Contact Dermatitis

Cutaneous Manifestations

Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.¹Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).

In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.² In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.³ Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.³

Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.

Cultural Considerations

In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.⁴ Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.⁵ Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.⁴

Clinical Presentation

“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.⁶ Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.² A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”⁷

Plant Facts

There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey⁸; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.

Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.

History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.

In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.

More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.

Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.⁹

Identifying Features

At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.¹⁰

Tulip Allergen

Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.⁶ So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.¹¹ With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.

Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.¹² The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.¹³

The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.¹⁴ Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.¹⁵

Symptoms of an allergic response to tulipalin A can be immediate or delayed.¹⁴ The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.¹⁴

The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.⁷

A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.^7,16

Prevention of Tulipa Dermatitis

Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.¹

Cutaneous Manifestations

Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.¹Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).

In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.² In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.³ Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.³

Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.

Cultural Considerations

In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.⁴ Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.⁵ Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.⁴

Clinical Presentation

“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.⁶ Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.² A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”⁷

Plant Facts

There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey⁸; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.

Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.

History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.

In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.

More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.

Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.⁹

Identifying Features

At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.¹⁰

Tulip Allergen

Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.⁶ So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.¹¹ With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.

Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.¹² The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.¹³

The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.¹⁴ Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.¹⁵

Symptoms of an allergic response to tulipalin A can be immediate or delayed.¹⁴ The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.¹⁴

The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.⁷

A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.^7,16

Prevention of Tulipa Dermatitis

Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.¹

Cutaneous Manifestations

Contact dermatitis is a common problem for individuals who work in the floral industry. Hand dermatitis has been reported in as many as 26% of floral employees.¹Tulipa species have been identified as one of the most common causes of hand dermatitis. Tulipalin A (α-methylene-γ-butyrolactone) is the main sensitizer in tulips (Figure 1) and its precursor tuliposide A also occurs both in tulips and the Peruvian lily (Alstroemeria).

In a 1996 study, 18% (9/51) of tulip workers were found to be allergic to tulipalin A.² In a more recent study of 164 tulip workers, 48 (29.3%) had clinical evidence of contact dermatitis and subsequently underwent patch testing; 17 (35.4%) showed a positive reaction to either tulipalin A or to tulip-bulb extract.³ Itching was the most common symptom (39 workers [81.3%]) and hand eczema at the tip of the thumb and index finger was the most common finding. In 9 (18.8%) workers, eczema had spread to other body parts including the forearm, face, legs, and abdomen.³

Peruvian lily is widely used in floral arrangements and has become a leading cause of hand dermatitis in florists (Figure 2). Large amounts of free tulipalin A are present in bulb scales of tulips, along with a small amount of tuliposide A. In young developing shoots, the situation is reversed: Both compounds are found in all parts of the plant to some degree, though tulipalin A is the major allergen, and more mature parts of the plant and bulb are most allergenic.

Cultural Considerations

In traditional Kurdish cuisine, raw herbs are part of snacking or are served as a side dish (sawza). Snacks often are consumed raw on the spot. Tulipa montana, Tulipa armena, and possibly other Tulipa species are consumed as a snack.⁴ Traditionally, Tulipa systola is consumed by the Kurds as an anti-inflammatory medicine and for pain relief. It also has been proposed that T systola has antioxidant properties.⁵ Cooked tulip also has been consumed in time of famine in Europe, though none of these dietary practices are recommended.⁴

Clinical Presentation

“Tulip fingers” describes the most common presentation of contact dermatitis caused by tulip bulbs. Erythematous scaling plaques are seen in the periungual skin and first and second fingertips of the dominant hand. Other manifestations include diffuse dry dermatitis of the hand; paronychia; pulpitis; and secondary spread to the face, neck, arms, and genitalia, with eczematous papules and plaques.⁶ Clinical signs include erythema, vesicles, hyperkeratosis, and exfoliation of the fingertips. The allergen also can cause airborne contact dermatitis and manifest as conjunctivitis, rhinitis, and asthma.² A considerable number of tulip workers develop paresthesia and tenderness in the fingertips within several hours after working with tulip bulbs, known as “tulip fire.”⁷

Plant Facts

There are approximately 250 genera of bulbous plants. Tulips are members of the genus Tulipa and family Liliaceae. Tulips often are thought of as native to southwest central Asia and Turkey⁸; however, Tulipa sylvestris is native to Portugal, Spain, and North Africa.

Etymology and Symbolism—The word tulip is derived from the Turkish word türbent meaning a turban, possibly because the flower is compared to turbans worn by men of the Ottoman Empire in the 16th century. In Turkish culture, the tulip is a symbol of paradise on earth and can have divine status. In the Netherlands, on the other hand, the tulip represents the briefness of life.

History—By 1562, tulip bulbs had already been introduced to Holland by merchants. However, the first shipment of tulip bulbs was mistaken by the Dutch for onions and were either roasted over a fire or perished when planted in gardens with vegetables. Carolus Clusius—botanist, director of the imperial medical garden in Vienna and recipient of many plants through diplomatic channels—was particularly fond of flower bulbs and contributed to the popularity of the tulip in Europe by sending bulbs and seeds to other European countries.

In the early 17th century, the tulip craze began in France, fueled by a viral disease of tulips that produced variegated color patterns on the petals; entire properties were sold in exchange for a single tulip bulb. The tulip craze drifted from France to Holland in 1634 for 3 years before the tulip market collapsed.

More recently, in 2003 investors started a multimillion-euro tulip fund in the Netherlands to develop new varieties of tulip. Tulip bulbs were used to create money with high percentages over the selling price. With exorbitant pricing and ever-changing ownership of bulbs—bulbs were bought and sold as many as 10 times—the tulip fund collapsed 1 year later and investors lost their money. Bulb speculators then took their profit abroad. In 2006, bulb owners were charged with fraud; the tulip craze often is cited as one of the early major stock market collapses.

Tulips continue to grow in popularity. Today, nearly 6000 cultivars are registered, with 40 new cultivars registered every 5 years.⁹

Identifying Features

At the base of the erect tulip plant is a cluster of 2 or 3 thick bluish-green leaves. Three petals and 3 sepals make up the solitary bell-shaped flower. Many tulips can propagate only by means of their scaly bulbs. The flowers arise from the tips of stems in different solid colors, except true blue—from pure white to all shades of yellow, red, and a deep purple that is almost black. Solid-color tulips are called “self-colored.” So-called broken tulips are individual flowers with multiple colors, a condition caused by a viral disease transmitted by aphids.¹⁰

Tulip Allergen

Tuliposide A is found in many species of the genera Tulipa, Alstroemeria, and Erythronium.⁶ So far, 7 analogs have been identified: 1-tuliposide A and B; 6-tuliposide A and B; and tuliposides D, E, and F. 6-Tuliposide A and B are the principal tuliposides found in tulip cultivars.¹¹ With trauma and maturation, tuliposides A and B are hydrolyzed to tulipalin A and tulipalin B, respectively.

Tulipalin A and tulipalin B have antimicrobial properties against bacteria and fungi; tulipalin A is mostly an antifungal agent, and tulipalin B has mostly bacteriostatic characteristics.¹² The highest concentration of tulipalin A is found in the outer layer of the bulb, followed by (in descending order) the stem, leaves, and petals.¹³

The prevalence of tulipalin A allergy led the German Federal Institute for Risk Assessment to assign tuliposide A and tulipalin A to category B, which is a “solid-based indication for contact allergenic effects”; both chemicals also are considered skin sensitizers, defined by the Globally Harmonized System of Classification and Labelling of Chemicals of the United Nations as a substance that will induce an allergic response following skin contact.¹⁴ Patients who are allergic to tulips have cross-sensitivity to Alstroemeria because tuliposide A and its metabolites are found in both plants.¹⁵

Symptoms of an allergic response to tulipalin A can be immediate or delayed.¹⁴ The most common allergic contact dermatitis caused by tulip bulbs is type IV hypersensitivity, though type I reactions can occur. Symptoms of a type I reaction including contact urticaria, rhinitis, hoarseness, and dyspnea have been reported.¹⁴

The variety of tulip handled also contributes to the severity of dermatitis. Handling bulbs of Rose Copeland variety tulips and cutting the flowers of Preludium tulips have been associated with more severe allergic dermatitis presentations, whereas the Red Emperor tulip was found to have less tuliposide A and thus provoke a weaker patch-test reaction.⁷

A Word About Garlic—Garlic is in the subfamily Allioideae (formerly Alliaceae) taxonomically related to the tulip family (Liliaceae). Garlic also can cause hand dermatitis in cooks, with a similar clinical appearance as tulip fingers. Gas chromatography has shown that garlic contains predominantly tuliposide B, which has been found to be much less allergenic than tuliposide A.^7,16

Prevention of Tulipa Dermatitis

Tuliposide A and its metabolites can be found in storehouses and trucks used to transport tulips, in clothing, and in any other place where dust containing the allergen has settled. The best prevention against contact dermatitis is to avoid the inciting plants. Gloves may prevent contact dermatitis due to tuliposide A, which penetrates vinyl but not nitrile gloves. Barrier creams have been proposed, but data are scant.¹

PORTLAND, ORE. – When patients present to Brandon L. Adler, MD, with dermatitis on the eyelid, face, or neck, he routinely asks them if they apply essential oils on their skin, or if they have an essential oil diffuser or nebulizer in their home.

“The answer is frequently ‘yes,’ ” Dr. Adler, clinical assistant professor of dermatology at the University of Southern California, Los Angeles, said at the annual meeting of the Pacific Dermatologic Association. “Essential oils are widely used throughout the wellness industry. They are contained in personal care products, beauty products, natural cleaning products, and they’re being diffused by our patients into the air. More than 75 essential oils are reported to cause allergic contact dermatitis.”

yangna/iStock/Getty Images

Natural chemical components contained in essential oils can cause skin reactions, especially linalool and limonene. “Linalool is most classically associated with lavender, while limonene is associated with citrus, but they’re found in many different plants,” said Dr. Adler, who directs USC’s contact dermatitis clinic. “On their own, linalool and limonene are not particularly allergenic; they’re not a big deal in the patch test clinic. The problem comes when we add air to the mix, because they oxidize to hydroperoxides of linalool and limonene. These are quite potent allergens.”

According to the most recent North American Contact Dermatitis Group data, 8.9% of patients undergoing patch testing tested positive to linalool hydroperoxides and 2.6% were positive to limonene hydroperoxides.

Dr. Adler discussed the case of a female massage therapist who presented with refractory hand dermatitis and was on methotrexate and dupilumab at the time of consultation but was still symptomatic. She patch-tested positive to limonene and linalool hydroperoxides as well as multiple essential oils that she had been using with her clients, ranging from sacred frankincense oil to basil oil, and she was advised to massage using only coconut or vegetable oils.

Essential oil allergy may also be related to cannabis allergy. According to Dr. Adler, allergic contact dermatitis to cannabis has been rarely reported, but in an analysis of 103 commercial topical cannabinoid preparations that he published with Vincent DeLeo, MD, also with USC, 84% contained a NACDG allergen, frequently essential oils.

More recently, Dr. Adler and colleagues reported the case of a 40-year-old woman who was referred for patch testing for nummular dermatitis that wasn’t responding to treatment. The patient was found to be using topical cannabis and also grew cannabis at home. “She asked to be patch-tested to her homegrown cannabis and had a strong positive patch test to the cannabis, linalool and limonene hydroperoxides, and other essential oils,” Dr. Adler recalled. “We sent her cannabis sample for analysis at a commercial lab and found that it contained limonene and other allergenic terpene chemicals.

“We’re just starting to unravel what this means in terms of our patients and how to manage them, but many are using topical cannabis and topical CBD. I suspect this is a lot less rare than we realize.”

Another recent case from Europe reported allergic contact dermatitis to Cannabis sativa (hemp) seed oil following topical application, with positive patch testing.

Dr. Adler disclosed that he has received research grants from the American Contact Dermatitis Society. He is also an investigator for AbbVie and a consultant for the Skin Research Institute.

PORTLAND, ORE. – When patients present to Brandon L. Adler, MD, with dermatitis on the eyelid, face, or neck, he routinely asks them if they apply essential oils on their skin, or if they have an essential oil diffuser or nebulizer in their home.

“The answer is frequently ‘yes,’ ” Dr. Adler, clinical assistant professor of dermatology at the University of Southern California, Los Angeles, said at the annual meeting of the Pacific Dermatologic Association. “Essential oils are widely used throughout the wellness industry. They are contained in personal care products, beauty products, natural cleaning products, and they’re being diffused by our patients into the air. More than 75 essential oils are reported to cause allergic contact dermatitis.”

yangna/iStock/Getty Images

Natural chemical components contained in essential oils can cause skin reactions, especially linalool and limonene. “Linalool is most classically associated with lavender, while limonene is associated with citrus, but they’re found in many different plants,” said Dr. Adler, who directs USC’s contact dermatitis clinic. “On their own, linalool and limonene are not particularly allergenic; they’re not a big deal in the patch test clinic. The problem comes when we add air to the mix, because they oxidize to hydroperoxides of linalool and limonene. These are quite potent allergens.”

According to the most recent North American Contact Dermatitis Group data, 8.9% of patients undergoing patch testing tested positive to linalool hydroperoxides and 2.6% were positive to limonene hydroperoxides.

Dr. Adler discussed the case of a female massage therapist who presented with refractory hand dermatitis and was on methotrexate and dupilumab at the time of consultation but was still symptomatic. She patch-tested positive to limonene and linalool hydroperoxides as well as multiple essential oils that she had been using with her clients, ranging from sacred frankincense oil to basil oil, and she was advised to massage using only coconut or vegetable oils.

Essential oil allergy may also be related to cannabis allergy. According to Dr. Adler, allergic contact dermatitis to cannabis has been rarely reported, but in an analysis of 103 commercial topical cannabinoid preparations that he published with Vincent DeLeo, MD, also with USC, 84% contained a NACDG allergen, frequently essential oils.

More recently, Dr. Adler and colleagues reported the case of a 40-year-old woman who was referred for patch testing for nummular dermatitis that wasn’t responding to treatment. The patient was found to be using topical cannabis and also grew cannabis at home. “She asked to be patch-tested to her homegrown cannabis and had a strong positive patch test to the cannabis, linalool and limonene hydroperoxides, and other essential oils,” Dr. Adler recalled. “We sent her cannabis sample for analysis at a commercial lab and found that it contained limonene and other allergenic terpene chemicals.

“We’re just starting to unravel what this means in terms of our patients and how to manage them, but many are using topical cannabis and topical CBD. I suspect this is a lot less rare than we realize.”

Another recent case from Europe reported allergic contact dermatitis to Cannabis sativa (hemp) seed oil following topical application, with positive patch testing.

Dr. Adler disclosed that he has received research grants from the American Contact Dermatitis Society. He is also an investigator for AbbVie and a consultant for the Skin Research Institute.

PORTLAND, ORE. – When patients present to Brandon L. Adler, MD, with dermatitis on the eyelid, face, or neck, he routinely asks them if they apply essential oils on their skin, or if they have an essential oil diffuser or nebulizer in their home.

“The answer is frequently ‘yes,’ ” Dr. Adler, clinical assistant professor of dermatology at the University of Southern California, Los Angeles, said at the annual meeting of the Pacific Dermatologic Association. “Essential oils are widely used throughout the wellness industry. They are contained in personal care products, beauty products, natural cleaning products, and they’re being diffused by our patients into the air. More than 75 essential oils are reported to cause allergic contact dermatitis.”

yangna/iStock/Getty Images

Natural chemical components contained in essential oils can cause skin reactions, especially linalool and limonene. “Linalool is most classically associated with lavender, while limonene is associated with citrus, but they’re found in many different plants,” said Dr. Adler, who directs USC’s contact dermatitis clinic. “On their own, linalool and limonene are not particularly allergenic; they’re not a big deal in the patch test clinic. The problem comes when we add air to the mix, because they oxidize to hydroperoxides of linalool and limonene. These are quite potent allergens.”

According to the most recent North American Contact Dermatitis Group data, 8.9% of patients undergoing patch testing tested positive to linalool hydroperoxides and 2.6% were positive to limonene hydroperoxides.

Dr. Adler discussed the case of a female massage therapist who presented with refractory hand dermatitis and was on methotrexate and dupilumab at the time of consultation but was still symptomatic. She patch-tested positive to limonene and linalool hydroperoxides as well as multiple essential oils that she had been using with her clients, ranging from sacred frankincense oil to basil oil, and she was advised to massage using only coconut or vegetable oils.

Essential oil allergy may also be related to cannabis allergy. According to Dr. Adler, allergic contact dermatitis to cannabis has been rarely reported, but in an analysis of 103 commercial topical cannabinoid preparations that he published with Vincent DeLeo, MD, also with USC, 84% contained a NACDG allergen, frequently essential oils.

More recently, Dr. Adler and colleagues reported the case of a 40-year-old woman who was referred for patch testing for nummular dermatitis that wasn’t responding to treatment. The patient was found to be using topical cannabis and also grew cannabis at home. “She asked to be patch-tested to her homegrown cannabis and had a strong positive patch test to the cannabis, linalool and limonene hydroperoxides, and other essential oils,” Dr. Adler recalled. “We sent her cannabis sample for analysis at a commercial lab and found that it contained limonene and other allergenic terpene chemicals.

“We’re just starting to unravel what this means in terms of our patients and how to manage them, but many are using topical cannabis and topical CBD. I suspect this is a lot less rare than we realize.”

Another recent case from Europe reported allergic contact dermatitis to Cannabis sativa (hemp) seed oil following topical application, with positive patch testing.

Dr. Adler disclosed that he has received research grants from the American Contact Dermatitis Society. He is also an investigator for AbbVie and a consultant for the Skin Research Institute.

To the Editor:

Calcinosis cutis is a condition characterized by the deposition of insoluble calcium salts in the skin. Dystrophic calcinosis cutis is the most common type, occurring in previously traumatized skin in the absence of abnormal blood calcium levels. It commonly is seen in patients with connective tissue diseases and is thought to be precipitated by chronic inflammation and vascular hypoxia.¹ Herein, we describe a case of calcinosis cutis arising after treatment with subcutaneous glatiramer acetate, an agent that is effective for the treatment of relapsing-remitting multiple sclerosis (MS). Diagnostic workup and treatment modalities for calcinosis cutis in this patient population should be considered in the context of minimizing interruption or discontinuation of this disease-modifying agent.

A 53-year-old woman with a history of relapsing-remitting MS and systemic lupus erythematosus (SLE) presented with multiple firm asymptomatic subcutaneous nodules on the thighs of 1 year’s duration that were increasing in number. The involved areas were the injection sites of subcutaneous glatiramer acetate, an immunomodulator for the treatment of MS, which our patient self-administered 3 times weekly. Physical examination revealed multiple flesh-colored to white, firm, and nontender nodules on the thighs (Figure). There was no epidermal change, and she had no other skin involvement. A punch biopsy of one of the nodules revealed calcium deposits in collagen bundles of the deep dermis. Calcium, phosphorus, parathyroid hormone, and vitamin D levels were within reference range. She declined further treatment for the calcinosis cutis and opted to continue treatment with glatiramer acetate, as her MS was well controlled on this medication.

Glatiramer acetate is an immunogenic polypeptide injectable that is approved by the US Food and Drug Administration for the treatment of relapsing-remitting MS.² It is composed of synthetic polypeptides and contains 4 naturally occurring amino acids. Glatiramer acetate is administered subcutaneously as 20 mg/mL/d or 40 mg/mL 3 times weekly. Transient injection-site reactions are the most common cutaneous adverse events and include localized edema, induration, erythema, pain, and pruritus.³ There have been multiple reports of lobular panniculitis and skin necrosis as well as embolia cutis medicamentosa (Nicolau syndrome).^4,5 Our case of calcinosis cutis related to glatiramer acetate is unique. The mechanism of calcinosis cutis in our patient likely was dystrophic due to tissue damage, rather than due to the injection of a calcium-containing substance. Our patient’s history of SLE is a notable risk factor for the development of calcinosis cutis, likely incited by the trauma occurring with subcutaneous injections.⁶

The mainstay of treatment for localized calcinosis cutis in the setting of connective tissue disease is surgical excision as well as treatment of the underlying disorder. Potential therapies include calcium channel blockers, warfarin, bisphosphonates, intravenous immunoglobulin, minocycline, colchicine, anti–tumor necrosis factor agents, intralesional corticosteroids, intravenous sodium thiosulfate, and CO₂ laser.^1,6 Our patient was already on intravenous immunoglobulin for MS and hydroxychloroquine for SLE. In select cases where the patient is asymptomatic and prefers not to pursue treatment, no treatment is necessary.

Although calcinosis cutis may occur in SLE alone, it is uncommon and usually is seen in chronic severe SLE, where calcification usually occurs in the setting of pre-existing cutaneous lupus.⁴ This case report of calcinosis cutis following treatment with glatiramer acetate highlights some of the cutaneous side effects associated with glatiramer acetate injections and should prompt practitioners to consider dystrophic calcinosis cutis in patients requiring subcutaneous medications, particularly in those with pre-existing connective tissue disease.

To the Editor:

Calcinosis cutis is a condition characterized by the deposition of insoluble calcium salts in the skin. Dystrophic calcinosis cutis is the most common type, occurring in previously traumatized skin in the absence of abnormal blood calcium levels. It commonly is seen in patients with connective tissue diseases and is thought to be precipitated by chronic inflammation and vascular hypoxia.¹ Herein, we describe a case of calcinosis cutis arising after treatment with subcutaneous glatiramer acetate, an agent that is effective for the treatment of relapsing-remitting multiple sclerosis (MS). Diagnostic workup and treatment modalities for calcinosis cutis in this patient population should be considered in the context of minimizing interruption or discontinuation of this disease-modifying agent.

A 53-year-old woman with a history of relapsing-remitting MS and systemic lupus erythematosus (SLE) presented with multiple firm asymptomatic subcutaneous nodules on the thighs of 1 year’s duration that were increasing in number. The involved areas were the injection sites of subcutaneous glatiramer acetate, an immunomodulator for the treatment of MS, which our patient self-administered 3 times weekly. Physical examination revealed multiple flesh-colored to white, firm, and nontender nodules on the thighs (Figure). There was no epidermal change, and she had no other skin involvement. A punch biopsy of one of the nodules revealed calcium deposits in collagen bundles of the deep dermis. Calcium, phosphorus, parathyroid hormone, and vitamin D levels were within reference range. She declined further treatment for the calcinosis cutis and opted to continue treatment with glatiramer acetate, as her MS was well controlled on this medication.

Glatiramer acetate is an immunogenic polypeptide injectable that is approved by the US Food and Drug Administration for the treatment of relapsing-remitting MS.² It is composed of synthetic polypeptides and contains 4 naturally occurring amino acids. Glatiramer acetate is administered subcutaneously as 20 mg/mL/d or 40 mg/mL 3 times weekly. Transient injection-site reactions are the most common cutaneous adverse events and include localized edema, induration, erythema, pain, and pruritus.³ There have been multiple reports of lobular panniculitis and skin necrosis as well as embolia cutis medicamentosa (Nicolau syndrome).^4,5 Our case of calcinosis cutis related to glatiramer acetate is unique. The mechanism of calcinosis cutis in our patient likely was dystrophic due to tissue damage, rather than due to the injection of a calcium-containing substance. Our patient’s history of SLE is a notable risk factor for the development of calcinosis cutis, likely incited by the trauma occurring with subcutaneous injections.⁶

The mainstay of treatment for localized calcinosis cutis in the setting of connective tissue disease is surgical excision as well as treatment of the underlying disorder. Potential therapies include calcium channel blockers, warfarin, bisphosphonates, intravenous immunoglobulin, minocycline, colchicine, anti–tumor necrosis factor agents, intralesional corticosteroids, intravenous sodium thiosulfate, and CO₂ laser.^1,6 Our patient was already on intravenous immunoglobulin for MS and hydroxychloroquine for SLE. In select cases where the patient is asymptomatic and prefers not to pursue treatment, no treatment is necessary.

Although calcinosis cutis may occur in SLE alone, it is uncommon and usually is seen in chronic severe SLE, where calcification usually occurs in the setting of pre-existing cutaneous lupus.⁴ This case report of calcinosis cutis following treatment with glatiramer acetate highlights some of the cutaneous side effects associated with glatiramer acetate injections and should prompt practitioners to consider dystrophic calcinosis cutis in patients requiring subcutaneous medications, particularly in those with pre-existing connective tissue disease.

To the Editor:

Calcinosis cutis is a condition characterized by the deposition of insoluble calcium salts in the skin. Dystrophic calcinosis cutis is the most common type, occurring in previously traumatized skin in the absence of abnormal blood calcium levels. It commonly is seen in patients with connective tissue diseases and is thought to be precipitated by chronic inflammation and vascular hypoxia.¹ Herein, we describe a case of calcinosis cutis arising after treatment with subcutaneous glatiramer acetate, an agent that is effective for the treatment of relapsing-remitting multiple sclerosis (MS). Diagnostic workup and treatment modalities for calcinosis cutis in this patient population should be considered in the context of minimizing interruption or discontinuation of this disease-modifying agent.

A 53-year-old woman with a history of relapsing-remitting MS and systemic lupus erythematosus (SLE) presented with multiple firm asymptomatic subcutaneous nodules on the thighs of 1 year’s duration that were increasing in number. The involved areas were the injection sites of subcutaneous glatiramer acetate, an immunomodulator for the treatment of MS, which our patient self-administered 3 times weekly. Physical examination revealed multiple flesh-colored to white, firm, and nontender nodules on the thighs (Figure). There was no epidermal change, and she had no other skin involvement. A punch biopsy of one of the nodules revealed calcium deposits in collagen bundles of the deep dermis. Calcium, phosphorus, parathyroid hormone, and vitamin D levels were within reference range. She declined further treatment for the calcinosis cutis and opted to continue treatment with glatiramer acetate, as her MS was well controlled on this medication.

Glatiramer acetate is an immunogenic polypeptide injectable that is approved by the US Food and Drug Administration for the treatment of relapsing-remitting MS.² It is composed of synthetic polypeptides and contains 4 naturally occurring amino acids. Glatiramer acetate is administered subcutaneously as 20 mg/mL/d or 40 mg/mL 3 times weekly. Transient injection-site reactions are the most common cutaneous adverse events and include localized edema, induration, erythema, pain, and pruritus.³ There have been multiple reports of lobular panniculitis and skin necrosis as well as embolia cutis medicamentosa (Nicolau syndrome).^4,5 Our case of calcinosis cutis related to glatiramer acetate is unique. The mechanism of calcinosis cutis in our patient likely was dystrophic due to tissue damage, rather than due to the injection of a calcium-containing substance. Our patient’s history of SLE is a notable risk factor for the development of calcinosis cutis, likely incited by the trauma occurring with subcutaneous injections.⁶

The mainstay of treatment for localized calcinosis cutis in the setting of connective tissue disease is surgical excision as well as treatment of the underlying disorder. Potential therapies include calcium channel blockers, warfarin, bisphosphonates, intravenous immunoglobulin, minocycline, colchicine, anti–tumor necrosis factor agents, intralesional corticosteroids, intravenous sodium thiosulfate, and CO₂ laser.^1,6 Our patient was already on intravenous immunoglobulin for MS and hydroxychloroquine for SLE. In select cases where the patient is asymptomatic and prefers not to pursue treatment, no treatment is necessary.

Although calcinosis cutis may occur in SLE alone, it is uncommon and usually is seen in chronic severe SLE, where calcification usually occurs in the setting of pre-existing cutaneous lupus.⁴ This case report of calcinosis cutis following treatment with glatiramer acetate highlights some of the cutaneous side effects associated with glatiramer acetate injections and should prompt practitioners to consider dystrophic calcinosis cutis in patients requiring subcutaneous medications, particularly in those with pre-existing connective tissue disease.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

An ancient tree of the Ginkgoaceae family, Ginkgo biloba is known as a living fossil because its genome has been identified in fossils older than 200 million years.¹ An individual tree can live longer than 1000 years. Originating in China, G biloba (here, “ginkgo”) is cultivated worldwide for its attractive foliage (Figure 1). Ginkgo extract has long been used in traditional Chinese medicine; however, contact with the plant proper can provoke allergic contact dermatitis.

Dermatitis-Inducing Components

The allergenic component of the ginkgo tree is ginkgolic acid, which is structurally similar to urushiol and anacardic acid.^2,3 This compound can cause a cross-reaction in a person previously sensitized by contact with other plants. Urushiol is found in poison ivy(Toxicodendron radicans); anacardic acid is found in the cashew tree (Anacardium occidentale). Both plants belong to the family Anacardiaceae, commonly known as the cashew family.

Members of Anacardiaceae are the most common causes of plant-induced allergic contact dermatitis and include the cashew tree, mango tree, poison ivy, poison oak, and poison sumac. These plants can cross-react to cause contact dermatitis (Table).³ Patch tests have revealed that some individuals who are sensitive to components of the ginkgo tree also demonstrate sensitivity to poison ivy and poison sumac^4,5; countering this finding, Lepoittevin and colleagues⁶ demonstrated in animal studies that there was no cross-reactivity between ginkgo and urushiol, suggesting that patients with a reported cross-reaction might truly have been previously sensitized to both plants. In general, patients who have a history of a reaction to any Anacardiaceae plant should take precautions when handling them.

Therapeutic Benefit of Ginkgo

Ginkgo extract is sold as the herbal supplement EGB761, which acts as an antioxidant.⁷ In France, Germany, and China, it is a commonly prescribed herbal medicine.⁸ It is purported to support memory and attention; studies have shown improvement in cognition and in involvement with activities of daily living for patients with dementia.^9,10 Ginkgo extract might lessen peripheral vascular disease and cerebral circulatory disease, having been shown in vitro and in animal models to prevent platelet aggregation induced by platelet-activating factor and to stimulate vasodilation by increasing production of nitric oxide.^11,12

Furthermore, purified ginkgo extract might have beneficial effects on skin. A study in rats showed that when intraperitoneal ginkgo extract was given prior to radiation therapy, 100% of rats receiving placebo developed radiation dermatitis vs 13% of those that received ginkgo extract (P<.0001). An excisional skin biopsy showed a decrease in markers of oxidative stress in rats that received ginkgo extract prior to radiation.⁷

A randomized, double-blind clinical trial showed a significant reduction in disease progression in vitiligo patients assigned to receive ginkgo extract orally compared to placebo (P=.006).¹³ Research for many possible uses of ginkgo extract is ongoing.

Cutaneous Manifestations

Contact with the fruit of the ginkgo tree can induce allergic contact dermatitis,¹⁴ most often as erythematous papules, vesicles, and in some cases edema.^5,15

Exposures While Picking Berries—In 1939, Bolus¹⁵ reported the case of a patient who presented with edema, erythema, and vesicular lesions involving the hands and face after picking berries from a ginkgo tree. Later, patch testing on this patient, using ginkgo fruit, resulted in burning and stinging that necessitated removal of the patch, suggesting an irritant reaction. This was followed by a vesicular reaction that then developed within 24 hours, which was more consistent with allergy. Similarly, in 1988, a case series of contact dermatitis was reported in 3 patients after gathering ginkgo fruit.⁵

Incidental Exposure While Walking—In 1965, dermatitis broke out in 35 high school students, mainly affecting exposed portions of the leg, after ginkgo fruit fell and its pulp was exposed on a path at their school.⁴ Subsequently, patch testing was performed on 29 volunteers—some who had been exposed to ginkgo on that path, others without prior exposure. It was established that testing with ginkgo pulp directly caused an irritant reaction in all students, regardless of prior ginkgo exposure, but all prior ginkgo-exposed students in this study reacted positively to an acetone extract of ginkgo pulp and either poison ivy extract or pentadecylcatechol.⁴

Systemic Contact After Eating Fruit—An illustrative case of dermatitis, stomatitis, and proctitis was reported in a man with history of poison oak contact dermatitis who had eaten fruit from a ginkgo tree, suggesting systemic contact dermatitis. Weeks after resolution of symptoms, he reacted positively to ginkgo fruit and poison ivy extracts on patch testing.¹⁶

Ginkgo dermatitis tends to resolve upon removal of the inciting agent and application of a topical steroid.^8,17 Although many reported cases involve the fruit, allergic contact dermatitis can result from exposure to any part of the plant. In a reported case, a woman developed airborne contact dermatitis from working with sarcotesta of the ginkgo plant.¹⁸ Despite wearing rubber gloves, she broke out 1 week after exposure with erythema on the face and arms and severe facial edema.

Ginkgo leaves also can cause allergic contact dermatitis.¹⁹ Precautions should be taken when handling any component of the ginkgo tree.

Oral ginkgo supplementation has been implicated in a variety of other cutaneous reactions—from benign to life-threatening. When the ginkgo allergen concentration is too high within the supplement, as has been noted in some formulations, patients have presented with a diffuse morbilliform eruption within 1 or 2 weeks after taking ginkgo.²⁰ One patient—who was not taking any other medication—experienced an episode of acute generalized exanthematous pustulosis 48 hours after taking ginkgo.²¹ Ingestion of ginkgo extract also has been associated with Stevens-Johnson syndrome.^22-24

Other Adverse Reactions

The adverse effects of ginkgo supplement vary widely. In addition to dermatitis, ginkgo supplement can cause headaches, palpitations, tachycardia, vasculitis, nausea, and other symptoms.¹⁴

Metabolic Disturbance—One patient taking ginkgo who died after a seizure was found to have subtherapeutic levels of valproate and phenytoin,²⁵ which could be due to ginkgo’s effect on cytochrome p450 enzyme CYP2C19.²⁶ Ginkgo interactions with many cytochrome enzymes have been studied for potential drug interactions. Any other direct effects remain variable and controversial.^27,28

Hemorrhage—Another serious effect associated with taking ginkgo supplements is hemorrhage, often in conjunction with warfarin¹⁴; however, a meta-analysis indicated that ginkgo generally does not increase the risk of bleeding.²⁹ Other studies have shown that taking ginkgo with warfarin showed no difference in clotting status, and ginkgo with aspirin resulted in no clinically significant difference in bruising, bleeding, or platelet function in an analysis over a period of 1 month.^30,31 These findings notwithstanding, pregnant women, surgical patients, and those taking a blood thinner are advised as a general precaution not to take ginkgo extract.

Carcinogenesis—Ginkgo extract has antioxidant properties, but there is evidence that it might act as a carcinogen. An animal study reported by the US National Toxicology Program found that ginkgo induced mutagenic activity in the liver, thyroid, and nose of mice and rats. Over time, rodent liver underwent changes consistent with hepatic enzyme induction.³² More research is needed to clarify the role of ginkgo in this process.

Toxicity by Ingestion—Ginkgo seeds can cause food poisoning due to the compound 4’-O-methylpyridoxine (also known as ginkgotoxin).³³ Because methylpyridoxine can cause depletion of pyridoxal phosphate (a form of vitamin B₆ necessary for the synthesis of γ-aminobutyric acid), overconsumption of ginkgo seeds, even when fully cooked, might result in convulsions and even death.³³

Nomenclature and Distribution of Plants

Gingko biloba belongs to the Ginkgoaceae family (class Ginkgophytes). The tree originated in China but might no longer exist in a truly wild form. It is grown worldwide for its beauty and longevity. The female ginkgo tree is a gymnosperm, producing fruit with seeds that are not coated by an ovary wall¹⁵; male (nonfruiting) trees are preferentially planted because the fruit is surrounded by a pulp that, when dropped, emits a sour smell described variously as rancid butter, vomit, or excrement.⁵

Identifying Features and Plant Facts

The deciduous ginkgo tree has unique fan-shaped leaves and is cultivated for its beauty and resistance to disease (Figure 2).^4,34 It is nicknamed the maidenhair tree because the leaves are similar to the pinnae of the maidenhair fern.³⁴ Because G biloba is resistant to pollution, it often is planted along city streets.¹⁷ The leaf—5- to 8-cm wide and a symbol of the city of Tokyo, Japan³⁴—grows in clusters (Figure 3)⁵ and is green but turns yellow before it falls in autumn.³⁴ Leaf veins branch out into the blade without anastomosing.³⁴

Male flowers grow in a catkinlike pattern; female flowers grow on long stems.⁵ The fruit is small, dark, and shriveled, with a hint of silver⁴; it typically is 2 to 2.5 cm in diameter and contains the ginkgo nut or seed. The kernel of the ginkgo nut is edible when roasted and is used in traditional Chinese and Japanese cuisine as a dish served on special occasions in autumn.³³

Final Thoughts

Given that G biloba is a beautiful, commonly planted ornamental tree, gardeners and landscapers should be aware of the risk for allergic contact dermatitis and use proper protection. Dermatologists should be aware of its cross-reactivity with other common plants such as poison ivy and poison oak to help patients identify the cause of their reactions and avoid the inciting agent. Because ginkgo extract also can cause a cutaneous reaction or interact with other medications, providers should remember to take a thorough medication history that includes herbal medicines and supplements.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

No time of the year is more exciting than the unveiling of the American Contact Dermatitis Society Allergen of the Year. Sometimes the selected allergen represents a completely novel cause of allergic contact dermatitis (ACD) with an unpronounceable chemical name. Not this time! The 2022 Allergen of the Year is likely to be lurking in your kitchen drawer at this very moment, as this year aluminum was chosen for this most prestigious honor.¹ But do not throw out your aluminum foil just yet—aluminum allergy tends to be confined to specific scenarios. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum ACD, unique sources of exposure, and nuances of patch testing to this metal.

Aluminum Is All Around Us

As the third most common element in the Earth’s crust, aluminum can be found quite literally everywhere.¹ However, aluminum rarely is found in its pure elemental form; instead, it reacts with other elements around it, most commonly oxygen, to form aluminum-containing compounds. Known for their stability and safety, aluminum and its salts are incorporated in myriad products ranging from electronic equipment to foods and their packaging, medications, cosmetics, orthopedic and dental implants, and even tattoos. Aluminum also is found in the air and water supply and may even be encountered in certain workplaces, such as aircraft and machine industries. As such, contact with aluminum is all but certain in modern life.

The use of aluminum in consumer products is widely accepted as safe by public health agencies in the United States.² Although there has been public concern that aluminum could be linked to development of breast cancer or Alzheimer disease, there is no clear evidence that these conditions are associated with routine aluminum exposure through ingestion or consumer products.^3-5

Aluminum Contact Allergy

In part because of its ubiquity and in part because of the stability of aluminum-containing compounds, it was long thought that aluminum was nonallergenic. Contact allergy to elemental aluminum is rare; on the other hand, aluminum salts (the forms we are likely to encounter in daily life) are now recognized in the field of contact dermatitis as allergens of significance, particularly in the pediatric population.^1,6

First reported as a possible occupational allergen in 1944,⁷ aluminum allergy came to prominence in the 1990s in association with vaccines. Aluminum is included in some vaccines as an adjuvant that bolsters the immune response⁸; the eTable lists currently available aluminum-containing vaccines in the United States; of note, none of the COVID-19 vaccines approved in the United States or Europe contain aluminum.¹¹ Although the use of aluminum in vaccines is considered to be safe by the US Food and Drug Administration and Centers for Disease Control and Prevention,^12,13 a small number of children become sensitized to aluminum through vaccines and may develop persistent pruritic subcutaneous nodules (also known as vaccination granulomas) at the injection site; however, the incidence of this adverse effect was less than 1% in large studies including as many as 76,000 children, suggesting that it is relatively rare.^14,15 Upon patch testing, aluminum allergy has been detected in 77% to 95% of such cases.¹⁴ There is wide variation in the onset of the nodules ranging from weeks to years following vaccination.¹⁵ Due to pruritus, the examination may reveal accompanying excoriations, hyperpigmentation, and sometimes hypertrichosis at the injection site. Aluminum allergy related to vaccination also can manifest with widespread eruptions representing systemic contact dermatitis.¹⁶

Along with vaccines, the second major source of aluminum sensitization is allergen-specific immunotherapies administered by allergists/immunologists, many of which contain aluminum hydroxide.^17,18

On the consumer product front, antiperspirants are the most common source of cutaneous exposure to aluminum. Aluminum complexes react with electrolytes in sweat to form plugs in eccrine ducts, thereby preventing sweat excretion.⁶ Allergic contact dermatitis to these products presents with axillary-vault dermatitis. There also have been reports of ACD to aluminum in sunscreen and toothpaste, with the latter implicated in causing systemic ACD.^19,20

Prevalence of Sensitization to Aluminum

There have been a few large-scale studies evaluating rates of sensitization to aluminum in general patch-test patient populations; additionally, because of the complexities of testing this metal, investigators have utilized differing formulations for patch testing. A recent Swedish study found that 0.9% of 5448 adults and 5.1% of 196 children showed positive reactions to aluminum chloride hexahydrate (ACH) 10% in petrolatum and/or aluminum lactate 12% in petrolatum.²¹ Notably, there was a significant association between aluminum allergy and history of atopy for both adults (P=.0056) and children (P=.046), which remains to be further explored. A systematic review and meta-analysis found comparable rates of aluminum allergy in 0.4% of adults and 5.6% of children without vaccine granulomas who were tested.²² With this evidence in mind, it has been recommended by contact dermatitis experts that aluminum be included in pediatric baseline patch test series and also investigated for potential inclusion in baseline series for adults.¹

Differential Diagnosis of Aluminum ACD

The differential diagnosis for subcutaneous nodules following vaccination is broad and includes various forms of panniculitis, sarcoidosis, foreign body reactions, vascular malformations, infections, and malignancies.^23-25 The diagnosis may be obscured in cases with delayed onset. Biopsy is not mandatory to establish the diagnosis; although variable histopathologic findings have been reported, a common feature is histiocytes with abundant granular cytoplasm.²⁶ It may be possible to demonstrate the presence of aluminum particles in tissue using electron microscopy and X-ray microanalysis.

For those patients who present with axillary-vault dermatitis, the differential includes ACD to more common allergens in antiperspirants (eg, fragrance), as well as other axillary dermatoses including inverse psoriasis, erythrasma, Hailey-Hailey disease, and various forms of intertrigo. Dermatitis localized to the axillary rim suggests textile allergy.

Patch Testing to Aluminum

Due to its physicochemical properties, patch testing for aluminum allergy is complicated, and historically there has been a lack of consensus on the ideal test formulation.^1,27,28 At this time, it appears that the most sensitive formulation for patch testing to aluminum is ACH 10% in petrolatum.¹ Some contact dermatitis experts recommend that children younger than 8 years should be tested with ACH 2% in petrolatum to minimize the risk of extreme patch test reactions.^29,30 In some patients sensitized to aluminum, the use of aluminum patch test chambers has been noted to produce false-positive reactions, taking the form of multiple ring-shaped reactions to the chambers themselves or reactions to certain allergens whose chemical properties cause corrosion of the aluminum within the chambers.^31-33 Therefore, when testing for suspected aluminum allergy, plastic chambers should be used; given the higher prevalence of aluminum allergy in children, some clinics routinely use plastic chambers for all pediatric patch testing.³⁴ Importantly, elemental aluminum, including empty aluminum test chambers or aluminum foil, alone is not sufficient for patch testing as it lacks sensitivity.¹ Additionally, nearly 20% of positive tests will be missed if a day 7 reading is not performed, making delayed reading a must in cases with high suspicion for aluminum allergy.²¹

Management of Aluminum Allergy

The development of pruritic subcutaneous nodules is uncomfortable for children and their guardians alike and may be associated with prolonged symptoms that negatively impact quality of life^35,36; nonetheless, expert authorities have determined that the preventive benefits of childhood vaccination far outweigh any risk posed by the presence of aluminum in vaccines.^12,13,37 Because aluminum-free formulations may not be available for all vaccines, it is essential to educate patients and families who may be at risk for developing vaccine hesitancy or avoidance.^35,36,38 Given the hypothesis that epidermal dendritic cells mediate aluminum sensitization, it has been proposed that vaccine administration via deep intramuscular rather than subcutaneous injection may mitigate the risk, but more evidence is needed to support this approach.^39,40 The good news is that the nodules tend to fade with age, with a median time to resolution of 18 to 49 months.¹⁴ In addition, patients may experience loss of sensitization to aluminum over time⁴¹; in one study, 77% of 241 children lost patch test reactivity when retested 5 to 9 years later.⁴² The exact reason for this diminishment of reactivity is not well understood. Adjunctive treatments to relieve symptoms of vaccine granulomas include topical and intralesional corticosteroids and antihistamines.

For patients reacting to aluminum in antiperspirants, there are many aluminum-free formulations on the market as well as recipes for homemade antiperspirants.⁶ On a case-by-case basis, patients may need to avoid aluminum-containing medications, permanent tattoos, and orthopedic or dental implants. To the best of our knowledge, there is no evidence suggesting a need to avoid aluminum in foods and their containers in routine daily life; although some patients report exacerbations of their symptoms associated with food-related aluminum exposures (eg, canned food, dried fruit) and improvement with dietary modification, further investigation is needed to confirm the relevance of these sources of contact.^36,38 For patients who require allergen-specific immunotherapy, aluminum-free allergen extracts are available.⁶

Final Interpretation

Exposure to aluminum is ubiquitous; although relatively uncommon, awareness of the potential for ACD to aluminum is increasingly important, particularly in children. Given the prevalence of aluminum contact allergy, it has been recommended by contact dermatitis experts for inclusion in baseline pediatric patch test series.¹ Although it is a complex issue, the development of ACD in a small proportion of children exposed to aluminum in vaccines does not outweigh the benefit of vaccination for almost all children. When conducting patch testing to aluminum, studies support testing to ACH 10% in petrolatum for adults, and consider reducing the concentration to ACH 2% for children.

Acknowledgment—The authors thank Ian Fritz, MD (South Portland, Maine), for his critical input during preparation of this article.

Devices that help children control their diabetes and lead fuller lives may also give them contact dermatitis, report the authors of a new study that calls for mandatory labeling of ingredients for allergy patch testing.

“A high share of patients showed positive reactions to isobornyl acrylate adhesive (IBOA) and/or their medical devices (insulin pumps or glucose devices),” the study authors write in Contact Dermatitis. “A third of patients showed positive reactions to benzoyl peroxide (BP),” used in adhesives.

“The presence of additional unidentified allergens cannot be excluded,” they add. “Overall, our experience once more highlights the importance of having access to a full description of the chemical composition of diabetes devices and related medical devices to efficiently manage patients (including children) who experience adverse skin reactions from such devices.”

Lead study author Catarina Alves da Silva, MD, of the department of dermatology and venereology of Aarhus (Denmark) University Hospital, and her colleagues conducted a retrospective study of 15 referred patients younger than 18 years who had type 1 diabetes. The children were patch tested in the university’s dermatology clinic between 2018 and 2020 in a study of skin reactions linked with diabetes devices.
 

Contact dermatitis from device-related allergens may be common

Many children in the study reacted to chemical compounds related to their devices.

• Of the 15 patients, seven showed positive patch test reactions to IBOA, and five showed positive reactions to BP.
• Ten children had positive patch test reactions to materials from glucose sensors and insulin pumps.
• Three showed positive reactions to adhesive remover wipes.
• Five reacted to .

Marcia Hogeling, MD, a pediatric dermatologist at UCLA Health in Santa Monica, Calif., told this news organization that she expected acrylates to cause problems but was surprised that BP caused positive patch test reactions.

BP is known to be a strong irritant but a weak allergen, the authors wrote.

“It was important to identify the allergens in these devices. Hopefully, this information will be used by manufacturers to create safer products for patients,” Dr. Hogeling, who was not involved in the study, said in an email.

Dr. Hogeling acknowledged that the small sample size is a weakness of the study, although she added that the findings may help providers select devices that do not contain their patients’ contact allergens.

Ryan J. McDonough, DO, a pediatric endocrinologist and the codirector of the Diabetes Center at Children’s Mercy Kansas City (Mo.), said in an email that, despite the small sample size, the study “highlights important device-related experiences of those living with type 1 diabetes that clinicians often encounter.

“We often spend considerable time aiding patients and their families in finding ways to mitigate the reactions,” he explained. “Having a broader understanding of these chemical compositions would help clinicians choose the right devices for their patients and prevent and treat these types of reactions.”

Dr. McDonough, who was not involved in the study, noted that the patients were in Denmark, and they were able to easily transition between insulin pumps and glucose monitoring devices.

“In the U.S., it is often more challenging to switch between devices, due to insurance-related concerns.

“The true rates of reaction in the broad type 1 diabetes population are difficult to assess,” Dr. McDonough said. “The study participants were drawn from patients referred to a dermatology clinic for evaluation of reaction. Many patients either don’t develop reactions or are treated for mild symptoms locally by their endocrinologists.

“This study should serve as a call to action for continued improvements in the transparency of the components that make up the devices and adhesives, and it can provide an opportunity to develop additional interventions to prevent these reactions,” he advised.

No information regarding funding for the study was provided. The authors, Dr. Hogeling, and Dr. McDonough reported no relevant financial relationships.

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

Devices that help children control their diabetes and lead fuller lives may also give them contact dermatitis, report the authors of a new study that calls for mandatory labeling of ingredients for allergy patch testing.

“A high share of patients showed positive reactions to isobornyl acrylate adhesive (IBOA) and/or their medical devices (insulin pumps or glucose devices),” the study authors write in Contact Dermatitis. “A third of patients showed positive reactions to benzoyl peroxide (BP),” used in adhesives.

“The presence of additional unidentified allergens cannot be excluded,” they add. “Overall, our experience once more highlights the importance of having access to a full description of the chemical composition of diabetes devices and related medical devices to efficiently manage patients (including children) who experience adverse skin reactions from such devices.”

Lead study author Catarina Alves da Silva, MD, of the department of dermatology and venereology of Aarhus (Denmark) University Hospital, and her colleagues conducted a retrospective study of 15 referred patients younger than 18 years who had type 1 diabetes. The children were patch tested in the university’s dermatology clinic between 2018 and 2020 in a study of skin reactions linked with diabetes devices.
 

Contact dermatitis from device-related allergens may be common

Many children in the study reacted to chemical compounds related to their devices.

• Of the 15 patients, seven showed positive patch test reactions to IBOA, and five showed positive reactions to BP.
• Ten children had positive patch test reactions to materials from glucose sensors and insulin pumps.
• Three showed positive reactions to adhesive remover wipes.
• Five reacted to .

Marcia Hogeling, MD, a pediatric dermatologist at UCLA Health in Santa Monica, Calif., told this news organization that she expected acrylates to cause problems but was surprised that BP caused positive patch test reactions.

BP is known to be a strong irritant but a weak allergen, the authors wrote.

“It was important to identify the allergens in these devices. Hopefully, this information will be used by manufacturers to create safer products for patients,” Dr. Hogeling, who was not involved in the study, said in an email.

Dr. Hogeling acknowledged that the small sample size is a weakness of the study, although she added that the findings may help providers select devices that do not contain their patients’ contact allergens.

Ryan J. McDonough, DO, a pediatric endocrinologist and the codirector of the Diabetes Center at Children’s Mercy Kansas City (Mo.), said in an email that, despite the small sample size, the study “highlights important device-related experiences of those living with type 1 diabetes that clinicians often encounter.

“We often spend considerable time aiding patients and their families in finding ways to mitigate the reactions,” he explained. “Having a broader understanding of these chemical compositions would help clinicians choose the right devices for their patients and prevent and treat these types of reactions.”

Dr. McDonough, who was not involved in the study, noted that the patients were in Denmark, and they were able to easily transition between insulin pumps and glucose monitoring devices.

“In the U.S., it is often more challenging to switch between devices, due to insurance-related concerns.

“The true rates of reaction in the broad type 1 diabetes population are difficult to assess,” Dr. McDonough said. “The study participants were drawn from patients referred to a dermatology clinic for evaluation of reaction. Many patients either don’t develop reactions or are treated for mild symptoms locally by their endocrinologists.

“This study should serve as a call to action for continued improvements in the transparency of the components that make up the devices and adhesives, and it can provide an opportunity to develop additional interventions to prevent these reactions,” he advised.

No information regarding funding for the study was provided. The authors, Dr. Hogeling, and Dr. McDonough reported no relevant financial relationships.

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

Devices that help children control their diabetes and lead fuller lives may also give them contact dermatitis, report the authors of a new study that calls for mandatory labeling of ingredients for allergy patch testing.

“A high share of patients showed positive reactions to isobornyl acrylate adhesive (IBOA) and/or their medical devices (insulin pumps or glucose devices),” the study authors write in Contact Dermatitis. “A third of patients showed positive reactions to benzoyl peroxide (BP),” used in adhesives.

“The presence of additional unidentified allergens cannot be excluded,” they add. “Overall, our experience once more highlights the importance of having access to a full description of the chemical composition of diabetes devices and related medical devices to efficiently manage patients (including children) who experience adverse skin reactions from such devices.”

Lead study author Catarina Alves da Silva, MD, of the department of dermatology and venereology of Aarhus (Denmark) University Hospital, and her colleagues conducted a retrospective study of 15 referred patients younger than 18 years who had type 1 diabetes. The children were patch tested in the university’s dermatology clinic between 2018 and 2020 in a study of skin reactions linked with diabetes devices.
 

Contact dermatitis from device-related allergens may be common

Many children in the study reacted to chemical compounds related to their devices.

• Of the 15 patients, seven showed positive patch test reactions to IBOA, and five showed positive reactions to BP.
• Ten children had positive patch test reactions to materials from glucose sensors and insulin pumps.
• Three showed positive reactions to adhesive remover wipes.
• Five reacted to .

Marcia Hogeling, MD, a pediatric dermatologist at UCLA Health in Santa Monica, Calif., told this news organization that she expected acrylates to cause problems but was surprised that BP caused positive patch test reactions.

BP is known to be a strong irritant but a weak allergen, the authors wrote.

“It was important to identify the allergens in these devices. Hopefully, this information will be used by manufacturers to create safer products for patients,” Dr. Hogeling, who was not involved in the study, said in an email.

Dr. Hogeling acknowledged that the small sample size is a weakness of the study, although she added that the findings may help providers select devices that do not contain their patients’ contact allergens.

Ryan J. McDonough, DO, a pediatric endocrinologist and the codirector of the Diabetes Center at Children’s Mercy Kansas City (Mo.), said in an email that, despite the small sample size, the study “highlights important device-related experiences of those living with type 1 diabetes that clinicians often encounter.

“We often spend considerable time aiding patients and their families in finding ways to mitigate the reactions,” he explained. “Having a broader understanding of these chemical compositions would help clinicians choose the right devices for their patients and prevent and treat these types of reactions.”

Dr. McDonough, who was not involved in the study, noted that the patients were in Denmark, and they were able to easily transition between insulin pumps and glucose monitoring devices.

“In the U.S., it is often more challenging to switch between devices, due to insurance-related concerns.

“The true rates of reaction in the broad type 1 diabetes population are difficult to assess,” Dr. McDonough said. “The study participants were drawn from patients referred to a dermatology clinic for evaluation of reaction. Many patients either don’t develop reactions or are treated for mild symptoms locally by their endocrinologists.

“This study should serve as a call to action for continued improvements in the transparency of the components that make up the devices and adhesives, and it can provide an opportunity to develop additional interventions to prevent these reactions,” he advised.

No information regarding funding for the study was provided. The authors, Dr. Hogeling, and Dr. McDonough reported no relevant financial relationships.

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

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Lupus erythematosus tumidus (LET) is a rare photosensitive dermatosis¹ that previously was considered a subtype of chronic cutaneous lupus erythematosus; however, the clinical course and favorable prognosis of LET led to its reclassification into another category, called intermittent cutaneous lupus erythematosus.² Although known about for more than 100 years, the association of LET with systemic lupus erythematosus (SLE), its autoantibody profile, and its prognosis are not well characterized. The purpose of this study was to describe the demographics, clinical characteristics, autoantibody profile, comorbidities, and treatment of LET based on a retrospective review of patients with LET.

Methods

A retrospective review was conducted in patients with histologically diagnosed LET who presented to the Department of Dermatology at the Wake Forest School of Medicine (Winston-Salem, North Carolina) over 6 years (July 2012 to July 2018). Inclusion criteria included males or females aged 18 to 75 years with clinical and histopathology-proven LET, which was defined as a superficial and deep lymphocytic infiltrate with abundant mucin deposition in the reticular dermis and absent or focal dermoepidermal junction alterations. Exclusion criteria included males or females younger than 18 years or older than 75 years or patients without clinical and histopathologically proven LET. Medical records were evaluated for demographics, clinical characteristics, diagnoses, autoantibodies, treatment, and recurrence. Photosensitivity was confirmed by clinical history. This study was approved by the Wake Forest School of Medicine institutional review board.

Results

Twenty-five patients were included in the study (eTable). The mean age (SD) at diagnosis was 46 (10.9) years, with a male to female ratio of 1:4. Twenty-two (88%) patients were White non-Hispanic, whereas 3 (12%) were Black. Lupus erythematosus tumidus most commonly affected the trunk (18/25 [72%]) and upper extremities (18/25 [72%]), followed by the head and neck (15/25 [60%]) and lower extremities (8/25 [32%])(Figure 1). The most common morphologies were plaques (18/25 [72%]), papules (17/25 [68%]), and nodules (6/25 [24%])(Figures 2 and 3). Most patients experienced painful (14/25 [56%]) or pruritic (13/25 [52%]) lesions as well as photosensitivity (13/25 [52%]). Of all measured autoantibodies, 5 of 22 (23%) patients had positive antinuclear antibody (ANA) titers greater than 1:80, 1 of 14 (7%) patients had positive anti-Ro (anti-SSA), 1 of 14 (7%) had positive anti-La (anti-SSB), 2 of 10 (20%) had positive anti–double-stranded DNA, and 0 of 6 (0%) patients had positive anti-Smith antibodies. Four (16%) patients with SLE had skin and joint involvement, whereas 1 had lupus nephritis. One (4%) patient had discoid lupus erythematosus (DLE). Seventeen (68%) patients reported recurrences or flares. The mean duration of symptoms (SD) was 28 (44) months.

Topical corticosteroids (21/25 [84%]) and hydroxychloroquine (20/25 [80%]) were the most commonly prescribed treatments. Hydroxychloroquine monotherapy achieved clearance or almost clearance in 12 (60%) patients. Four patients were prescribed thalidomide after hydroxychloroquine monotherapy failed; 2 achieved complete clearance with thalidomide and hydroxychloroquine, 1 achieved complete clearance with thalidomide monotherapy, and 1 improved but did not clear. Four patients were concurrently started on quinacrine (mepacrine) after hydroxychloroquine monotherapy failed; 1 patient had no clearance, 1 discontinued because of allergy, 1 improved, and 1 cleared. Four patients had short courses of prednisone lasting 1 to 4 weeks. Three of 4 patients treated with methotrexate discontinued because of adverse effects, and 1 patient improved. Other prescribed treatments included topical calcineurin inhibitors (10/25 [40%]), dapsone (1/25 [4%]), and clofazimine (1/25 [4%]).

Comment

Prevalence of LET—Although other European LET case series reported a male predominance or equal male to female ratio, our case series reported female predominance (1:4).^1,3-5 Our male to female ratio resembles similar ratios in DLE and subacute lupus erythematosus, whereas relative to our study, SLE male to female ratios favored females over males.^6,7

Clinical Distribution of LET—In one study enrolling 24 patients with LET, 79% (19/24) of patients had facial involvement, 50% (12/24) had V-neck involvement, 50% (12/24) had back involvement, and 46% (11/24) had arm involvement,² whereas our study reported 72% involvement of the trunk, 72% involvement of the upper extremities, 60% involvement of the head and neck region, and 32% involvement of the lower extremities. Although our study reported more lower extremity involvement, the aforementioned study used precise topographic locations, whereas we used more generalized topographic locations. Therefore, it was difficult to compare disease distribution between both studies.²

Presence of Autoantibodies and Comorbidities—Of the 22 patients tested for ANA, 23% reported titers greater than 1:80, similar to the 20% positive ANA prevalence in an LET case series of 25 patients.⁵ Of 4 patients diagnosed with SLE, 3 had articular and skin involvement, and 1 had renal involvement. These findings resemble a similar LET case series.² Nonetheless, given the numerous skin criteria in the American College of Rheumatology SLE classification criteria, patients with predominant skin disease and positive autoantibodies are diagnosed as having SLE without notable extracutaneous involvement.² Therefore, SLE diagnosis in the setting of LET could be reassessed periodically in this population. One patient in our study was diagnosed with DLE several years later. It is uncommon for LET to be reported concomitantly with DLE.⁸

Treatment of LET—Evidence supporting efficacious treatment options for LET is limited to case series. Sun protection is recommended in all patients with LET. Earlier case series reported a high response rate with sun protection and topical corticosteroids, with 19% to 55% of patients requiring subsequent systemic antimalarials.^3,4 However, one case series presented a need for systemic antimalarials,⁵ similar to our study. Hydroxychloroquine 200 to 400 mg daily is considered the first-line systemic treatment for LET. Its response rate varies among studies and may be influenced by dosage.^1,3 Second-line treatments include methotrexate 7.5 to 25 mg once weekly, thalidomide 50 to 100 mg daily, and quinacrine. However, quinacrine is not currently commercially available. Thalidomide and quinacrine represented useful alternatives when hydroxychloroquine monotherapy failed. As with other immunomodulators, adverse effects should be monitored periodically.

Conclusion

Lupus erythematosus tumidus is characterized by erythematous papules and plaques that may be tender or pruritic. It follows an intermittent course and rarely is associated with SLE. Hydroxychloroquine is considered the first-line systemic treatment; however, recalcitrant disease could be managed with other immunomodulators, including methotrexate, thalidomide, or quinacrine.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

Airbags are lifesaving during motor vehicle accidents (MVAs), but their deployment has been associated with skin issues such as irritant dermatitis¹; lacerations²; abrasions³; and thermal, friction, and chemical burns.^4-6 Ocular issues such as alkaline chemical keratitis⁷ and ocular alkali injuries⁸ also have been described.

Airbag deployment is triggered by rapid deceleration and impact, which ignite a sodium azide cartridge, causing the woven nylon bag to inflate with hydrocarbon gases.⁸ This leads to release of sodium hydroxide, sodium bicarbonate, and metallic oxides in an aerosolized form. If a tear in the meshwork of the airbag occurs, exposure to an even larger amount of powder containing caustic alkali chemicals can occur.⁸

We describe a patient who developed a bullous reaction to airbag contents after he was involved in an MVA in which the airbag deployed.

Case Report

A 35-year-old man with a history of type 2 diabetes mellitus and chronic hepatitis B presented to the dermatology clinic for an evaluation of new-onset blisters. The rash occurred 1 day after the patient was involved in an MVA in which he was exposed to the airbag’s contents after it burst. He had been evaluated twice in the emergency department for the skin eruption before being referred to dermatology. He noted the lesions were pruritic and painful. Prior treatments included silver sulfadiazine cream 1% and clobetasol cream 0.05%, though he discontinued using the latter because of burning with application. Physical examination revealed tense vesicles and bullae on an erythematous base on the right lower flank, forearms, and legs, with the exception of the lower right leg where a cast had been from a prior injury (Figure 1).

Two punch biopsies of the left arm were performed and sent for hematoxylin and eosin staining and direct immunofluorescence to rule out bullous diseases, such as bullous pemphigoid, linear IgA, and bullous lupus. Hematoxylin and eosin staining revealed extensive spongiosis with blister formation and a dense perivascular infiltrate in the superficial and mid dermis composed of lymphocytes with numerous scattered eosinophils (Figures 2 and 3). Direct immunofluorescence studies were negative. Treatment with oral prednisone and oral antihistamines was initiated.

At 10-day follow-up, the patient had a few residual bullae; most lesions were demonstrating various stages of healing (Figure 4). The patient’s cast had been removed, and there were no lesions in this previously covered area. At 6-week follow-up he had continued healing of the bullae and erosions as well as postinflammatory hyperpigmentation (Figure 5).

Comment

With the advent of airbags for safety purposes, these potentially lifesaving devices also have been known to cause injury.⁹ In 1998, the most commonly reported airbag injuries were ocular injuries.¹⁰ Cutaneous manifestations of airbag injury are less well known.¹¹

Two cases of airbag deployment with skin blistering have been reported in the literature based on a PubMed search of articles indexed for MEDLINE using the terms airbag blistering or airbag bullae^12,13; however, the blistering was described in the context of a burn. One case of the effects of airbag deployment residue highlights a patient arriving to the emergency department with erythema and blisters on the hands within 48 hours of airbag deployment in an MVA, and the treatment was standard burn therapy.¹² Another case report described a patient with a second-degree burn with a 12-cm blister occurring on the radial side of the hand and distal forearm following an MVA and airbag deployment, which was treated conservatively.¹³ Cases of thermal burns, chemical burns, and irritant contact dermatitis after airbag deployment have been described in the literature.^{4-6,11,12,14,15} Our patient’s distal right lower leg was covered with a cast for osteomyelitis, and no blisters had developed in this area. It is likely that the transfer of airbag contents occurred during the process of unbuckling his seatbelt, which could explain the bullae that developed on the right flank. Per the Centers for Disease Control and Prevention, individuals should quickly remove clothing and wash their body with large amounts of soap and water following exposure to sodium azide.¹⁶

In 1989, the Federal Motor Vehicle Safety Standard No. 208 (occupant crash protection) became effective, stating all cars must have vehicle crash protection.¹² Prior to 1993, it was reported that there had been no associated chemical injuries with airbag deployment. Subsequently, a 6-month retrospective study in 1993 showed that dermal injuries were found in connection with the presence of sodium hydroxide in automobile airbags.¹² By 2004, it was known that airbags could cause chemical and thermal burns in addition to traumatic injuries from deployment.¹ Since 2007, all motor vehicles have been required to have advanced airbags, which are engineered to sense the presence of passengers and determine if the airbag will deploy, and if so, how much to deploy to minimize airbag-related injury.³

The brand of car that our patient drove during the MVA is one with known airbag recalls due to safety defects; however, the year and actual model of the vehicle are not known, so specific information about the airbag in question is not available. It has been noted that some defective airbag inflators that were exposed to excess moisture during the manufacturing process could explode during deployment, causing shrapnel and airbag rupture, which has been linked to nearly 300 injuries worldwide.¹⁷

Conclusion

It is evident that the use of airbag devices reduces morbidity and mortality due to MVAs.⁹ It also had been reported that up to 96% of airbag-related injuries are relatively minor, which many would argue justifies their use.¹⁸ Furthermore, it has been reported that 99.8% of skin injuries following airbag deployment are minor.¹⁹ In the United States, it is mandated that every vehicle have functional airbags installed.⁸

This case highlights the potential for substantial airbag-induced skin reactions, specifically a bullous reaction, following airbag deployment. The persistent pruritus and lasting postinflammatory hyperpigmentation seen in this case were certainly worrisome for our patient. We also present this case to remind dermatology providers of possible treatment approaches to these skin reactions. Immediate cleansing of the affected areas of skin may help avoid such reactions.

To the Editor:

Wolf isotopic response describes the development of a skin disorder at the site of another healed and unrelated skin disease. Skin disorders presenting as isotopic responses have included inflammatory, malignant, granulomatous, and infectious processes. Discoid lupus erythematosus (DLE) is a rare isotopic response. We report a cutaneous lupus erythematosus–like isotopic response that presented at the site of a recent herpes zoster infection in a liver transplant recipient.

A 74-year-old immunocompromised woman was referred to the dermatology clinic for evaluation of a rash on the right leg. She was being treated with maintenance valganciclovir due to cytomegalovirus viremia, as well as tacrolimus, azathioprine, and prednisone following liver transplantation due to autoimmune hepatitis for 8 months prior to presentation. Eighteen days prior to the current presentation, she was clinically diagnosed with herpes zoster. As the grouped vesicles from the herpes zoster resolved, she developed pink scaly papules in the same distribution as the original vesicular eruption.

Physical examination revealed numerous erythematous, 2- to 3-mm, scaly papules that coalesced into small plaques with serous crusts; they originated above the supragluteal cleft and extended rightward in the L3 and L4 dermatomes to the right knee (Figure 1). A 3-mm punch biopsy specimen was obtained from the right anterior thigh. Histologic analysis revealed interface lymphocytic inflammation with squamatization of basal keratinocytes, basement membrane thickening, and follicular plugging by keratin (Figure 2). There was a moderately intense perivascular and periadnexal inflammatory infiltrate of mature lymphocytes with rare eosinophils within the papillary and superficial reticular dermis. There was no evidence of a viral cytopathic effect, and an immunohistochemical stain for varicella-zoster virus protein was negative. The histologic findings were suggestive of cutaneous involvement by DLE. A diagnosis of a cutaneous lupus erythematosus–like Wolf isotopic response was made, and the patient’s rash resolved with the use of triamcinolone cream 0.1% applied twice daily for 2 weeks. At 6-week follow-up, there were postinflammatory pigmentation changes at the sites of the prior rash and persistent postherpetic neuralgia. Recent antinuclear antibody screening was negative, coupled with the patient’s lack of systemic symptoms and quick resolution of rash, indicating that additional testing for systemic lupus was not warranted.

Wolf isotopic response describes the occurrence of a new skin disorder at the site of a previously healed and unrelated skin disorder. The second disease may appear within days to years after the primary disease subsides and is clearly differentiated from the isomorphic response of the Koebner phenomenon, which describes an established skin disorder appearing at a previously uninvolved anatomic site following trauma.¹ As in our case, the initial cutaneous eruption resulting in a subsequent Wolf isotopic response frequently is herpes zoster and less commonly is herpes simplex virus.² The most common reported isotopic response is a granulomatous reaction.² Rare reports of leukemic infiltration, lymphoma, lichen planus, morphea, reactive perforating collagenosis, psoriasis, discoid lupus, lichen simplex chronicus, contact dermatitis, xanthomatous changes, malignant tumors, cutaneous graft-vs-host disease, pityriasis rosea, erythema annulare centrifugum, and other infectious-based isotopic responses exist.^2-6

Our patient presented with Wolf isotopic response that histologically mimicked DLE. A PubMed search of articles indexed for MEDLINE using the terms isotopic response and lupus revealed only 3 cases of cutaneous lupus erythematosus presenting as an isotopic response in the English-language literature. One of those cases occurred in a patient with preexisting systemic lupus erythematosus, making a diagnosis of Koebner isomorphic phenomenon more appropriate than an isotopic response at the site of prior herpes zoster infection.⁷ The remaining 2 cases were clinically defined DLE lesions occurring at sites of prior infection—cutaneous leishmaniasis and herpes zoster—in patients without a prior history of cutaneous or systemic lupus erythematosus.^8,9 The latter case of DLE-like isotopic response occurring after herpes zoster infection was further complicated by local injections at the zoster site for herpes-related local pain. Injection sites are reported as a distinct nidus for Wolf isotopic response.⁹

The pathogenesis of Wolf isotopic response is unclear. Possible explanations include local interactions between persistent viral particles at prior herpes infection sites, vascular injury, neural injury, and an altered immune response.^1,5,6,10 The destruction of sensory nerve fibers by herpesviruses cause the release of neuropeptides that then modulate the local immune system and angiogenic responses.^5,6 Our patient’s immunocompromised state may have further propagated a local altered immune cell infiltrate at the site of the isotopic response. Despite its unclear etiology, Wolf isotopic response should be considered in the differential diagnosis for any patient who presents with a dermatomal eruption at the site of a prior cutaneous infection, particularly after infection with herpes zoster. Treatment with topical or intralesional corticosteroids usually suffices for inflammatory-based isotopic responses with an excellent prognosis.¹¹

We present a case of a cutaneous lupus erythematosus–like isotopic response that occurred at the site of a recent herpes zoster eruption in an immunocompromised patient without prior history of systemic or cutaneous lupus erythematosus. Clinical recognition of Wolf isotopic response is important for accurate histopathologic diagnosis and management. Continued investigation into the underlying pathogenesis should be performed to fully understand and better treat this process.

To the Editor:

Wolf isotopic response describes the development of a skin disorder at the site of another healed and unrelated skin disease. Skin disorders presenting as isotopic responses have included inflammatory, malignant, granulomatous, and infectious processes. Discoid lupus erythematosus (DLE) is a rare isotopic response. We report a cutaneous lupus erythematosus–like isotopic response that presented at the site of a recent herpes zoster infection in a liver transplant recipient.

A 74-year-old immunocompromised woman was referred to the dermatology clinic for evaluation of a rash on the right leg. She was being treated with maintenance valganciclovir due to cytomegalovirus viremia, as well as tacrolimus, azathioprine, and prednisone following liver transplantation due to autoimmune hepatitis for 8 months prior to presentation. Eighteen days prior to the current presentation, she was clinically diagnosed with herpes zoster. As the grouped vesicles from the herpes zoster resolved, she developed pink scaly papules in the same distribution as the original vesicular eruption.

Physical examination revealed numerous erythematous, 2- to 3-mm, scaly papules that coalesced into small plaques with serous crusts; they originated above the supragluteal cleft and extended rightward in the L3 and L4 dermatomes to the right knee (Figure 1). A 3-mm punch biopsy specimen was obtained from the right anterior thigh. Histologic analysis revealed interface lymphocytic inflammation with squamatization of basal keratinocytes, basement membrane thickening, and follicular plugging by keratin (Figure 2). There was a moderately intense perivascular and periadnexal inflammatory infiltrate of mature lymphocytes with rare eosinophils within the papillary and superficial reticular dermis. There was no evidence of a viral cytopathic effect, and an immunohistochemical stain for varicella-zoster virus protein was negative. The histologic findings were suggestive of cutaneous involvement by DLE. A diagnosis of a cutaneous lupus erythematosus–like Wolf isotopic response was made, and the patient’s rash resolved with the use of triamcinolone cream 0.1% applied twice daily for 2 weeks. At 6-week follow-up, there were postinflammatory pigmentation changes at the sites of the prior rash and persistent postherpetic neuralgia. Recent antinuclear antibody screening was negative, coupled with the patient’s lack of systemic symptoms and quick resolution of rash, indicating that additional testing for systemic lupus was not warranted.

Wolf isotopic response describes the occurrence of a new skin disorder at the site of a previously healed and unrelated skin disorder. The second disease may appear within days to years after the primary disease subsides and is clearly differentiated from the isomorphic response of the Koebner phenomenon, which describes an established skin disorder appearing at a previously uninvolved anatomic site following trauma.¹ As in our case, the initial cutaneous eruption resulting in a subsequent Wolf isotopic response frequently is herpes zoster and less commonly is herpes simplex virus.² The most common reported isotopic response is a granulomatous reaction.² Rare reports of leukemic infiltration, lymphoma, lichen planus, morphea, reactive perforating collagenosis, psoriasis, discoid lupus, lichen simplex chronicus, contact dermatitis, xanthomatous changes, malignant tumors, cutaneous graft-vs-host disease, pityriasis rosea, erythema annulare centrifugum, and other infectious-based isotopic responses exist.^2-6

Our patient presented with Wolf isotopic response that histologically mimicked DLE. A PubMed search of articles indexed for MEDLINE using the terms isotopic response and lupus revealed only 3 cases of cutaneous lupus erythematosus presenting as an isotopic response in the English-language literature. One of those cases occurred in a patient with preexisting systemic lupus erythematosus, making a diagnosis of Koebner isomorphic phenomenon more appropriate than an isotopic response at the site of prior herpes zoster infection.⁷ The remaining 2 cases were clinically defined DLE lesions occurring at sites of prior infection—cutaneous leishmaniasis and herpes zoster—in patients without a prior history of cutaneous or systemic lupus erythematosus.^8,9 The latter case of DLE-like isotopic response occurring after herpes zoster infection was further complicated by local injections at the zoster site for herpes-related local pain. Injection sites are reported as a distinct nidus for Wolf isotopic response.⁹

The pathogenesis of Wolf isotopic response is unclear. Possible explanations include local interactions between persistent viral particles at prior herpes infection sites, vascular injury, neural injury, and an altered immune response.^1,5,6,10 The destruction of sensory nerve fibers by herpesviruses cause the release of neuropeptides that then modulate the local immune system and angiogenic responses.^5,6 Our patient’s immunocompromised state may have further propagated a local altered immune cell infiltrate at the site of the isotopic response. Despite its unclear etiology, Wolf isotopic response should be considered in the differential diagnosis for any patient who presents with a dermatomal eruption at the site of a prior cutaneous infection, particularly after infection with herpes zoster. Treatment with topical or intralesional corticosteroids usually suffices for inflammatory-based isotopic responses with an excellent prognosis.¹¹

We present a case of a cutaneous lupus erythematosus–like isotopic response that occurred at the site of a recent herpes zoster eruption in an immunocompromised patient without prior history of systemic or cutaneous lupus erythematosus. Clinical recognition of Wolf isotopic response is important for accurate histopathologic diagnosis and management. Continued investigation into the underlying pathogenesis should be performed to fully understand and better treat this process.

To the Editor:

Wolf isotopic response describes the development of a skin disorder at the site of another healed and unrelated skin disease. Skin disorders presenting as isotopic responses have included inflammatory, malignant, granulomatous, and infectious processes. Discoid lupus erythematosus (DLE) is a rare isotopic response. We report a cutaneous lupus erythematosus–like isotopic response that presented at the site of a recent herpes zoster infection in a liver transplant recipient.

A 74-year-old immunocompromised woman was referred to the dermatology clinic for evaluation of a rash on the right leg. She was being treated with maintenance valganciclovir due to cytomegalovirus viremia, as well as tacrolimus, azathioprine, and prednisone following liver transplantation due to autoimmune hepatitis for 8 months prior to presentation. Eighteen days prior to the current presentation, she was clinically diagnosed with herpes zoster. As the grouped vesicles from the herpes zoster resolved, she developed pink scaly papules in the same distribution as the original vesicular eruption.

Physical examination revealed numerous erythematous, 2- to 3-mm, scaly papules that coalesced into small plaques with serous crusts; they originated above the supragluteal cleft and extended rightward in the L3 and L4 dermatomes to the right knee (Figure 1). A 3-mm punch biopsy specimen was obtained from the right anterior thigh. Histologic analysis revealed interface lymphocytic inflammation with squamatization of basal keratinocytes, basement membrane thickening, and follicular plugging by keratin (Figure 2). There was a moderately intense perivascular and periadnexal inflammatory infiltrate of mature lymphocytes with rare eosinophils within the papillary and superficial reticular dermis. There was no evidence of a viral cytopathic effect, and an immunohistochemical stain for varicella-zoster virus protein was negative. The histologic findings were suggestive of cutaneous involvement by DLE. A diagnosis of a cutaneous lupus erythematosus–like Wolf isotopic response was made, and the patient’s rash resolved with the use of triamcinolone cream 0.1% applied twice daily for 2 weeks. At 6-week follow-up, there were postinflammatory pigmentation changes at the sites of the prior rash and persistent postherpetic neuralgia. Recent antinuclear antibody screening was negative, coupled with the patient’s lack of systemic symptoms and quick resolution of rash, indicating that additional testing for systemic lupus was not warranted.

Wolf isotopic response describes the occurrence of a new skin disorder at the site of a previously healed and unrelated skin disorder. The second disease may appear within days to years after the primary disease subsides and is clearly differentiated from the isomorphic response of the Koebner phenomenon, which describes an established skin disorder appearing at a previously uninvolved anatomic site following trauma.¹ As in our case, the initial cutaneous eruption resulting in a subsequent Wolf isotopic response frequently is herpes zoster and less commonly is herpes simplex virus.² The most common reported isotopic response is a granulomatous reaction.² Rare reports of leukemic infiltration, lymphoma, lichen planus, morphea, reactive perforating collagenosis, psoriasis, discoid lupus, lichen simplex chronicus, contact dermatitis, xanthomatous changes, malignant tumors, cutaneous graft-vs-host disease, pityriasis rosea, erythema annulare centrifugum, and other infectious-based isotopic responses exist.^2-6

Our patient presented with Wolf isotopic response that histologically mimicked DLE. A PubMed search of articles indexed for MEDLINE using the terms isotopic response and lupus revealed only 3 cases of cutaneous lupus erythematosus presenting as an isotopic response in the English-language literature. One of those cases occurred in a patient with preexisting systemic lupus erythematosus, making a diagnosis of Koebner isomorphic phenomenon more appropriate than an isotopic response at the site of prior herpes zoster infection.⁷ The remaining 2 cases were clinically defined DLE lesions occurring at sites of prior infection—cutaneous leishmaniasis and herpes zoster—in patients without a prior history of cutaneous or systemic lupus erythematosus.^8,9 The latter case of DLE-like isotopic response occurring after herpes zoster infection was further complicated by local injections at the zoster site for herpes-related local pain. Injection sites are reported as a distinct nidus for Wolf isotopic response.⁹

The pathogenesis of Wolf isotopic response is unclear. Possible explanations include local interactions between persistent viral particles at prior herpes infection sites, vascular injury, neural injury, and an altered immune response.^1,5,6,10 The destruction of sensory nerve fibers by herpesviruses cause the release of neuropeptides that then modulate the local immune system and angiogenic responses.^5,6 Our patient’s immunocompromised state may have further propagated a local altered immune cell infiltrate at the site of the isotopic response. Despite its unclear etiology, Wolf isotopic response should be considered in the differential diagnosis for any patient who presents with a dermatomal eruption at the site of a prior cutaneous infection, particularly after infection with herpes zoster. Treatment with topical or intralesional corticosteroids usually suffices for inflammatory-based isotopic responses with an excellent prognosis.¹¹

We present a case of a cutaneous lupus erythematosus–like isotopic response that occurred at the site of a recent herpes zoster eruption in an immunocompromised patient without prior history of systemic or cutaneous lupus erythematosus. Clinical recognition of Wolf isotopic response is important for accurate histopathologic diagnosis and management. Continued investigation into the underlying pathogenesis should be performed to fully understand and better treat this process.

Dupilumab is a humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis. Through inhibition of the IL-4R α subunit, it prevents activation of the IL-4/IL-13 signaling cascade. This dampens the T _H 2 inflammatory response, thereby improving the symptoms associated with atopic dermatitis. ^1,2 Recent literature suggests that dupilumab may be useful in the treatment of other chronic dermatologic conditions, including allergic contact dermatitis (ACD) refractory to allergen avoidance and other treatments. Herein, we provide an overview of ACD, the role that dupilumab may play in its management, and its impact on patch testing results.

Pathogenesis of ACD

Allergic contact dermatitis is a cell-mediated type IV hypersensitivity reaction that develops through 2 distinct stages. In the sensitization phase, an allergen penetrates the skin and subsequently is engulfed by a cutaneous antigen-presenting cell. The allergen is then combined with a peptide to form a complex that is presented to naïve T lymphocytes in regional lymph nodes. The result is clonal expansion of a T-cell population that recognizes the allergen. In the elicitation phase, repeat exposure to the allergen leads to the recruitment of primed T cells to the skin, followed by cytokine release, inflammation, and resultant dermatitis.³

Historically, ACD was thought to be primarily driven by the T_H1 inflammatory response; however, it is now known that T_H2, T_H9, T_H17, and T_H22 also may play a role in its pathogenesis.^4,5 Another key finding is that the immune response in ACD appears to be at least partially allergen specific. Molecular profiling has revealed that nickel primarily induces a T_H1/T_H17 response, while allergens such as fragrance and rubber primarily induce a T_H2 response.⁴

Management of ACD

Allergen avoidance is the mainstay of ACD treatment; however, in some patients, this approach does not always improve symptoms. In addition, eliminating the source of the allergen may not be possible in those with certain occupational, environmental, or medical exposures.

There are no FDA-approved treatments for ACD. When allergen avoidance alone is insufficient, first-line pharmacologic therapy typically includes topical or oral corticosteroids, the choice of which depends on the extent and severity of the dermatitis; however, a steroid-sparing agent often is preferred to avoid the unfavorable effects of long-term steroid use. Other systemic treatments for ACD include methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.⁶ These agents are used for severe ACD and typically are chosen as a last resort due to their immunosuppressive activity.

Phototherapy is another option, often as an adjunct to other therapies. Narrowband UVB and psoralen plus UVA have both been used. Psoralen plus UVA tends to have more side effects; therefore, narrowband UVB often is preferred.^7,8

Use of Dupilumab in ACD

Biologics are unique, as they can target a single step in the immune response to improve a wide variety of symptoms. Research investigating their role as a treatment modality for ACD is still evolving alongside our increasing knowledge of its pathophysiology.⁹ Of note, studies examining the anti–IL-17 biologic secukinumab revealed it to be ineffective against ACD,^10,11 which suggests that targeting specific immune components may not always result in improvement of ACD symptoms, likely because its pathophysiology involves several pathways.

There have been multiple reports demonstrating the effectiveness of dupilumab in the treatment of ACD (eTable).^12-20 The findings from these studies show that dupilumab can improve recalcitrant dermatitis caused by a broad range of contact allergens, including nickel. This highlights its ability to improve ACD caused by allergens with a T_H1 bias, despite its primarily T_H2-dampening effects. Notably, several studies have reported successful use of dupilumab for systemic ACD.^12,18 In addition, dupilumab may be able to improve symptoms of ACD in as little as 1 to 4 weeks. Unlike some systemic therapies for ACD, dupilumab also benefits from its lack of notable immunosuppressive effects.⁹ A phase 4 clinical trial at Brigham and Women’s Hospital (Boston, Massachusetts) is recruiting participants, with a primary goal of investigating dupilumab’s impact on ACD in patients who have not improved despite allergen avoidance (ClinicalTrials.gov identifier NCT03935971).

There are a few potential disadvantages to dupilumab. Because it is not yet FDA approved for the treatment of ACD, insurance companies may deny coverage, making it likely to be unaffordable for most patients. Furthermore, the side-effect profile has not been fully characterized. In addition to ocular adverse effects, a growing number of studies have reported face and neck erythema after starting dupilumab. Although the cause is unclear, one theory is that the inhibition of IL-4/IL-13 leads to T_H1/T_H17 polarization, thereby worsening ACD caused by allergens that activate a T_H1-predominant response.²¹ Finally, not all cases of ACD respond to dupilumab.²²

Patch Testing While on Dupilumab

Diagnosing ACD is a challenging process. An accurate history and physical examination are critical, and patch testing remains the gold standard when it comes to identifying the source of the contact allergen(s).

There is ongoing debate among contact dermatitis experts regarding the diagnostic accuracy of patch testing for those on immunomodulators or immunosuppressants, as these medications can dampen positive results and increase the risk for false-negative readings.²³ Consequently, some have questioned whether patch testing on dupilumab is accurate or feasible.²⁴ Contact dermatitis experts have examined patch testing results before and after initiation of dupilumab to further investigate. Puza and Atwater²⁵ established that patients are able to mount a positive patch test reaction while on dupilumab. Moreover, a retrospective review by Raffi et al²⁶ found that out of 125 before therapy/on therapy patch test pairs, only 13 were lost after administration of dupilumab. Although this would suggest that dupilumab has little impact on patch testing, Jo et al²⁷ found in a systematic review that patch test reactions may remain positive, change to negative, or become newly positive after dupilumab initiation.

This inconsistency in results may relate to the allergen-specific pathogenesis of ACD—one allergen may have a different response to the mechanism of dupilumab than another.^28,29 More recently, de Wijs et al³⁰ reported a series of 20 patients in whom more than two-thirds of prior positive patch test reactions were lost after retesting on dupilumab; there were no clear trends according to the immune polarity of the allergens. This finding suggests that patient-specific factors also should be considered, as this too could have an impact on the reliability of patch test findings after starting dupilumab.²⁹

Final Interpretation

Given its overall excellent safety profile, dupilumab may be a feasible off-label option for patients with ACD that does not respond to allergen avoidance or for those who experience adverse effects from traditional therapies; however, it remains difficult to obtain through insurance because it is not yet FDA approved for ACD. Likewise, its impact on the accuracy of patch testing is not yet well defined. Further investigations are needed to elucidate the pathophysiology of ACD and to guide further use of dupilumab in its treatment.

Dupilumab is a humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis. Through inhibition of the IL-4R α subunit, it prevents activation of the IL-4/IL-13 signaling cascade. This dampens the T _H 2 inflammatory response, thereby improving the symptoms associated with atopic dermatitis. ^1,2 Recent literature suggests that dupilumab may be useful in the treatment of other chronic dermatologic conditions, including allergic contact dermatitis (ACD) refractory to allergen avoidance and other treatments. Herein, we provide an overview of ACD, the role that dupilumab may play in its management, and its impact on patch testing results.

Pathogenesis of ACD

Allergic contact dermatitis is a cell-mediated type IV hypersensitivity reaction that develops through 2 distinct stages. In the sensitization phase, an allergen penetrates the skin and subsequently is engulfed by a cutaneous antigen-presenting cell. The allergen is then combined with a peptide to form a complex that is presented to naïve T lymphocytes in regional lymph nodes. The result is clonal expansion of a T-cell population that recognizes the allergen. In the elicitation phase, repeat exposure to the allergen leads to the recruitment of primed T cells to the skin, followed by cytokine release, inflammation, and resultant dermatitis.³

Historically, ACD was thought to be primarily driven by the T_H1 inflammatory response; however, it is now known that T_H2, T_H9, T_H17, and T_H22 also may play a role in its pathogenesis.^4,5 Another key finding is that the immune response in ACD appears to be at least partially allergen specific. Molecular profiling has revealed that nickel primarily induces a T_H1/T_H17 response, while allergens such as fragrance and rubber primarily induce a T_H2 response.⁴

Management of ACD

Allergen avoidance is the mainstay of ACD treatment; however, in some patients, this approach does not always improve symptoms. In addition, eliminating the source of the allergen may not be possible in those with certain occupational, environmental, or medical exposures.

There are no FDA-approved treatments for ACD. When allergen avoidance alone is insufficient, first-line pharmacologic therapy typically includes topical or oral corticosteroids, the choice of which depends on the extent and severity of the dermatitis; however, a steroid-sparing agent often is preferred to avoid the unfavorable effects of long-term steroid use. Other systemic treatments for ACD include methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.⁶ These agents are used for severe ACD and typically are chosen as a last resort due to their immunosuppressive activity.

Phototherapy is another option, often as an adjunct to other therapies. Narrowband UVB and psoralen plus UVA have both been used. Psoralen plus UVA tends to have more side effects; therefore, narrowband UVB often is preferred.^7,8

Use of Dupilumab in ACD

Biologics are unique, as they can target a single step in the immune response to improve a wide variety of symptoms. Research investigating their role as a treatment modality for ACD is still evolving alongside our increasing knowledge of its pathophysiology.⁹ Of note, studies examining the anti–IL-17 biologic secukinumab revealed it to be ineffective against ACD,^10,11 which suggests that targeting specific immune components may not always result in improvement of ACD symptoms, likely because its pathophysiology involves several pathways.

There have been multiple reports demonstrating the effectiveness of dupilumab in the treatment of ACD (eTable).^12-20 The findings from these studies show that dupilumab can improve recalcitrant dermatitis caused by a broad range of contact allergens, including nickel. This highlights its ability to improve ACD caused by allergens with a T_H1 bias, despite its primarily T_H2-dampening effects. Notably, several studies have reported successful use of dupilumab for systemic ACD.^12,18 In addition, dupilumab may be able to improve symptoms of ACD in as little as 1 to 4 weeks. Unlike some systemic therapies for ACD, dupilumab also benefits from its lack of notable immunosuppressive effects.⁹ A phase 4 clinical trial at Brigham and Women’s Hospital (Boston, Massachusetts) is recruiting participants, with a primary goal of investigating dupilumab’s impact on ACD in patients who have not improved despite allergen avoidance (ClinicalTrials.gov identifier NCT03935971).

There are a few potential disadvantages to dupilumab. Because it is not yet FDA approved for the treatment of ACD, insurance companies may deny coverage, making it likely to be unaffordable for most patients. Furthermore, the side-effect profile has not been fully characterized. In addition to ocular adverse effects, a growing number of studies have reported face and neck erythema after starting dupilumab. Although the cause is unclear, one theory is that the inhibition of IL-4/IL-13 leads to T_H1/T_H17 polarization, thereby worsening ACD caused by allergens that activate a T_H1-predominant response.²¹ Finally, not all cases of ACD respond to dupilumab.²²

Patch Testing While on Dupilumab

Diagnosing ACD is a challenging process. An accurate history and physical examination are critical, and patch testing remains the gold standard when it comes to identifying the source of the contact allergen(s).

There is ongoing debate among contact dermatitis experts regarding the diagnostic accuracy of patch testing for those on immunomodulators or immunosuppressants, as these medications can dampen positive results and increase the risk for false-negative readings.²³ Consequently, some have questioned whether patch testing on dupilumab is accurate or feasible.²⁴ Contact dermatitis experts have examined patch testing results before and after initiation of dupilumab to further investigate. Puza and Atwater²⁵ established that patients are able to mount a positive patch test reaction while on dupilumab. Moreover, a retrospective review by Raffi et al²⁶ found that out of 125 before therapy/on therapy patch test pairs, only 13 were lost after administration of dupilumab. Although this would suggest that dupilumab has little impact on patch testing, Jo et al²⁷ found in a systematic review that patch test reactions may remain positive, change to negative, or become newly positive after dupilumab initiation.

This inconsistency in results may relate to the allergen-specific pathogenesis of ACD—one allergen may have a different response to the mechanism of dupilumab than another.^28,29 More recently, de Wijs et al³⁰ reported a series of 20 patients in whom more than two-thirds of prior positive patch test reactions were lost after retesting on dupilumab; there were no clear trends according to the immune polarity of the allergens. This finding suggests that patient-specific factors also should be considered, as this too could have an impact on the reliability of patch test findings after starting dupilumab.²⁹

Final Interpretation

Given its overall excellent safety profile, dupilumab may be a feasible off-label option for patients with ACD that does not respond to allergen avoidance or for those who experience adverse effects from traditional therapies; however, it remains difficult to obtain through insurance because it is not yet FDA approved for ACD. Likewise, its impact on the accuracy of patch testing is not yet well defined. Further investigations are needed to elucidate the pathophysiology of ACD and to guide further use of dupilumab in its treatment.

Dupilumab is a humanized monoclonal antibody approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe atopic dermatitis. Through inhibition of the IL-4R α subunit, it prevents activation of the IL-4/IL-13 signaling cascade. This dampens the T _H 2 inflammatory response, thereby improving the symptoms associated with atopic dermatitis. ^1,2 Recent literature suggests that dupilumab may be useful in the treatment of other chronic dermatologic conditions, including allergic contact dermatitis (ACD) refractory to allergen avoidance and other treatments. Herein, we provide an overview of ACD, the role that dupilumab may play in its management, and its impact on patch testing results.

Pathogenesis of ACD

Allergic contact dermatitis is a cell-mediated type IV hypersensitivity reaction that develops through 2 distinct stages. In the sensitization phase, an allergen penetrates the skin and subsequently is engulfed by a cutaneous antigen-presenting cell. The allergen is then combined with a peptide to form a complex that is presented to naïve T lymphocytes in regional lymph nodes. The result is clonal expansion of a T-cell population that recognizes the allergen. In the elicitation phase, repeat exposure to the allergen leads to the recruitment of primed T cells to the skin, followed by cytokine release, inflammation, and resultant dermatitis.³

Historically, ACD was thought to be primarily driven by the T_H1 inflammatory response; however, it is now known that T_H2, T_H9, T_H17, and T_H22 also may play a role in its pathogenesis.^4,5 Another key finding is that the immune response in ACD appears to be at least partially allergen specific. Molecular profiling has revealed that nickel primarily induces a T_H1/T_H17 response, while allergens such as fragrance and rubber primarily induce a T_H2 response.⁴

Management of ACD

Allergen avoidance is the mainstay of ACD treatment; however, in some patients, this approach does not always improve symptoms. In addition, eliminating the source of the allergen may not be possible in those with certain occupational, environmental, or medical exposures.

There are no FDA-approved treatments for ACD. When allergen avoidance alone is insufficient, first-line pharmacologic therapy typically includes topical or oral corticosteroids, the choice of which depends on the extent and severity of the dermatitis; however, a steroid-sparing agent often is preferred to avoid the unfavorable effects of long-term steroid use. Other systemic treatments for ACD include methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine.⁶ These agents are used for severe ACD and typically are chosen as a last resort due to their immunosuppressive activity.

Phototherapy is another option, often as an adjunct to other therapies. Narrowband UVB and psoralen plus UVA have both been used. Psoralen plus UVA tends to have more side effects; therefore, narrowband UVB often is preferred.^7,8

Use of Dupilumab in ACD

Biologics are unique, as they can target a single step in the immune response to improve a wide variety of symptoms. Research investigating their role as a treatment modality for ACD is still evolving alongside our increasing knowledge of its pathophysiology.⁹ Of note, studies examining the anti–IL-17 biologic secukinumab revealed it to be ineffective against ACD,^10,11 which suggests that targeting specific immune components may not always result in improvement of ACD symptoms, likely because its pathophysiology involves several pathways.

There have been multiple reports demonstrating the effectiveness of dupilumab in the treatment of ACD (eTable).^12-20 The findings from these studies show that dupilumab can improve recalcitrant dermatitis caused by a broad range of contact allergens, including nickel. This highlights its ability to improve ACD caused by allergens with a T_H1 bias, despite its primarily T_H2-dampening effects. Notably, several studies have reported successful use of dupilumab for systemic ACD.^12,18 In addition, dupilumab may be able to improve symptoms of ACD in as little as 1 to 4 weeks. Unlike some systemic therapies for ACD, dupilumab also benefits from its lack of notable immunosuppressive effects.⁹ A phase 4 clinical trial at Brigham and Women’s Hospital (Boston, Massachusetts) is recruiting participants, with a primary goal of investigating dupilumab’s impact on ACD in patients who have not improved despite allergen avoidance (ClinicalTrials.gov identifier NCT03935971).

There are a few potential disadvantages to dupilumab. Because it is not yet FDA approved for the treatment of ACD, insurance companies may deny coverage, making it likely to be unaffordable for most patients. Furthermore, the side-effect profile has not been fully characterized. In addition to ocular adverse effects, a growing number of studies have reported face and neck erythema after starting dupilumab. Although the cause is unclear, one theory is that the inhibition of IL-4/IL-13 leads to T_H1/T_H17 polarization, thereby worsening ACD caused by allergens that activate a T_H1-predominant response.²¹ Finally, not all cases of ACD respond to dupilumab.²²

Patch Testing While on Dupilumab

Diagnosing ACD is a challenging process. An accurate history and physical examination are critical, and patch testing remains the gold standard when it comes to identifying the source of the contact allergen(s).

There is ongoing debate among contact dermatitis experts regarding the diagnostic accuracy of patch testing for those on immunomodulators or immunosuppressants, as these medications can dampen positive results and increase the risk for false-negative readings.²³ Consequently, some have questioned whether patch testing on dupilumab is accurate or feasible.²⁴ Contact dermatitis experts have examined patch testing results before and after initiation of dupilumab to further investigate. Puza and Atwater²⁵ established that patients are able to mount a positive patch test reaction while on dupilumab. Moreover, a retrospective review by Raffi et al²⁶ found that out of 125 before therapy/on therapy patch test pairs, only 13 were lost after administration of dupilumab. Although this would suggest that dupilumab has little impact on patch testing, Jo et al²⁷ found in a systematic review that patch test reactions may remain positive, change to negative, or become newly positive after dupilumab initiation.

This inconsistency in results may relate to the allergen-specific pathogenesis of ACD—one allergen may have a different response to the mechanism of dupilumab than another.^28,29 More recently, de Wijs et al³⁰ reported a series of 20 patients in whom more than two-thirds of prior positive patch test reactions were lost after retesting on dupilumab; there were no clear trends according to the immune polarity of the allergens. This finding suggests that patient-specific factors also should be considered, as this too could have an impact on the reliability of patch test findings after starting dupilumab.²⁹

Final Interpretation

Given its overall excellent safety profile, dupilumab may be a feasible off-label option for patients with ACD that does not respond to allergen avoidance or for those who experience adverse effects from traditional therapies; however, it remains difficult to obtain through insurance because it is not yet FDA approved for ACD. Likewise, its impact on the accuracy of patch testing is not yet well defined. Further investigations are needed to elucidate the pathophysiology of ACD and to guide further use of dupilumab in its treatment.