articles were screened against the exclusion criteria, which included case reports and case series, articles not focused on Afro-textured hair, and cancer-related hair loss. Three additional fulltext articles were identified via resources from Wayne State University library (Detroit, Michigan) that were not available on PubMed. A total of 29 full-text articles were included in our review.

Background on Hair Care and Styling in African Populations

It is difficult to understand the history of hair in those of African ancestry in the United States.² Prior to slavery, hair styling was considered a way of identification, classification, and communication as well as a medium through which to connect with the spiritual world in many parts of Africa. Hair-styling practices in Africa included elaborate cornrows, threading, and braiding with many accessories. Notable hair-styling products included natural butters, herbs, and powders to assist with moisture retention. Scarves also were used during this time for ceremonies or protection.³ During the mass enslavement of African populations and their transportation to the Americas by Europeans, slaveholders routinely cut off all the hair of both men and women in order to objectify and erase the culture of African hair styling passed down through generations.^4,5 Hair texture then was weaponized to create a caste system in plantation life, in which Black slaves with straight hair textures were granted the “privilege” of domestic work, while those with kinky hair were relegated to arduous manual labor in the fields.⁴ Years later, during the 1800s, laws were enacted in the United States to prohibit Black women from wearing tightly coiled natural hair in public places.⁵ Over the next few centuries from the 1800s to the early 2000s, various hair-styling trends such as the use of hot combs, perms, afros, and Jheri curls developed as a means for Black individuals to conform to societal pressure to adopt more European features; however, as time progressed, afros, braids, locs, and natural hair would become more dominant as statements against these same societal pressures.⁵

The natural hair movement, which emerged in the United States in the 2000s, encouraged Black women to abandon the use of toxic chemical hair straighteners, cultivate healthier hair care practices, disrupt Eurocentric standards of wearing straightened hair, and facilitate self-definition of beauty ideals from the Civil Rights Movement of the 1960s.^4,5 It is estimated that between 30% and 70% of all Black women in the United States wear natural hair, including 79% of millennial Black women younger than 30 years⁶; however, several new trends such as wigs and weaves have grown in popularity since the early 2000s due to mainstream pop culture and improvements in creating natural hairlines.^7,8

Key Features of Afro-Textured Hair

Individuals of African descent have the most diverse hair texture phenotypes, ranging from straight to tightly coiled.⁹ Although hair is chemically similar across various racial groups, differences are noted mainly in the shape of the hair shaft, with elliptical and curved shapes seen in Afrotextured hair. These differences yield more tightly curled strands than in other hair types; however, these features also contribute to fragility, as it creates points of weakness and decreases the tensile strength of the hair shaft.¹⁰ This inherent fragility leads to higher rates of hair breakage as well as lower moisture content and slower growth rates, which is why Afro-textured hair requires special care.⁹

Afro-textured hair generally falls into 2 main categories of the Andre Walker hair typing system: 4A-4C and 3A-3C.¹¹ In the 4A-4C category, hair is described as coily or kinky. Common concerns related to this hair type include dryness and brittleness with increased susceptibility to breakage. The 3A-3C category is described as loose to corkscrew curls, with a common concern of dryness.^11,12 Additionally, Loussouarn et al¹³ established a method to further define natural hair curliness using curve diameter and curl meters on glass plates to measure the curvature of hair strands. This method allows for assessing diversity and range of curliness within various races without relying on ethnic origin.¹³

Common Hair Care Practices

A description of each hair type and recommended styling practices with their levels of evidence can be found in the eTable.

Natural Hair—Natural hair is classified as hair that has not been chemically changed by perms, heat, or other straightening treatments.^12,14 For natural hair, retaining the moisture of the hair shaft should be the main focus, as moisture loss leads to considerable dryness.¹⁴ Generally, it is recommended to wash natural hair once per week or every other week; however, this can change based on hair length and oil production on the scalp. Washing daily may be ideal for shorter hair and monthly for longer hair to help prevent product build-up that can have a drying effect.¹⁵ Avoid shampoos that are drying (eg, sulfate and silicone products). The co-washing method also can be utilized, which entails washing the hair with a conditioning cleanser instead of shampoo and conditioner. However, this technique is not meant to completely replace shampoo.¹⁶ In fact, a clarifying shampoo is recommended after co-washing 3 or 4 times.¹⁶ The use of a hot oil treatment twice per month can promote moisture retention and reduce split-end formation.¹⁷ For maintenance between washes, many utilize the liquid, oil, cream (LOC) or liquid, cream, oil (LCO) methods, which describe regimens that utilize water, an oil of choice, and cream such as shea butter to lock in moisture.¹⁸ This method can be used as often as needed for dry hair.

Due to the susceptibility of Afro-textured hair to tangle and knot, using a wide-tooth comb, detangling brush, or detangling conditioners is a grade B recommendation for care (eTable). Though not widely documented in the literature, many of our patients have had anecdotal success detangling their hair simply by pulling hair strands apart by hand or “finger detangling” as well as using wide-tooth combs. Although both hair types are healthier in their natural states, kinky hair (type 4A-4C) is extremely fragile and more difficult to manage than less kinky hair (type 3A-3C).¹⁸

Special care is needed when detangling due to strands being weaker when wet.¹⁹ Detangling should be performed in a retrograde fashion. Deep conditioning can aid in moisture retention and should be performed weekly or biweekly.^17-20 Depending on the health of the hair, protein treatments can be considered on a monthly basis to help preserve the cuticle. Styling with braids, twists, or other protective styles can then be completed on an individual basis.

Thermal Straightening—A blowout involves straightening the hair after a wash with the use of a hair dryer.²¹ This common hair-styling method does not employ the use of chemicals beyond light hair oils and heat-protectant creams or sprays, typically resulting in a less kinky afro or semi-straight hair. Thermal straightening utilizes heat to temporarily straighten hair strands. Flat irons with heated metal plates then can be used after blow-drying the hair to fully straighten and smooth the strands. These processes combined commonly are known as a silk press.^21-22

For thermally straightened hair, it is recommended to either wrap the hair around the scalp to keep it flat or pin curl the hair and cover with a bonnet to sleep. Safe straightening techniques with the use of a flat iron include setting the temperature no higher than 175 °F or a low/medium setting while also limiting use to once per week if possible.²³ The number of passes of the flat iron also should be limited to 1 to 2 to reduce breakage. A heat-protectant cream or spray also can be applied to the hair before flat ironing to minimize damage. Applying heat protectant to the hair prior to styling will help minimize heat damage by distributing the heat along the hair fiber surface, avoiding water boiling in the hair shaft and the development of bubble hair leading to damage.²⁴

Chemical Straightening—Similar to how relaxers, perms, and Jheri curl treatments chemically modify hair texture using distinct chemicals yielding different curl patterns, the Brazilian blowout similarly straightens hair using a hair dryer and chemicals applied to hair strands after washing.^21-24 Relaxers utilize sodium or guanidine hydroxide for straightening, perms use ammonium thioglycolate for curling, and Jheri curl treatments employ thioglycolates or mercaptans for defined curls. However, these treatments generally are cautioned against due to potential hair damage and recent associations with uterine and breast cancer in Black women. Research has suggested that endocrine disrupters in these products, especially those marketed to Black women, contribute to hormone-related disease processes.^25,26 One study found higher concentrations of alkylphenols, the fragrance marker diethyl phthalate, and parabens in relaxers²⁷; however, more research is needed to determine specific chemicals associated with these cancers.

Braids and Locs—Braiding is a technique that involves interlocking 3 or more sections of hair that may or may not be fixated to the scalp like a cornrow,¹¹ and one can utilize extensions or natural hair depending on the desired outcome. Intended for long-term wear (ie, weeks to months), braids minimize breakage and reduce daily styling needs. Two popular styles—cornrows and individual braids—differ in preparation and weaving techniques. Cornrows are an Afro-centric style involving uniform, tightly woven braids that are close to the scalp, creating distinct patterns. Conversely, individual braids weave separate hair sections, offering diverse styling possibilities. Braiding practices should exclude hairline edges—often termed baby hairs—to prevent traction alopecia. Minimal use of edge gel, which helps to tame the vellus hairs at the frontotemporal scalp, as well as mindful weave volume, weight, and length are recommended to avert breakage. Braids that cause pain are too tight, can damage hair, and may cause traction alopecia.¹¹ Braids should not be worn for longer than 3 months at a time and require biweekly washing with diluted shampoo and conditioner. Proper drying by wringing the hair with a microfiber towel is essential to avoid frizz and mold formation.

Locs are a low-maintenance hairstyle considered permanent until cut.²⁸ This style involves twisting, palm rolling, or using tools such as crochet hooks to “lock” the hair. Regular maintenance with retwisting and cleaning is vital for loc health. Increased weight and tight twisting of locs can cause damage to the scalp and hair strands; however, locs are known to increase hair volume over time, often due to the accumulation of hairs that would otherwise have been shed in the telogen phase.²⁸

Wigs and Weaves—Wigs consist of synthetic or human hair that can be strapped to the head with an adjustable band or glued to the scalp depending on the desired style.²⁹ Wigs are removed daily, which allows for quick access to hair for cleansing and moisturizing. In contrast, weaves typically are sewn into the natural hair, which may make it difficult to reach the scalp for cleansing, leading to dryness and product build-up.²⁹ Notably, there is evidence of a relationship between long-term use of weaves and traction alopecia.³⁰

Wigs can have a fully synthetic hair line or lace hair line and can range from very affordable to expensive. When applied correctly, both styles offer an easy way to cover and protect the natural hair by reducing the amount of physical trauma related to daily hair styling. A lace-front wig contains a frontal thin mesh or lace that camouflages the natural frontal hairline.^29,30 A risk of lace-front wigs is that they can cause friction alopecia secondary to repeated use of adhesives and repeated friction against the hairline. Generally, wigs and weaves should be cared for as one would care for one’s own hair.

Hair Care in Black Children—Children’s hair care begins with washing the hair and scalp with shampoo, applying conditioner, and detangling as needed.³¹ After rinsing out the conditioner, a leave-in conditioner can assist with moisture retention and further detangling. The hair is then styled, either wet or dry. Recommendations for hair care practices in Black children include loose hairstyles that do not strain hair roots and nightly removal of root-securing accessories (eg, barrettes, elastic hairbeads). Frequent cornrow styling and friction on chemically straightened hair were identified by a survey as considerable traction alopecia risk factors.³² Thus, educating caregivers on appropriate hair-grooming practices for children is important.

Hair Protection—Proactive steps to reduce hair loss include wearing satin bonnets and/or using satin pillowcases while sleeping regardless of hairstyle. Although evidence is limited, it is thought that satin and silk allow the hair to retain its moisture and natural oils, preventing breakage and friction.^33,34 Frequent hair trimming every 2 to 4 months can reduce breakage when doing thermal treatments.^35,36 When prolonged or repetitive styles are used, it is encouraged to give the hair a break between styles to recover from the repeated stress. Wearing an intermittent updo or high bun—a hairstyle in which the hair is pulled upward—can prevent breakage by reducing heavy strain on the hair; however, it is important to avoid the use of rubber bands due to friction and risk for tangling of hair strands. Instead, the use of covered elastic ties and/or those without metal is preferred.¹¹ Alternatively, if a polished and neat appearance with slicked-back hair is desired, the practice of tautly pulling the hair is not recommended. Instead, use of an alcohol-free gel is suggested along with a satin scarf wrapped around the hairline to facilitate the setting of the hair in place.¹¹

A common practice to preserve curly hairstyles while sleeping is known as the pineapple method, which protects the hair and aids in preserving the freshness and style of the curls.³⁷ It consists of a loosely tied high ponytail at the top of the head allowing the curls to fall forward. This minimizes frizz and prevents the curls from forming knots.

Conclusion

Hair care recommendations in Black women can be complex due to a wide range of personal care preferences and styling techniques in this population. While evidence in the literature is limited, it still is important for dermatologists to be familiar with the different hair care practices utilized by Black women so they can effectively counsel patients and improve hair health. Knowledge of optimal hair care practices can aid in the prevention of common hair disorders that disproportionately affect this patient population, such as traction alopecia and trichorrhexis nodosa or breakage.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunologic phenomenon characterized by a systemic inflammatory response syndrome—like clinical picture with additional features, including hepatosplenomegaly, hyperferritinemia, and increased natural killer cell activity. Clinical manifestations of HLH often are nonspecific, making HLH diagnosis challenging. High persistent fever is a key feature of HLH; patients also may report gastrointestinal distress, lethargy, and/or widespread rash.¹

Hemophagocytic lymphohistiocytosis is believed to stem from inherited defects in several genes, such as perforin (PRF1), as well as immune dysregulation due to infections, rheumatologic diseases, hematologic malignancies, or drug reactions.² The primary mechanism of HLH is hypothesized to be driven by aberrant immune activation, interferon gamma released from CD8+ T cells, and uncontrolled phagocytosis by activated macrophages. The cytokine cascade results in tissue injury and multiorgan dysfunction.^3,4

Although HLH historically has been categorized as primary (familial) or secondary (acquired), the most recent guidelines suggest the etiology is not always binary.^3,5 That said, the concept of secondary causes is useful in understanding risk factors for developing HLH. Both forms of the disease are thought to be elicited by a trigger (eg, infection), even when inherited genetic mutations exist.⁶ The primary form commonly affects the pediatric population,^4,6-8 whereas the secondary form is more common in adults.⁷

Several sets of diagnostic criteria for HLH have been developed, the most well-known being the HLH-2004 criteria.^1,3 The HLH-2009 modified criteria were developed after further evidence provided a refined sense of how the HLH-2004 criteria should be stratified.⁹ Finally, Fardet et al¹⁰ presented the HScore as an estimation of likelihood of diagnosis of HLH. These sets of HLH criteria include clinical and laboratory features that demonstrate inflammation, natrual killer cell activity, hemophagocytosis, end-organ damage, and cell lineage effects. The HScore differs from the other sets of HLH criteria in that it is designed to estimate an individual patient’s risk of having reactive hemophagocytic syndrome, which likely is equivalent to secondary HLH, although the authors do not use this exact terminology.¹⁰

While these criteria provide a framework for diagnosing HLH, they may fail to distinguish between HLH disease and HLH disease mimics, a concept described by the North American Consortium for Histiocytosis that may impact the success of immunosuppressive treatment.³ Individuals with HLH syndrome meet the aforementioned diagnostic criteria; HLH syndrome is further divided into HLH disease and HLH disease mimics (Figure 1). The “disease” label describes the traditional concept of HLH, driven by aberrant immune overactivation, in which patients benefit from immunosuppression. In contrast, HLH mimics include a subset of patients who meet the HLH criteria but are unlikely to benefit from immunosuppression because the primary mechanism driving their condition is not owed to immune overactivation, as is the case with HLH disease. Examples of HLH mimics include certain infections, such as Epstein-Barr virus (EBV), that may demonstrate clinical findings consistent with HLH but would not benefit from immunosuppression. Ironically, infections (including EBV) also are known triggers of HLH disease, making this concept difficult to understand and adopt. In this study, we refer to HLH disease simply as HLH.

Although cutaneous manifestations of HLH are not included in the diagnostic criteria, skin findings are common and may coincide with the severity and progression of the disease.¹¹ Despite the fact that HLH can manifest with rash,¹ comprehensive reviews of reported cutaneous findings in adult HLH are lacking. Thus, the goal of this study was to provide an organized characterization of reported cutaneous findings in adults with HLH and context for how the dermatologic examination may support the diagnosis or uncover the underlying etiology of this condition.

Methods

A search of PubMed articles indexed for MEDLINE using the phrase (cutaneous OR dermatologic OR skin) findings) AND hemophagocytic lymphohistiocytosis performed on September 20, 2023, yielded 423 results (Figure 2). Filters to exclude non–English language publications and pediatric populations were applied, resulting in 161 articles. Other exclusion criteria included the absence of a description of dermatologic findings. Seventy-five articles remained after screening titles and abstracts, and full-text review yielded 55 articles that were deemed appropriate for inclusion in the study. Subsequent reference searches and use of the online resource Litmaps revealed 45 additional publications that underwent full-text screening; of these articles, 5 were included in the final review.

Results

Sixty studies were included in this systematic review.^5,7,11-68 The reported prevalence of skin findings among patients with HLH from the included retrospective studies ranged from 15% to 85%.^12-15 Several literature reviews reported similarly varied prevalence among adult patients with HLH.^7,16 Fardet et al¹⁴ categorized cutaneous manifestations of HLH into 3 types: direct manifestations of HLH not explained by systemic features (eg, generalized maculopapular eruption), indirect manifestations of HLH that are explained by systemic features of the disease (eg, purpura due to HLH-induced coagulopathy), and findings specific to the underlying etiology of HLH (eg, malar rash seen in systemic lupus erythematosus [SLE]–associated HLH). This categorization served as the outline for the results below, providing an organized review of cutaneous findings and context for how they may support the diagnosis or uncover the underlying etiology of HLH.

Category I: Direct Manifestations of HLH

Several articles reported cutaneous findings that seemed to be the direct result of HLH and not attributed to an underlying trigger or sequalae of HLH.^11,14,16-31 The most common descriptions were a generalized, morbilliform, or nonspecific eruption that encompasses large areas of the skin, commonly the trunk and extremities, sometimes extending to the face and scalp.^{14,16-23,25,31,32} There were variations in secondary features such as pruritus and tenderness; some studies also described violaceous discoloration in addition to erythema.^16,23

Other skin findings thought to be a direct result of HLH were described in detail by Zerah and DeWitt¹¹ in their retrospective study, including pyoderma gangrenosum, panniculitis, Stevens-Johnson syndrome, atypical targetoid lesions, and bullous eruptions. The authors also analyzed dermatopathologic data that ultimately revealed that pathologic analysis was largely inconsistent and nondescript.¹¹ There was a single case report of purpura fulminans arising alongside signs and symptoms of HLH,²⁶ and several case reports described Sweet syndrome developing around the same time as HLH.^27-29 Lastly, Collins et al³⁰ described a case of HLH manifesting with violaceous ulcerating papules and nodules scattered across the legs, abdomen, and arms. Biopsy of this patient’s lesions showed a diffuse dermal infiltrate of histiocytes and hemophagocytosis.

Category II: Secondary Complications and Sequelae of HLH

This was the smallest group among the 3 categories, comprising a few case reports and retrospective cohort studies primarily reporting jaundice/icterus and hemorrhagic lesions such as purpura, petechiae, and scleral hemorrhage.^{11,21,23,33-35} Several literature reviews described these conditions as nonspecific findings in HLH.^16,20 The cause of jaundice in HLH likely can be attributed to its characteristic hepatic dysfunction, whereas hemorrhagic lesions likely are the result of both hepatic and bone marrow dysfunction resulting in coagulopathy.

Category III: Manifestations of Underlying Etiology or Triggers of HLH

Infectious—Infection is known to be one of the most common triggers of HLH, with several retrospective studies reporting infectious triggers in approximately 20% of cases.^13,15 Although many pathogens have been implicated, only a few of these infection-induced HLH reports described cutaneous findings, which included a case of varicella zoster virus, Escherichia coli necrotizing fasciitis, leprosy, EBV reactivation, parvovirus B19, and both focal and disseminated herpes simplex virus 2.^36-42 Most of these patients presented with classic findings of each disease. The case of varicella zoster virus exhibited pruritic erythematous papules on the face, trunk, and limbs.³⁶ The necrotizing fasciitis case presented with tender erythematous swelling of the lower extremity.³⁷ The patient with leprosy exhibited leonine facies and numerous erythematous nodules, plaques, and superficial ulcerating plaques over the trunk and limbs with palmoplantar involvement,³⁹ and both cases of herpes simplex virus 2 reported small bullae either diffusely over the face, trunk, and extremities or over the genitalia.^38,40 Interestingly, the cases of parvovirus B19 and EBV reactivation both exhibited polyarteritis nodosa and occurred in patients with underlying autoimmune conditions, raising the question of whether these cases of HLH had a single trigger or were the result of the overall immunologic dysregulation induced by both infection and autoimmunity.^41,42

Rheumatologic—Several articles reported dermatologic findings associated with macrophage activation syndrome, a term that often is used to describe HLH associated with autoimmune conditions. Cases of HLH in adult-onset Still disease, dermatomyositis, polyarteritis nodosa, and SLE described skin findings characteristic of the underlying rheumatologic disease, sometimes with acutely worse dermatologic findings at the time of HLH presentation.^35,41-48 With regard to SLE, the acute manifestation of classic findings of the disease with HLH has sometimes been described as acute lupus hemophagocytic syndrome (HPS).⁴⁸ Lambotte at al⁴⁸ described common findings of acute lupus hemophagocytic syndrome in their retrospective study as malar rash, weight loss, polyarthralgia, and nephritis in addition to classic HLH findings including fever, lymphadenopathy, and hepatosplenomegaly. Many other rheumatologic conditions have been associated with HLH, including rheumatoid arthritis, mixed connective tissue disease, systemic sclerosis, and Sjögren disease. All these conditions can have dermatologic manifestations; however, no descriptions of dermatologic findings in cases of HLH associated with these diseases were found.¹³

Malignancy—Several cases of malignancy-induced HLH described cutaneous findings, the majority being cutaneous lymphomas, namely subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Other less commonly reported malignancies in this group included Kaposi sarcoma, intravascular lymphoma, Sézary syndrome, mycosis fungoides, cutaneous diffuse large B-cell lymphoma, and several subtypes of primary cutaneous T-cell lymphoma.^2,32,49-60 The most common description of SPTCL included multiple scattered plaques and subcutaneous nodules, some associated with tenderness, induration, drainage, or hemorrhagic features.^{32,50,52,55,57,60} Cases of mycosis fungoides and Sézary syndrome presented with variations in size and distribution of erythroderma with associated lymphadenopathy.² A unique case of HLH developing in a patient with intravascular lymphoma described an eruption of multiple telangiectasias and petechial hemorrhages on the trunk,⁵⁸ while one case associated with primary cutaneous anaplastic large cell lymphoma presented with a rapidly enlarging tumor with central ulceration and eschar.⁵⁹

Drug Induced—Interestingly, most of the drug-induced cases of HLH identified in our search were secondary to biologic therapies used in the treatment of metastatic melanoma, specifically the immune checkpoint inhibitors (ICIs), which have been reported to have an association with HLH in prior literature reviews.^61-65 Choi et al⁶⁶ described an interesting case of ICI-induced HLH presenting with a concurrent severe lichenoid drug eruption that progressed from a pruritic truncal rash to mucocutaneous bullae, erosions, and desquamation resembling a Stevens-Johnson syndrome–type picture. This patient had treatment-refractory, HIV-negative Kaposi sarcoma, where the underlying immunologic dysregulation may explain the more severe cutaneous presentation not observed in other reported cases of ICI-induced HLH.

Yang et al’s⁶⁷ review of 23 cases with concurrent diagnoses of HLH and DIHS found that 61% (14/23) of cases were diagnosed initially as DIHS before failing treatment and receiving a diagnosis of HLH several weeks later. Additionally, the authors found that several cases met criteria for one diagnosis while clinically presenting strongly for the other.⁶⁷ This overlap in clinical presentation also was demonstrated in Zerah and DeWitt’s11 retrospective study regarding cutaneous findings in HLH, in which several of the morbilliform eruptions thought to be contributed to HLH ultimately were decided to be drug reactions.

Comment

Regarding direct (or primary) cutaneous findings in HLH (category I), there seem to be 2 groups of features associated with the onset of HLH that are not related to its characteristic hepatic dysfunction (category II) nor its underlying triggers (category III): a nonspecific, generalized, erythematous eruption; and dermatologic conditions separate from HLH itself (eg, Sweet syndrome, pyoderma gangrenosum). Whether the latter group truly is a direct manifestation of HLH is difficult to discern with the evidence available. Nevertheless, we can conclude that there is some type of association between these dermatologic diseases and HLH, and this association can serve as both a diagnostic tool for clinicians and a point of interest for further clinical research.

The relatively low number of articles identified through our systematic review that specifically reported secondary findings, such as jaundice or coagulopathy-associated hemorrhagic lesions, may lead one to believe that these are not common findings in HLH; however, it is possible that these are not regularly reported in the literature simply because these findings are nonspecific and can be considered expected results of the characteristic organ dysfunction in HLH.

As suspected, the skin findings in category III were the most broad given the variety of underlying etiologies that have been associated with HLH. Like the other 2 categories, these skin findings generally are nonspecific to HLH; however, the ones in category III are specific to underlying etiology of HLH and may aid in identifying and treating the underlying cause of a patient’s HLH when indicated.

Most of the rheumatologic diseases seem to have been known at the time of HLH development and diagnosis, which may highlight the importance of considering a diagnosis of HLH early on in patients with known autoimmune disease and systemic signs of illness or acutely worsening signs and symptoms of their underlying autoimmune disease.

Interestingly, several cases of malignancy-associated HLH reported signs and symptoms of HLH at initial presentation of the malignant disease.^32,50,59 This situation seems to be somewhat common, as Go and Wester’s⁶⁸ systematic analysis of 156 patients with SPTCL found HLH was the presenting feature in 37% of patients included in their study. This may call attention to the importance of considering cutaneous lymphomas as the cause of skin lesions in patients with signs and symptoms of HLH, where it may be easy to assume that skin findings are a result of their systemic disease.

In highlighting cases of HLH related to medication use, we found it pertinent to include and discuss the complex relationship between drug-induced hypersensitivity syndrome (DIHS [formerly known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) and HLH. The results of this study suggest that DIHS may have considerable clinical overlap with HLH¹¹ and may even lead to development of HLH,⁶⁷ creating difficulty in distinguishing between these conditions where there may be similar findings, such as cutaneous eruptions, fever, and hepatic or other internal organ involvement. We agree with Yang et al⁶⁷ that there can be large overlap in symptomology between these two conditions and that more investigation is necessary to explore the relationship between them.

Conclusion

Diagnosis of HLH in adults continues to be challenging, with several diagnostic tools but no true gold standard. In addition to the nonspecific symptomology, there is a myriad of cutaneous findings that can be present in adults with HLH (eTable), all of which are also nonspecific. Even so, awareness of which dermatologic findings have been associated with HLH may provide a cue to consider HLH in the systemically ill patient with a notable dermatologic examination. Furthermore, there are several avenues for further investigation that can be drawn, including further dermatologic analysis among nonspecific eruptions attributed to HLH, clinical and pathologic differentiation between DIHS/DRESS and HLH, and correlation between severity of skin manifestations and severity of HLH disease.

Limitations of this study included a lack of clarity in diagnosis of HLH in patients described in the included articles, as some reports use variable terminology (HLH vs hemophagocytic syndrome vs macrophage activation syndrome, etc), and it is impossible to know if all authors used the same diagnostic criteria—or any validated diagnostic criteria—unless specifically stated. Additionally, including case reports in our study limited the amount and quality of information described in each report. Despite its limitations, this systematic review outlines the cutaneous manifestations associated with HLH. These data will promote clinical awareness of this complex condition and allow for consideration of HLH in patients meeting criteria for HLH syndrome. More studies ultimately are needed to differentiate HLH from its mimics.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunologic phenomenon characterized by a systemic inflammatory response syndrome—like clinical picture with additional features, including hepatosplenomegaly, hyperferritinemia, and increased natural killer cell activity. Clinical manifestations of HLH often are nonspecific, making HLH diagnosis challenging. High persistent fever is a key feature of HLH; patients also may report gastrointestinal distress, lethargy, and/or widespread rash.¹

Hemophagocytic lymphohistiocytosis is believed to stem from inherited defects in several genes, such as perforin (PRF1), as well as immune dysregulation due to infections, rheumatologic diseases, hematologic malignancies, or drug reactions.² The primary mechanism of HLH is hypothesized to be driven by aberrant immune activation, interferon gamma released from CD8+ T cells, and uncontrolled phagocytosis by activated macrophages. The cytokine cascade results in tissue injury and multiorgan dysfunction.^3,4

Although HLH historically has been categorized as primary (familial) or secondary (acquired), the most recent guidelines suggest the etiology is not always binary.^3,5 That said, the concept of secondary causes is useful in understanding risk factors for developing HLH. Both forms of the disease are thought to be elicited by a trigger (eg, infection), even when inherited genetic mutations exist.⁶ The primary form commonly affects the pediatric population,^4,6-8 whereas the secondary form is more common in adults.⁷

Several sets of diagnostic criteria for HLH have been developed, the most well-known being the HLH-2004 criteria.^1,3 The HLH-2009 modified criteria were developed after further evidence provided a refined sense of how the HLH-2004 criteria should be stratified.⁹ Finally, Fardet et al¹⁰ presented the HScore as an estimation of likelihood of diagnosis of HLH. These sets of HLH criteria include clinical and laboratory features that demonstrate inflammation, natrual killer cell activity, hemophagocytosis, end-organ damage, and cell lineage effects. The HScore differs from the other sets of HLH criteria in that it is designed to estimate an individual patient’s risk of having reactive hemophagocytic syndrome, which likely is equivalent to secondary HLH, although the authors do not use this exact terminology.¹⁰

While these criteria provide a framework for diagnosing HLH, they may fail to distinguish between HLH disease and HLH disease mimics, a concept described by the North American Consortium for Histiocytosis that may impact the success of immunosuppressive treatment.³ Individuals with HLH syndrome meet the aforementioned diagnostic criteria; HLH syndrome is further divided into HLH disease and HLH disease mimics (Figure 1). The “disease” label describes the traditional concept of HLH, driven by aberrant immune overactivation, in which patients benefit from immunosuppression. In contrast, HLH mimics include a subset of patients who meet the HLH criteria but are unlikely to benefit from immunosuppression because the primary mechanism driving their condition is not owed to immune overactivation, as is the case with HLH disease. Examples of HLH mimics include certain infections, such as Epstein-Barr virus (EBV), that may demonstrate clinical findings consistent with HLH but would not benefit from immunosuppression. Ironically, infections (including EBV) also are known triggers of HLH disease, making this concept difficult to understand and adopt. In this study, we refer to HLH disease simply as HLH.

Although cutaneous manifestations of HLH are not included in the diagnostic criteria, skin findings are common and may coincide with the severity and progression of the disease.¹¹ Despite the fact that HLH can manifest with rash,¹ comprehensive reviews of reported cutaneous findings in adult HLH are lacking. Thus, the goal of this study was to provide an organized characterization of reported cutaneous findings in adults with HLH and context for how the dermatologic examination may support the diagnosis or uncover the underlying etiology of this condition.

Methods

A search of PubMed articles indexed for MEDLINE using the phrase (cutaneous OR dermatologic OR skin) findings) AND hemophagocytic lymphohistiocytosis performed on September 20, 2023, yielded 423 results (Figure 2). Filters to exclude non–English language publications and pediatric populations were applied, resulting in 161 articles. Other exclusion criteria included the absence of a description of dermatologic findings. Seventy-five articles remained after screening titles and abstracts, and full-text review yielded 55 articles that were deemed appropriate for inclusion in the study. Subsequent reference searches and use of the online resource Litmaps revealed 45 additional publications that underwent full-text screening; of these articles, 5 were included in the final review.

Results

Sixty studies were included in this systematic review.^5,7,11-68 The reported prevalence of skin findings among patients with HLH from the included retrospective studies ranged from 15% to 85%.^12-15 Several literature reviews reported similarly varied prevalence among adult patients with HLH.^7,16 Fardet et al¹⁴ categorized cutaneous manifestations of HLH into 3 types: direct manifestations of HLH not explained by systemic features (eg, generalized maculopapular eruption), indirect manifestations of HLH that are explained by systemic features of the disease (eg, purpura due to HLH-induced coagulopathy), and findings specific to the underlying etiology of HLH (eg, malar rash seen in systemic lupus erythematosus [SLE]–associated HLH). This categorization served as the outline for the results below, providing an organized review of cutaneous findings and context for how they may support the diagnosis or uncover the underlying etiology of HLH.

Category I: Direct Manifestations of HLH

Several articles reported cutaneous findings that seemed to be the direct result of HLH and not attributed to an underlying trigger or sequalae of HLH.^11,14,16-31 The most common descriptions were a generalized, morbilliform, or nonspecific eruption that encompasses large areas of the skin, commonly the trunk and extremities, sometimes extending to the face and scalp.^{14,16-23,25,31,32} There were variations in secondary features such as pruritus and tenderness; some studies also described violaceous discoloration in addition to erythema.^16,23

Other skin findings thought to be a direct result of HLH were described in detail by Zerah and DeWitt¹¹ in their retrospective study, including pyoderma gangrenosum, panniculitis, Stevens-Johnson syndrome, atypical targetoid lesions, and bullous eruptions. The authors also analyzed dermatopathologic data that ultimately revealed that pathologic analysis was largely inconsistent and nondescript.¹¹ There was a single case report of purpura fulminans arising alongside signs and symptoms of HLH,²⁶ and several case reports described Sweet syndrome developing around the same time as HLH.^27-29 Lastly, Collins et al³⁰ described a case of HLH manifesting with violaceous ulcerating papules and nodules scattered across the legs, abdomen, and arms. Biopsy of this patient’s lesions showed a diffuse dermal infiltrate of histiocytes and hemophagocytosis.

Category II: Secondary Complications and Sequelae of HLH

This was the smallest group among the 3 categories, comprising a few case reports and retrospective cohort studies primarily reporting jaundice/icterus and hemorrhagic lesions such as purpura, petechiae, and scleral hemorrhage.^{11,21,23,33-35} Several literature reviews described these conditions as nonspecific findings in HLH.^16,20 The cause of jaundice in HLH likely can be attributed to its characteristic hepatic dysfunction, whereas hemorrhagic lesions likely are the result of both hepatic and bone marrow dysfunction resulting in coagulopathy.

Category III: Manifestations of Underlying Etiology or Triggers of HLH

Infectious—Infection is known to be one of the most common triggers of HLH, with several retrospective studies reporting infectious triggers in approximately 20% of cases.^13,15 Although many pathogens have been implicated, only a few of these infection-induced HLH reports described cutaneous findings, which included a case of varicella zoster virus, Escherichia coli necrotizing fasciitis, leprosy, EBV reactivation, parvovirus B19, and both focal and disseminated herpes simplex virus 2.^36-42 Most of these patients presented with classic findings of each disease. The case of varicella zoster virus exhibited pruritic erythematous papules on the face, trunk, and limbs.³⁶ The necrotizing fasciitis case presented with tender erythematous swelling of the lower extremity.³⁷ The patient with leprosy exhibited leonine facies and numerous erythematous nodules, plaques, and superficial ulcerating plaques over the trunk and limbs with palmoplantar involvement,³⁹ and both cases of herpes simplex virus 2 reported small bullae either diffusely over the face, trunk, and extremities or over the genitalia.^38,40 Interestingly, the cases of parvovirus B19 and EBV reactivation both exhibited polyarteritis nodosa and occurred in patients with underlying autoimmune conditions, raising the question of whether these cases of HLH had a single trigger or were the result of the overall immunologic dysregulation induced by both infection and autoimmunity.^41,42

Rheumatologic—Several articles reported dermatologic findings associated with macrophage activation syndrome, a term that often is used to describe HLH associated with autoimmune conditions. Cases of HLH in adult-onset Still disease, dermatomyositis, polyarteritis nodosa, and SLE described skin findings characteristic of the underlying rheumatologic disease, sometimes with acutely worse dermatologic findings at the time of HLH presentation.^35,41-48 With regard to SLE, the acute manifestation of classic findings of the disease with HLH has sometimes been described as acute lupus hemophagocytic syndrome (HPS).⁴⁸ Lambotte at al⁴⁸ described common findings of acute lupus hemophagocytic syndrome in their retrospective study as malar rash, weight loss, polyarthralgia, and nephritis in addition to classic HLH findings including fever, lymphadenopathy, and hepatosplenomegaly. Many other rheumatologic conditions have been associated with HLH, including rheumatoid arthritis, mixed connective tissue disease, systemic sclerosis, and Sjögren disease. All these conditions can have dermatologic manifestations; however, no descriptions of dermatologic findings in cases of HLH associated with these diseases were found.¹³

Malignancy—Several cases of malignancy-induced HLH described cutaneous findings, the majority being cutaneous lymphomas, namely subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Other less commonly reported malignancies in this group included Kaposi sarcoma, intravascular lymphoma, Sézary syndrome, mycosis fungoides, cutaneous diffuse large B-cell lymphoma, and several subtypes of primary cutaneous T-cell lymphoma.^2,32,49-60 The most common description of SPTCL included multiple scattered plaques and subcutaneous nodules, some associated with tenderness, induration, drainage, or hemorrhagic features.^{32,50,52,55,57,60} Cases of mycosis fungoides and Sézary syndrome presented with variations in size and distribution of erythroderma with associated lymphadenopathy.² A unique case of HLH developing in a patient with intravascular lymphoma described an eruption of multiple telangiectasias and petechial hemorrhages on the trunk,⁵⁸ while one case associated with primary cutaneous anaplastic large cell lymphoma presented with a rapidly enlarging tumor with central ulceration and eschar.⁵⁹

Drug Induced—Interestingly, most of the drug-induced cases of HLH identified in our search were secondary to biologic therapies used in the treatment of metastatic melanoma, specifically the immune checkpoint inhibitors (ICIs), which have been reported to have an association with HLH in prior literature reviews.^61-65 Choi et al⁶⁶ described an interesting case of ICI-induced HLH presenting with a concurrent severe lichenoid drug eruption that progressed from a pruritic truncal rash to mucocutaneous bullae, erosions, and desquamation resembling a Stevens-Johnson syndrome–type picture. This patient had treatment-refractory, HIV-negative Kaposi sarcoma, where the underlying immunologic dysregulation may explain the more severe cutaneous presentation not observed in other reported cases of ICI-induced HLH.

Yang et al’s⁶⁷ review of 23 cases with concurrent diagnoses of HLH and DIHS found that 61% (14/23) of cases were diagnosed initially as DIHS before failing treatment and receiving a diagnosis of HLH several weeks later. Additionally, the authors found that several cases met criteria for one diagnosis while clinically presenting strongly for the other.⁶⁷ This overlap in clinical presentation also was demonstrated in Zerah and DeWitt’s11 retrospective study regarding cutaneous findings in HLH, in which several of the morbilliform eruptions thought to be contributed to HLH ultimately were decided to be drug reactions.

Comment

Regarding direct (or primary) cutaneous findings in HLH (category I), there seem to be 2 groups of features associated with the onset of HLH that are not related to its characteristic hepatic dysfunction (category II) nor its underlying triggers (category III): a nonspecific, generalized, erythematous eruption; and dermatologic conditions separate from HLH itself (eg, Sweet syndrome, pyoderma gangrenosum). Whether the latter group truly is a direct manifestation of HLH is difficult to discern with the evidence available. Nevertheless, we can conclude that there is some type of association between these dermatologic diseases and HLH, and this association can serve as both a diagnostic tool for clinicians and a point of interest for further clinical research.

The relatively low number of articles identified through our systematic review that specifically reported secondary findings, such as jaundice or coagulopathy-associated hemorrhagic lesions, may lead one to believe that these are not common findings in HLH; however, it is possible that these are not regularly reported in the literature simply because these findings are nonspecific and can be considered expected results of the characteristic organ dysfunction in HLH.

As suspected, the skin findings in category III were the most broad given the variety of underlying etiologies that have been associated with HLH. Like the other 2 categories, these skin findings generally are nonspecific to HLH; however, the ones in category III are specific to underlying etiology of HLH and may aid in identifying and treating the underlying cause of a patient’s HLH when indicated.

Most of the rheumatologic diseases seem to have been known at the time of HLH development and diagnosis, which may highlight the importance of considering a diagnosis of HLH early on in patients with known autoimmune disease and systemic signs of illness or acutely worsening signs and symptoms of their underlying autoimmune disease.

Interestingly, several cases of malignancy-associated HLH reported signs and symptoms of HLH at initial presentation of the malignant disease.^32,50,59 This situation seems to be somewhat common, as Go and Wester’s⁶⁸ systematic analysis of 156 patients with SPTCL found HLH was the presenting feature in 37% of patients included in their study. This may call attention to the importance of considering cutaneous lymphomas as the cause of skin lesions in patients with signs and symptoms of HLH, where it may be easy to assume that skin findings are a result of their systemic disease.

In highlighting cases of HLH related to medication use, we found it pertinent to include and discuss the complex relationship between drug-induced hypersensitivity syndrome (DIHS [formerly known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) and HLH. The results of this study suggest that DIHS may have considerable clinical overlap with HLH¹¹ and may even lead to development of HLH,⁶⁷ creating difficulty in distinguishing between these conditions where there may be similar findings, such as cutaneous eruptions, fever, and hepatic or other internal organ involvement. We agree with Yang et al⁶⁷ that there can be large overlap in symptomology between these two conditions and that more investigation is necessary to explore the relationship between them.

Conclusion

Diagnosis of HLH in adults continues to be challenging, with several diagnostic tools but no true gold standard. In addition to the nonspecific symptomology, there is a myriad of cutaneous findings that can be present in adults with HLH (eTable), all of which are also nonspecific. Even so, awareness of which dermatologic findings have been associated with HLH may provide a cue to consider HLH in the systemically ill patient with a notable dermatologic examination. Furthermore, there are several avenues for further investigation that can be drawn, including further dermatologic analysis among nonspecific eruptions attributed to HLH, clinical and pathologic differentiation between DIHS/DRESS and HLH, and correlation between severity of skin manifestations and severity of HLH disease.

Limitations of this study included a lack of clarity in diagnosis of HLH in patients described in the included articles, as some reports use variable terminology (HLH vs hemophagocytic syndrome vs macrophage activation syndrome, etc), and it is impossible to know if all authors used the same diagnostic criteria—or any validated diagnostic criteria—unless specifically stated. Additionally, including case reports in our study limited the amount and quality of information described in each report. Despite its limitations, this systematic review outlines the cutaneous manifestations associated with HLH. These data will promote clinical awareness of this complex condition and allow for consideration of HLH in patients meeting criteria for HLH syndrome. More studies ultimately are needed to differentiate HLH from its mimics.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunologic phenomenon characterized by a systemic inflammatory response syndrome—like clinical picture with additional features, including hepatosplenomegaly, hyperferritinemia, and increased natural killer cell activity. Clinical manifestations of HLH often are nonspecific, making HLH diagnosis challenging. High persistent fever is a key feature of HLH; patients also may report gastrointestinal distress, lethargy, and/or widespread rash.¹

Hemophagocytic lymphohistiocytosis is believed to stem from inherited defects in several genes, such as perforin (PRF1), as well as immune dysregulation due to infections, rheumatologic diseases, hematologic malignancies, or drug reactions.² The primary mechanism of HLH is hypothesized to be driven by aberrant immune activation, interferon gamma released from CD8+ T cells, and uncontrolled phagocytosis by activated macrophages. The cytokine cascade results in tissue injury and multiorgan dysfunction.^3,4

Although HLH historically has been categorized as primary (familial) or secondary (acquired), the most recent guidelines suggest the etiology is not always binary.^3,5 That said, the concept of secondary causes is useful in understanding risk factors for developing HLH. Both forms of the disease are thought to be elicited by a trigger (eg, infection), even when inherited genetic mutations exist.⁶ The primary form commonly affects the pediatric population,^4,6-8 whereas the secondary form is more common in adults.⁷

Several sets of diagnostic criteria for HLH have been developed, the most well-known being the HLH-2004 criteria.^1,3 The HLH-2009 modified criteria were developed after further evidence provided a refined sense of how the HLH-2004 criteria should be stratified.⁹ Finally, Fardet et al¹⁰ presented the HScore as an estimation of likelihood of diagnosis of HLH. These sets of HLH criteria include clinical and laboratory features that demonstrate inflammation, natrual killer cell activity, hemophagocytosis, end-organ damage, and cell lineage effects. The HScore differs from the other sets of HLH criteria in that it is designed to estimate an individual patient’s risk of having reactive hemophagocytic syndrome, which likely is equivalent to secondary HLH, although the authors do not use this exact terminology.¹⁰

While these criteria provide a framework for diagnosing HLH, they may fail to distinguish between HLH disease and HLH disease mimics, a concept described by the North American Consortium for Histiocytosis that may impact the success of immunosuppressive treatment.³ Individuals with HLH syndrome meet the aforementioned diagnostic criteria; HLH syndrome is further divided into HLH disease and HLH disease mimics (Figure 1). The “disease” label describes the traditional concept of HLH, driven by aberrant immune overactivation, in which patients benefit from immunosuppression. In contrast, HLH mimics include a subset of patients who meet the HLH criteria but are unlikely to benefit from immunosuppression because the primary mechanism driving their condition is not owed to immune overactivation, as is the case with HLH disease. Examples of HLH mimics include certain infections, such as Epstein-Barr virus (EBV), that may demonstrate clinical findings consistent with HLH but would not benefit from immunosuppression. Ironically, infections (including EBV) also are known triggers of HLH disease, making this concept difficult to understand and adopt. In this study, we refer to HLH disease simply as HLH.

Although cutaneous manifestations of HLH are not included in the diagnostic criteria, skin findings are common and may coincide with the severity and progression of the disease.¹¹ Despite the fact that HLH can manifest with rash,¹ comprehensive reviews of reported cutaneous findings in adult HLH are lacking. Thus, the goal of this study was to provide an organized characterization of reported cutaneous findings in adults with HLH and context for how the dermatologic examination may support the diagnosis or uncover the underlying etiology of this condition.

Methods

A search of PubMed articles indexed for MEDLINE using the phrase (cutaneous OR dermatologic OR skin) findings) AND hemophagocytic lymphohistiocytosis performed on September 20, 2023, yielded 423 results (Figure 2). Filters to exclude non–English language publications and pediatric populations were applied, resulting in 161 articles. Other exclusion criteria included the absence of a description of dermatologic findings. Seventy-five articles remained after screening titles and abstracts, and full-text review yielded 55 articles that were deemed appropriate for inclusion in the study. Subsequent reference searches and use of the online resource Litmaps revealed 45 additional publications that underwent full-text screening; of these articles, 5 were included in the final review.

Results

Sixty studies were included in this systematic review.^5,7,11-68 The reported prevalence of skin findings among patients with HLH from the included retrospective studies ranged from 15% to 85%.^12-15 Several literature reviews reported similarly varied prevalence among adult patients with HLH.^7,16 Fardet et al¹⁴ categorized cutaneous manifestations of HLH into 3 types: direct manifestations of HLH not explained by systemic features (eg, generalized maculopapular eruption), indirect manifestations of HLH that are explained by systemic features of the disease (eg, purpura due to HLH-induced coagulopathy), and findings specific to the underlying etiology of HLH (eg, malar rash seen in systemic lupus erythematosus [SLE]–associated HLH). This categorization served as the outline for the results below, providing an organized review of cutaneous findings and context for how they may support the diagnosis or uncover the underlying etiology of HLH.

Category I: Direct Manifestations of HLH

Several articles reported cutaneous findings that seemed to be the direct result of HLH and not attributed to an underlying trigger or sequalae of HLH.^11,14,16-31 The most common descriptions were a generalized, morbilliform, or nonspecific eruption that encompasses large areas of the skin, commonly the trunk and extremities, sometimes extending to the face and scalp.^{14,16-23,25,31,32} There were variations in secondary features such as pruritus and tenderness; some studies also described violaceous discoloration in addition to erythema.^16,23

Other skin findings thought to be a direct result of HLH were described in detail by Zerah and DeWitt¹¹ in their retrospective study, including pyoderma gangrenosum, panniculitis, Stevens-Johnson syndrome, atypical targetoid lesions, and bullous eruptions. The authors also analyzed dermatopathologic data that ultimately revealed that pathologic analysis was largely inconsistent and nondescript.¹¹ There was a single case report of purpura fulminans arising alongside signs and symptoms of HLH,²⁶ and several case reports described Sweet syndrome developing around the same time as HLH.^27-29 Lastly, Collins et al³⁰ described a case of HLH manifesting with violaceous ulcerating papules and nodules scattered across the legs, abdomen, and arms. Biopsy of this patient’s lesions showed a diffuse dermal infiltrate of histiocytes and hemophagocytosis.

Category II: Secondary Complications and Sequelae of HLH

This was the smallest group among the 3 categories, comprising a few case reports and retrospective cohort studies primarily reporting jaundice/icterus and hemorrhagic lesions such as purpura, petechiae, and scleral hemorrhage.^{11,21,23,33-35} Several literature reviews described these conditions as nonspecific findings in HLH.^16,20 The cause of jaundice in HLH likely can be attributed to its characteristic hepatic dysfunction, whereas hemorrhagic lesions likely are the result of both hepatic and bone marrow dysfunction resulting in coagulopathy.

Category III: Manifestations of Underlying Etiology or Triggers of HLH

Infectious—Infection is known to be one of the most common triggers of HLH, with several retrospective studies reporting infectious triggers in approximately 20% of cases.^13,15 Although many pathogens have been implicated, only a few of these infection-induced HLH reports described cutaneous findings, which included a case of varicella zoster virus, Escherichia coli necrotizing fasciitis, leprosy, EBV reactivation, parvovirus B19, and both focal and disseminated herpes simplex virus 2.^36-42 Most of these patients presented with classic findings of each disease. The case of varicella zoster virus exhibited pruritic erythematous papules on the face, trunk, and limbs.³⁶ The necrotizing fasciitis case presented with tender erythematous swelling of the lower extremity.³⁷ The patient with leprosy exhibited leonine facies and numerous erythematous nodules, plaques, and superficial ulcerating plaques over the trunk and limbs with palmoplantar involvement,³⁹ and both cases of herpes simplex virus 2 reported small bullae either diffusely over the face, trunk, and extremities or over the genitalia.^38,40 Interestingly, the cases of parvovirus B19 and EBV reactivation both exhibited polyarteritis nodosa and occurred in patients with underlying autoimmune conditions, raising the question of whether these cases of HLH had a single trigger or were the result of the overall immunologic dysregulation induced by both infection and autoimmunity.^41,42

Rheumatologic—Several articles reported dermatologic findings associated with macrophage activation syndrome, a term that often is used to describe HLH associated with autoimmune conditions. Cases of HLH in adult-onset Still disease, dermatomyositis, polyarteritis nodosa, and SLE described skin findings characteristic of the underlying rheumatologic disease, sometimes with acutely worse dermatologic findings at the time of HLH presentation.^35,41-48 With regard to SLE, the acute manifestation of classic findings of the disease with HLH has sometimes been described as acute lupus hemophagocytic syndrome (HPS).⁴⁸ Lambotte at al⁴⁸ described common findings of acute lupus hemophagocytic syndrome in their retrospective study as malar rash, weight loss, polyarthralgia, and nephritis in addition to classic HLH findings including fever, lymphadenopathy, and hepatosplenomegaly. Many other rheumatologic conditions have been associated with HLH, including rheumatoid arthritis, mixed connective tissue disease, systemic sclerosis, and Sjögren disease. All these conditions can have dermatologic manifestations; however, no descriptions of dermatologic findings in cases of HLH associated with these diseases were found.¹³

Malignancy—Several cases of malignancy-induced HLH described cutaneous findings, the majority being cutaneous lymphomas, namely subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Other less commonly reported malignancies in this group included Kaposi sarcoma, intravascular lymphoma, Sézary syndrome, mycosis fungoides, cutaneous diffuse large B-cell lymphoma, and several subtypes of primary cutaneous T-cell lymphoma.^2,32,49-60 The most common description of SPTCL included multiple scattered plaques and subcutaneous nodules, some associated with tenderness, induration, drainage, or hemorrhagic features.^{32,50,52,55,57,60} Cases of mycosis fungoides and Sézary syndrome presented with variations in size and distribution of erythroderma with associated lymphadenopathy.² A unique case of HLH developing in a patient with intravascular lymphoma described an eruption of multiple telangiectasias and petechial hemorrhages on the trunk,⁵⁸ while one case associated with primary cutaneous anaplastic large cell lymphoma presented with a rapidly enlarging tumor with central ulceration and eschar.⁵⁹

Drug Induced—Interestingly, most of the drug-induced cases of HLH identified in our search were secondary to biologic therapies used in the treatment of metastatic melanoma, specifically the immune checkpoint inhibitors (ICIs), which have been reported to have an association with HLH in prior literature reviews.^61-65 Choi et al⁶⁶ described an interesting case of ICI-induced HLH presenting with a concurrent severe lichenoid drug eruption that progressed from a pruritic truncal rash to mucocutaneous bullae, erosions, and desquamation resembling a Stevens-Johnson syndrome–type picture. This patient had treatment-refractory, HIV-negative Kaposi sarcoma, where the underlying immunologic dysregulation may explain the more severe cutaneous presentation not observed in other reported cases of ICI-induced HLH.

Yang et al’s⁶⁷ review of 23 cases with concurrent diagnoses of HLH and DIHS found that 61% (14/23) of cases were diagnosed initially as DIHS before failing treatment and receiving a diagnosis of HLH several weeks later. Additionally, the authors found that several cases met criteria for one diagnosis while clinically presenting strongly for the other.⁶⁷ This overlap in clinical presentation also was demonstrated in Zerah and DeWitt’s11 retrospective study regarding cutaneous findings in HLH, in which several of the morbilliform eruptions thought to be contributed to HLH ultimately were decided to be drug reactions.

Comment

Regarding direct (or primary) cutaneous findings in HLH (category I), there seem to be 2 groups of features associated with the onset of HLH that are not related to its characteristic hepatic dysfunction (category II) nor its underlying triggers (category III): a nonspecific, generalized, erythematous eruption; and dermatologic conditions separate from HLH itself (eg, Sweet syndrome, pyoderma gangrenosum). Whether the latter group truly is a direct manifestation of HLH is difficult to discern with the evidence available. Nevertheless, we can conclude that there is some type of association between these dermatologic diseases and HLH, and this association can serve as both a diagnostic tool for clinicians and a point of interest for further clinical research.

The relatively low number of articles identified through our systematic review that specifically reported secondary findings, such as jaundice or coagulopathy-associated hemorrhagic lesions, may lead one to believe that these are not common findings in HLH; however, it is possible that these are not regularly reported in the literature simply because these findings are nonspecific and can be considered expected results of the characteristic organ dysfunction in HLH.

As suspected, the skin findings in category III were the most broad given the variety of underlying etiologies that have been associated with HLH. Like the other 2 categories, these skin findings generally are nonspecific to HLH; however, the ones in category III are specific to underlying etiology of HLH and may aid in identifying and treating the underlying cause of a patient’s HLH when indicated.

Most of the rheumatologic diseases seem to have been known at the time of HLH development and diagnosis, which may highlight the importance of considering a diagnosis of HLH early on in patients with known autoimmune disease and systemic signs of illness or acutely worsening signs and symptoms of their underlying autoimmune disease.

Interestingly, several cases of malignancy-associated HLH reported signs and symptoms of HLH at initial presentation of the malignant disease.^32,50,59 This situation seems to be somewhat common, as Go and Wester’s⁶⁸ systematic analysis of 156 patients with SPTCL found HLH was the presenting feature in 37% of patients included in their study. This may call attention to the importance of considering cutaneous lymphomas as the cause of skin lesions in patients with signs and symptoms of HLH, where it may be easy to assume that skin findings are a result of their systemic disease.

In highlighting cases of HLH related to medication use, we found it pertinent to include and discuss the complex relationship between drug-induced hypersensitivity syndrome (DIHS [formerly known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) and HLH. The results of this study suggest that DIHS may have considerable clinical overlap with HLH¹¹ and may even lead to development of HLH,⁶⁷ creating difficulty in distinguishing between these conditions where there may be similar findings, such as cutaneous eruptions, fever, and hepatic or other internal organ involvement. We agree with Yang et al⁶⁷ that there can be large overlap in symptomology between these two conditions and that more investigation is necessary to explore the relationship between them.

Conclusion

Diagnosis of HLH in adults continues to be challenging, with several diagnostic tools but no true gold standard. In addition to the nonspecific symptomology, there is a myriad of cutaneous findings that can be present in adults with HLH (eTable), all of which are also nonspecific. Even so, awareness of which dermatologic findings have been associated with HLH may provide a cue to consider HLH in the systemically ill patient with a notable dermatologic examination. Furthermore, there are several avenues for further investigation that can be drawn, including further dermatologic analysis among nonspecific eruptions attributed to HLH, clinical and pathologic differentiation between DIHS/DRESS and HLH, and correlation between severity of skin manifestations and severity of HLH disease.

Limitations of this study included a lack of clarity in diagnosis of HLH in patients described in the included articles, as some reports use variable terminology (HLH vs hemophagocytic syndrome vs macrophage activation syndrome, etc), and it is impossible to know if all authors used the same diagnostic criteria—or any validated diagnostic criteria—unless specifically stated. Additionally, including case reports in our study limited the amount and quality of information described in each report. Despite its limitations, this systematic review outlines the cutaneous manifestations associated with HLH. These data will promote clinical awareness of this complex condition and allow for consideration of HLH in patients meeting criteria for HLH syndrome. More studies ultimately are needed to differentiate HLH from its mimics.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Pemphigoid gestationis (PG), which manifests in the second or third trimester of pregnancy, is thought to result from an excessive type 2 inflammatory response that leads to the formation of antibodies primarily targeting BP180 antigens with resultant damage to the skin basement membrane.¹ Maternal antibodies can be transferred to the fetus, resulting in neonatal pemphigoid with the development of widespread vesicles and bullae.² Maternal morbidity from placental insufficiency, intrauterine growth restriction, and premature labor are common comorbidities of PG, underscoring the critical need for safe and effective treatments for this condition.³

Systemic corticosteroids currently are the first-line treatment for moderate to severe PG but carry considerable risks to both the mother and fetus, including preterm labor and intrauterine growth restriction.^4,5 Dupilumab is approved by the US Food and Drug Administration for moderate to severe atopic dermatitis in children aged 6 months and older. Dupilumab inhibits downstream signaling of IL-4Rα, reducing IL-4 and IL-13. Use of dupilumab to target the type 2 inflammatory response has shown significant promise in the treatment of BP, where it met primary and secondary endpoints in adults with moderate to severe disease, but studies in PG are limited.^6-8 There are multiple reports in the literature demonstrating the safety of dupilumab in pregnancy and postpartum,^9-27 including a pharmacovigilance report that found no adverse drug reactions from dupilumab reported during pregnancy.⁹ There also are 4 reports of pregnant patients who were diagnosed with PG and treated with dupilumab, all of whom were initially started on prednisone prior to treatment initiation.^9-12 In this article, we report 2 additional cases of dupilumab treatment in patients with PG.

Case Reports

Patient 1—A 39-year-old G5P1 woman presented to the dermatology department at 27.5 weeks’ gestation with a widespread eruption of erythematous, annular, urticarial, edematous papules and plaques on the abdomen of 4 weeks’ duration (Figure 1A). Direct immunofluorescence was positive, indirect immunofluorescence confirmed an IgG-positive epidermal pattern, and serum BP180 levels were elevated, supporting a diagnosis of PG. The patient was prescribed prednisone (60 mg/d) but developed type 1 diabetes mellitus after 1 week of treatment. Following insurance approval, dupilumab therapy was initiated 3 weeks later at a dose of 300 mg subcutaneously every 2 weeks. Rapid and complete resolution of papules and plaques as well as symptomatic relief from pruritus was noted within 2 weeks of treatment (Figure 1B). The prednisone dose was tapered to 2.5 mg every other day at 6 weeks prior to induction of labor; the diabetes resolved 7 weeks after initiation of dupilumab.

At the recommendation of the patient’s high-risk maternal-fetal medicine team, 100 mg of stress-dose hydrocortisone was administered intravenously just prior to delivery to prevent flaring of PG. She delivered a healthy infant at 37 weeks and 3 days’ gestation without bullous disease and was discharged from the hospital the day after delivery on a prednisone dose of 2.5 mg every other day.

The patient subsequently developed localized pruritic papules on the hands and feet at 2 weeks postpartum. Based on shared decision-making and the patient’s concern for the severity of the previous pruritic eruption, prednisone was increased to 10 mg daily for 5 days and then was tapered over 2 weeks without flaring. Dupilumab was continued until 12 weeks postpartum with complete resolution of PG and no further sequelae.

Patient 2—A 30-year-old G1P0 woman presented to the dermatology department at 25 weeks’ gestation with a widespread eruption of 1 week’s duration on the abdomen, hands, thighs, legs, buttocks, and feet that was clinically consistent with PG (Figure 2A). Direct immunofluorescence was positive, indirect immunofluorescence showed an IgG-positive epidermal pattern, and an enzyme-linked immunosorbent assay for BP180 was elevated, confirming a diagnosis of PG. The patient was started on 40 mg of prednisone and topical steroids daily, with improvement of the pruritus but persistence of the eruption after 3 to 4 days. Five days after the initial presentation following expedited insurance approval, dupilumab 300 mg was initiated subcutaneously every 2 weeks along with a slow taper of prednisone to 5 mg, with complete clearance of the eruption within 4 weeks (Figure 2B). She delivered a healthy infant at 38 weeks’ gestation without bullous disease.

In contrast to patient 1, this patient did not receive corticosteroids at the time of delivery and did not experience flaring of her disease. The patient remained on dupilumab 5 weeks postpartum without subsequent recurrence after treatment discontinuation.

Comment

Although a myriad of effective treatments exist for bullous pemphigoid, there are very few options for PG due to the need for treatment during pregnancy. Systemic corticosteroids—the treatment of choice in severe PG disease—are not without risk in pregnancy and complicate assessment of morbidity, as both PG and chronic steroid exposure are associated with preterm labor and intrauterine growth restriction.³

Dupilumab currently is undergoing phase III trials (Clinicaltrials.gov identifiers NCT02277743 and NCT02277769) for the treatment of bullous pemphigoid, with interim reports suggesting efficacy across all primary and key secondary endpoints in moderate to severe disease, including notable steroid-sparing effects.⁸ In our patients, treatment with dupilumab resulted in resolution of cutaneous disease and was well tolerated, facilitating the tapering of corticosteroids and resolution of type 1 diabetes in patient 1. Although the response to dupilumab in both cases may have been confounded by concomitant steroid administration, which was started due to the severity of symptoms and uncertainty regarding insurance approval, the dose was tapered in both patients after initiation of dupilumab. Patient 1 was given a stress dose of hydrocortisone during delivery and developed a mild flare following delivery, consistent with previous literature.^{28, 29} Because the flare was localized to the hands and feet, she might have responded to clobetasol in addition to dupilumab, but given the severity of disease at presentation and her concern that it might worsen, low-dose prednisone was added with resolution of the flare within 2 weeks.

Dupilumab dosing regimens have not been studied in a controlled prospective manner for PG. We acknowledge that dupilumab (at least using the conventional atopic dermatitis dosing regimen) may be insufficient as monotherapy to control PG, as both patients received steroids prior to initiation of dupilumab, in part due to concern that the insurance might delay or deny approval. Previous World Health Organization vigilance reporting has suggested that dupilumab appears safe during pregnancy although it lacks pregnancy categorization in the United States due to limited studies in this population.^9-28 This observation supports the conclusion that, like bullous pemphigoid, PG also is driven by Th2–mediated inflammation. Treatment with dupilumab may be safe and effective in pregnancy, reducing maternal complications from long-term corticosteroids. Additional studies are needed to confirm these hypotheses.

Amputees who use prosthetic devices are particularly susceptible to contact dermatitis due to moisture, irritation, and prolonged contact with components of the device. Contact dermatitis accounts for approximately one-third of the dermatoses encountered by amputees who wear a prosthesis.¹ Diagnosing allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) is challenging due to errors of omission from the differential and the substantial clinical overlap with other eczematous dermatoses. Diagnosis relies on patient history, clinical examination, exposure assessment, diagnostic testing, and a high index of suspicion. Conventionally, ACD comprises approximately 20% of all contact dermatitis cases, whereas ICD accounts for 80%.² Symptoms vary between the 2 conditions, with pruritus more common in ACD and burning and soreness more common in ICD.³ Onset of dermatitis relative to exposure is crucial, with ICD often manifesting more quickly and ACD requiring an initial sensitization phase.⁴ Additionally, the complexity of ICD as a condition with variable features adds to the diagnostic difficulty, especially when allergens also have irritant effects.

Understanding these 2 primary types of contact dermatitis is crucial for effective management and prevention strategies in amputees who use prosthetics. In this article, we describe common causes of ACD and ICD related to amputee prosthetics and propose a tailored patch testing panel in order to better diagnose ACD in this patient population.

Allergic Contact Dermatitis

Allergic contact dermatitis occurs when the skin comes into contact with a substance to which the individual is sensitized. In amputees who use prosthetics, the socket and sock liner materials are frequent culprits for triggering allergic reactions. Components such as rubber, metals (eg, nickel), adhesives, and various plastic monomers can induce ACD in susceptible individuals. Additionally, chronic friction and sweat augment hapten penetration, increasing the risk of developing ACD.⁵

Contact allergens (typically small molecules under 500 Da) penetrate the skin, engage dendritic cells, activate T lymphocytes, and trigger the immune response and memory.⁶ The skin contains a substantial population of memory T cells, with CD8+ T cells in the epidermis and CD4+ T cells in the dermis, expressing markers that facilitate skin reactivity. The balance between effector and regulatory T cells, which can produce suppressive cytokines such as IL-10, promotes clinical tolerance to allergens such as nickel.

Textile-driven ACD presents with a distinct clinical pattern, often manifesting as patchy generalized dermatitis that coincides with sites where garments fit most snugly. This presentation can mimic other forms of dermatitis, such as nummular or asteatotic dermatitis. The skin beneath undergarments such as underwear or prosthetic socks may be spared, as these act as shields from contact allergens. Notably, the face and hands typically are spared unless the patient has a cross-reaction to formaldehyde-based preservatives found in personal care products.⁴

Allergy to Components of the Prosthetic Socket and Sock Liner

A prosthesis consists of several key components, including a socket, sleeve, liner, and stump shrinker (eFigure 1). The prosthetic socket, custom-made to fit the residual limb, is the upper part of the prosthesis, while the lower part consists of prosthetic components such as joints and terminal devices ordered to meet individual needs. Prosthetic sleeves provide suspension by securely holding the prosthetic limb in place, while liners offer cushioning and protection to the residual limb, enhancing comfort and reducing friction. Stump shrinkers aid in reducing swelling and shaping the residual limb, facilitating a better fit for the prosthetic socket. Together, these components work in harmony to optimize stability, comfort, and functionality for the user, enabling them to navigate daily activities with greater ease and confidence. Common allergens found in components of the socket and sock liner include rubbers and other elastomers, metals, plastics, adhesives, and textiles.

Rubbers and Other Elastomers—Consumables, including liners, knee sleeves, and socks, are tailored to each client and utilize materials such as silicone and natural and synthetic rubbers for comfort and secure fit. Allergic reactions to natural rubber latex, more commonly used in earlier prosthetics, are associated with both type I and type IV hypersensitivity reactions.⁴ Proteins inherent to natural rubber are overwhelmingly associated with an immediate urticarial eruption, whereas chemical additives used to produce latex are mostly linked to delayed hypersensitivity reactions, manifesting as allergic reactions ranging from mild itching to severe skin blistering.⁴

Vulcanization is the process of using heat and other accelerators to manufacture rubber. Common rubber accelerators include thiurams (the most common allergen associated with rubbers and other elastomers), carbamates/carba mix, 1,3-diphenylguanidine, and mercaptobenzothiazole.⁴ Thiourea is an implicated cause of ACD to neoprene rubber.⁷ These sensitizing chemicals are all included in the North American 80 Comprehensive Series; only thiuram mix, carba mix, and mercaptobenzothiazole are available in the T.R.U.E. TEST (SmartPractice). Sensitization often occurs due to repeated exposure, particularly in individuals who have undergone multiple prosthetic fittings. Many modern prospective liners utilize a medical-grade silicone as an elastomer for its high flexibility; silicone is considered biologically nonreactive and generally is considered a rare cause of ACD.⁸

Metals—Nickel, a ubiquitous allergen found in metal alloys used in prosthetic hardware, can cause localized itching, redness, and even blistering upon contact with the skin. Other metals, such as cobalt and chromium, also may trigger allergic reactions in susceptible individuals. Though many elastic fitting prosthetic socks contain silver fibers to reduce odors and friction-causing blisters, pure silver used in clothing or jewelry rarely causes dermatitis.⁴

Plastics and Adhesives—Leg prosthesis sockets typically are finished with the application of varnish, plastics, and/or resins—all potential allergens—to improve the appearance of the device and protect it from external agents.⁹ Polyester plastics themselves can cause ICD, only rarely leading to ACD.⁴ Incomplete curing during their manufacture may result in inadvertent exposure to epoxy resins or other phenol- formaldehyde resins such as 4-tert-butylcatechol and 4-tert-butylphenol formaldehyde, demonstrated causes of ACD in amputees.¹⁰ Adhesives used in sock liners or tapes to secure prosthetic devices can contain ingredients such as acrylates (a well-known cause of nail allergens) and other formaldehyde resins.⁴ Additionally, benzophenone commonly is added to paints and rubbers as a UV light absorber, reducing UV degradation and enhancing the material’s durability under light exposure.¹¹

Textiles—Cotton, a common component in prosthetic sock liners, is almost 100% cellulose and typically does not cause ACD; however, synthetic fibers such as polypropylene and elastane (spandex) can elicit allergic reactions.⁴ Allergy to textiles often is driven by the chemicals used in the manufacturing process, particularly textile finishes, dyes, and formaldehyde resins, which are commonly used as fabric treatments. Disperse dyes are another common cause of allergic reactions. Para-phenylenediamine, a dye found in permanent hair dye and other darkly colored fabrics, is a potent sensitizer that may cross-react with other compounds that also contain similar amine groups, such as ester anesthetics, sunscreens containing para-aminobenzoic acid, other para dyes, and sulfonamides.¹² Sweat can exacerbate these reactions by causing allergens to leach out of textiles, increasing skin exposure. Additionally, prosthetics containing leather may trigger allergies to potassium dichromate and other chromium compounds used in the leather-tanning process.¹²

Allergy to Personal Care Products

Skin protectants and prosthetic cleansers are crucial in dermatologic care for amputees, working together to safeguard the skin and maintain prosthetic hygiene. Skin protectants form a barrier against irritation, friction, and moisture, protecting the residual limb from damage and enhancing comfort and mobility. Meanwhile, prosthetic cleansers remove sweat, oils, and bacteria from the prosthetic socket, reducing the risk of infections and odors and ensuring the longevity and optimal function of the prosthetic device. Together, they support skin health, comfort, and overall quality of life for amputees.

The socket should be cleaned with warm water prior to use, but more importantly, immediately after removing the prosthesis. If cleaning products are used at night, residual haptens may remain on the device, increasing the risk of sensitization. Common contact irritants found in personal care products utilized in amputee care include sulfates, surfactants, preservatives, and fragrances (eTable 1).⁴ Additionally, common household cleaners and disinfectants can damage the prosthesis, leading to breakdown and the release of the monomers, precipitating ACD.

Patch Testing to Identify Causative Allergens

Patch testing is a valuable tool for identifying specific allergens responsible for ACD in amputees. This procedure involves applying small amounts of suspected allergens to the patient’s skin under occlusion and leaving the patches in place for 48 hours. After removal, the skin is assessed for reactions at 48 hours, with additional assessments conducted according to International Contact Dermatitis Research Group guidelines, typically at 72 and 96 hours, to identify delayed responses. This diagnostic approach helps pinpoint the substances to which the individual is allergic, enabling targeted avoidance strategies and treatment recommendations. Two widely used patch tests—the T.R.U.E. TEST, a preassembled patch test encompassing 35 allergens, and the North American 80 Comprehensive Series, which includes 80 allergens—demonstrate a sensitivity range between 70% and 80%.^13,14 eTable 2 shows a recommended custom contact dermatitis panel to assess the most common causes of ACD related to amputee care.

Irritant Contact Dermatitis

Irritant contact dermatitis occurs when the skin’s protective barrier is damaged by repeated exposure to a particular irritant. In amputees, perspiration, friction, and pressure from prosthetic devices can exacerbate irritant reactions, leading to skin maceration, breakdown, and increased transepidermal penetration. Sweat accumulation within the prosthetic socket creates a moist environment conducive to ICD. The combination of sweat and friction can strip the skin of its natural oils, leading to dryness, chafing, and maceration. Continuous exposure to moisture also can exacerbate existing dermatitis and compromise skin integrity.⁴ Additionally, chronic irritation may increase transepidermal penetration of haptens, potentiating the development of ACD.¹⁵

Management of ICD in amputees involves a combination of treatments aimed at reducing friction, reducing sweating, and restoring barrier protection. Strategies to minimize mechanical trauma to the skin include ensuring proper socket fit, managing moisture, and protecting the skin. Using moisture-wicking sock liners and breathable prosthetic materials can help keep the skin dry. Topical antiperspirants containing aluminum chloride or similar compounds that help to block sweat glands often are the first line of treatment. Oral anticholinergics may be prescribed to reduce overall sweating, though they can have systemic side effects. Iontophoresis, a procedure where the affected area is exposed to a mild electrical current, can also be effective, especially for sweating of the hands and feet, though its application in amputees might be more limited.¹⁴

Recently, 2 treatments have emerged as options for managing excessive sweating (hyperhidrosis) in amputees: botulinum toxin injections and laser hair removal. By inhibiting the release of acetylcholine from sweat glands, botulinum toxin effectively reduces sweat production, thereby alleviating perspiration-induced skin irritation. Approximately 2 to 3 units of botulinum toxin at a dilution of 100 units in 1 mL of bacteriostatic saline 0.9% are injected transdermally at 1-cm intervals in a circumferential pattern on the skin covered by the prosthesis socket (typically a total of 300-500 units are utilized in the procedure)(eFigure 2).¹⁶ Laser hair removal can assist amputees with hyperhidrosis by reducing hair in the residual limb area, which decreases sweat retention and the potential for skin irritation due to friction.

Final Thoughts

In amputee dermatologic care, individuals with limb loss are particularly prone to contact dermatitis due to moisture, friction, and prolonged contact with prosthetic components. Diagnosing ACD and ICD is challenging due to overlapping symptoms and the potential for simultaneous occurrence. Distinguishing between these conditions is crucial for effective management. Understanding their causes, particularly in relation to prosthetic use, is essential for developing targeted prevention and treatment strategies, including the use of tailored patch testing panels to better diagnose ACD in amputees.

Amputees who use prosthetic devices are particularly susceptible to contact dermatitis due to moisture, irritation, and prolonged contact with components of the device. Contact dermatitis accounts for approximately one-third of the dermatoses encountered by amputees who wear a prosthesis.¹ Diagnosing allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) is challenging due to errors of omission from the differential and the substantial clinical overlap with other eczematous dermatoses. Diagnosis relies on patient history, clinical examination, exposure assessment, diagnostic testing, and a high index of suspicion. Conventionally, ACD comprises approximately 20% of all contact dermatitis cases, whereas ICD accounts for 80%.² Symptoms vary between the 2 conditions, with pruritus more common in ACD and burning and soreness more common in ICD.³ Onset of dermatitis relative to exposure is crucial, with ICD often manifesting more quickly and ACD requiring an initial sensitization phase.⁴ Additionally, the complexity of ICD as a condition with variable features adds to the diagnostic difficulty, especially when allergens also have irritant effects.

Understanding these 2 primary types of contact dermatitis is crucial for effective management and prevention strategies in amputees who use prosthetics. In this article, we describe common causes of ACD and ICD related to amputee prosthetics and propose a tailored patch testing panel in order to better diagnose ACD in this patient population.

Allergic Contact Dermatitis

Allergic contact dermatitis occurs when the skin comes into contact with a substance to which the individual is sensitized. In amputees who use prosthetics, the socket and sock liner materials are frequent culprits for triggering allergic reactions. Components such as rubber, metals (eg, nickel), adhesives, and various plastic monomers can induce ACD in susceptible individuals. Additionally, chronic friction and sweat augment hapten penetration, increasing the risk of developing ACD.⁵

Contact allergens (typically small molecules under 500 Da) penetrate the skin, engage dendritic cells, activate T lymphocytes, and trigger the immune response and memory.⁶ The skin contains a substantial population of memory T cells, with CD8+ T cells in the epidermis and CD4+ T cells in the dermis, expressing markers that facilitate skin reactivity. The balance between effector and regulatory T cells, which can produce suppressive cytokines such as IL-10, promotes clinical tolerance to allergens such as nickel.

Textile-driven ACD presents with a distinct clinical pattern, often manifesting as patchy generalized dermatitis that coincides with sites where garments fit most snugly. This presentation can mimic other forms of dermatitis, such as nummular or asteatotic dermatitis. The skin beneath undergarments such as underwear or prosthetic socks may be spared, as these act as shields from contact allergens. Notably, the face and hands typically are spared unless the patient has a cross-reaction to formaldehyde-based preservatives found in personal care products.⁴

Allergy to Components of the Prosthetic Socket and Sock Liner

A prosthesis consists of several key components, including a socket, sleeve, liner, and stump shrinker (eFigure 1). The prosthetic socket, custom-made to fit the residual limb, is the upper part of the prosthesis, while the lower part consists of prosthetic components such as joints and terminal devices ordered to meet individual needs. Prosthetic sleeves provide suspension by securely holding the prosthetic limb in place, while liners offer cushioning and protection to the residual limb, enhancing comfort and reducing friction. Stump shrinkers aid in reducing swelling and shaping the residual limb, facilitating a better fit for the prosthetic socket. Together, these components work in harmony to optimize stability, comfort, and functionality for the user, enabling them to navigate daily activities with greater ease and confidence. Common allergens found in components of the socket and sock liner include rubbers and other elastomers, metals, plastics, adhesives, and textiles.

Rubbers and Other Elastomers—Consumables, including liners, knee sleeves, and socks, are tailored to each client and utilize materials such as silicone and natural and synthetic rubbers for comfort and secure fit. Allergic reactions to natural rubber latex, more commonly used in earlier prosthetics, are associated with both type I and type IV hypersensitivity reactions.⁴ Proteins inherent to natural rubber are overwhelmingly associated with an immediate urticarial eruption, whereas chemical additives used to produce latex are mostly linked to delayed hypersensitivity reactions, manifesting as allergic reactions ranging from mild itching to severe skin blistering.⁴

Vulcanization is the process of using heat and other accelerators to manufacture rubber. Common rubber accelerators include thiurams (the most common allergen associated with rubbers and other elastomers), carbamates/carba mix, 1,3-diphenylguanidine, and mercaptobenzothiazole.⁴ Thiourea is an implicated cause of ACD to neoprene rubber.⁷ These sensitizing chemicals are all included in the North American 80 Comprehensive Series; only thiuram mix, carba mix, and mercaptobenzothiazole are available in the T.R.U.E. TEST (SmartPractice). Sensitization often occurs due to repeated exposure, particularly in individuals who have undergone multiple prosthetic fittings. Many modern prospective liners utilize a medical-grade silicone as an elastomer for its high flexibility; silicone is considered biologically nonreactive and generally is considered a rare cause of ACD.⁸

Metals—Nickel, a ubiquitous allergen found in metal alloys used in prosthetic hardware, can cause localized itching, redness, and even blistering upon contact with the skin. Other metals, such as cobalt and chromium, also may trigger allergic reactions in susceptible individuals. Though many elastic fitting prosthetic socks contain silver fibers to reduce odors and friction-causing blisters, pure silver used in clothing or jewelry rarely causes dermatitis.⁴

Plastics and Adhesives—Leg prosthesis sockets typically are finished with the application of varnish, plastics, and/or resins—all potential allergens—to improve the appearance of the device and protect it from external agents.⁹ Polyester plastics themselves can cause ICD, only rarely leading to ACD.⁴ Incomplete curing during their manufacture may result in inadvertent exposure to epoxy resins or other phenol- formaldehyde resins such as 4-tert-butylcatechol and 4-tert-butylphenol formaldehyde, demonstrated causes of ACD in amputees.¹⁰ Adhesives used in sock liners or tapes to secure prosthetic devices can contain ingredients such as acrylates (a well-known cause of nail allergens) and other formaldehyde resins.⁴ Additionally, benzophenone commonly is added to paints and rubbers as a UV light absorber, reducing UV degradation and enhancing the material’s durability under light exposure.¹¹

Textiles—Cotton, a common component in prosthetic sock liners, is almost 100% cellulose and typically does not cause ACD; however, synthetic fibers such as polypropylene and elastane (spandex) can elicit allergic reactions.⁴ Allergy to textiles often is driven by the chemicals used in the manufacturing process, particularly textile finishes, dyes, and formaldehyde resins, which are commonly used as fabric treatments. Disperse dyes are another common cause of allergic reactions. Para-phenylenediamine, a dye found in permanent hair dye and other darkly colored fabrics, is a potent sensitizer that may cross-react with other compounds that also contain similar amine groups, such as ester anesthetics, sunscreens containing para-aminobenzoic acid, other para dyes, and sulfonamides.¹² Sweat can exacerbate these reactions by causing allergens to leach out of textiles, increasing skin exposure. Additionally, prosthetics containing leather may trigger allergies to potassium dichromate and other chromium compounds used in the leather-tanning process.¹²

Allergy to Personal Care Products

Skin protectants and prosthetic cleansers are crucial in dermatologic care for amputees, working together to safeguard the skin and maintain prosthetic hygiene. Skin protectants form a barrier against irritation, friction, and moisture, protecting the residual limb from damage and enhancing comfort and mobility. Meanwhile, prosthetic cleansers remove sweat, oils, and bacteria from the prosthetic socket, reducing the risk of infections and odors and ensuring the longevity and optimal function of the prosthetic device. Together, they support skin health, comfort, and overall quality of life for amputees.

The socket should be cleaned with warm water prior to use, but more importantly, immediately after removing the prosthesis. If cleaning products are used at night, residual haptens may remain on the device, increasing the risk of sensitization. Common contact irritants found in personal care products utilized in amputee care include sulfates, surfactants, preservatives, and fragrances (eTable 1).⁴ Additionally, common household cleaners and disinfectants can damage the prosthesis, leading to breakdown and the release of the monomers, precipitating ACD.

Patch Testing to Identify Causative Allergens

Patch testing is a valuable tool for identifying specific allergens responsible for ACD in amputees. This procedure involves applying small amounts of suspected allergens to the patient’s skin under occlusion and leaving the patches in place for 48 hours. After removal, the skin is assessed for reactions at 48 hours, with additional assessments conducted according to International Contact Dermatitis Research Group guidelines, typically at 72 and 96 hours, to identify delayed responses. This diagnostic approach helps pinpoint the substances to which the individual is allergic, enabling targeted avoidance strategies and treatment recommendations. Two widely used patch tests—the T.R.U.E. TEST, a preassembled patch test encompassing 35 allergens, and the North American 80 Comprehensive Series, which includes 80 allergens—demonstrate a sensitivity range between 70% and 80%.^13,14 eTable 2 shows a recommended custom contact dermatitis panel to assess the most common causes of ACD related to amputee care.

Irritant Contact Dermatitis

Irritant contact dermatitis occurs when the skin’s protective barrier is damaged by repeated exposure to a particular irritant. In amputees, perspiration, friction, and pressure from prosthetic devices can exacerbate irritant reactions, leading to skin maceration, breakdown, and increased transepidermal penetration. Sweat accumulation within the prosthetic socket creates a moist environment conducive to ICD. The combination of sweat and friction can strip the skin of its natural oils, leading to dryness, chafing, and maceration. Continuous exposure to moisture also can exacerbate existing dermatitis and compromise skin integrity.⁴ Additionally, chronic irritation may increase transepidermal penetration of haptens, potentiating the development of ACD.¹⁵

Management of ICD in amputees involves a combination of treatments aimed at reducing friction, reducing sweating, and restoring barrier protection. Strategies to minimize mechanical trauma to the skin include ensuring proper socket fit, managing moisture, and protecting the skin. Using moisture-wicking sock liners and breathable prosthetic materials can help keep the skin dry. Topical antiperspirants containing aluminum chloride or similar compounds that help to block sweat glands often are the first line of treatment. Oral anticholinergics may be prescribed to reduce overall sweating, though they can have systemic side effects. Iontophoresis, a procedure where the affected area is exposed to a mild electrical current, can also be effective, especially for sweating of the hands and feet, though its application in amputees might be more limited.¹⁴

Recently, 2 treatments have emerged as options for managing excessive sweating (hyperhidrosis) in amputees: botulinum toxin injections and laser hair removal. By inhibiting the release of acetylcholine from sweat glands, botulinum toxin effectively reduces sweat production, thereby alleviating perspiration-induced skin irritation. Approximately 2 to 3 units of botulinum toxin at a dilution of 100 units in 1 mL of bacteriostatic saline 0.9% are injected transdermally at 1-cm intervals in a circumferential pattern on the skin covered by the prosthesis socket (typically a total of 300-500 units are utilized in the procedure)(eFigure 2).¹⁶ Laser hair removal can assist amputees with hyperhidrosis by reducing hair in the residual limb area, which decreases sweat retention and the potential for skin irritation due to friction.

Final Thoughts

In amputee dermatologic care, individuals with limb loss are particularly prone to contact dermatitis due to moisture, friction, and prolonged contact with prosthetic components. Diagnosing ACD and ICD is challenging due to overlapping symptoms and the potential for simultaneous occurrence. Distinguishing between these conditions is crucial for effective management. Understanding their causes, particularly in relation to prosthetic use, is essential for developing targeted prevention and treatment strategies, including the use of tailored patch testing panels to better diagnose ACD in amputees.

Amputees who use prosthetic devices are particularly susceptible to contact dermatitis due to moisture, irritation, and prolonged contact with components of the device. Contact dermatitis accounts for approximately one-third of the dermatoses encountered by amputees who wear a prosthesis.¹ Diagnosing allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD) is challenging due to errors of omission from the differential and the substantial clinical overlap with other eczematous dermatoses. Diagnosis relies on patient history, clinical examination, exposure assessment, diagnostic testing, and a high index of suspicion. Conventionally, ACD comprises approximately 20% of all contact dermatitis cases, whereas ICD accounts for 80%.² Symptoms vary between the 2 conditions, with pruritus more common in ACD and burning and soreness more common in ICD.³ Onset of dermatitis relative to exposure is crucial, with ICD often manifesting more quickly and ACD requiring an initial sensitization phase.⁴ Additionally, the complexity of ICD as a condition with variable features adds to the diagnostic difficulty, especially when allergens also have irritant effects.

Understanding these 2 primary types of contact dermatitis is crucial for effective management and prevention strategies in amputees who use prosthetics. In this article, we describe common causes of ACD and ICD related to amputee prosthetics and propose a tailored patch testing panel in order to better diagnose ACD in this patient population.

Allergic Contact Dermatitis

Allergic contact dermatitis occurs when the skin comes into contact with a substance to which the individual is sensitized. In amputees who use prosthetics, the socket and sock liner materials are frequent culprits for triggering allergic reactions. Components such as rubber, metals (eg, nickel), adhesives, and various plastic monomers can induce ACD in susceptible individuals. Additionally, chronic friction and sweat augment hapten penetration, increasing the risk of developing ACD.⁵

Contact allergens (typically small molecules under 500 Da) penetrate the skin, engage dendritic cells, activate T lymphocytes, and trigger the immune response and memory.⁶ The skin contains a substantial population of memory T cells, with CD8+ T cells in the epidermis and CD4+ T cells in the dermis, expressing markers that facilitate skin reactivity. The balance between effector and regulatory T cells, which can produce suppressive cytokines such as IL-10, promotes clinical tolerance to allergens such as nickel.

Textile-driven ACD presents with a distinct clinical pattern, often manifesting as patchy generalized dermatitis that coincides with sites where garments fit most snugly. This presentation can mimic other forms of dermatitis, such as nummular or asteatotic dermatitis. The skin beneath undergarments such as underwear or prosthetic socks may be spared, as these act as shields from contact allergens. Notably, the face and hands typically are spared unless the patient has a cross-reaction to formaldehyde-based preservatives found in personal care products.⁴

Allergy to Components of the Prosthetic Socket and Sock Liner

A prosthesis consists of several key components, including a socket, sleeve, liner, and stump shrinker (eFigure 1). The prosthetic socket, custom-made to fit the residual limb, is the upper part of the prosthesis, while the lower part consists of prosthetic components such as joints and terminal devices ordered to meet individual needs. Prosthetic sleeves provide suspension by securely holding the prosthetic limb in place, while liners offer cushioning and protection to the residual limb, enhancing comfort and reducing friction. Stump shrinkers aid in reducing swelling and shaping the residual limb, facilitating a better fit for the prosthetic socket. Together, these components work in harmony to optimize stability, comfort, and functionality for the user, enabling them to navigate daily activities with greater ease and confidence. Common allergens found in components of the socket and sock liner include rubbers and other elastomers, metals, plastics, adhesives, and textiles.

Rubbers and Other Elastomers—Consumables, including liners, knee sleeves, and socks, are tailored to each client and utilize materials such as silicone and natural and synthetic rubbers for comfort and secure fit. Allergic reactions to natural rubber latex, more commonly used in earlier prosthetics, are associated with both type I and type IV hypersensitivity reactions.⁴ Proteins inherent to natural rubber are overwhelmingly associated with an immediate urticarial eruption, whereas chemical additives used to produce latex are mostly linked to delayed hypersensitivity reactions, manifesting as allergic reactions ranging from mild itching to severe skin blistering.⁴

Vulcanization is the process of using heat and other accelerators to manufacture rubber. Common rubber accelerators include thiurams (the most common allergen associated with rubbers and other elastomers), carbamates/carba mix, 1,3-diphenylguanidine, and mercaptobenzothiazole.⁴ Thiourea is an implicated cause of ACD to neoprene rubber.⁷ These sensitizing chemicals are all included in the North American 80 Comprehensive Series; only thiuram mix, carba mix, and mercaptobenzothiazole are available in the T.R.U.E. TEST (SmartPractice). Sensitization often occurs due to repeated exposure, particularly in individuals who have undergone multiple prosthetic fittings. Many modern prospective liners utilize a medical-grade silicone as an elastomer for its high flexibility; silicone is considered biologically nonreactive and generally is considered a rare cause of ACD.⁸

Metals—Nickel, a ubiquitous allergen found in metal alloys used in prosthetic hardware, can cause localized itching, redness, and even blistering upon contact with the skin. Other metals, such as cobalt and chromium, also may trigger allergic reactions in susceptible individuals. Though many elastic fitting prosthetic socks contain silver fibers to reduce odors and friction-causing blisters, pure silver used in clothing or jewelry rarely causes dermatitis.⁴

Plastics and Adhesives—Leg prosthesis sockets typically are finished with the application of varnish, plastics, and/or resins—all potential allergens—to improve the appearance of the device and protect it from external agents.⁹ Polyester plastics themselves can cause ICD, only rarely leading to ACD.⁴ Incomplete curing during their manufacture may result in inadvertent exposure to epoxy resins or other phenol- formaldehyde resins such as 4-tert-butylcatechol and 4-tert-butylphenol formaldehyde, demonstrated causes of ACD in amputees.¹⁰ Adhesives used in sock liners or tapes to secure prosthetic devices can contain ingredients such as acrylates (a well-known cause of nail allergens) and other formaldehyde resins.⁴ Additionally, benzophenone commonly is added to paints and rubbers as a UV light absorber, reducing UV degradation and enhancing the material’s durability under light exposure.¹¹

Textiles—Cotton, a common component in prosthetic sock liners, is almost 100% cellulose and typically does not cause ACD; however, synthetic fibers such as polypropylene and elastane (spandex) can elicit allergic reactions.⁴ Allergy to textiles often is driven by the chemicals used in the manufacturing process, particularly textile finishes, dyes, and formaldehyde resins, which are commonly used as fabric treatments. Disperse dyes are another common cause of allergic reactions. Para-phenylenediamine, a dye found in permanent hair dye and other darkly colored fabrics, is a potent sensitizer that may cross-react with other compounds that also contain similar amine groups, such as ester anesthetics, sunscreens containing para-aminobenzoic acid, other para dyes, and sulfonamides.¹² Sweat can exacerbate these reactions by causing allergens to leach out of textiles, increasing skin exposure. Additionally, prosthetics containing leather may trigger allergies to potassium dichromate and other chromium compounds used in the leather-tanning process.¹²

Allergy to Personal Care Products

Skin protectants and prosthetic cleansers are crucial in dermatologic care for amputees, working together to safeguard the skin and maintain prosthetic hygiene. Skin protectants form a barrier against irritation, friction, and moisture, protecting the residual limb from damage and enhancing comfort and mobility. Meanwhile, prosthetic cleansers remove sweat, oils, and bacteria from the prosthetic socket, reducing the risk of infections and odors and ensuring the longevity and optimal function of the prosthetic device. Together, they support skin health, comfort, and overall quality of life for amputees.

The socket should be cleaned with warm water prior to use, but more importantly, immediately after removing the prosthesis. If cleaning products are used at night, residual haptens may remain on the device, increasing the risk of sensitization. Common contact irritants found in personal care products utilized in amputee care include sulfates, surfactants, preservatives, and fragrances (eTable 1).⁴ Additionally, common household cleaners and disinfectants can damage the prosthesis, leading to breakdown and the release of the monomers, precipitating ACD.

Patch Testing to Identify Causative Allergens

Patch testing is a valuable tool for identifying specific allergens responsible for ACD in amputees. This procedure involves applying small amounts of suspected allergens to the patient’s skin under occlusion and leaving the patches in place for 48 hours. After removal, the skin is assessed for reactions at 48 hours, with additional assessments conducted according to International Contact Dermatitis Research Group guidelines, typically at 72 and 96 hours, to identify delayed responses. This diagnostic approach helps pinpoint the substances to which the individual is allergic, enabling targeted avoidance strategies and treatment recommendations. Two widely used patch tests—the T.R.U.E. TEST, a preassembled patch test encompassing 35 allergens, and the North American 80 Comprehensive Series, which includes 80 allergens—demonstrate a sensitivity range between 70% and 80%.^13,14 eTable 2 shows a recommended custom contact dermatitis panel to assess the most common causes of ACD related to amputee care.

Irritant Contact Dermatitis

Irritant contact dermatitis occurs when the skin’s protective barrier is damaged by repeated exposure to a particular irritant. In amputees, perspiration, friction, and pressure from prosthetic devices can exacerbate irritant reactions, leading to skin maceration, breakdown, and increased transepidermal penetration. Sweat accumulation within the prosthetic socket creates a moist environment conducive to ICD. The combination of sweat and friction can strip the skin of its natural oils, leading to dryness, chafing, and maceration. Continuous exposure to moisture also can exacerbate existing dermatitis and compromise skin integrity.⁴ Additionally, chronic irritation may increase transepidermal penetration of haptens, potentiating the development of ACD.¹⁵

Management of ICD in amputees involves a combination of treatments aimed at reducing friction, reducing sweating, and restoring barrier protection. Strategies to minimize mechanical trauma to the skin include ensuring proper socket fit, managing moisture, and protecting the skin. Using moisture-wicking sock liners and breathable prosthetic materials can help keep the skin dry. Topical antiperspirants containing aluminum chloride or similar compounds that help to block sweat glands often are the first line of treatment. Oral anticholinergics may be prescribed to reduce overall sweating, though they can have systemic side effects. Iontophoresis, a procedure where the affected area is exposed to a mild electrical current, can also be effective, especially for sweating of the hands and feet, though its application in amputees might be more limited.¹⁴

Recently, 2 treatments have emerged as options for managing excessive sweating (hyperhidrosis) in amputees: botulinum toxin injections and laser hair removal. By inhibiting the release of acetylcholine from sweat glands, botulinum toxin effectively reduces sweat production, thereby alleviating perspiration-induced skin irritation. Approximately 2 to 3 units of botulinum toxin at a dilution of 100 units in 1 mL of bacteriostatic saline 0.9% are injected transdermally at 1-cm intervals in a circumferential pattern on the skin covered by the prosthesis socket (typically a total of 300-500 units are utilized in the procedure)(eFigure 2).¹⁶ Laser hair removal can assist amputees with hyperhidrosis by reducing hair in the residual limb area, which decreases sweat retention and the potential for skin irritation due to friction.

Final Thoughts

In amputee dermatologic care, individuals with limb loss are particularly prone to contact dermatitis due to moisture, friction, and prolonged contact with prosthetic components. Diagnosing ACD and ICD is challenging due to overlapping symptoms and the potential for simultaneous occurrence. Distinguishing between these conditions is crucial for effective management. Understanding their causes, particularly in relation to prosthetic use, is essential for developing targeted prevention and treatment strategies, including the use of tailored patch testing panels to better diagnose ACD in amputees.

To the Editor:

Scabies infestation, which has been recognized as a neglected tropical disease by the World Health Organization since 2017, is caused by the human itch mite (Sarcoptes scabiei var hominis).¹ Infected individuals experience a pruritic papular rash when the mite burrows into the epidermis, where it lives and lays eggs.^2,3 Infected individuals also may develop bacterial superinfections if the skin barrier becomes compromised, leading to systemic complications and considerable morbidity.³

In countries with high human development indices, scabies outbreaks are linked to densely populated living conditions, such as those found in nursing homes or prisons.^3,4 Scabies also is transmitted via sexual contact in adults. Beyond immunosuppression, little is known about other comorbid conditions or lifestyle risk factors associated with scabies infestation.² Because scabies can mimic a range of other dermatologic conditions such as folliculitis, atopic dermatitis, and arthropod bites, misdiagnosis is common and can lead to delayed treatment and increased transmission risk.⁴ In this study, we sought to examine comorbid conditions and/or lifestyle risk factors associated with scabies infestation.

A matched case-control study was performed using the Registered Tier dataset of the National Institutes of Health All of Us Research Program Curated Data Repository version 7, which includes more than 400,000 unique participants aged 18 years or older from across the United States. The All of Us Research Program excludes adults who are unable to consent independently as well as incarcerated populations and children younger than 18 years. Participants diagnosed with scabies were identified using SNOMED code 62752005 and compared to a control group matched 1:4 based on age, sex, and selfidentified race. SNOMED codes also were used to identify various comorbidities and lifestyle risk factors, including depression, bipolar disorder, anxiety, schizophrenia, peripheral vascular disease (PVD), HIV, type 2 diabetes mellitus (T2DM), unsheltered status, tobacco use, difficulty with activities of daily living, insurance status, and any recent travel history. Logistic regression models were used to calculate odds ratios (ORs) and estimate effect sizes, with statistical significance set at P<.05.

We identified 691 cases of scabies infestation and 2073 controls. The average age of the patients diagnosed with scabies was 55.1 years. Seventy percent (481/691) identified as female and 32.4% (224/491) identified as Black or African American. Matched controls were similar for all analyzed demographic characteristics (P=1.0)(eTable 1). Patients diagnosed with scabies were more likely to be unsheltered (OR, 2.33 [95% CI, 1.91-2.85]), use tobacco (OR 1.77 [95% CI, 1.48-2.11]) and have a comorbid diagnosis of HIV (OR, 3.08 [95% CI, 2.03-4.66]), T2DM (OR, 2.05 [95% CI, 1.57- 2.66]) or PVD (OR, 2.06 [95% CI, 1.43-2.97]) compared with controls (P<.001). Psychiatric comorbidities were more common in the patients diagnosed with scabies, including depression (OR, 3.07 [95% CI, 2.54-3.72]), anxiety (OR, 2.48 [95% CI, 2.06-2.98]), bipolar disorder (OR, 3.08 [95% CI, 2.34-4.05]), and schizophrenia (OR, 4.68 [95% CI, 2.93-7.49])(P<.001). Difficulties with activities of daily living, including running errands alone (OR, 2.32 [95% CI, 1.43-3.76]) and concentrating (OR, 5.78; 95% CI, 3.86-8.64), were more prevalent in the scabies group compared to controls (both P<.05). In a multivariate logistic regression model including unsheltered status as a covariate, all associations remained statistically significant (P<.05)(eTable 2).

This large diverse study demonstrated an association between scabies infestation and unsheltered status. Previous studies have shown that unsheltered populations are at increased risk for many dermatologic conditions, perhaps due to decreased access to health care and social support, lack of access to hygiene facilities (eg, public showers), and increased prevalence of substance use and psychiatric disorders among this population.⁵ In a cross-sectional analysis of hospitalized patients, 8.6% of unsheltered patients (n=197) had an ectoparasitic disease (including scabies) compared with 1.0% of patients with stable housing (n=1018), with a 9.43-fold increased risk for ectoparasitic infestation among unsheltered patients (95% CI, 3.79-23.47; P<.001).⁶ Increased attention to public health initiatives among unsheltered populations— including access to hygiene facilities and increased dermatologic services—are needed, as ectoparasitic infections are both preventable and treatable, and these initiatives could reduce morbidity associated with superimposed bacterial infections for which unsheltered patients are at increased risk.⁶

Our results also showed that individuals diagnosed with scabies were more likely than the controls to have been diagnosed with HIV, T2DM, and PVD. Our findings are similar to those of a systematic review of immunosuppressive factors associated with crusted scabies (a severe form of scabies infestation) in which 10.2% and 15.7% of patients (n=683) had comorbid HIV and T2DM, respectively.⁷ A functioning cell-mediated response to scabies mite antigens limits proliferation of the human itch mite; thus, infection with HIV/AIDS, which induces the destruction of CD4+ T cells, limits the immune system’s ability to mount an effective response against these antigens. The association of scabies with T2DM likely is multifactorial; for example, chronic hyperglycemia may lead to immune system impairment, and peripheral neuropathy may reduce the itch sensation, allowing scabies mites to proliferate without removal by scratching.⁷ In a descriptive epidemiologic study in Japan, 11.7% of patients with scabies (N=857) had comorbid PVD.⁸ Peripheral vascular disease can lead to the development of ulcers, gangrene, and stasis dermatitis, all of which compromise the skin barrier and increase susceptibility to infection.⁹ Notably, these associations remained even when unsheltered status was considered as a confounding variable. Because individuals with HIV, T2DM, and PVD may be at higher risk for serious complications of scabies infestation (eg, secondary bacterial infections, invasive group A streptococcal infections), prompt detection and treatment of scabies are crucial in curbing morbidity in these at-risk populations.

Our study also demonstrated that psychiatric comorbidities including depression, anxiety, bipolar disorder, and schizophrenia were associated with scabies infestation, even when controlling for unsheltered status, which may have a bidirectional relationship with mental health disorders.¹⁰ In a cross-sectional study of 83 adult patients diagnosed with scabies, 72.2% (60/83) reported moderate to extremely large effect of scabies infestation on quality of life using the Dermatology Life Quality Index, and these scores positively correlated with increased Beck Depression Scale and Beck Anxiety Scale scores (r_s=0.448 and r_s=0.456 0.456, respectively; both P=.000). The results of this study suggest that scabies negatively impacts quality of life, which might increase symptoms of depression and anxiety.¹¹

Studies are needed to assess whether patients with pre-existing depression and anxiety face increased risk for scabies infestation. In a retrospective case-control study using data from the National Health Insurance Research Database of Taiwan, 0.8% (58/7096) of patients with scabies (n=7096) and 0.4% of controls (n=28,375) were newly diagnosed with bipolar disorder over a 7-year period, indicating a 1.55-fold increased risk for bipolar disorder in patients with scabies compared to those without (95% CI, 1.12-2.09; P<.05).¹² Future studies are needed to determine whether the relationship between bipolar disorder and scabies is bidirectional, with pre-existing bipolar disorder evaluated as a risk factor for subsequent scabies infestation. Increased difficulties with activities of daily living, including running errands independently and concentrating, were associated with scabies. These difficulties may reflect sequelae of psychiatric illness or pruritus associated with scabies affecting daily living.

Physician awareness of comorbidities and lifestyle risk factors associated with scabies infestation may improve diagnosis and prevent treatment delays. In a retrospective study at a single dermatology outpatient clinic, 45.3% of patients with scabies (n=428) had previously been misdiagnosed with another dermatologic condition, and the most common erroneous diagnosis was atopic dermatitis.¹³ Our study provides a framework of comorbidities and lifestyle risk factors associated with scabies infestation that dermatologists can use to stratify patients who may be at greater risk for this condition, allowing dermatologists to select appropriate treatment when clinical signs are ambiguous.

Limitations of our study included the potential for miscoding in the database, lack of information about treatment regimens employed (if any), and lack of information about the temporal relationship between associations.

In summary, it is recommended that patients with pruritus and other characteristic clinical findings of scabies receive appropriate workup for scabies regardless of risk factors; however, the medical and psychiatric comorbidities and lifestyle risk factors identified in this study may help to identify at-risk patients. Our study showed that unsheltered patients are at increased risk for scabies, potentially due to unique dermatologic challenges and lack of access to health care and hygiene facilities. Positive correlations between scabies and HIV, T2DM, and PVD suggest that patients with chronic immunocompromising illnesses who live in group homes or other crowded quarters and present with symptoms could be evaluated for scabies infestation to prevent widespread and difficult- to-control outbreaks in these communities. Based on our findings, scabies also should be included in the differential diagnosis for patients with psychiatric illness and suggestive symptoms. Early identification and treatment of scabies infestation could prevent misdiagnosis and treatment delays.

To the Editor:

Scabies infestation, which has been recognized as a neglected tropical disease by the World Health Organization since 2017, is caused by the human itch mite (Sarcoptes scabiei var hominis).¹ Infected individuals experience a pruritic papular rash when the mite burrows into the epidermis, where it lives and lays eggs.^2,3 Infected individuals also may develop bacterial superinfections if the skin barrier becomes compromised, leading to systemic complications and considerable morbidity.³

In countries with high human development indices, scabies outbreaks are linked to densely populated living conditions, such as those found in nursing homes or prisons.^3,4 Scabies also is transmitted via sexual contact in adults. Beyond immunosuppression, little is known about other comorbid conditions or lifestyle risk factors associated with scabies infestation.² Because scabies can mimic a range of other dermatologic conditions such as folliculitis, atopic dermatitis, and arthropod bites, misdiagnosis is common and can lead to delayed treatment and increased transmission risk.⁴ In this study, we sought to examine comorbid conditions and/or lifestyle risk factors associated with scabies infestation.

A matched case-control study was performed using the Registered Tier dataset of the National Institutes of Health All of Us Research Program Curated Data Repository version 7, which includes more than 400,000 unique participants aged 18 years or older from across the United States. The All of Us Research Program excludes adults who are unable to consent independently as well as incarcerated populations and children younger than 18 years. Participants diagnosed with scabies were identified using SNOMED code 62752005 and compared to a control group matched 1:4 based on age, sex, and selfidentified race. SNOMED codes also were used to identify various comorbidities and lifestyle risk factors, including depression, bipolar disorder, anxiety, schizophrenia, peripheral vascular disease (PVD), HIV, type 2 diabetes mellitus (T2DM), unsheltered status, tobacco use, difficulty with activities of daily living, insurance status, and any recent travel history. Logistic regression models were used to calculate odds ratios (ORs) and estimate effect sizes, with statistical significance set at P<.05.

We identified 691 cases of scabies infestation and 2073 controls. The average age of the patients diagnosed with scabies was 55.1 years. Seventy percent (481/691) identified as female and 32.4% (224/491) identified as Black or African American. Matched controls were similar for all analyzed demographic characteristics (P=1.0)(eTable 1). Patients diagnosed with scabies were more likely to be unsheltered (OR, 2.33 [95% CI, 1.91-2.85]), use tobacco (OR 1.77 [95% CI, 1.48-2.11]) and have a comorbid diagnosis of HIV (OR, 3.08 [95% CI, 2.03-4.66]), T2DM (OR, 2.05 [95% CI, 1.57- 2.66]) or PVD (OR, 2.06 [95% CI, 1.43-2.97]) compared with controls (P<.001). Psychiatric comorbidities were more common in the patients diagnosed with scabies, including depression (OR, 3.07 [95% CI, 2.54-3.72]), anxiety (OR, 2.48 [95% CI, 2.06-2.98]), bipolar disorder (OR, 3.08 [95% CI, 2.34-4.05]), and schizophrenia (OR, 4.68 [95% CI, 2.93-7.49])(P<.001). Difficulties with activities of daily living, including running errands alone (OR, 2.32 [95% CI, 1.43-3.76]) and concentrating (OR, 5.78; 95% CI, 3.86-8.64), were more prevalent in the scabies group compared to controls (both P<.05). In a multivariate logistic regression model including unsheltered status as a covariate, all associations remained statistically significant (P<.05)(eTable 2).

This large diverse study demonstrated an association between scabies infestation and unsheltered status. Previous studies have shown that unsheltered populations are at increased risk for many dermatologic conditions, perhaps due to decreased access to health care and social support, lack of access to hygiene facilities (eg, public showers), and increased prevalence of substance use and psychiatric disorders among this population.⁵ In a cross-sectional analysis of hospitalized patients, 8.6% of unsheltered patients (n=197) had an ectoparasitic disease (including scabies) compared with 1.0% of patients with stable housing (n=1018), with a 9.43-fold increased risk for ectoparasitic infestation among unsheltered patients (95% CI, 3.79-23.47; P<.001).⁶ Increased attention to public health initiatives among unsheltered populations— including access to hygiene facilities and increased dermatologic services—are needed, as ectoparasitic infections are both preventable and treatable, and these initiatives could reduce morbidity associated with superimposed bacterial infections for which unsheltered patients are at increased risk.⁶

Our results also showed that individuals diagnosed with scabies were more likely than the controls to have been diagnosed with HIV, T2DM, and PVD. Our findings are similar to those of a systematic review of immunosuppressive factors associated with crusted scabies (a severe form of scabies infestation) in which 10.2% and 15.7% of patients (n=683) had comorbid HIV and T2DM, respectively.⁷ A functioning cell-mediated response to scabies mite antigens limits proliferation of the human itch mite; thus, infection with HIV/AIDS, which induces the destruction of CD4+ T cells, limits the immune system’s ability to mount an effective response against these antigens. The association of scabies with T2DM likely is multifactorial; for example, chronic hyperglycemia may lead to immune system impairment, and peripheral neuropathy may reduce the itch sensation, allowing scabies mites to proliferate without removal by scratching.⁷ In a descriptive epidemiologic study in Japan, 11.7% of patients with scabies (N=857) had comorbid PVD.⁸ Peripheral vascular disease can lead to the development of ulcers, gangrene, and stasis dermatitis, all of which compromise the skin barrier and increase susceptibility to infection.⁹ Notably, these associations remained even when unsheltered status was considered as a confounding variable. Because individuals with HIV, T2DM, and PVD may be at higher risk for serious complications of scabies infestation (eg, secondary bacterial infections, invasive group A streptococcal infections), prompt detection and treatment of scabies are crucial in curbing morbidity in these at-risk populations.

Our study also demonstrated that psychiatric comorbidities including depression, anxiety, bipolar disorder, and schizophrenia were associated with scabies infestation, even when controlling for unsheltered status, which may have a bidirectional relationship with mental health disorders.¹⁰ In a cross-sectional study of 83 adult patients diagnosed with scabies, 72.2% (60/83) reported moderate to extremely large effect of scabies infestation on quality of life using the Dermatology Life Quality Index, and these scores positively correlated with increased Beck Depression Scale and Beck Anxiety Scale scores (r_s=0.448 and r_s=0.456 0.456, respectively; both P=.000). The results of this study suggest that scabies negatively impacts quality of life, which might increase symptoms of depression and anxiety.¹¹

Studies are needed to assess whether patients with pre-existing depression and anxiety face increased risk for scabies infestation. In a retrospective case-control study using data from the National Health Insurance Research Database of Taiwan, 0.8% (58/7096) of patients with scabies (n=7096) and 0.4% of controls (n=28,375) were newly diagnosed with bipolar disorder over a 7-year period, indicating a 1.55-fold increased risk for bipolar disorder in patients with scabies compared to those without (95% CI, 1.12-2.09; P<.05).¹² Future studies are needed to determine whether the relationship between bipolar disorder and scabies is bidirectional, with pre-existing bipolar disorder evaluated as a risk factor for subsequent scabies infestation. Increased difficulties with activities of daily living, including running errands independently and concentrating, were associated with scabies. These difficulties may reflect sequelae of psychiatric illness or pruritus associated with scabies affecting daily living.

Physician awareness of comorbidities and lifestyle risk factors associated with scabies infestation may improve diagnosis and prevent treatment delays. In a retrospective study at a single dermatology outpatient clinic, 45.3% of patients with scabies (n=428) had previously been misdiagnosed with another dermatologic condition, and the most common erroneous diagnosis was atopic dermatitis.¹³ Our study provides a framework of comorbidities and lifestyle risk factors associated with scabies infestation that dermatologists can use to stratify patients who may be at greater risk for this condition, allowing dermatologists to select appropriate treatment when clinical signs are ambiguous.

Limitations of our study included the potential for miscoding in the database, lack of information about treatment regimens employed (if any), and lack of information about the temporal relationship between associations.

In summary, it is recommended that patients with pruritus and other characteristic clinical findings of scabies receive appropriate workup for scabies regardless of risk factors; however, the medical and psychiatric comorbidities and lifestyle risk factors identified in this study may help to identify at-risk patients. Our study showed that unsheltered patients are at increased risk for scabies, potentially due to unique dermatologic challenges and lack of access to health care and hygiene facilities. Positive correlations between scabies and HIV, T2DM, and PVD suggest that patients with chronic immunocompromising illnesses who live in group homes or other crowded quarters and present with symptoms could be evaluated for scabies infestation to prevent widespread and difficult- to-control outbreaks in these communities. Based on our findings, scabies also should be included in the differential diagnosis for patients with psychiatric illness and suggestive symptoms. Early identification and treatment of scabies infestation could prevent misdiagnosis and treatment delays.

To the Editor:

Scabies infestation, which has been recognized as a neglected tropical disease by the World Health Organization since 2017, is caused by the human itch mite (Sarcoptes scabiei var hominis).¹ Infected individuals experience a pruritic papular rash when the mite burrows into the epidermis, where it lives and lays eggs.^2,3 Infected individuals also may develop bacterial superinfections if the skin barrier becomes compromised, leading to systemic complications and considerable morbidity.³

In countries with high human development indices, scabies outbreaks are linked to densely populated living conditions, such as those found in nursing homes or prisons.^3,4 Scabies also is transmitted via sexual contact in adults. Beyond immunosuppression, little is known about other comorbid conditions or lifestyle risk factors associated with scabies infestation.² Because scabies can mimic a range of other dermatologic conditions such as folliculitis, atopic dermatitis, and arthropod bites, misdiagnosis is common and can lead to delayed treatment and increased transmission risk.⁴ In this study, we sought to examine comorbid conditions and/or lifestyle risk factors associated with scabies infestation.

A matched case-control study was performed using the Registered Tier dataset of the National Institutes of Health All of Us Research Program Curated Data Repository version 7, which includes more than 400,000 unique participants aged 18 years or older from across the United States. The All of Us Research Program excludes adults who are unable to consent independently as well as incarcerated populations and children younger than 18 years. Participants diagnosed with scabies were identified using SNOMED code 62752005 and compared to a control group matched 1:4 based on age, sex, and selfidentified race. SNOMED codes also were used to identify various comorbidities and lifestyle risk factors, including depression, bipolar disorder, anxiety, schizophrenia, peripheral vascular disease (PVD), HIV, type 2 diabetes mellitus (T2DM), unsheltered status, tobacco use, difficulty with activities of daily living, insurance status, and any recent travel history. Logistic regression models were used to calculate odds ratios (ORs) and estimate effect sizes, with statistical significance set at P<.05.

We identified 691 cases of scabies infestation and 2073 controls. The average age of the patients diagnosed with scabies was 55.1 years. Seventy percent (481/691) identified as female and 32.4% (224/491) identified as Black or African American. Matched controls were similar for all analyzed demographic characteristics (P=1.0)(eTable 1). Patients diagnosed with scabies were more likely to be unsheltered (OR, 2.33 [95% CI, 1.91-2.85]), use tobacco (OR 1.77 [95% CI, 1.48-2.11]) and have a comorbid diagnosis of HIV (OR, 3.08 [95% CI, 2.03-4.66]), T2DM (OR, 2.05 [95% CI, 1.57- 2.66]) or PVD (OR, 2.06 [95% CI, 1.43-2.97]) compared with controls (P<.001). Psychiatric comorbidities were more common in the patients diagnosed with scabies, including depression (OR, 3.07 [95% CI, 2.54-3.72]), anxiety (OR, 2.48 [95% CI, 2.06-2.98]), bipolar disorder (OR, 3.08 [95% CI, 2.34-4.05]), and schizophrenia (OR, 4.68 [95% CI, 2.93-7.49])(P<.001). Difficulties with activities of daily living, including running errands alone (OR, 2.32 [95% CI, 1.43-3.76]) and concentrating (OR, 5.78; 95% CI, 3.86-8.64), were more prevalent in the scabies group compared to controls (both P<.05). In a multivariate logistic regression model including unsheltered status as a covariate, all associations remained statistically significant (P<.05)(eTable 2).

This large diverse study demonstrated an association between scabies infestation and unsheltered status. Previous studies have shown that unsheltered populations are at increased risk for many dermatologic conditions, perhaps due to decreased access to health care and social support, lack of access to hygiene facilities (eg, public showers), and increased prevalence of substance use and psychiatric disorders among this population.⁵ In a cross-sectional analysis of hospitalized patients, 8.6% of unsheltered patients (n=197) had an ectoparasitic disease (including scabies) compared with 1.0% of patients with stable housing (n=1018), with a 9.43-fold increased risk for ectoparasitic infestation among unsheltered patients (95% CI, 3.79-23.47; P<.001).⁶ Increased attention to public health initiatives among unsheltered populations— including access to hygiene facilities and increased dermatologic services—are needed, as ectoparasitic infections are both preventable and treatable, and these initiatives could reduce morbidity associated with superimposed bacterial infections for which unsheltered patients are at increased risk.⁶

Our results also showed that individuals diagnosed with scabies were more likely than the controls to have been diagnosed with HIV, T2DM, and PVD. Our findings are similar to those of a systematic review of immunosuppressive factors associated with crusted scabies (a severe form of scabies infestation) in which 10.2% and 15.7% of patients (n=683) had comorbid HIV and T2DM, respectively.⁷ A functioning cell-mediated response to scabies mite antigens limits proliferation of the human itch mite; thus, infection with HIV/AIDS, which induces the destruction of CD4+ T cells, limits the immune system’s ability to mount an effective response against these antigens. The association of scabies with T2DM likely is multifactorial; for example, chronic hyperglycemia may lead to immune system impairment, and peripheral neuropathy may reduce the itch sensation, allowing scabies mites to proliferate without removal by scratching.⁷ In a descriptive epidemiologic study in Japan, 11.7% of patients with scabies (N=857) had comorbid PVD.⁸ Peripheral vascular disease can lead to the development of ulcers, gangrene, and stasis dermatitis, all of which compromise the skin barrier and increase susceptibility to infection.⁹ Notably, these associations remained even when unsheltered status was considered as a confounding variable. Because individuals with HIV, T2DM, and PVD may be at higher risk for serious complications of scabies infestation (eg, secondary bacterial infections, invasive group A streptococcal infections), prompt detection and treatment of scabies are crucial in curbing morbidity in these at-risk populations.

Our study also demonstrated that psychiatric comorbidities including depression, anxiety, bipolar disorder, and schizophrenia were associated with scabies infestation, even when controlling for unsheltered status, which may have a bidirectional relationship with mental health disorders.¹⁰ In a cross-sectional study of 83 adult patients diagnosed with scabies, 72.2% (60/83) reported moderate to extremely large effect of scabies infestation on quality of life using the Dermatology Life Quality Index, and these scores positively correlated with increased Beck Depression Scale and Beck Anxiety Scale scores (r_s=0.448 and r_s=0.456 0.456, respectively; both P=.000). The results of this study suggest that scabies negatively impacts quality of life, which might increase symptoms of depression and anxiety.¹¹

Studies are needed to assess whether patients with pre-existing depression and anxiety face increased risk for scabies infestation. In a retrospective case-control study using data from the National Health Insurance Research Database of Taiwan, 0.8% (58/7096) of patients with scabies (n=7096) and 0.4% of controls (n=28,375) were newly diagnosed with bipolar disorder over a 7-year period, indicating a 1.55-fold increased risk for bipolar disorder in patients with scabies compared to those without (95% CI, 1.12-2.09; P<.05).¹² Future studies are needed to determine whether the relationship between bipolar disorder and scabies is bidirectional, with pre-existing bipolar disorder evaluated as a risk factor for subsequent scabies infestation. Increased difficulties with activities of daily living, including running errands independently and concentrating, were associated with scabies. These difficulties may reflect sequelae of psychiatric illness or pruritus associated with scabies affecting daily living.

Physician awareness of comorbidities and lifestyle risk factors associated with scabies infestation may improve diagnosis and prevent treatment delays. In a retrospective study at a single dermatology outpatient clinic, 45.3% of patients with scabies (n=428) had previously been misdiagnosed with another dermatologic condition, and the most common erroneous diagnosis was atopic dermatitis.¹³ Our study provides a framework of comorbidities and lifestyle risk factors associated with scabies infestation that dermatologists can use to stratify patients who may be at greater risk for this condition, allowing dermatologists to select appropriate treatment when clinical signs are ambiguous.

Limitations of our study included the potential for miscoding in the database, lack of information about treatment regimens employed (if any), and lack of information about the temporal relationship between associations.

In summary, it is recommended that patients with pruritus and other characteristic clinical findings of scabies receive appropriate workup for scabies regardless of risk factors; however, the medical and psychiatric comorbidities and lifestyle risk factors identified in this study may help to identify at-risk patients. Our study showed that unsheltered patients are at increased risk for scabies, potentially due to unique dermatologic challenges and lack of access to health care and hygiene facilities. Positive correlations between scabies and HIV, T2DM, and PVD suggest that patients with chronic immunocompromising illnesses who live in group homes or other crowded quarters and present with symptoms could be evaluated for scabies infestation to prevent widespread and difficult- to-control outbreaks in these communities. Based on our findings, scabies also should be included in the differential diagnosis for patients with psychiatric illness and suggestive symptoms. Early identification and treatment of scabies infestation could prevent misdiagnosis and treatment delays.

Vitiligo is a common autoimmune disorder characterized by cutaneous depigmentation that has a substantial impact on patient quality of life.¹ Vitiligo affects approximately 28.5 million individuals globally, with the highest lifetime prevalence occurring in Central Europe and South Asia.² In the United States, Asian American and Hispanic/Latine populations most commonly are affected.³ The accompanying psychosocial burdens of vitiligo are particularly substantial among individuals with darker skin types, as evidenced by higher rates of concomitant anxiety and depression in these patients.⁴ Despite this, patients with skin of color are underrepresented in vitiligo research.²

Treatment algorithms developed based on worldwide expert consensus recommendations provide valuable insights into the management of segmental and nonsegmental vitiligo.⁵ The mainstay therapeutics include topical and oral corticosteroids, topical calcineurin inhibitors, and phototherapy. While vitiligo pathogenesis is not completely understood, recent advances have focused on the role of the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Interferon gamma drives vitiligo pathogenesis through this pathway, upregulating C-X-C motif chemokine ligand 10 and promoting CD8+ T-cell recruitment, resulting in targeted melanocyte destruction.⁶ The emergence of targeted therapeutics may address equity and inclusion gaps. Herein, we highlight innovations in vitiligo treatment with a focus on oral and topical JAK inhibitors.

Oral JAK Inhibitors for Vitiligo

The therapeutic potential of JAK inhibitors for vitiligo was first reported when patients with alopecia areata and comorbid vitiligo experienced repigmentation of the skin following administration of oral ruxolitinib.⁷ Since this discovery, other oral JAK inhibitors have been investigated for vitiligo treatment. A phase 2b randomized clinical trial (RCT) of 364 patients examined oral ritlecitinib, a JAK3 inhibitor, and found it to be effective in treating active nonsegmental vitiligo.⁸ Patients aged 18 to 65 years with active nonsegmental vitiligo that had been present for 3 months or more as well as 4% to 50% body surface area (BSA) affected excluding acral surfaces and at least 0.25% facial involvement were included. Treatment groups received 50 mg (with or without a 100- or 200- mg loading dose), 30 mg, or 10 mg daily for 24 weeks. The primary endpoint measured the percentage change in Facial Vitiligo Area Scoring Index (F-VASI) score. Significant differences in F-VASI percentage change compared with placebo occurred for those in the 50-mg group who received a loading dose (-21.2 vs 2.1 [P<.001]) and those who did not receive a loading dose (–18.5 vs 2.1 [P<.001]) as well as the 30-mg group (-14.6 vs 2.1 [P=.01]). Continued repigmentation of the skin was observed in the 24-week extension period, indicating that longer treatment periods may be necessary for optimal repigmentation results. Ritlecitinib generally was well tolerated, and the most common treatment-emergent adverse events were nasopharyngitis (15.9%), upper respiratory tract infection (11.5%), and headache (8.8%). Most patients identified as White (67.6%), with 23.6% identifying as Asian and 2.7% identifying as Black. The authors stated that continued improvement was observed in the extension period across all skin types; however, the data were not reported.⁸

Upadacitnib, an oral selective JAK1 inhibitor, also has demonstrated efficacy in nonsegmental vitiligo in a phase 2 RCT.⁹ Adult patients (N=185) with nonsegmental vitiligo were randomized to receive upadacitinib 6 mg, 11 mg, or 22 mg or placebo (the placebo group subsequently was switched to upadacitinib 11 mg or 22 mg after 24 weeks). The primary endpoint measured the percentage change in F-VASI score at 24 weeks. The higher doses of upadacitinib resulted in significant changes in F-VASI scored compared with placebo (6 mg: -7.60 [95% CI, -22.18 to 6.97][P=.30]; 11 mg: -21.27 [95% CI, -36.02 to -6.52][P=.01]; 22 mg: -19.60 [95% CI, -35.04 to –4.16][P=.01]). As with ritlecitinib, continued repigmentation was observed beyond the initial 24-week period. Of the 185 participants, 5.9% identified as Black and 13.5% identified as Asian. The investigators reported that the percentage change in F-VASI score was consistent across skin types.⁹ The results of these phase 2 RCTs are encouraging, and we anticipate the findings of 2 phase 3 RCTs for ritlecitinib and upadacitinib that currently are underway (Clinicaltrials.gov identifiers NCT05583526 and NCT06118411).

Topical JAK Inhibitors for Vitiligo

Tofacitinib cream 2%, a selective JAK3 inhibitor, has shown therapeutic potential for treatment of vitiligo. One of the earliest pilot studies on topical tofacitinib examined the efficacy of tofacitinib cream 2% applied twice daily combined with narrowband UVB therapy 3 times weekly for facial vitiligo. The investigators reported repigmentation of the skin in all 11 patients (which included 4 Asian patients and 1 Hispanic patient), with a mean improvement of 70% in F-VASI score (range, 50%-87%).¹⁰ In a nonrandomized cohort study of 16 patients later that year, twice-daily application of tofacitinib cream 2% on facial and nonfacial vitiligo lesions resulted in partial repigmentation in 81.3% of patients: 4 (25%) achieved greater than 90% improvement, 5 (31.3%) achieved improvement of 25% to 75%, and 4 (25%) achieved 5% to 15% improvement.¹¹ The researchers also found that tofacitinib cream 2% was significantly more effective in facial than nonfacial lesions (P=.02).

While tofacitinib has shown promise in early studies, recent advancements have led to US Food and Drug Administration approval of ruxolitinib cream 1.5%, another topical JAK inhibitor that has undergone robust clinical testing for vitiligo.^12-14 Ruxolitinib, a JAK1, JAK2, and JAK3 inhibitor, is the first and only US Food and Drug Administration–approved topical JAK inhibitor for vitiligo.^14,15 Two phase 3, double-blind, vehicle-controlled trials of identical design conducted across 101 centers in North America and Europe (TRuE-V1 and TRuE-V2) assessed the efficacy of ruxolitinib cream 1.5% in 674 patients aged 12 years and older with nonsegmental vitiligo covering 10% or lower total BSA.¹³ In both trials, twice-daily application of topical ruxolitinib resulted in greater facial repigmentation and improvement in F-VASI75 score (ie, a reduction of at least 75% from baseline) at 24 weeks in 29.9% (66/221) and 30.1% (69/222) of patients in TRuE-V1 and TRuE-V2, respectively. Continued application through 52 weeks resulted in F-VASI75 response in 52.6% (91/173) and 48.0% (85/177) of patients in TRuE-V1 and TRuE-V2, respectively. The most frequently reported adverse events were acne (6.3% [14/221] and 6.6% [15/228]), nasopharyngitis (5.4% [12/221] and 6.1% [14/228]), and pruritus (5.4% [12/221] and 5.3% [12/228]). These findings align with prior subgroup analyses of an earlier phase 2 double- blind RCT of ruxolitinib cream 1.5% that indicated similar improvement in vitiligo among patients with differing skin tones.¹⁷

There are no additional large-scale RCTs examining topical JAK inhibitors with intentional subanalysis of diverse skin tones.^16,17,18 Studies examining topical JAK inhibitors have expanded to be more inclusive, providing hope for the future of topical vitiligo therapeutics for all patients.

Final Thoughts

It is imperative to increase racial/ethnic and skin type diversity in research on JAK inhibitors for vitiligo. While the studies mentioned here are inclusive of an array of races and skin tones, it is crucial that future research continue to expand the number of diverse participants, especially given the increased psychosocial burdens of vitiligo in patients with darker skin types.⁴ Intentional subgroup analyses across skin tones are vital to characterize and unmask potential differences between lighter and darker skin types. This point was exemplified by a 2024 RCT that investigated ritlecitinib efficacy with biomarker analysis across skin types.¹⁹ For patients receiving ritlecitinib 50 mg, IL-9 and IL-22 expression were decreased in darker vs lighter skin tones (P<.05). This intentional and inclusive analysis revealed a potential immunologic mechanism for why darker skin tones respond to JAK inhibitor therapy earlier than lighter skin tones.¹⁹

In the expanding landscape of oral and topical JAK inhibitors for vitiligo, continued efforts to assess these therapies across a range of skin tones and racial/ ethnic groups are critical. The efficacy of JAK inhibitors in other populations, including pediatric patients and patients with refractory segmental disease, have been reported.^20,21 As larger studies are developed based on the success of individual cases, researchers should investigate the efficacy of JAK inhibitors for various vitiligo subtypes (eg, segmental, nonsegmental) and recalcitrant disease and conduct direct comparisons with traditional treatments across diverse skin tones and racial/ethnic subgroup analyses to ensure broad therapeutic applicability.

Vitiligo is a common autoimmune disorder characterized by cutaneous depigmentation that has a substantial impact on patient quality of life.¹ Vitiligo affects approximately 28.5 million individuals globally, with the highest lifetime prevalence occurring in Central Europe and South Asia.² In the United States, Asian American and Hispanic/Latine populations most commonly are affected.³ The accompanying psychosocial burdens of vitiligo are particularly substantial among individuals with darker skin types, as evidenced by higher rates of concomitant anxiety and depression in these patients.⁴ Despite this, patients with skin of color are underrepresented in vitiligo research.²

Treatment algorithms developed based on worldwide expert consensus recommendations provide valuable insights into the management of segmental and nonsegmental vitiligo.⁵ The mainstay therapeutics include topical and oral corticosteroids, topical calcineurin inhibitors, and phototherapy. While vitiligo pathogenesis is not completely understood, recent advances have focused on the role of the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Interferon gamma drives vitiligo pathogenesis through this pathway, upregulating C-X-C motif chemokine ligand 10 and promoting CD8+ T-cell recruitment, resulting in targeted melanocyte destruction.⁶ The emergence of targeted therapeutics may address equity and inclusion gaps. Herein, we highlight innovations in vitiligo treatment with a focus on oral and topical JAK inhibitors.

Oral JAK Inhibitors for Vitiligo

The therapeutic potential of JAK inhibitors for vitiligo was first reported when patients with alopecia areata and comorbid vitiligo experienced repigmentation of the skin following administration of oral ruxolitinib.⁷ Since this discovery, other oral JAK inhibitors have been investigated for vitiligo treatment. A phase 2b randomized clinical trial (RCT) of 364 patients examined oral ritlecitinib, a JAK3 inhibitor, and found it to be effective in treating active nonsegmental vitiligo.⁸ Patients aged 18 to 65 years with active nonsegmental vitiligo that had been present for 3 months or more as well as 4% to 50% body surface area (BSA) affected excluding acral surfaces and at least 0.25% facial involvement were included. Treatment groups received 50 mg (with or without a 100- or 200- mg loading dose), 30 mg, or 10 mg daily for 24 weeks. The primary endpoint measured the percentage change in Facial Vitiligo Area Scoring Index (F-VASI) score. Significant differences in F-VASI percentage change compared with placebo occurred for those in the 50-mg group who received a loading dose (-21.2 vs 2.1 [P<.001]) and those who did not receive a loading dose (–18.5 vs 2.1 [P<.001]) as well as the 30-mg group (-14.6 vs 2.1 [P=.01]). Continued repigmentation of the skin was observed in the 24-week extension period, indicating that longer treatment periods may be necessary for optimal repigmentation results. Ritlecitinib generally was well tolerated, and the most common treatment-emergent adverse events were nasopharyngitis (15.9%), upper respiratory tract infection (11.5%), and headache (8.8%). Most patients identified as White (67.6%), with 23.6% identifying as Asian and 2.7% identifying as Black. The authors stated that continued improvement was observed in the extension period across all skin types; however, the data were not reported.⁸

Upadacitnib, an oral selective JAK1 inhibitor, also has demonstrated efficacy in nonsegmental vitiligo in a phase 2 RCT.⁹ Adult patients (N=185) with nonsegmental vitiligo were randomized to receive upadacitinib 6 mg, 11 mg, or 22 mg or placebo (the placebo group subsequently was switched to upadacitinib 11 mg or 22 mg after 24 weeks). The primary endpoint measured the percentage change in F-VASI score at 24 weeks. The higher doses of upadacitinib resulted in significant changes in F-VASI scored compared with placebo (6 mg: -7.60 [95% CI, -22.18 to 6.97][P=.30]; 11 mg: -21.27 [95% CI, -36.02 to -6.52][P=.01]; 22 mg: -19.60 [95% CI, -35.04 to –4.16][P=.01]). As with ritlecitinib, continued repigmentation was observed beyond the initial 24-week period. Of the 185 participants, 5.9% identified as Black and 13.5% identified as Asian. The investigators reported that the percentage change in F-VASI score was consistent across skin types.⁹ The results of these phase 2 RCTs are encouraging, and we anticipate the findings of 2 phase 3 RCTs for ritlecitinib and upadacitinib that currently are underway (Clinicaltrials.gov identifiers NCT05583526 and NCT06118411).

Topical JAK Inhibitors for Vitiligo

Tofacitinib cream 2%, a selective JAK3 inhibitor, has shown therapeutic potential for treatment of vitiligo. One of the earliest pilot studies on topical tofacitinib examined the efficacy of tofacitinib cream 2% applied twice daily combined with narrowband UVB therapy 3 times weekly for facial vitiligo. The investigators reported repigmentation of the skin in all 11 patients (which included 4 Asian patients and 1 Hispanic patient), with a mean improvement of 70% in F-VASI score (range, 50%-87%).¹⁰ In a nonrandomized cohort study of 16 patients later that year, twice-daily application of tofacitinib cream 2% on facial and nonfacial vitiligo lesions resulted in partial repigmentation in 81.3% of patients: 4 (25%) achieved greater than 90% improvement, 5 (31.3%) achieved improvement of 25% to 75%, and 4 (25%) achieved 5% to 15% improvement.¹¹ The researchers also found that tofacitinib cream 2% was significantly more effective in facial than nonfacial lesions (P=.02).

While tofacitinib has shown promise in early studies, recent advancements have led to US Food and Drug Administration approval of ruxolitinib cream 1.5%, another topical JAK inhibitor that has undergone robust clinical testing for vitiligo.^12-14 Ruxolitinib, a JAK1, JAK2, and JAK3 inhibitor, is the first and only US Food and Drug Administration–approved topical JAK inhibitor for vitiligo.^14,15 Two phase 3, double-blind, vehicle-controlled trials of identical design conducted across 101 centers in North America and Europe (TRuE-V1 and TRuE-V2) assessed the efficacy of ruxolitinib cream 1.5% in 674 patients aged 12 years and older with nonsegmental vitiligo covering 10% or lower total BSA.¹³ In both trials, twice-daily application of topical ruxolitinib resulted in greater facial repigmentation and improvement in F-VASI75 score (ie, a reduction of at least 75% from baseline) at 24 weeks in 29.9% (66/221) and 30.1% (69/222) of patients in TRuE-V1 and TRuE-V2, respectively. Continued application through 52 weeks resulted in F-VASI75 response in 52.6% (91/173) and 48.0% (85/177) of patients in TRuE-V1 and TRuE-V2, respectively. The most frequently reported adverse events were acne (6.3% [14/221] and 6.6% [15/228]), nasopharyngitis (5.4% [12/221] and 6.1% [14/228]), and pruritus (5.4% [12/221] and 5.3% [12/228]). These findings align with prior subgroup analyses of an earlier phase 2 double- blind RCT of ruxolitinib cream 1.5% that indicated similar improvement in vitiligo among patients with differing skin tones.¹⁷

There are no additional large-scale RCTs examining topical JAK inhibitors with intentional subanalysis of diverse skin tones.^16,17,18 Studies examining topical JAK inhibitors have expanded to be more inclusive, providing hope for the future of topical vitiligo therapeutics for all patients.

Final Thoughts

It is imperative to increase racial/ethnic and skin type diversity in research on JAK inhibitors for vitiligo. While the studies mentioned here are inclusive of an array of races and skin tones, it is crucial that future research continue to expand the number of diverse participants, especially given the increased psychosocial burdens of vitiligo in patients with darker skin types.⁴ Intentional subgroup analyses across skin tones are vital to characterize and unmask potential differences between lighter and darker skin types. This point was exemplified by a 2024 RCT that investigated ritlecitinib efficacy with biomarker analysis across skin types.¹⁹ For patients receiving ritlecitinib 50 mg, IL-9 and IL-22 expression were decreased in darker vs lighter skin tones (P<.05). This intentional and inclusive analysis revealed a potential immunologic mechanism for why darker skin tones respond to JAK inhibitor therapy earlier than lighter skin tones.¹⁹

In the expanding landscape of oral and topical JAK inhibitors for vitiligo, continued efforts to assess these therapies across a range of skin tones and racial/ ethnic groups are critical. The efficacy of JAK inhibitors in other populations, including pediatric patients and patients with refractory segmental disease, have been reported.^20,21 As larger studies are developed based on the success of individual cases, researchers should investigate the efficacy of JAK inhibitors for various vitiligo subtypes (eg, segmental, nonsegmental) and recalcitrant disease and conduct direct comparisons with traditional treatments across diverse skin tones and racial/ethnic subgroup analyses to ensure broad therapeutic applicability.

Vitiligo is a common autoimmune disorder characterized by cutaneous depigmentation that has a substantial impact on patient quality of life.¹ Vitiligo affects approximately 28.5 million individuals globally, with the highest lifetime prevalence occurring in Central Europe and South Asia.² In the United States, Asian American and Hispanic/Latine populations most commonly are affected.³ The accompanying psychosocial burdens of vitiligo are particularly substantial among individuals with darker skin types, as evidenced by higher rates of concomitant anxiety and depression in these patients.⁴ Despite this, patients with skin of color are underrepresented in vitiligo research.²

Treatment algorithms developed based on worldwide expert consensus recommendations provide valuable insights into the management of segmental and nonsegmental vitiligo.⁵ The mainstay therapeutics include topical and oral corticosteroids, topical calcineurin inhibitors, and phototherapy. While vitiligo pathogenesis is not completely understood, recent advances have focused on the role of the Janus kinase (JAK)/signal transducer and activator of transcription pathway. Interferon gamma drives vitiligo pathogenesis through this pathway, upregulating C-X-C motif chemokine ligand 10 and promoting CD8+ T-cell recruitment, resulting in targeted melanocyte destruction.⁶ The emergence of targeted therapeutics may address equity and inclusion gaps. Herein, we highlight innovations in vitiligo treatment with a focus on oral and topical JAK inhibitors.

Oral JAK Inhibitors for Vitiligo

The therapeutic potential of JAK inhibitors for vitiligo was first reported when patients with alopecia areata and comorbid vitiligo experienced repigmentation of the skin following administration of oral ruxolitinib.⁷ Since this discovery, other oral JAK inhibitors have been investigated for vitiligo treatment. A phase 2b randomized clinical trial (RCT) of 364 patients examined oral ritlecitinib, a JAK3 inhibitor, and found it to be effective in treating active nonsegmental vitiligo.⁸ Patients aged 18 to 65 years with active nonsegmental vitiligo that had been present for 3 months or more as well as 4% to 50% body surface area (BSA) affected excluding acral surfaces and at least 0.25% facial involvement were included. Treatment groups received 50 mg (with or without a 100- or 200- mg loading dose), 30 mg, or 10 mg daily for 24 weeks. The primary endpoint measured the percentage change in Facial Vitiligo Area Scoring Index (F-VASI) score. Significant differences in F-VASI percentage change compared with placebo occurred for those in the 50-mg group who received a loading dose (-21.2 vs 2.1 [P<.001]) and those who did not receive a loading dose (–18.5 vs 2.1 [P<.001]) as well as the 30-mg group (-14.6 vs 2.1 [P=.01]). Continued repigmentation of the skin was observed in the 24-week extension period, indicating that longer treatment periods may be necessary for optimal repigmentation results. Ritlecitinib generally was well tolerated, and the most common treatment-emergent adverse events were nasopharyngitis (15.9%), upper respiratory tract infection (11.5%), and headache (8.8%). Most patients identified as White (67.6%), with 23.6% identifying as Asian and 2.7% identifying as Black. The authors stated that continued improvement was observed in the extension period across all skin types; however, the data were not reported.⁸

Upadacitnib, an oral selective JAK1 inhibitor, also has demonstrated efficacy in nonsegmental vitiligo in a phase 2 RCT.⁹ Adult patients (N=185) with nonsegmental vitiligo were randomized to receive upadacitinib 6 mg, 11 mg, or 22 mg or placebo (the placebo group subsequently was switched to upadacitinib 11 mg or 22 mg after 24 weeks). The primary endpoint measured the percentage change in F-VASI score at 24 weeks. The higher doses of upadacitinib resulted in significant changes in F-VASI scored compared with placebo (6 mg: -7.60 [95% CI, -22.18 to 6.97][P=.30]; 11 mg: -21.27 [95% CI, -36.02 to -6.52][P=.01]; 22 mg: -19.60 [95% CI, -35.04 to –4.16][P=.01]). As with ritlecitinib, continued repigmentation was observed beyond the initial 24-week period. Of the 185 participants, 5.9% identified as Black and 13.5% identified as Asian. The investigators reported that the percentage change in F-VASI score was consistent across skin types.⁹ The results of these phase 2 RCTs are encouraging, and we anticipate the findings of 2 phase 3 RCTs for ritlecitinib and upadacitinib that currently are underway (Clinicaltrials.gov identifiers NCT05583526 and NCT06118411).

Topical JAK Inhibitors for Vitiligo

Tofacitinib cream 2%, a selective JAK3 inhibitor, has shown therapeutic potential for treatment of vitiligo. One of the earliest pilot studies on topical tofacitinib examined the efficacy of tofacitinib cream 2% applied twice daily combined with narrowband UVB therapy 3 times weekly for facial vitiligo. The investigators reported repigmentation of the skin in all 11 patients (which included 4 Asian patients and 1 Hispanic patient), with a mean improvement of 70% in F-VASI score (range, 50%-87%).¹⁰ In a nonrandomized cohort study of 16 patients later that year, twice-daily application of tofacitinib cream 2% on facial and nonfacial vitiligo lesions resulted in partial repigmentation in 81.3% of patients: 4 (25%) achieved greater than 90% improvement, 5 (31.3%) achieved improvement of 25% to 75%, and 4 (25%) achieved 5% to 15% improvement.¹¹ The researchers also found that tofacitinib cream 2% was significantly more effective in facial than nonfacial lesions (P=.02).

While tofacitinib has shown promise in early studies, recent advancements have led to US Food and Drug Administration approval of ruxolitinib cream 1.5%, another topical JAK inhibitor that has undergone robust clinical testing for vitiligo.^12-14 Ruxolitinib, a JAK1, JAK2, and JAK3 inhibitor, is the first and only US Food and Drug Administration–approved topical JAK inhibitor for vitiligo.^14,15 Two phase 3, double-blind, vehicle-controlled trials of identical design conducted across 101 centers in North America and Europe (TRuE-V1 and TRuE-V2) assessed the efficacy of ruxolitinib cream 1.5% in 674 patients aged 12 years and older with nonsegmental vitiligo covering 10% or lower total BSA.¹³ In both trials, twice-daily application of topical ruxolitinib resulted in greater facial repigmentation and improvement in F-VASI75 score (ie, a reduction of at least 75% from baseline) at 24 weeks in 29.9% (66/221) and 30.1% (69/222) of patients in TRuE-V1 and TRuE-V2, respectively. Continued application through 52 weeks resulted in F-VASI75 response in 52.6% (91/173) and 48.0% (85/177) of patients in TRuE-V1 and TRuE-V2, respectively. The most frequently reported adverse events were acne (6.3% [14/221] and 6.6% [15/228]), nasopharyngitis (5.4% [12/221] and 6.1% [14/228]), and pruritus (5.4% [12/221] and 5.3% [12/228]). These findings align with prior subgroup analyses of an earlier phase 2 double- blind RCT of ruxolitinib cream 1.5% that indicated similar improvement in vitiligo among patients with differing skin tones.¹⁷

There are no additional large-scale RCTs examining topical JAK inhibitors with intentional subanalysis of diverse skin tones.^16,17,18 Studies examining topical JAK inhibitors have expanded to be more inclusive, providing hope for the future of topical vitiligo therapeutics for all patients.

Final Thoughts

It is imperative to increase racial/ethnic and skin type diversity in research on JAK inhibitors for vitiligo. While the studies mentioned here are inclusive of an array of races and skin tones, it is crucial that future research continue to expand the number of diverse participants, especially given the increased psychosocial burdens of vitiligo in patients with darker skin types.⁴ Intentional subgroup analyses across skin tones are vital to characterize and unmask potential differences between lighter and darker skin types. This point was exemplified by a 2024 RCT that investigated ritlecitinib efficacy with biomarker analysis across skin types.¹⁹ For patients receiving ritlecitinib 50 mg, IL-9 and IL-22 expression were decreased in darker vs lighter skin tones (P<.05). This intentional and inclusive analysis revealed a potential immunologic mechanism for why darker skin tones respond to JAK inhibitor therapy earlier than lighter skin tones.¹⁹

In the expanding landscape of oral and topical JAK inhibitors for vitiligo, continued efforts to assess these therapies across a range of skin tones and racial/ ethnic groups are critical. The efficacy of JAK inhibitors in other populations, including pediatric patients and patients with refractory segmental disease, have been reported.^20,21 As larger studies are developed based on the success of individual cases, researchers should investigate the efficacy of JAK inhibitors for various vitiligo subtypes (eg, segmental, nonsegmental) and recalcitrant disease and conduct direct comparisons with traditional treatments across diverse skin tones and racial/ethnic subgroup analyses to ensure broad therapeutic applicability.

THE DIAGNOSIS: Poroma

Poromas are benign adnexal neoplasms that often are classified into the broader category of acrospiromas. They most commonly affect areas with a high density of eccrine sweat glands, such as the palms and soles, but also can appear in any area of the body with sweat glands.¹ Poromas may have cuboidal eccrine cells with ovoid nuclei and a delicate vascularized stroma on histology or may show apocrinelike features with sebaceous cells.^2,3 Immunohistochemically, poromas stain positively for carcinoembryonic antigen, epithelial membrane antigen, and periodic acid–Schiff (PAS) with diastase sensitivity.^1,4 Cytokeratin (CK) 1 and CK-10 are expressed in the tumor nests.¹

Poromas are the benign counterpart of porocarcinomas, which can recur and may become invasive and metastasize. Porocarcinomas have been shown to undergo malignant transformation from poromas as well as develop de novo.⁵ Histologic differentiation between the 2 conditions is key in determining excisional margins for treatment and follow-up. Poromas are histologically similar to porocarcinomas, but the latter show invasion into the dermis, nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and increased mitotic activity.⁶ S-100 protein can be positive in porocarcinoma.⁷ Both poromas and porocarcinomas are associated with Yes-associated protein 1 (YAP1), Mastermind-like protein 2 (MAML2), and NUT midline carcinoma family member 1 (NUTM1) gene fusions.⁵

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. It rarely metastasizes but can be locally destructive.⁸ Basal cell carcinomas typically occur on sun-exposed skin in middle-aged and elderly patients and classically manifest as pink or flesh-colored pearly papules with rolled borders and overlying telangiectasia.⁹ Risk factors for BCC include a chronic sun exposure, lighter skin phenotypes, immunosuppression, and a family history of skin cancer. The 2 most common subtypes of BCC are nodular and superficial, which comprise around 85% of BCCs.¹⁰ Histologically, nodular BCCs demonstrate nests of malignant basaloid cells with central disorganization, peripheral palisading, tumor-stroma clefting, and a mucoid stroma with spindle cells (Figure 1). Superficial BCC manifests with small islands of malignant basaloid cells with peripheral palisading that connect with the epidermis, often with a lichenoid inflammatory infiltrate.⁹ Basal cell carcinomas stain positively for Ber-EP4 and are associated with patched 1 (PTCH1), patched 2 (PTCH2), and tumor protein 53 (TP53) gene mutations.^9,11

Spiradenomas are benign adnexal tumors manifesting as painful, usually singular, 1- to 3-cm nodules in younger adults.¹² Histologically, spiradenomas have large clusters of small irregularly shaped aggregations of small basaloid and large polygonal cells with surrounding hyalinized basement membrane material and intratumoral lymphocytes (Figure 2).⁴ Spiradenomas stain positive for p63, D2-40, and CK7 and are associated with cylindromatosis lysine 63 deubiquitinase (CYLD) and alpha-protein kinase 1 (ALPK1) gene mutations.⁵

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer worldwide.¹³ Lesions typically develop on sun-exposed skin and manifest as red, hyperkeratotic, and sometimes ulcerated plaques or nodules.¹⁴ Risk factors for SCC include chronic sun exposure, lighter skin phenotypes, increased age, and immunosuppression. Histologically, there are several variants of SCC: low-risk variants include keratoacanthomas, verrucous carcinomas, and clear cell SCC, and high-risk variants include acantholytic SCC, spindle cell SCC, and adenosquamous carcinoma.¹⁴ Generally, low-grade SCC will have well-differentiated or moderately differentiated intercellular bridges or keratin pearls with tumor cells in a solid or sheetlike pattern (Figure 3). High-grade SCC will be poorly differentiated with the presence of infiltrating individual tumor cells.¹⁵ Immunohistochemically, SCC stains positive for p63, p40, AE1/AE3, CK5/6, and MNF116 while Ber-Ep4 is negative.^14,15 Poorly differentiated SCCs have high rates of mutation, commonly in the tumor protein 53 (TP53), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras pathway, and notch receptor 1 (NOTCH-1) genes.¹³

Syringomas are benign adnexal tumors that manifest as multiple soft, yellow to flesh-colored, 1- to 2-mm papules typically located on the lower eyelids, most commonly in women of reproductive age.¹⁶ Syringomas are described on histology as small comma-shaped nests with cords of eosinophilic to clear cells with central ducts surrounded by a sclerotic stroma (Figure 4). They stain positively for carcinoembryonic antigen, epithelial membrane antigen, and CK-5 and are associated with genetic mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT serine/threonine kinase 1 (ATK1).⁴

Due to its regular exposure to sunlight, the eyelid accounts for 5% to 10% of all skin malignancies. Common eyelid lesions include squamous papilloma, seborrheic keratosis, epidermal inclusion cyst, hidrocystoma, intradermal nevus, BCC, SCC, and sebaceous carcinoma.¹⁷ Aside from syringomas, benign sweat gland tumors like poromas, hidradenomas, and spiradenomas usually do not manifest on the eyelids but should be included in the differential diagnosis of an unidentifiable lesion due to the small risk for malignant transformation. Eyelid poromas manifest polymorphically, most commonly being clinically diagnosed as BCC, making the histologic examination key for proper diagnosis and management.¹⁸

THE DIAGNOSIS: Poroma

Poromas are benign adnexal neoplasms that often are classified into the broader category of acrospiromas. They most commonly affect areas with a high density of eccrine sweat glands, such as the palms and soles, but also can appear in any area of the body with sweat glands.¹ Poromas may have cuboidal eccrine cells with ovoid nuclei and a delicate vascularized stroma on histology or may show apocrinelike features with sebaceous cells.^2,3 Immunohistochemically, poromas stain positively for carcinoembryonic antigen, epithelial membrane antigen, and periodic acid–Schiff (PAS) with diastase sensitivity.^1,4 Cytokeratin (CK) 1 and CK-10 are expressed in the tumor nests.¹

Poromas are the benign counterpart of porocarcinomas, which can recur and may become invasive and metastasize. Porocarcinomas have been shown to undergo malignant transformation from poromas as well as develop de novo.⁵ Histologic differentiation between the 2 conditions is key in determining excisional margins for treatment and follow-up. Poromas are histologically similar to porocarcinomas, but the latter show invasion into the dermis, nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and increased mitotic activity.⁶ S-100 protein can be positive in porocarcinoma.⁷ Both poromas and porocarcinomas are associated with Yes-associated protein 1 (YAP1), Mastermind-like protein 2 (MAML2), and NUT midline carcinoma family member 1 (NUTM1) gene fusions.⁵

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. It rarely metastasizes but can be locally destructive.⁸ Basal cell carcinomas typically occur on sun-exposed skin in middle-aged and elderly patients and classically manifest as pink or flesh-colored pearly papules with rolled borders and overlying telangiectasia.⁹ Risk factors for BCC include a chronic sun exposure, lighter skin phenotypes, immunosuppression, and a family history of skin cancer. The 2 most common subtypes of BCC are nodular and superficial, which comprise around 85% of BCCs.¹⁰ Histologically, nodular BCCs demonstrate nests of malignant basaloid cells with central disorganization, peripheral palisading, tumor-stroma clefting, and a mucoid stroma with spindle cells (Figure 1). Superficial BCC manifests with small islands of malignant basaloid cells with peripheral palisading that connect with the epidermis, often with a lichenoid inflammatory infiltrate.⁹ Basal cell carcinomas stain positively for Ber-EP4 and are associated with patched 1 (PTCH1), patched 2 (PTCH2), and tumor protein 53 (TP53) gene mutations.^9,11

Spiradenomas are benign adnexal tumors manifesting as painful, usually singular, 1- to 3-cm nodules in younger adults.¹² Histologically, spiradenomas have large clusters of small irregularly shaped aggregations of small basaloid and large polygonal cells with surrounding hyalinized basement membrane material and intratumoral lymphocytes (Figure 2).⁴ Spiradenomas stain positive for p63, D2-40, and CK7 and are associated with cylindromatosis lysine 63 deubiquitinase (CYLD) and alpha-protein kinase 1 (ALPK1) gene mutations.⁵

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer worldwide.¹³ Lesions typically develop on sun-exposed skin and manifest as red, hyperkeratotic, and sometimes ulcerated plaques or nodules.¹⁴ Risk factors for SCC include chronic sun exposure, lighter skin phenotypes, increased age, and immunosuppression. Histologically, there are several variants of SCC: low-risk variants include keratoacanthomas, verrucous carcinomas, and clear cell SCC, and high-risk variants include acantholytic SCC, spindle cell SCC, and adenosquamous carcinoma.¹⁴ Generally, low-grade SCC will have well-differentiated or moderately differentiated intercellular bridges or keratin pearls with tumor cells in a solid or sheetlike pattern (Figure 3). High-grade SCC will be poorly differentiated with the presence of infiltrating individual tumor cells.¹⁵ Immunohistochemically, SCC stains positive for p63, p40, AE1/AE3, CK5/6, and MNF116 while Ber-Ep4 is negative.^14,15 Poorly differentiated SCCs have high rates of mutation, commonly in the tumor protein 53 (TP53), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras pathway, and notch receptor 1 (NOTCH-1) genes.¹³

Syringomas are benign adnexal tumors that manifest as multiple soft, yellow to flesh-colored, 1- to 2-mm papules typically located on the lower eyelids, most commonly in women of reproductive age.¹⁶ Syringomas are described on histology as small comma-shaped nests with cords of eosinophilic to clear cells with central ducts surrounded by a sclerotic stroma (Figure 4). They stain positively for carcinoembryonic antigen, epithelial membrane antigen, and CK-5 and are associated with genetic mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT serine/threonine kinase 1 (ATK1).⁴

Due to its regular exposure to sunlight, the eyelid accounts for 5% to 10% of all skin malignancies. Common eyelid lesions include squamous papilloma, seborrheic keratosis, epidermal inclusion cyst, hidrocystoma, intradermal nevus, BCC, SCC, and sebaceous carcinoma.¹⁷ Aside from syringomas, benign sweat gland tumors like poromas, hidradenomas, and spiradenomas usually do not manifest on the eyelids but should be included in the differential diagnosis of an unidentifiable lesion due to the small risk for malignant transformation. Eyelid poromas manifest polymorphically, most commonly being clinically diagnosed as BCC, making the histologic examination key for proper diagnosis and management.¹⁸

THE DIAGNOSIS: Poroma

Poromas are benign adnexal neoplasms that often are classified into the broader category of acrospiromas. They most commonly affect areas with a high density of eccrine sweat glands, such as the palms and soles, but also can appear in any area of the body with sweat glands.¹ Poromas may have cuboidal eccrine cells with ovoid nuclei and a delicate vascularized stroma on histology or may show apocrinelike features with sebaceous cells.^2,3 Immunohistochemically, poromas stain positively for carcinoembryonic antigen, epithelial membrane antigen, and periodic acid–Schiff (PAS) with diastase sensitivity.^1,4 Cytokeratin (CK) 1 and CK-10 are expressed in the tumor nests.¹

Poromas are the benign counterpart of porocarcinomas, which can recur and may become invasive and metastasize. Porocarcinomas have been shown to undergo malignant transformation from poromas as well as develop de novo.⁵ Histologic differentiation between the 2 conditions is key in determining excisional margins for treatment and follow-up. Poromas are histologically similar to porocarcinomas, but the latter show invasion into the dermis, nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and increased mitotic activity.⁶ S-100 protein can be positive in porocarcinoma.⁷ Both poromas and porocarcinomas are associated with Yes-associated protein 1 (YAP1), Mastermind-like protein 2 (MAML2), and NUT midline carcinoma family member 1 (NUTM1) gene fusions.⁵

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. It rarely metastasizes but can be locally destructive.⁸ Basal cell carcinomas typically occur on sun-exposed skin in middle-aged and elderly patients and classically manifest as pink or flesh-colored pearly papules with rolled borders and overlying telangiectasia.⁹ Risk factors for BCC include a chronic sun exposure, lighter skin phenotypes, immunosuppression, and a family history of skin cancer. The 2 most common subtypes of BCC are nodular and superficial, which comprise around 85% of BCCs.¹⁰ Histologically, nodular BCCs demonstrate nests of malignant basaloid cells with central disorganization, peripheral palisading, tumor-stroma clefting, and a mucoid stroma with spindle cells (Figure 1). Superficial BCC manifests with small islands of malignant basaloid cells with peripheral palisading that connect with the epidermis, often with a lichenoid inflammatory infiltrate.⁹ Basal cell carcinomas stain positively for Ber-EP4 and are associated with patched 1 (PTCH1), patched 2 (PTCH2), and tumor protein 53 (TP53) gene mutations.^9,11

Spiradenomas are benign adnexal tumors manifesting as painful, usually singular, 1- to 3-cm nodules in younger adults.¹² Histologically, spiradenomas have large clusters of small irregularly shaped aggregations of small basaloid and large polygonal cells with surrounding hyalinized basement membrane material and intratumoral lymphocytes (Figure 2).⁴ Spiradenomas stain positive for p63, D2-40, and CK7 and are associated with cylindromatosis lysine 63 deubiquitinase (CYLD) and alpha-protein kinase 1 (ALPK1) gene mutations.⁵

Squamous cell carcinoma (SCC) is the second most common nonmelanoma skin cancer worldwide.¹³ Lesions typically develop on sun-exposed skin and manifest as red, hyperkeratotic, and sometimes ulcerated plaques or nodules.¹⁴ Risk factors for SCC include chronic sun exposure, lighter skin phenotypes, increased age, and immunosuppression. Histologically, there are several variants of SCC: low-risk variants include keratoacanthomas, verrucous carcinomas, and clear cell SCC, and high-risk variants include acantholytic SCC, spindle cell SCC, and adenosquamous carcinoma.¹⁴ Generally, low-grade SCC will have well-differentiated or moderately differentiated intercellular bridges or keratin pearls with tumor cells in a solid or sheetlike pattern (Figure 3). High-grade SCC will be poorly differentiated with the presence of infiltrating individual tumor cells.¹⁵ Immunohistochemically, SCC stains positive for p63, p40, AE1/AE3, CK5/6, and MNF116 while Ber-Ep4 is negative.^14,15 Poorly differentiated SCCs have high rates of mutation, commonly in the tumor protein 53 (TP53), Cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras pathway, and notch receptor 1 (NOTCH-1) genes.¹³

Syringomas are benign adnexal tumors that manifest as multiple soft, yellow to flesh-colored, 1- to 2-mm papules typically located on the lower eyelids, most commonly in women of reproductive age.¹⁶ Syringomas are described on histology as small comma-shaped nests with cords of eosinophilic to clear cells with central ducts surrounded by a sclerotic stroma (Figure 4). They stain positively for carcinoembryonic antigen, epithelial membrane antigen, and CK-5 and are associated with genetic mutations in phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AKT serine/threonine kinase 1 (ATK1).⁴

Due to its regular exposure to sunlight, the eyelid accounts for 5% to 10% of all skin malignancies. Common eyelid lesions include squamous papilloma, seborrheic keratosis, epidermal inclusion cyst, hidrocystoma, intradermal nevus, BCC, SCC, and sebaceous carcinoma.¹⁷ Aside from syringomas, benign sweat gland tumors like poromas, hidradenomas, and spiradenomas usually do not manifest on the eyelids but should be included in the differential diagnosis of an unidentifiable lesion due to the small risk for malignant transformation. Eyelid poromas manifest polymorphically, most commonly being clinically diagnosed as BCC, making the histologic examination key for proper diagnosis and management.¹⁸