Cutis

Fleas (order Siphonaptera) are vectors for various diseases, such as plague (as carriers of Yersinia pestis) and rickettsial infections.^1-4 The sticktight flea (Echidnophaga gallinacea) commonly is seen on birds and mammals, including ground squirrels, dogs, cats, and rodents, and can attach to its host for days at a time by burrowing its head into the skin. Similar to other fleas, the sticktight flea needs a blood supply to reproduce.⁵ Therefore, it is important to study the sticktight flea, its habitat, and infection patterns to improve public health and prevent infestation.

Identification

Echidnophaga gallinacea is named for the female flea’s behavior—it “sticks tight” to the surface of the host by embedding its head into the skin for days at a time.⁵ The sticktight flea and the rat flea (Xenopsylla cheopis) can be differentiated by the sticktight’s reduced thorax and lack of a pleural rod (the vertical ridge that divides the mesosternum above the second pair of legs)(Figure, A and B). The sticktight flea can be differentiated from the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) by its lack of genal ctenidia (horizontal combs in the mustache area) and pronotal ctenidia (vertical combs behind the head)(Figure, B and C).^6,7 Other defining features of E gallinacea include 2 pairs of large postantennal setae (hairs) on its anteriorly flattened head; a C-shaped reproductive organ known as the spermatheca; and broad maxillary lacinia (Figure, C).⁸

Habitat, Seasonality, and Behavior

Echidnophaga gallinacea commonly infests the comb, wattles, and surrounding ears of chickens; the flea also has been found on dogs, cats, rodents, and other species of birds.⁹ The sticktight flea is more prevalent in summer and autumn, which may explain its predominance in warmer climates, including California, Florida, Mexico, Egypt, Africa, and Iran.^1,9-11

When a female sticktight flea begins to feed, it stays on the host for days at a time, waiting for a male.⁵ The female deposits its fertilized eggs in nests on the host or in lesions caused by infestation. Eventually, eggs hatch and fall into soil, where they lay dormant or grow to adulthood.⁵

Cutaneous Reaction to Infestation

Flea bites cause a hypersensitivity reaction, with pruritic pustules and erythematous papules that have a central punctum.¹² In a reported case in Los Angeles, California, a female sticktight flea buried itself into the cheek of a young boy for more than 12 hours. The lesion was not marked by surrounding erythema, tenderness, pruritus, or swelling; however, several days after the flea was removed, erythema developed at the site then spontaneously resolved.⁷ In a study of dogs that were infested with E gallinacea, the flea never disengaged to attach to a human; when the flea was deliberately placed on a human, it fed and left hastily.¹¹

Management

Because E gallinacea burrows its head into the skin, the best removal method is applying slow gentle traction under sterile conditions to ensure removal of mouthparts.⁷ An oral antihistamine can be administered or a topical antihistamine or corticosteroid can be applied to the affected area.¹² Flea infestation should be treated with an insecticide. Affected animals should be treated by a veterinarian using a pesticide, such as fipronil, selamectin, imidacloprid, metaflumizone, nitenpyram, lufenuron, methoprene, or pyriproxyfen.¹³

Fleas (order Siphonaptera) are vectors for various diseases, such as plague (as carriers of Yersinia pestis) and rickettsial infections.^1-4 The sticktight flea (Echidnophaga gallinacea) commonly is seen on birds and mammals, including ground squirrels, dogs, cats, and rodents, and can attach to its host for days at a time by burrowing its head into the skin. Similar to other fleas, the sticktight flea needs a blood supply to reproduce.⁵ Therefore, it is important to study the sticktight flea, its habitat, and infection patterns to improve public health and prevent infestation.

Identification

Echidnophaga gallinacea is named for the female flea’s behavior—it “sticks tight” to the surface of the host by embedding its head into the skin for days at a time.⁵ The sticktight flea and the rat flea (Xenopsylla cheopis) can be differentiated by the sticktight’s reduced thorax and lack of a pleural rod (the vertical ridge that divides the mesosternum above the second pair of legs)(Figure, A and B). The sticktight flea can be differentiated from the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) by its lack of genal ctenidia (horizontal combs in the mustache area) and pronotal ctenidia (vertical combs behind the head)(Figure, B and C).^6,7 Other defining features of E gallinacea include 2 pairs of large postantennal setae (hairs) on its anteriorly flattened head; a C-shaped reproductive organ known as the spermatheca; and broad maxillary lacinia (Figure, C).⁸

Habitat, Seasonality, and Behavior

Echidnophaga gallinacea commonly infests the comb, wattles, and surrounding ears of chickens; the flea also has been found on dogs, cats, rodents, and other species of birds.⁹ The sticktight flea is more prevalent in summer and autumn, which may explain its predominance in warmer climates, including California, Florida, Mexico, Egypt, Africa, and Iran.^1,9-11

When a female sticktight flea begins to feed, it stays on the host for days at a time, waiting for a male.⁵ The female deposits its fertilized eggs in nests on the host or in lesions caused by infestation. Eventually, eggs hatch and fall into soil, where they lay dormant or grow to adulthood.⁵

Cutaneous Reaction to Infestation

Flea bites cause a hypersensitivity reaction, with pruritic pustules and erythematous papules that have a central punctum.¹² In a reported case in Los Angeles, California, a female sticktight flea buried itself into the cheek of a young boy for more than 12 hours. The lesion was not marked by surrounding erythema, tenderness, pruritus, or swelling; however, several days after the flea was removed, erythema developed at the site then spontaneously resolved.⁷ In a study of dogs that were infested with E gallinacea, the flea never disengaged to attach to a human; when the flea was deliberately placed on a human, it fed and left hastily.¹¹

Management

Because E gallinacea burrows its head into the skin, the best removal method is applying slow gentle traction under sterile conditions to ensure removal of mouthparts.⁷ An oral antihistamine can be administered or a topical antihistamine or corticosteroid can be applied to the affected area.¹² Flea infestation should be treated with an insecticide. Affected animals should be treated by a veterinarian using a pesticide, such as fipronil, selamectin, imidacloprid, metaflumizone, nitenpyram, lufenuron, methoprene, or pyriproxyfen.¹³

Fleas (order Siphonaptera) are vectors for various diseases, such as plague (as carriers of Yersinia pestis) and rickettsial infections.^1-4 The sticktight flea (Echidnophaga gallinacea) commonly is seen on birds and mammals, including ground squirrels, dogs, cats, and rodents, and can attach to its host for days at a time by burrowing its head into the skin. Similar to other fleas, the sticktight flea needs a blood supply to reproduce.⁵ Therefore, it is important to study the sticktight flea, its habitat, and infection patterns to improve public health and prevent infestation.

Identification

Echidnophaga gallinacea is named for the female flea’s behavior—it “sticks tight” to the surface of the host by embedding its head into the skin for days at a time.⁵ The sticktight flea and the rat flea (Xenopsylla cheopis) can be differentiated by the sticktight’s reduced thorax and lack of a pleural rod (the vertical ridge that divides the mesosternum above the second pair of legs)(Figure, A and B). The sticktight flea can be differentiated from the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) by its lack of genal ctenidia (horizontal combs in the mustache area) and pronotal ctenidia (vertical combs behind the head)(Figure, B and C).^6,7 Other defining features of E gallinacea include 2 pairs of large postantennal setae (hairs) on its anteriorly flattened head; a C-shaped reproductive organ known as the spermatheca; and broad maxillary lacinia (Figure, C).⁸

Habitat, Seasonality, and Behavior

Echidnophaga gallinacea commonly infests the comb, wattles, and surrounding ears of chickens; the flea also has been found on dogs, cats, rodents, and other species of birds.⁹ The sticktight flea is more prevalent in summer and autumn, which may explain its predominance in warmer climates, including California, Florida, Mexico, Egypt, Africa, and Iran.^1,9-11

When a female sticktight flea begins to feed, it stays on the host for days at a time, waiting for a male.⁵ The female deposits its fertilized eggs in nests on the host or in lesions caused by infestation. Eventually, eggs hatch and fall into soil, where they lay dormant or grow to adulthood.⁵

Cutaneous Reaction to Infestation

Flea bites cause a hypersensitivity reaction, with pruritic pustules and erythematous papules that have a central punctum.¹² In a reported case in Los Angeles, California, a female sticktight flea buried itself into the cheek of a young boy for more than 12 hours. The lesion was not marked by surrounding erythema, tenderness, pruritus, or swelling; however, several days after the flea was removed, erythema developed at the site then spontaneously resolved.⁷ In a study of dogs that were infested with E gallinacea, the flea never disengaged to attach to a human; when the flea was deliberately placed on a human, it fed and left hastily.¹¹

Management

Because E gallinacea burrows its head into the skin, the best removal method is applying slow gentle traction under sterile conditions to ensure removal of mouthparts.⁷ An oral antihistamine can be administered or a topical antihistamine or corticosteroid can be applied to the affected area.¹² Flea infestation should be treated with an insecticide. Affected animals should be treated by a veterinarian using a pesticide, such as fipronil, selamectin, imidacloprid, metaflumizone, nitenpyram, lufenuron, methoprene, or pyriproxyfen.¹³

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

Complex medical dermatology has become an emerging field in dermatology. Although a rather protean and broad term, complex medical dermatology encompasses patients with autoimmune conditions, bullous disease, connective tissue disease, vasculitis, severe dermatoses requiring immunomodulation, and inpatient consultations. Importantly, dermatology inpatient consultations aid in lowering health care costs due to accurate diagnoses, correct treatment, and decreased hospital stays.¹ A fellowship is not required for holding an inpatient role in the hospital system as a dermatologist but can be beneficial. There are combined internal medicine–dermatology programs available for medical students applying to dermatology residency, but a complex medical dermatology fellowship is an option after residency for those who are interested. I believe that a focused complex medical dermatology fellowship differs from the training offered in combined internal medicine–dermatology residency. My fellow colleagues in combined internal medicine–dermatology programs are exposed to systemic manifestations of cutaneous disease and are experts in the interplay between the skin and other organ systems. However, the focus of their programs is with the intention of becoming double boarded in internal medicine and dermatology with comprehensive exposure to both fields. In my fellowship, I am able to tailor my schedule to focus on any dermatologic disease such as connective tissue disease, pruritus, graft vs host disease, and Merkel cell carcinoma. I ultimately can determine a niche in dermatology and hone my skills for a year under supervision.

Available Fellowships

Fellowship Locations—Importantly, the complex medical dermatology fellowship is not accredited by the Accreditation Council for Graduate Medical Education, which can make it difficult to identify and apply to programs. The complex medical dermatology fellowship is different than a rheumatology-dermatology fellowship, cutaneous oncology fellowship, pediatric dermatology fellowship, or other subspecialty fellowships such as those in itch or autoimmune blistering diseases. The fellowship often encompasses gaining clinical expertise in many of these conditions. I performed a thorough search online and spoke with complex medical dermatologists to compile a list of programs that offer a complex medical dermatology fellowship: Brigham and Women’s Hospital (Boston, Massachusetts); University of California San Francisco (San Francisco, California); University of Pennsylvania (Philadelphia, Pennsylvania); Cleveland Clinic (Cleveland, Ohio); and New York University (New York, New York)(Table). Only 1 spot is offered at each of these programs.

Reason to Pursue the Fellowship—There are many reasons to pursue a fellowship in complex medical dermatology such as a desire to enhance exposure to the field, to practice in an academic center and develop a niche within dermatology, to practice dermatology in an inpatient setting, to improve delivery of health care to medically challenging populations in a community setting, and to become an expert on cutaneous manifestations of internal and systemic disease.

Application—There is no standardized application or deadline for this fellowship; however, there is a concerted attempt from some of the programs to offer interviews and decisions at a similar time. Deadlines and contact information are listed on the program websites, along with more details (Table).

Recommendations—I would recommend reaching out at the beginning of postgraduate year (PGY) 4 to these programs and voicing your interest in the fellowship. It is possible to set up an away rotation at some of the programs, and if your program offers elective time, pursuing an away rotation during PGY-3 or early in PGY-4 can prove to be advantageous. Furthermore, during my application cycle I toured the University of California San Francisco, University of Pennsylvania, and Brigham and Women’s Hospital to gain further insight into each program.

Brigham and Women’s Complex Medical Dermatology Fellowship

I am currently the complex medical dermatology fellow at Brigham and Women’s Hospital, and it has been an outstanding experience thus far. The program offers numerous subspecialty clinics focusing solely on cutaneous-oncodermatology, psoriasis, rheumatology-dermatology, skin of color, mole mapping backed by artificial intelligence, cosmetics, high-risk skin cancer, neutrophilic dermatoses, patch testing, phototherapy, psychodermatology, and transplant dermatology. In addition to a wide variety of subspecialty clinics, fellows have the opportunity to participate in inpatient dermatology rounds and act as a junior attending. I appreciate the flexibility of this program combined with the ability to work alongside worldwide experts. There are numerous teaching opportunities, and all of the faculty are amiable and intelligent and emphasize wellness, education, and autonomy. Overall, my experience and decision to pursue a complex medical dermatology fellowship has been extremely rewarding and invaluable. I am gaining additional skills to aid medically challenging patients while pursuing my true passion in dermatology.

Complex medical dermatology has become an emerging field in dermatology. Although a rather protean and broad term, complex medical dermatology encompasses patients with autoimmune conditions, bullous disease, connective tissue disease, vasculitis, severe dermatoses requiring immunomodulation, and inpatient consultations. Importantly, dermatology inpatient consultations aid in lowering health care costs due to accurate diagnoses, correct treatment, and decreased hospital stays.¹ A fellowship is not required for holding an inpatient role in the hospital system as a dermatologist but can be beneficial. There are combined internal medicine–dermatology programs available for medical students applying to dermatology residency, but a complex medical dermatology fellowship is an option after residency for those who are interested. I believe that a focused complex medical dermatology fellowship differs from the training offered in combined internal medicine–dermatology residency. My fellow colleagues in combined internal medicine–dermatology programs are exposed to systemic manifestations of cutaneous disease and are experts in the interplay between the skin and other organ systems. However, the focus of their programs is with the intention of becoming double boarded in internal medicine and dermatology with comprehensive exposure to both fields. In my fellowship, I am able to tailor my schedule to focus on any dermatologic disease such as connective tissue disease, pruritus, graft vs host disease, and Merkel cell carcinoma. I ultimately can determine a niche in dermatology and hone my skills for a year under supervision.

Available Fellowships

Fellowship Locations—Importantly, the complex medical dermatology fellowship is not accredited by the Accreditation Council for Graduate Medical Education, which can make it difficult to identify and apply to programs. The complex medical dermatology fellowship is different than a rheumatology-dermatology fellowship, cutaneous oncology fellowship, pediatric dermatology fellowship, or other subspecialty fellowships such as those in itch or autoimmune blistering diseases. The fellowship often encompasses gaining clinical expertise in many of these conditions. I performed a thorough search online and spoke with complex medical dermatologists to compile a list of programs that offer a complex medical dermatology fellowship: Brigham and Women’s Hospital (Boston, Massachusetts); University of California San Francisco (San Francisco, California); University of Pennsylvania (Philadelphia, Pennsylvania); Cleveland Clinic (Cleveland, Ohio); and New York University (New York, New York)(Table). Only 1 spot is offered at each of these programs.

Reason to Pursue the Fellowship—There are many reasons to pursue a fellowship in complex medical dermatology such as a desire to enhance exposure to the field, to practice in an academic center and develop a niche within dermatology, to practice dermatology in an inpatient setting, to improve delivery of health care to medically challenging populations in a community setting, and to become an expert on cutaneous manifestations of internal and systemic disease.

Application—There is no standardized application or deadline for this fellowship; however, there is a concerted attempt from some of the programs to offer interviews and decisions at a similar time. Deadlines and contact information are listed on the program websites, along with more details (Table).

Recommendations—I would recommend reaching out at the beginning of postgraduate year (PGY) 4 to these programs and voicing your interest in the fellowship. It is possible to set up an away rotation at some of the programs, and if your program offers elective time, pursuing an away rotation during PGY-3 or early in PGY-4 can prove to be advantageous. Furthermore, during my application cycle I toured the University of California San Francisco, University of Pennsylvania, and Brigham and Women’s Hospital to gain further insight into each program.

Brigham and Women’s Complex Medical Dermatology Fellowship

I am currently the complex medical dermatology fellow at Brigham and Women’s Hospital, and it has been an outstanding experience thus far. The program offers numerous subspecialty clinics focusing solely on cutaneous-oncodermatology, psoriasis, rheumatology-dermatology, skin of color, mole mapping backed by artificial intelligence, cosmetics, high-risk skin cancer, neutrophilic dermatoses, patch testing, phototherapy, psychodermatology, and transplant dermatology. In addition to a wide variety of subspecialty clinics, fellows have the opportunity to participate in inpatient dermatology rounds and act as a junior attending. I appreciate the flexibility of this program combined with the ability to work alongside worldwide experts. There are numerous teaching opportunities, and all of the faculty are amiable and intelligent and emphasize wellness, education, and autonomy. Overall, my experience and decision to pursue a complex medical dermatology fellowship has been extremely rewarding and invaluable. I am gaining additional skills to aid medically challenging patients while pursuing my true passion in dermatology.

Complex medical dermatology has become an emerging field in dermatology. Although a rather protean and broad term, complex medical dermatology encompasses patients with autoimmune conditions, bullous disease, connective tissue disease, vasculitis, severe dermatoses requiring immunomodulation, and inpatient consultations. Importantly, dermatology inpatient consultations aid in lowering health care costs due to accurate diagnoses, correct treatment, and decreased hospital stays.¹ A fellowship is not required for holding an inpatient role in the hospital system as a dermatologist but can be beneficial. There are combined internal medicine–dermatology programs available for medical students applying to dermatology residency, but a complex medical dermatology fellowship is an option after residency for those who are interested. I believe that a focused complex medical dermatology fellowship differs from the training offered in combined internal medicine–dermatology residency. My fellow colleagues in combined internal medicine–dermatology programs are exposed to systemic manifestations of cutaneous disease and are experts in the interplay between the skin and other organ systems. However, the focus of their programs is with the intention of becoming double boarded in internal medicine and dermatology with comprehensive exposure to both fields. In my fellowship, I am able to tailor my schedule to focus on any dermatologic disease such as connective tissue disease, pruritus, graft vs host disease, and Merkel cell carcinoma. I ultimately can determine a niche in dermatology and hone my skills for a year under supervision.

Available Fellowships

Fellowship Locations—Importantly, the complex medical dermatology fellowship is not accredited by the Accreditation Council for Graduate Medical Education, which can make it difficult to identify and apply to programs. The complex medical dermatology fellowship is different than a rheumatology-dermatology fellowship, cutaneous oncology fellowship, pediatric dermatology fellowship, or other subspecialty fellowships such as those in itch or autoimmune blistering diseases. The fellowship often encompasses gaining clinical expertise in many of these conditions. I performed a thorough search online and spoke with complex medical dermatologists to compile a list of programs that offer a complex medical dermatology fellowship: Brigham and Women’s Hospital (Boston, Massachusetts); University of California San Francisco (San Francisco, California); University of Pennsylvania (Philadelphia, Pennsylvania); Cleveland Clinic (Cleveland, Ohio); and New York University (New York, New York)(Table). Only 1 spot is offered at each of these programs.

Reason to Pursue the Fellowship—There are many reasons to pursue a fellowship in complex medical dermatology such as a desire to enhance exposure to the field, to practice in an academic center and develop a niche within dermatology, to practice dermatology in an inpatient setting, to improve delivery of health care to medically challenging populations in a community setting, and to become an expert on cutaneous manifestations of internal and systemic disease.

Application—There is no standardized application or deadline for this fellowship; however, there is a concerted attempt from some of the programs to offer interviews and decisions at a similar time. Deadlines and contact information are listed on the program websites, along with more details (Table).

Recommendations—I would recommend reaching out at the beginning of postgraduate year (PGY) 4 to these programs and voicing your interest in the fellowship. It is possible to set up an away rotation at some of the programs, and if your program offers elective time, pursuing an away rotation during PGY-3 or early in PGY-4 can prove to be advantageous. Furthermore, during my application cycle I toured the University of California San Francisco, University of Pennsylvania, and Brigham and Women’s Hospital to gain further insight into each program.

Brigham and Women’s Complex Medical Dermatology Fellowship

I am currently the complex medical dermatology fellow at Brigham and Women’s Hospital, and it has been an outstanding experience thus far. The program offers numerous subspecialty clinics focusing solely on cutaneous-oncodermatology, psoriasis, rheumatology-dermatology, skin of color, mole mapping backed by artificial intelligence, cosmetics, high-risk skin cancer, neutrophilic dermatoses, patch testing, phototherapy, psychodermatology, and transplant dermatology. In addition to a wide variety of subspecialty clinics, fellows have the opportunity to participate in inpatient dermatology rounds and act as a junior attending. I appreciate the flexibility of this program combined with the ability to work alongside worldwide experts. There are numerous teaching opportunities, and all of the faculty are amiable and intelligent and emphasize wellness, education, and autonomy. Overall, my experience and decision to pursue a complex medical dermatology fellowship has been extremely rewarding and invaluable. I am gaining additional skills to aid medically challenging patients while pursuing my true passion in dermatology.

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Pseudofolliculitis barbae (PFB)(also referred to as razor bumps) is a skin disease of the face and neck caused by shaving and remains prevalent in the US Military. As the sharpened ends of curly hair strands penetrate back into the epidermis, they can trigger inflammatory reactions, leading to papules and pustules as well as hyperpigmentation and scarring.¹ Although anyone with thick curly hair can develop PFB, Black individuals are disproportionately affected, with 45% to 83% reporting PFB symptoms compared with 18% of White individuals.² In this article, we review the treatments and current policies on PFB in the military.

Treatment Options

Shaving Guidelines—Daily shaving remains the grooming standard for US service members who are encouraged to follow prescribed grooming techniques to prevent mild cases of PFB, defined as having “few, scattered papules with scant hair growth of the beard area,” according to the technical bulletin of the US Army, which provides the most detailed guidelines among the branches.³ The bulletin recommends hydrating the face with warm water, followed by a preshave lotion and shaving with a single pass superiorly to inferiorly. Following shaving, postrazor hydration lotion is recommended. Single-bladed razors are preferred, as there is less trauma to existing PFB and less potential for hair retraction under the epidermis, though multibladed razors can be used with adequate preshave and postrazor hydration.⁴ Shaving can be undertaken in the evening to ensure adequate time for preshave preparation and postshave hydration. Waterless shaving uses waterless soaps or lotions containing α-hydroxy acid just prior to shaving in lieu of preshaving and postshaving procedures.⁴

Topical Medications—For PFB cases that are recalcitrant to management by changes in shaving, topical retinoids are commonly prescribed, as they reduce follicular hyperkeratosis that may lead to PFB.⁵ The Army medical bulletin recommends a pea-sized amount of tretinoin cream or gel 0.025%, 0.05%, or 0.1% for moderate cases, defined as “heavier beard growth, more scattered papules, no evidence of pustules or denudation.”³ Adapalene cream 0.1% may be used instead of tretinoin for sensitive skin. Oral doxycycline or topical benzoyl peroxide–clindamycin may be added for secondary bacterial skin infections. Clinical trials have demonstrated that combination benzoyl peroxide–clindamycin significantly reduces papules and pustules in up to 63% of patients with PFB (P<.029).⁶ Azelaic acid can be prescribed for prominent postinflammatory hyperpigmentation. The bulletin also suggests depilatories such as barium sulfide to obtund the hair ends and make them less likely to re-enter the skin surface, though it notes low compliance rates due to strong sulfur odor, messy application, and irritation and reactions to ingredients in the preparations.⁴

Shaving Waivers and Laser Hair Removal—The definitive treatment of PFB is to not shave, and a shaving waiver or laser hair removal (LHR) are the best options for severe PFB or PFB refractory to other treatments. A shaving waiver (or shaving profile) allows for growth of up to 0.25 inches of facial hair with maintenance of the length using clippers. The shaving profile typically is issued by the referring primary care manager (PCM) but also can be recommended by a dermatologist. Each military branch implements different regulations on shaving profiles, which complicates care delivery at joint-service military treatment facilities (MTFs). The Table provides guidelines that govern the management of PFB by the US Army, Air Force, Navy, and Marine Corps. The issuance and duration of shaving waivers vary by service.

Laser hair removal therapy uses high-wavelength lasers that largely bypass the melanocyte-containing basal layer and selectively target hair follicles located deeper in the skin, which results in precise hair reduction with relative sparing of the epidermis.¹⁶ Clinical trials at military clinics have demonstrated that treatments with the 1064-nm long-pulse Nd:YAG laser generally are safe and effective in impeding hair growth in Fitzpatrick skin types IV, V, and VI.¹⁷ This laser, along with the Alexandrite 755-nm long-pulse laser for Fitzpatrick skin types I to III, is widely available and used for LHR at MTFs that house dermatologists. Eflornithine cream 13.9%, which is approved by the US Food and Drug Administration to treat hirsutism, can be used as monotherapy for treatment of PFB and has a synergistic depilatory effect in PFB patients when used in conjunction with LHR.^18,19 Laser hair removal treatments can induce a permanent change in facial hair density and pattern of growth. Side effects and complications of LHR include discomfort during treatment and, in rare instances, blistering and dyspigmentation of the skin as well as paradoxical hair growth.¹⁷

TRICARE, the uniformed health care program, covers LHR in the civilian sector if the following criteria are met: candidates must work in an environment that may require breathing protection, and they must have failed conservative therapy; an MTF dermatologist must evaluate each case and attempt LHR at an MTF to limit outside referrals; and the MTF dermatologist must process each outside referral claim to completion and ensure that the LHR is rendered by a civilian dermatologist and is consistent with branch-specific policies.²⁰

Service Policies on PFB

Army—The Army technical bulletin breaks down the treatment of PFB based on mild, moderate, and severe conditions.³ For mild conditions, a trial of shaving every 2 or 3 days until resolution is recommended. For moderate PFB, topical tretinoin as well as shaving every 2 to 3 days is recommended. For severe conditions, temporary beard growth with issuance of a temporary shaving profile up to 90 days is authorized.³

The technical bulletin also allows a permanent shaving profile for soldiers who demonstrate a severe adverse reaction to treatment or progression of the disease despite a trial of all these methods.³ The regulation stipulates that 0.125 to 0.25 inches of beard growth usually is sufficient to prevent PFB. Patients on profiles must be re-evaluated by a PCM or a dermatologist at least once a year.³

Air Force—Air Force Instruction 44-102 delegates PFB treatment and management strategies to each individual MTF, which allows for decentralized management of PFB, resulting in treatment protocols that can differ from one MTF to another.⁷ Since 2020, waivers have been valid for 5 years regardless of deployment or permanent change of station location. Previously, shaving profiles required annual renewals.⁷ Special duties, such as Honor Guard, Thunderbirds, Special Warfare Mission Support, recruiters, and the Air Force Band, often follow the professional appearance standards more strictly. Until recently, the Honor Guard used to reassign those with long-term medical shaving waivers but now allows airmen with shaving profiles to serve with exceptions (eg, shaving before ceremonies).²¹

Navy—BUPERS (Bureau of Naval Personnel) Instruction 1000.22C divides PFB severity into 2 categories.⁸ For mild to moderate PFB cases, topical tretinoin and adapalene are recommended, along with improved shaving hygiene practices. As an alternative to topical steroids, topical eflornithine monotherapy can be used twice daily for 60 days. For moderate to severe PFB cases, continued grooming modifications and LHR at military clinics with dermatologic services are expected.⁸

Naval administrative memorandum NAVADMIN 064/22 (released in 2022) no longer requires sailors with a shaving “chit,” or shaving waiver, to fully grow out their beards.⁹ Sailors may now outline or edge their beards as long as doing so does not trigger a skin irritation or outbreak. Furthermore, sailors are no longer required to carry a physical copy of their shaving chit at all times. Laser hair removal for sailors with PFB is now considered optional, whereas sailors with severe PFB were previously expected to receive LHR.⁹

Marine Corps—The Marine Corps endorses a 4-phase treatment algorithm (Table). As of January 2022, permanent shaving chits are authorized. Marines no longer need to carry physical copies of their chits at all times and cannot be separated from service because of PFB.¹⁰ New updates explicitly state that medical officers, not the commanding officers, now have final authority for granting shaving chits.¹¹

Final Thoughts

The Army provides the most detailed bulletin, which defines the clinical features and treatments expected for each stage of PFB. All 4 service branches permit temporary profiles, albeit for different lengths of time. However, only the Army and the Marine Corps currently authorize permanent shaving waivers if all treatments mentioned in their respective bulletins have failed.

The Air Force has adopted the most decentralized approach, in which each MTF is responsible for implementing its own treatment protocols and definitions. Air Force regulations now authorize a 5-year shaving profile for medical reasons, including PFB. The Air Force also has spearheaded efforts to create more inclusive policies. A study of 10,000 active-duty male Air Force members conducted by Air Force physicians found that shaving waivers were associated with longer times to promotion. Although self-identified race was not independently linked to longer promotion times, more Black service members were affected because of a higher prevalence of PFB and shaving profiles.²²

The Navy has outlined the most specific timeline for therapy for PFB. The regulations allow a 60-day temporary shaving chit that expires on the day of the appointment with the dermatologist or PCM. Although sailors were previously mandated to fully grow out their beards without modifications during the 60-day shaving chit period, Navy leadership recently overturned these requirements. However, permanent shaving chits are still not authorized in the Navy.

Service members are trying to destigmatize shaving profiles and facial hair in our military. A Facebook group called DoD Beard Action Initiative has more than 17,000 members and was created in 2021 to compile testimonies and data regarding the effects of PFB on airmen.²³ Soldiers also have petitioned for growing beards in the garrison environment with more than 100,000 signatures, citing that North Atlantic Treaty Organization allied nations permit beard growth in their respective ranks.²⁴ A Sikh marine captain recently won a lawsuit against the US Department of the Navy to maintain a beard with a turban in uniform on religious grounds.²⁵

The clean-shaven look remains standard across the military, not only for uniformity of appearance but also for safety concerns. The Naval Safety Center’s ALSAFE report concluded that any facial hair impedes a tight fit of gas masks, which can be lethal in chemical warfare. However, the report did not explore how different hair lengths would affect the seal of gas masks.²⁶ It remains unknown how 0.25 inch of facial hair, the maximum hair length authorized for most PFB patients, affects the seal. Department of Defense occupational health researchers currently are assessing how each specific facial hair length diminishes the effectiveness of gas masks.²⁷

Furthermore, the COVID-19 pandemic has led to frequent N95 respirator wear in the military. It is likely that growing a long beard disrupts the fitting of N95 respirators and could endanger service members, especially in clinical settings. However, one study confirmed that 0.125 inch of facial hair still results in 98% effectiveness in filtering particles for the respirator wearers.²⁸ Although unverified, it is surmisable that 0.25 inch of facial hair will likely not render all respirators useless. However, current Occupational Safety and Health Administration guidelines require fit tests to be conducted only on clean-shaven faces.²⁹ Effectively, service members with facial hair cannot be fit-tested for N95 respirators.

More research is needed to optimize treatment protocols and regulations for PFB in our military. As long as the current grooming standards remain in place, treatment of PFB will be a controversial topic. Guidelines will need to be continuously updated to balance the needs of our service members and to minimize risk to unit safety and mission success. Department of Defense Instruction 6130.03, Volume 1, revised in late 2022, now no longer designates PFB as a condition that disqualifies a candidate from entering service in any military branch.³⁰ The Department of Defense is demonstrating active research and adoption of policies regarding PFB that will benefit our service members.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

Acrylates are a ubiquitous family of synthetic thermoplastic resins that are employed in a wide array of products. Since the discovery of acrylic acid in 1843 and its industrialization in the early 20th century, acrylates have been used by many different sectors of industry.¹ Today, acrylates can be found in diverse sources such as adhesives, coatings, electronics, nail cosmetics, dental materials, and medical devices. Although these versatile compounds have revolutionized numerous sectors, their potential to trigger allergic contact dermatitis (ACD) has garnered considerable attention in recent years. In 2012, acrylates as a group were named Allergen of the Year by the American Contact Dermatitis Society,² and one member—isobornyl acrylate—also was given the infamous award in 2020.³ In this article, we highlight the chemistry of acrylates, the growing prevalence of acrylate contact allergy, common sources of exposure, patch testing considerations, and management/prevention strategies.

Chemistry and Uses of Acrylates

Acrylates are widely used due to their pliable and resilient properties.⁴ They begin as liquid monomers of (meth)acrylic acid or cyanoacrylic acid that are molded to the desired application before being cured or hardened by one of several means: spontaneously, using chemical catalysts, or with heat, UV light, or a light-emitting diode. Once cured, the final polymers (ie, [meth]acrylates, cyanoacrylates) serve a myriad of different purposes. Table 1 includes some of the more clinically relevant sources of acrylate exposure. Although this list is not comprehensive, it offers a glimpse into the vast array of uses for acrylates.

Acrylate Contact Allergy

Acrylic monomers are potent contact allergens, but the polymerized final products are not considered allergenic, assuming they are completely cured; however, ACD can occur with incomplete curing.⁶ It is of clinical importance that once an individual becomes sensitized to one type of acrylate, they may develop cross-reactions to others contained in different products. Notably, cyanoacrylates generally do not cross-react with (meth)acrylates; this has important implications for choosing safe alternative products in sensitized patients, though independent sensitization to cyanoacrylates is possible.^7,8

Epidemiology and Risk Factors

The prevalence of acrylate allergy in the general population is unknown; however, there is a trend of increased patch test positivity in studies of patients referred for patch testing. A 2018 study by the European Environmental Contact Dermatitis Research Group reported positive patch tests to acrylates in 1.1% of 18,228 patients tested from 2013 to 2015.⁹ More recently, a multicenter European study (2019-2020) reported a 2.3% patch test positivity to 2-hydroxyethyl methacrylate (HEMA) among 7675 tested individuals,¹⁰ and even higher HEMA positivity was reported in Spain (3.7% of 1884 patients in 2019-2020).¹¹ In addition, the North American Contact Dermatitis Group (NACDG) reported positive patch test reactions to HEMA in 3.2% of 4111 patients tested from 2019 to 2020, a statistically significant increase compared with those tested in 2009 to 2018 (odds ratio, 1.25 [95% CI, 1.03-1.51]; P=.02).¹²

Historically, acrylate sensitization primarily stemmed from occupational exposure. A retrospective analysis of occupational dermatitis performed by the NACDG (2001-2016) showed that HEMA was among the top 10 most common occupational allergens (3.4% positivity [83/2461]) and had the fifth highest percentage of occupationally relevant reactions (73.5% [83/113]).¹³ High-risk occupations include dental providers and nail technicians. Dentistry utilizes many materials containing acrylates, including uncured plastic resins used in dental prostheses, dentin bonding materials, and glass ionomers.¹⁴ A retrospective analysis of 585 dental personnel who were patch tested by the NACDG (2001-2018) found that more than 20% of occupational ACD cases were related to acrylates.¹⁵ Nail technicians are another group routinely exposed to acrylates through a variety of modern nail cosmetics. In a 7-year study from Portugal evaluating acrylate ACD, 68% (25/37) of cases were attributed to occupation, 80% (20/25) of which were in nail technicians.¹⁶ Likewise, among 28 nail technicians in Sweden who were referred for patch testing, 57% (16/28) tested positive for at least 1 acrylate.¹⁷

Modern Sources of Acrylate Exposure

Once thought to be a predominantly occupational exposure, acrylates have rapidly made their way into everyday consumer products. Clinicians should be aware of several sources of clinically relevant acrylate exposure, including nail cosmetics, consumer electronics, and medical/surgical adhesives.

A 2016 study found a shift to nail cosmetics as the most common source of acrylate sensitization.¹⁸ Nail cosmetics that contain acrylates include traditional acrylic, gel (shellac), dipped, and press-on (false) nails.¹⁹ The NACDG found that the most common allergen in patients experiencing ACD associated with nail products (2001-2016) was HEMA (56.6% [273/482]), far ahead of the traditional nail polish allergen tosylamide (36.2% [273/755]). Over the study period, the frequency of positive patch tests statistically increased for HEMA (P=.0069) and decreased for tosylamide (P<.0001).²⁰ There is concern that the use of home gel nail kits, which can be purchased online at the click of a button, may be associated with a risk for acrylate sensitization.^21,22 A recent study surveyed a Facebook support group for individuals with self-reported reactions to nail cosmetics, finding that 78% of the 199 individuals had used at-home gel nail kits, and more than 80% of them first developed skin reactions after starting to use at-home kits.²³ The risks for sensitization are thought to be greater when self-applying nail acrylates compared to having them done professionally because individuals are more likely to spill allergenic monomers onto the skin at home; it also is possible that home techniques could lead to incomplete curing. Table 2 reviews the different types of acrylic nail cosmetics.

Medical adhesives and equipment are other important areas where acrylates can be encountered in abundance. A review by Spencer et al¹⁸ cautioned wound dressings as an up-and-coming source of sensitization, and this has been demonstrated in the literature as coming to fruition.²⁶ Another study identified acrylates in 15 of 16 (94%) tested medical adhesives; among 7 medical adhesives labeled as hypoallergenic, 100% still contained acrylates and/or abietic acid.²⁷ Multiple case reports have described ACD to adhesives of electrocardiogram electrodes containing acrylates.^28-31 Physicians providing care to patients with diabetes mellitus also must be aware of acrylates in glucose monitors and insulin pumps, either found in the adhesives or leaching from the inside of the device to reach the skin.³² Isobornyl acrylate in particular has made quite the name for itself in this sector, being crowned the 2020 Allergen of the Year owing to its key role in cases of ACD to diabetes devices.³

Cyanoacrylate-based tissue adhesives (eg, 2‐octyl cyanoacrylate) are now well documented to cause postoperative ACD.^33,34 Although robust prospective data are limited, studies suggest that 2% to 14% of patients develop postoperative skin reactions following 2-octyl cyanoacrylate application.^35-37 It has been shown that sensitization to tissue adhesives often occurs after the first application, followed by an eruption of ACD as long as a month later, which can create confusion about the nature of the rash for patients and health care providers alike, who may for instance attribute it to infection rather than allergy.³⁸ In the orthopedic literature, a woman with a known history of acrylic nail ACD had knee arthroplasty failure attributed to acrylic bone cement with resolution of the joint symptoms after changing to a cementless device.³⁹

Awareness of the common use of acrylates is important to identify the cause of reactions from products that would otherwise seem nonallergenic. A case of occupational ACD to isobornyl acrylate in UV-cured phone screen protectors has been reported⁴⁰; several cases of ACD to acrylates in headphones^41,42 as well as one related to a wearable fitness device also have been reported.⁴³ Given all these possible sources of exposure, ACD to acrylates should be on your radar.

When to Consider Acrylate ACD

When working up a patient with dermatitis, it is essential to ask about occupational history and hobbies to get a sense of potential contact allergen exposures. The typical presentation of occupational acrylate-associated ACD is hand eczema, specifically involving the fingertips.^5,24,25,44 Acrylate ACD should be considered in patients with nail dystrophy and a history of wearing acrylic nails.⁴⁵ There can even be involvement of the face and eyelids secondary to airborne contact or ectopic spread from the hands.²⁴ Spreading vesicular eruptions associated with adhesives also should raise concern. The Figure depicts several possible presentations of ACD to acrylates. In a time of abundant access to products containing acrylates, dermatologists should consider this allergy in their differential diagnosis and consider patch testing.

Photographs courtesy of Brandon L. Adler, MD.

Patch Testing to Acrylates

The gold standard for ACD diagnosis is patch testing. It should be noted that no acrylates are included in the thin-layer rapid use epicutaneous (T.R.U.E.) test series. Several acrylates are tested in expanded patch test series including the American Contact Dermatitis Society Core Allergen series and North American 80 Comprehensive Series. 2-Hydroxyethyl methacrylate is thought to be the most important screening allergen to test. Ramos et al¹⁶ reported a positive patch test to HEMA in 81% (30/37) of patients who had any type of acrylate allergy.

If initial testing to a limited number of acrylates is negative but clinical suspicion remains high, expanded acrylates/plastics and glue series also are available from commercial patch test suppliers. Testing to an expanded panel of acrylates is especially pertinent to consider in suspected occupational cases given the risk of workplace absenteeism and even disability that come with continued exposure to the allergen. Of note, isobornyl acrylate is not included in the baseline patch test series and must be tested separately, particularly because it usually does not cross-react with other acrylates, and therefore allergy could be missed if not tested on its own.

Acrylates are volatile substances that have been shown to degrade at room temperature and to a lesser degree when refrigerated. Ideally, they should be stored in a freezer and not used beyond their expiration date. Furthermore, it is advised that acrylate patch tests be prepared immediately prior to placement on the patient and to discard the initial extrusion from the syringe, as the concentration at the tip may be decreased.^46,47

With regard to tissue adhesives, the actual product should be tested as-is because these are not commercially available patch test substances.⁴⁸ Occasionally, patients who are sensitized to the tissue adhesive will not react when patch tested on intact skin. If clinical suspicion remains high, scratch patch testing may confirm contact allergy in cases of negative testing on intact skin.⁴⁹

Management and Prevention

Once a diagnosis of ACD secondary to acrylates has been established, counseling patients on allergen avoidance strategies is essential. For (meth)acrylate-allergic patients who want to continue using modern nail products, cyanoacrylate-based options (eg, dipped, press-on nails) can be considered as an alternative, as they do not cross-react, though independent sensitization is still possible. However, traditional nail polish is the safest option to recommend.

The concern with acrylate sensitization extends beyond the immediate issue that brought the patient into your clinic. Dermatologists must counsel patients who are sensitized to acrylates on the possible sequelae of acrylate-containing dental or orthopedic procedures. Oral lichenoid lesions, denture stomatitis, burning mouth syndrome, or even acute facial swelling have been reported following dental work in patients with acrylate allergy.^50-53 Dentists of patients with acrylate ACD should be informed of the diagnosis so acrylates can be avoided during dental work; if unavoidable, all possible steps should be taken to ensure complete curing of the monomers. In the surgical setting, patients sensitized to cyanoacrylate-based tissue adhesives should be offered wound closure alternatives such as sutures or staples.³⁴

In patients with diabetes mellitus who develop ACD to their glucose monitor or insulin pump, ideally they should be switched to a device that does not contain acrylates. Problematically, these devices are constantly being reformulated, and manufacturers do not always divulge their components, which can make it challenging to determine safe alternative options.^32,54 Various barrier products may help on a case-by-case basis.⁵⁵Preventative measures should be implemented in workplaces that utilize acrylates, including dental practices and nail salons. Acrylic monomers have been shown to penetrate most gloves within minutes of exposure.^56,57 Double gloving with nitrile gloves affords some protection for no longer than 60 minutes.⁶ 4H gloves have been shown to provide true protection but result in a loss of dexterity.⁵⁸ The fingerstall technique involves removing the fingers from a 4H glove, inserting them on the fingers, and applying a more flexible glove on top to hold them in place; this offers a hybrid between protection and finger dexterity.⁵⁹

Final Interpretation

In a world characterized by technological advancements and increasing accessibility to acrylate-containing products, we hope this brief review serves as a resource and reminder to dermatologists to consider acrylates as a potential cause of ACD with diverse presentations and important future implications for affected individuals. The rising trend of acrylate allergy necessitates comprehensive assessment and shared decision-making between physicians and patients. As we navigate the ever-changing landscape of materials and technologies, clinicians must remain vigilant to avoid some potentially sticky situations for patients.

To the Editor:

Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.¹ Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.² In 2020, Smirnova et al³ reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.⁴

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).

Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).

Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.⁵ Additionally, Harazin et al⁶ discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.⁶

Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.

To the Editor:

Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.¹ Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.² In 2020, Smirnova et al³ reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.⁴

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).

Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).

Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.⁵ Additionally, Harazin et al⁶ discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.⁶

Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.

To the Editor:

Atopic dermatitis (AD) is an inflammatory skin condition that affects approximately 16.5 million adults in the United States.¹ Atopic dermatitis is associated with skin barrier dysfunction and the activation of type 2 inflammatory cytokines. Multiorgan involvement of AD has been demonstrated, as patients with AD are more prone to asthma, allergic rhinitis, and other systemic diseases.² In 2020, Smirnova et al³ reported a significant association (adjusted odds ratio [AOR], 1.58; 95% CI, 1.30-1.92) between AD and chronic obstructive pulmonary disease (COPD) in a large Swedish population. Currently, there is a lack of research evaluating the association between AD and COPD in a population of US adults. Therefore, we explored the association between AD and COPD (chronic bronchitis or emphysema) in a population of US adults utilizing the 1999-2006 National Health and Nutrition Examination Survey (NHANES), as these were the latest data for AD available in NHANES.⁴

We conducted a population-based, cross-sectional study focused on patients 20 years and older with psoriasis from the 1999-2006 NHANES database. Three outcome variables—emphysema, chronic bronchitis, and COPD—and numerous confounding variables for each participant were extracted from the NHANES database. The original cohort consisted of 13,134 participants, and 43 patients were excluded from our analysis owing to the lack of response to survey questions regarding AD and COPD status. The relationship between AD and COPD was evaluated by multivariable logistic regression analyses utilizing Stata/MP 17 (StataCorp LLC). In our logistic regression models, we controlled for age, sex, race/ethnicity, education, income, tobacco usage, diabetes mellitus and asthma status, and body mass index (eTable).

Our study consisted of 13,091 participants. Multivariable logistic regressions were utilized to examine the association between AD and COPD (Table). Approximately 12.5% (weighted) of the patients in our analysis had AD. Additionally, 9.7% (weighted) of patients with AD had received a diagnosis of COPD; conversely, 5.9% (weighted) of patients without AD had received a diagnosis of COPD. More patients with AD reported a diagnosis of chronic bronchitis (9.2%) rather than emphysema (0.9%). Our analysis revealed a significant association between AD and COPD among adults aged 20 to 59 years (AOR, 1.43; 95% CI, 1.13-1.80; P=.003) after controlling for potential confounding variables. Subsequently, we performed subgroup analyses, including exclusion of patients with an asthma diagnosis, to further explore the association between AD and COPD. After excluding participants with asthma, there was still a significant association between AD and COPD (AOR, 1.57; 95% CI, 1.14-2.16; P=.007). Moreover, the odds of receiving a COPD diagnosis were significantly higher among male patients with AD (AOR, 1.54; 95% CI, 1.06-2.25; P=.03).

Our results support the association between AD and COPD, more specifically chronic bronchitis. This finding may be due to similar pathogenic mechanisms in both conditions, including overlapping cytokine production and immune pathways.⁵ Additionally, Harazin et al⁶ discussed the role of a novel gene, collagen 29A1 (COL29A1), in the pathogenesis of AD, COPD, and asthma. Variations in this gene may predispose patients to not only atopic diseases but also COPD.⁶

Limitations of our study include self-reported diagnoses and lack of patients older than 59 years. Self-reported diagnoses could have resulted in some misclassification of COPD, as some individuals may have reported a diagnosis of COPD rather than their true diagnosis of asthma. We mitigated this limitation by constructing a subpopulation model with exclusion of individuals with asthma. Further studies with spirometry-diagnosed COPD are needed to explore this relationship and the potential contributory pathophysiologic mechanisms. Understanding this association may increase awareness of potential comorbidities and assist clinicians with adequate management of patients with AD.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.^1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.^3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.⁶ The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,^7,8 nutritional deficiencies,^4,9 and/or major surgery.¹⁰

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.¹¹ Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.¹² This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.¹² First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.^13,14 Retinoids modulate sebum production,¹⁵ keratinocyte proliferation,¹⁶ and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.^13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,¹⁸ psoriasis,¹⁹ and ichthyosis.²⁰ The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.²¹ Retinoid-associated alopecia is dose and duration dependent.^19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.²³ A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.²⁴ In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m² alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.²⁵ In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.²⁶ Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.^14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.²⁸ Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.²⁹ A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.³⁰ The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.³⁰ Fluconazole-induced TE was reproducible in an animal model using Wistar rats³¹; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.³² Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.³² Voriconazole and fluconazole share structural similarity not present with other triazoles.^33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.³¹

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.^35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.³⁷ A systemic review and meta-analysis by Wang et al³⁸ estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,³⁸ a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.³⁹ A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).⁴⁰ Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.^41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,⁴³ and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.⁴¹ Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.^44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.⁴⁴ In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.⁴⁵ Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).⁴⁶ Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.^39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.⁴⁸ Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.⁴⁹ A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.⁵⁰ The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study⁴⁰ and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.⁵¹ Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.⁵² Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use⁵³; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).⁵⁴

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors^55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.⁵⁷ Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.^58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.⁶³ A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.⁶⁴ Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.⁶⁴ Several other case reports have described alopecia following treatment with SSRIs, including sertraline,⁶⁵ fluvoxamine,⁶⁶ paroxetine,⁶⁷ fluoxetine,⁶⁸ and escitalopram.⁶⁹

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.^1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.^3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.⁶ The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,^7,8 nutritional deficiencies,^4,9 and/or major surgery.¹⁰

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.¹¹ Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.¹² This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.¹² First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.^13,14 Retinoids modulate sebum production,¹⁵ keratinocyte proliferation,¹⁶ and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.^13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,¹⁸ psoriasis,¹⁹ and ichthyosis.²⁰ The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.²¹ Retinoid-associated alopecia is dose and duration dependent.^19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.²³ A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.²⁴ In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m² alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.²⁵ In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.²⁶ Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.^14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.²⁸ Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.²⁹ A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.³⁰ The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.³⁰ Fluconazole-induced TE was reproducible in an animal model using Wistar rats³¹; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.³² Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.³² Voriconazole and fluconazole share structural similarity not present with other triazoles.^33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.³¹

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.^35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.³⁷ A systemic review and meta-analysis by Wang et al³⁸ estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,³⁸ a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.³⁹ A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).⁴⁰ Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.^41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,⁴³ and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.⁴¹ Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.^44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.⁴⁴ In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.⁴⁵ Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).⁴⁶ Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.^39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.⁴⁸ Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.⁴⁹ A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.⁵⁰ The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study⁴⁰ and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.⁵¹ Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.⁵² Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use⁵³; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).⁵⁴

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors^55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.⁵⁷ Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.^58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.⁶³ A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.⁶⁴ Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.⁶⁴ Several other case reports have described alopecia following treatment with SSRIs, including sertraline,⁶⁵ fluvoxamine,⁶⁶ paroxetine,⁶⁷ fluoxetine,⁶⁸ and escitalopram.⁶⁹

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Alopecia is a commonly reported side effect of various medications. Anagen effluvium and telogen effluvium (TE) are considered the most common mechanisms underlying medication-related hair loss. Anagen effluvium is associated with chemotherapeutic agents and radiation therapy, with anagen shedding typically occurring within 2 weeks of medication administration.^1,2 Medication-induced TE is a diffuse nonscarring alopecia that is a reversible reactive process.^3-5 Telogen effluvium is clinically apparent as a generalized shedding of scalp hair 1 to 6 months after an inciting cause.⁶ The underlying cause of TE may be multifactorial and difficult to identify given the delay between the trigger and the onset of clinically apparent hair loss. Other known triggers of TE include acute illness,^7,8 nutritional deficiencies,^4,9 and/or major surgery.¹⁰

Each hair follicle independently and sequentially progresses through anagen growth, catagen transition, and telogen resting phases. In the human scalp, the telogen phase typically lasts 3 months, at the end of which the telogen hair is extruded from the scalp. Anagen and telogen follicles typically account for an average of 90% and 10% of follicles on the human scalp, respectively.¹¹ Immediate anagen release is hypothesized to be the mechanism underlying medication-induced TE.¹² This theory suggests that an increased percentage of anagen follicles prematurely enter the telogen phase, with a notable increase in hair shedding at the conclusion of the telogen phase approximately 1 to 6 months later.¹² First-line management of medication-induced TE is identification and cessation of the causative agent, if possible. Notable regrowth of hair is expected several months after removal of the inciting medication. In part 1 of this 2-part series, we review the existing literature to identify common culprits of medication-induced TE, including retinoids, antifungals, and psychotropic medications.

Retinoids

Retinoids are vitamin A derivatives used in the treatment of a myriad of dermatologic and nondermatologic conditions.^13,14 Retinoids modulate sebum production,¹⁵ keratinocyte proliferation,¹⁶ and epithelial differentiation through signal transduction downstream of the ligand-activated nuclear retinoic acid receptors and retinoid X receptors.^13,14,17 The recommended daily dosage of retinol is 900 µg retinol activity equivalent (3000 IU) for men and 700 µg retinol activity equivalent (2333 IU) for women. Retinoids are used in the treatment of acne vulgaris,¹⁸ psoriasis,¹⁹ and ichthyosis.²⁰ The most commonly reported adverse effects of systemic retinoid therapy include cheilitis, alopecia, and xerosis.²¹ Retinoid-associated alopecia is dose and duration dependent.^19,21-24 A prospective study of acitretin therapy in plaque psoriasis reported that more than 63% (42/66) of patients on 50 mg or more of acitretin daily for 6 months or longer experienced alopecia that reversed with discontinuation.²³ A systematic review of isotretinoin use in acne showed alopecia was seen in 3.2% (18/565) of patients on less than 0.5 mg/kg/d of isotretinoin and in 5.7% (192/3375) of patients on 0.5 mg/kg/d or less of isotretinoin.²⁴ In a phase 2 clinical trial of orally administered 9-cis-retinoic acid (alitretinoin) in the treatment of Kaposi sarcoma related to AIDS, 42% (24/57) of adult male patients receiving 60, 100, or 140 mg/m² alitretinoin daily (median treatment duration, 15.1 weeks) reported alopecia as an adverse effect of treatment.²⁵ In one case report, a patient who ingested 500,000 IU of vitamin A daily for 4 months and then 100,000 IU monthly for 6 months experienced diffusely increased shedding of scalp hair along with muscle soreness, nail dystrophy, diffuse skin rash, and refractory ascites; he was found to have severe liver damage secondary to hypervitaminosis A that required liver transplantation.²⁶ Regarding the pathomechanism of retinoid-induced alopecia, animal and in vitro studies similarly have demonstrated that all-trans-retinoic acid appears to exert its inhibitory effects on hair follicle growth via the influence of the transforming growth factor β2 and SMAD2/3 pathway influence on dermal papillae cells.^14,27 Development of hair loss secondary to systemic retinoid therapy may be managed with dose reduction or cessation.

Antifungals

Azole medications have broad-spectrum fungistatic activity against a wide range of yeast and filamentous fungi. Azoles inhibit sterol 14α-demethylase activity, impairing ergosterol synthesis and thereby disrupting plasma membrane synthesis and activity of membrane-bound enzymes.²⁸ Fluconazole is a systemic oral agent in this class that was first approved by the US Food and Drug Administration (FDA) for use in the 1990s.²⁹ A retrospective study by the National Institute of Allergy and Infectious Disease Mycoses Study Group followed the clinical course of 33 patients who developed alopecia while receiving fluconazole therapy for various mycoses.³⁰ The majority (88% [29/33]) of patients received 400 mg or more of fluconazole daily. The median time to hair loss after starting fluconazole was 3 months, and the scalp was involved in all cases. In 97% (32/33) of patients, resolution of alopecia was noted following discontinuation of fluconazole or a dose reduction of 50% or more. In 85% (28/33) of patients, complete resolution of alopecia occurred within 6 months of fluconazole cessation or dose reduction.³⁰ Fluconazole-induced TE was reproducible in an animal model using Wistar rats³¹; however, further studies are required to clarify the molecular pathways of its effect on hair growth.

Voriconazole is an azole approved for the treatment of invasive aspergillosis, candidemia, and fungal infections caused by Scedosporium apiospermum and Fusarium species. A retrospective survey study of patients who received voriconazole for 1 month or longer found a considerable proportion of patients developed diffuse reversible hair loss.³² Scalp alopecia was noted in 79% (120/152) of patients who completed the survey, with a mean (SD) time to alopecia of 75 (54) days after initiation of voriconazole. Notable regrowth was reported in 69% (79/114) of patients who discontinued voriconazole for at least 3 months. A subgroup of 32 patients were changed to itraconazole or posaconazole, and hair loss stopped in 84% (27/32) with regrowth noted in 69% (22/32) of patients.³² Voriconazole and fluconazole share structural similarity not present with other triazoles.^33,34 Because voriconazole-associated alopecia was reversed in the majority of patients who switched to itraconazole or posaconazole, the authors hypothesized that structural similarity of fluconazole and voriconazole may underly the greater risk for TE that is not a class effect of azole medications.³¹

Psychotropic Medications

Various psychotropic medications have been associated with hair loss. Valproic acid (or sodium valproate) is an anticonvulsant and mood-stabilizing agent used for the treatment of seizures, bipolar disorder (BD), migraines, and neuropathic pain.^35,36 Divalproex sodium (or divalproex) is an enteric-coated formulation of sodium valproate and valproic acid with similar indications. Valproate is a notorious culprit of medication-induced hair loss, with alopecia listed among the most common adverse reactions (reported >5%) on its structure product labeling document.³⁷ A systemic review and meta-analysis by Wang et al³⁸ estimated the overall incidence of valproate-related alopecia to be 11% (95% CI, 0.08-0.13). Although this meta-analysis did not find an association between incidence of alopecia and dose or duration of valproate therapy,³⁸ a separate review suggested that valproate-induced alopecia is dose dependent and can be managed with dose reduction.³⁹ A 12-month, randomized, double-blind study of treatment of BD with divalproex (valproate derivative), lithium, or placebo (2:1:1 ratio) showed a significantly higher frequency of alopecia in the divalproex group compared with placebo (16% [30/187] vs 6% [6/94]; P=.03).⁴⁰ Valproate-related hair loss is characteristically diffuse and nonscarring, often noted 3 to 6 months following initiation of valproate.^41,42 The proposed mechanism of valproate-induced alopecia includes chelation of zinc and selenium,⁴³ and a reduction in serum biotinidase activity, thereby decreasing the availability of these essential micronutrients required for hair growth.⁴¹ Studies examining the effects of valproate administration and serum biotinidase activity in patients have yielded conflicting results.^44-46 In a study of children with seizures including 57 patients treated with valproic acid, 17 treated with carbamazepine, and 75 age- and sex-matched healthy controls, the authors found no significant differences in serum biotinidase enzyme activity across the 3 groups.⁴⁴ In contrast, a study of 75 children with seizures on valproic acid therapy stratified by dose (mean [SD])—group A: 28.7 [8.5] mg/kg/d; group B: 41.6 [4.9] mg/kg/d; group C: 64.5 [5.8] mg/kg/d—found that patients receiving higher doses (groups B and C) had significantly reduced serum biotinidase activity (1.22 [1.11] and 0.97 [0.07] mmol/min/L, respectively) compared with 50 healthy pediatric controls (5.20 [0.90] mmol/min/L; P<.001). The same study found biotin supplementation at 10 mg/d for 20 days led to resolution of alopecia in 22% (2/9) of patients with alopecia on valproic acid therapy.⁴⁵ Despite hypothesized effects of valproate on micronutrients, the role of mineral supplementation in treating valproate-associated hair loss remains unclear. There is evidence to suggest that valproic acid–associated alterations in serum biotinidase activity may be transient. In a study of 32 pediatric patients receiving valproic acid for the treatment of epilepsy, serum biotinidase activity was significantly lower after 3 months of valproic acid therapy compared with pretreatment levels (P<.05); at 6 months, the serum biotinidase activity was increased compared with 3 months (P<.05) and not significantly different from pretreatment levels (P>.05).⁴⁶ Hair regrowth has been observed following discontinuation or dose reduction of valproate therapy in some cases.^39,47

Lithium carbonate (lithium) is used in the treatment of BD. Despite its efficacy and low cost, its potential for adverse effects, narrow therapeutic index, and subsequent need for routine monitoring are factors that limit its use.⁴⁸ Some reported dermatologic adverse reactions on its structure product labeling include xerosis, thinning of hair, alopecia, xerosis cutis, psoriasis onset/exacerbation, and generalized pruritus.⁴⁹ A systematic review and meta-analysis of 385 studies identified 24 publications reporting adverse effects of lithium on hair with no significantly increased risk of alopecia overall.⁵⁰ The analysis included 2 randomized controlled trials comparing the effects of lithium and placebo on hair loss in patients with BD. Hair loss was reported in 7% (7/94) of patients taking lithium and 6% (6/94) of the placebo group in the 12-month study⁴⁰ and in 3% (1/32) of the lithium group and 0% (0/28) of the divalproex group in the 20-month study.⁵¹ Despite anecdotal reports of alopecia associated with lithium, there is a lack of high-quality evidence to support this claim. Of note, hypothyroidism is a known complication of lithium use, and serum testing of thyroid function at 6-month intervals is recommended for patients on lithium treatment.⁵² Because thyroid abnormalities can cause alopecia distinct from TE, new-onset alopecia during lithium use should prompt serum testing of thyroid function. The development of hypothyroidism secondary to lithium is not a direct contraindication to its use⁵³; rather, treatment should be focused on correction with thyroid replacement therapy (eg, supplementation with thyroxine).⁵⁴

Commonly prescribed antidepressant medications include selective serotonin reuptake inhibitors (SSRIs) and bupropion. Selective serotonin reuptake inhibitors affect the neuronal serotonin transporter, increasing the concentration of serotonin in the synaptic cleft available for stimulation of postsynaptic serotonin receptors^55,56; bupropion is an antidepressant medication that inhibits norepinephrine and dopamine reuptake at the synaptic cleft.⁵⁷ Alopecia is an infrequent (1 in 100 to 1 in 1000 patients) adverse effect for several SSRIs.^58-62 A recent systematic review identified a total of 71 cases of alopecia associated with SSRI use including citalopram (n=11), escitalopram (n=7), fluoxetine (n=27), fluoxvamine (n=5), paroxetine (n=4), and sertraline (n=20), with a median time to onset of hair shedding of 8.6 weeks (range, 3 days to 5 years). Discontinuation of the suspected culprit SSRI led to improvement and/or resolution in 63% (51/81) episodes of alopecia, with a median time to improvement and/or resolution of 4 weeks.⁶³ A comparative retrospective cohort study using a large US health claims database from 2006 to 2014 included more than 1 million new and mutually exclusive patients taking fluoxetine, fluvoxamine, sertraline, citalopram, escitalopram, paroxetine, duloxetine, venlafaxine, desvenlafaxine, and bupropion.⁶⁴ Overall, 1% (1569/150,404) of patients treated with bupropion received 1 or more physician visits for alopecia. Patients on SSRIs generally had a lower risk for hair loss compared with patients using bupropion (citalopram: hazard ratio [HR], 0.80 [95% CI, 0.74-0.86]; escitalopram: HR, 0.79 [95% CI, 0.74-0.86]; fluoxetine: HR, 0.68 [95% CI, 0.63-0.74]; paroxetine: HR, 0.68 [95% CI, 0.62-0.74]; sertraline: HR, 0.74 [95% CI, 0.69-0.79]), with the exception of fluvoxamine (HR, 0.93 [95% CI, 0.64-1.37]). However, the type of alopecia, time to onset, and time to resolution were not reported, making it difficult to assess whether the reported hair loss was consistent with medication-induced TE. Additionally, the authors acknowledged that bupropion may have been prescribed for smoking cessation, which may carry a different risk profile for the development of alopecia.⁶⁴ Several other case reports have described alopecia following treatment with SSRIs, including sertraline,⁶⁵ fluvoxamine,⁶⁶ paroxetine,⁶⁷ fluoxetine,⁶⁸ and escitalopram.⁶⁹

Overall, it appears that the use of SSRIs portends relatively low risk for alopecia and medication-induced TE. Little is known regarding the molecular effects of SSRIs on hair growth and the pathomechanism of SSRI-induced TE. The potential benefits of discontinuing a suspected culprit medication should be carefully weighed against the risks of medication cessation, and consideration should be given to alternative medications in the same class that also may be associated with TE. In patients requiring antidepressant therapy with suspected medication-induced TE, consider transitioning to a different class of medication with lower risk of medication-induced alopecia; for example, discontinuing bupropion in favor of an SSRI.

Final Thoughts

Medication-induced alopecia is an undesired side effect of many commonly used drugs and drug classes, including retinoids, azole antifungals, and mood stabilizers. Although the precise pathomechanisms of medication-induced TE remain unclear, the recommended management often requires identification of the likely causative agent and its discontinuation, if possible. Suspicion for medication-induced TE should prompt a thorough history of recent changes to medications, risk factors for nutritional deficiencies, underlying illnesses, and recent surgical procedures. Underlying nutritional, electrolyte, and/or metabolic disturbances should be corrected. In part 2 of this series, we will discuss medication-induced alopecia associated with anticoagulant and antihypertensive medications.

Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.¹ In the United States, Black patients are 3.4-times more likely than White patients to have PN.² The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.

Treatment Guidelines

In 2020, an expert panel published consensus treatment guidelines for PN.¹ The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.¹

FDA-Approved Therapy

In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.³ Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.³

The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.^4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.⁶

Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.⁷ In a recent review of 701 patients with PN, the mean age was 64.8 years,⁵ highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.

Investigation of Janus Kinase Inhibitors

Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.^8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.¹⁰ Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.¹¹ The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.

Other New Therapies

Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.^12,13 Sustained remission was noted even after discontinuation of the medication.¹² Alitretinoin, which has been demonstrated to be effective in treating dermatitis,¹⁴ was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.

Topical cannabinoids have shown benefit in the treatment of pruritus¹⁵ and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.

Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.¹⁶ Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.¹⁷ Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.¹⁸

Final Thoughts

Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.

Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.¹ In the United States, Black patients are 3.4-times more likely than White patients to have PN.² The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.

Treatment Guidelines

In 2020, an expert panel published consensus treatment guidelines for PN.¹ The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.¹

FDA-Approved Therapy

In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.³ Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.³

The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.^4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.⁶

Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.⁷ In a recent review of 701 patients with PN, the mean age was 64.8 years,⁵ highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.

Investigation of Janus Kinase Inhibitors

Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.^8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.¹⁰ Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.¹¹ The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.

Other New Therapies

Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.^12,13 Sustained remission was noted even after discontinuation of the medication.¹² Alitretinoin, which has been demonstrated to be effective in treating dermatitis,¹⁴ was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.

Topical cannabinoids have shown benefit in the treatment of pruritus¹⁵ and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.

Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.¹⁶ Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.¹⁷ Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.¹⁸

Final Thoughts

Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.

Prurigo nodularis (PN), a condition that historically has been a challenge to treat, now has a US Food and Drug Administration (FDA)–approved therapy—dupilumab—with other agents in the pipeline. As clinicians, we recognize PN as typically symmetric, keratotic, papular and nodular lesions presenting in older adults with chronic pruritus; patients with atopic dermatitis make up roughly half of patients with PN, but a workup for pruritus is indicated in other settings.¹ In the United States, Black patients are 3.4-times more likely than White patients to have PN.² The differential diagnosis includes conditions such nodular scabies, pemphigoid nodularis, acquired perforating disorders, and hypertrophic lichen planus, which also should be considered, especially in cases that are refractory to first-line therapies. Recent breakthroughs in therapy have come from substantial progress in our understanding of the pathogenesis of PN as driven by disorders of cytokine expression and/or neurocutaneous aberrations. We review progress in the treatment of PN over the last 3 years.

Treatment Guidelines

In 2020, an expert panel published consensus treatment guidelines for PN.¹ The panel, which proposed a 4-tiered approach targeting both neural and immunologic mechanisms in the pathogenesis of PN, emphasized the importance of tailoring treatment to the individual patient. Topical therapies remained the mainstay of treatment, with agents such as topical capsaicin, ketamine, lidocaine, and amitriptyline targeting the neural component and topical corticosteroids, calcineurin inhibitors, and calcipotriol and intralesional corticosteroids targeting the immunologic component. Phototherapy, methotrexate, cyclosporine, antidepressants, and gabapentinoids used with varying degrees of success were noted to have acceptable tolerability.¹

FDA-Approved Therapy

In September 2022, the FDA approved dupilumab for the treatment of PN. An antagonist of the IL-4 receptor, dupilumab was found to reduce both pruritus and skin lesions over a 24-week period in 2 phase 3 clinical trials.³ Results also demonstrated progressive improvements in measures assessing quality of life and pruritus over the study period, suggesting that continued treatment could lead to even further improvements in these measures. Adverse events were minimal and similar between the dupilumab- and placebo-treated groups.³

The FDA approval of dupilumab is a promising step in decreasing the disease burden of widespread or refractory PN, both for patients and the health care system. The treatment of patients with PN has been more challenging due to comorbidities, including mental health conditions, endocrine disorders, cardiovascular conditions, renal conditions, malignancy, and HIV.^4,5 These comorbidities can complicate the use of traditional systemic and immunosuppressive agents. Dupilumab has virtually no contraindications and has demonstrated safety in almost all patient populations.⁶

Consistent insurance coverage for patients who respond to dupilumab remains to be determined. A review investigating the use of dupilumab in patients with atopic dermatitis at the University of Pittsburgh Medical Center (Pittsburgh, Pennsylvania) found that of 179 patients, 67 (37.4%) did not start dupilumab, mainly due to insurance denial (34/179 [19%]) or copay (20/179 [11%]). Medicare patients were less likely to receive treatment compared to those on private insurance or Medicaid.⁷ In a recent review of 701 patients with PN, the mean age was 64.8 years,⁵ highlighting the concern about obtaining insurance coverage for dupilumab in this population given the higher likelihood that these patients will be on Medicare. Prescribers should be aware that coverage denials are likely and should be prepared to advocate for their patients by citing recent studies to hopefully obtain coverage for dupilumab in the treatment of PN. Resources such as the Dupixent MyWay program (https://www.dupixent.com/support-savings/dupixent-my-way) can provide useful recommendations for pursuing insurance approval for this agent.

Investigation of Janus Kinase Inhibitors

Emerging data suggest that Janus kinase (JAK) inhibitors may be beneficial in the treatment of PN. Patients with refractory PN have been treated off label with the JAK inhibitor tofacitinib at a dosage of 5 mg twice daily with improvement in symptoms and minimal side effects.^8,9 Similarly, a case report showed that off-label use of the JAK inhibitor baricitinib resulted in marked improvement in pruritus and clearance of lesions at a dosage of 4 mg daily, with reduction in pruritus seen as early as 1 week after treatment initiation.¹⁰ Although most patients are able to tolerate JAK inhibitors, known side effects include acne, viral infections, gastrointestinal tract upset, and the potential increased risk for malignancy.¹¹ The use of topical JAK inhibitors such as ruxolitinib has not yet been studied in PN, though cost may limit use to localized disease.

Other New Therapies

Recent case reports and case series have found the vitamin A derivative alitretinoin to be an effective treatment for recalcitrant PN, typically at a dosage of 30 mg daily.^12,13 Sustained remission was noted even after discontinuation of the medication.¹² Alitretinoin, which has been demonstrated to be effective in treating dermatitis,¹⁴ was well tolerated. Similar to JAK inhibitors, there are minimal data investigating the use of topical retinoids in the treatment of localized PN.

Topical cannabinoids have shown benefit in the treatment of pruritus¹⁵ and may be beneficial for the treatment of PN, though there currently are limited data in the literature. With the use of both medical and legal recreational marijuana on the rise, there is an increased interest in cannabinoids, particularly as many patients consider these agents to be more “natural”—and therefore preferable—treatment options. As the use of cannabis derivatives become more commonplace in both traditional and complementary medicine, providers should be prepared to field questions from patients about their potential for PN.

Finally, the IL-31RA inhibitor nemolizumab also has shown promise in the treatment of PN. A recent study suggested that nemolizumab helps modulate inflammatory and neural signaling in PN.¹⁶ Nemolizumab has been granted breakthrough therapy designation for the treatment of pruritus in PN based on a phase 2 study that demonstrated improvement in pruritus and skin lesions in a group of 70 patients with moderate to severe PN.¹⁷ Nemolizumab, which is used to treat pruritus in atopic dermatitis, has minimal side effects including upper respiratory tract infections and peripheral edema.¹⁸

Final Thoughts

Prurigo nodularis historically has been considered difficult to treat, particularly in those with widespread lesions. Dupilumab—the first FDA-approved treatment of PN—is now an exciting option, not just for patients with underlying atopic dermatitis. Not all patients will respond to the medication, and the ease of obtaining insurance approval has yet to be established; therefore, having other treatment options will be imperative. In patients with recalcitrant disease, several other treatment options have shown promise in the treatment of PN; in particular, JAK inhibitors, alitretinoin, and nemolizumab should be considered in patients with widespread refractory PN who are willing to try alternative agents. Ongoing research should be focused on these medications as well as on the development of other novel treatments aimed at relieving affected patients.

Practice Gap

In low-resource settings, dermatologists may not have the preferred tools to evaluate a patient or perform a procedure. Commonplace affordable supplies can be substituted when needed.

Traditionally, tools readily available for comedone extraction in dermatology clinics include sterile disposable hypodermic needles to open the skin and either a comedone extractor or 2 cotton-tip applicators to apply pressure for extraction. However, when these tools are not available, resourceful techniques have been utilized. Ashique and Srinivas¹ described a less-painful method for extracting conchae comedones that they called “pen punching,” which involved using the rim of the tip of a ballpoint pen to apply pressure to extract lesions. Mukhtar and Gupta² used a 3-mL disposable syringe as a comedone extractor; the syringe was cut at the needle hub using a surgical blade, with one half at 30° to 45°. Kaya et al³ used sharp-tipped cautery to puncture closed macrocomedones. Cvancara and Meffert⁴ described how an autoclaved paper clip could be fashioned into a disposable comedone extractor, highlighting its potential use in humanitarian work or military deployments. A sterilized safety pin has been demonstrated to be an inexpensive tool to extract open and closed comedones without a surgical blade.⁵ We describe the use of a blood glucose testing lancet and a paper clip for comedone extraction.

Tools and Technique

A patient presented to a satellite clinic requesting extraction of multiple bothersome milia. A comedone extractor was unavailable at that location, and the patient’s access to care elsewhere was limited.

To perform extraction of milia in this case, we used a sterile, twist-top, stainless steel, 30-gauge blood glucose testing lancet and a paper clip sterilized with an isopropyl alcohol wipe (Figure). The beveled edge of the lancet was used to make a superficial opening to the skin, and the end loop of the paper clip was used as a comedone extractor. Applying moderate vertical pressure, 15 milia were expressed from the forearms. The patient tolerated the procedure well and reported minimal pain.

Practical Implications

The cost of the paper clip and lancet for our technique was $0.07. These materials are affordable, easy to use, and readily found in a variety of settings, making them a feasible option for performing this procedure. 

Practice Gap

In low-resource settings, dermatologists may not have the preferred tools to evaluate a patient or perform a procedure. Commonplace affordable supplies can be substituted when needed.

Traditionally, tools readily available for comedone extraction in dermatology clinics include sterile disposable hypodermic needles to open the skin and either a comedone extractor or 2 cotton-tip applicators to apply pressure for extraction. However, when these tools are not available, resourceful techniques have been utilized. Ashique and Srinivas¹ described a less-painful method for extracting conchae comedones that they called “pen punching,” which involved using the rim of the tip of a ballpoint pen to apply pressure to extract lesions. Mukhtar and Gupta² used a 3-mL disposable syringe as a comedone extractor; the syringe was cut at the needle hub using a surgical blade, with one half at 30° to 45°. Kaya et al³ used sharp-tipped cautery to puncture closed macrocomedones. Cvancara and Meffert⁴ described how an autoclaved paper clip could be fashioned into a disposable comedone extractor, highlighting its potential use in humanitarian work or military deployments. A sterilized safety pin has been demonstrated to be an inexpensive tool to extract open and closed comedones without a surgical blade.⁵ We describe the use of a blood glucose testing lancet and a paper clip for comedone extraction.

Tools and Technique

A patient presented to a satellite clinic requesting extraction of multiple bothersome milia. A comedone extractor was unavailable at that location, and the patient’s access to care elsewhere was limited.

To perform extraction of milia in this case, we used a sterile, twist-top, stainless steel, 30-gauge blood glucose testing lancet and a paper clip sterilized with an isopropyl alcohol wipe (Figure). The beveled edge of the lancet was used to make a superficial opening to the skin, and the end loop of the paper clip was used as a comedone extractor. Applying moderate vertical pressure, 15 milia were expressed from the forearms. The patient tolerated the procedure well and reported minimal pain.

Practical Implications

The cost of the paper clip and lancet for our technique was $0.07. These materials are affordable, easy to use, and readily found in a variety of settings, making them a feasible option for performing this procedure. 

Practice Gap

In low-resource settings, dermatologists may not have the preferred tools to evaluate a patient or perform a procedure. Commonplace affordable supplies can be substituted when needed.

Traditionally, tools readily available for comedone extraction in dermatology clinics include sterile disposable hypodermic needles to open the skin and either a comedone extractor or 2 cotton-tip applicators to apply pressure for extraction. However, when these tools are not available, resourceful techniques have been utilized. Ashique and Srinivas¹ described a less-painful method for extracting conchae comedones that they called “pen punching,” which involved using the rim of the tip of a ballpoint pen to apply pressure to extract lesions. Mukhtar and Gupta² used a 3-mL disposable syringe as a comedone extractor; the syringe was cut at the needle hub using a surgical blade, with one half at 30° to 45°. Kaya et al³ used sharp-tipped cautery to puncture closed macrocomedones. Cvancara and Meffert⁴ described how an autoclaved paper clip could be fashioned into a disposable comedone extractor, highlighting its potential use in humanitarian work or military deployments. A sterilized safety pin has been demonstrated to be an inexpensive tool to extract open and closed comedones without a surgical blade.⁵ We describe the use of a blood glucose testing lancet and a paper clip for comedone extraction.

Tools and Technique

A patient presented to a satellite clinic requesting extraction of multiple bothersome milia. A comedone extractor was unavailable at that location, and the patient’s access to care elsewhere was limited.

To perform extraction of milia in this case, we used a sterile, twist-top, stainless steel, 30-gauge blood glucose testing lancet and a paper clip sterilized with an isopropyl alcohol wipe (Figure). The beveled edge of the lancet was used to make a superficial opening to the skin, and the end loop of the paper clip was used as a comedone extractor. Applying moderate vertical pressure, 15 milia were expressed from the forearms. The patient tolerated the procedure well and reported minimal pain.

Practical Implications

The cost of the paper clip and lancet for our technique was $0.07. These materials are affordable, easy to use, and readily found in a variety of settings, making them a feasible option for performing this procedure.