Case Letter

To the Editor:

Cutaneous myiasis is a skin infestation with dipterous larvae that feed on the host’s tissue and cause a wide range of manifestations depending on the location of infestation. Cutaneous myiasis, which includes furuncular, wound, and migratory types, is the most common clinical form of this condition.¹ It is endemic to tropical and subtropical areas and is not common in the United States, thus it can pose a diagnostic challenge when presenting in nonendemic areas. We present the case of a woman from Michigan who acquired furuncular myiasis without travel history to a tropical or subtropical locale.

A 72-year-old woman presented to our clinic with a chief concern of a burning, pruritic, migratory skin lesion on the left arm of approximately 1 week’s duration. She had a medical history of squamous cell carcinoma, keratoacanthoma, and multiple tick bites. She reported that the lesion started on the distal aspect of the left arm as an eraser-sized, perfectly round, raised bruise with a dark pepperlike bump in the center. The lesion then spread proximally over the course of 1 week, creating 3 more identical lesions. As one lesion resolved, a new lesion appeared approximately 2 to 4 cm proximal to the preceding lesion. The patient had traveled to England, Scotland, and Ireland 2 months prior but otherwise denied leaving the state of Michigan. She reported frequent exposure to gardens, meadows, and wetlands in search of milkweed and monarch butterfly larvae that she raises in northeast Michigan. She denied any recent illness or associated systemic symptoms. Initial evaluation by a primary care physician resulted in a diagnosis of a furuncle or tick bite; she completed a 10-day course of amoxicillin and a methylprednisolone dose pack without improvement.

Physical examination revealed a 1-cm, firm, violaceous nodule with a small distinct central punctum and surrounding erythema on the proximal aspect of the left arm. Dermoscopy revealed a pulsating motion and expulsion of serosanguineous fluid from the central punctum (Figure 1). Further inspection of the patient’s left arm exposed several noninflammatory puncta distal to the primary lesion spaced at 2- to 4-cm intervals.

Gross examination of a 6-mm punch biopsy from the primary inflammatory nodule uncovered a small, motile, gray-white larval organism in the inferior portion of the specimen (Figure 2). Histopathology revealed superficial and deep eosinophil-rich inflammation, fibrosis, and hemorrhage. There was a complex wedge-shaped organism with extensive internal muscle bounded by a thin cuticle bearing rows of chitinous hooklets located at one side within the deep dermis (Figure 3). The findings were consistent with a diagnosis of cutaneous myiasis. No further treatment was required, as the organism was completely excised with the biopsy.

The most common causative agents of furuncular myiasis obtained from travelers returning from Mexico and Central and South America are Dermatobia hominis and Cordylobia anthropophaga. Cases of furuncular myiasis acquired in the United States without recent foreign travel are rare. Most of these cases are caused by larvae of the Cuterebra species (also known as the rabbit botfly or rodent botfly).² In a 2003 literature review by Safdar et al³ on 56 cases of furuncular myiasis in the United States, the median age of patients was 14 years, 87% of cases occurred in August and September, and most involved exposure in rural or suburban settings; 53% of cases presented in the northeastern United States.

Furuncular myiasis occurs when the organism’s ova are deposited on the skin of a human host by the parent organism or a mosquito vector. The heat of the skin causes the eggs to hatch and the dipteran larvae must penetrate the skin within 20 days.¹ Signs of infection typically are seen 6 to 10 days after infestation.³ The larvae then feed on human tissue and burrow deep in the dermis, forming an erythematous furunculoid nodule containing one or multiple maggots. After 5 to 10 weeks, the adult larvae drop to the ground, where they mature into adult organisms in the soil.¹

The most reported symptoms of furuncular myiasis include pruritus, pain, and movement sensation, typically occurring suddenly at night.⁴ The most common presentation is a furunclelike lesion that exudes serosanguineous or purulent fluid,¹ but there have been reports of vesicular, bullous, pustular, erosive, ecchymotic, and ulcerative lesions.⁵Dermatobia hominis usually presents on an exposed site, such as the scalp, face, and extremities. It may present with paroxysmal episodes of lancinating pain. Over time, the lesion usually heals without a scar, though hyperpigmentation and scarring can occur. The most reported complication is secondary bacterial infection.⁴ Local lymphadenopathy or systemic symptoms should raise concern for infection. Staphylococcus aureus and group B Streptococcus have been cultured from lesions.^6,7

The differential diagnosis for myiasis should include furuncle, insect bite, insect prurigo, pyoderma, inflamed cyst, and tungiasis. Myiasis also can present similarly to severe soft tissue infections or cellulitis. If located on the breasts, it can be mistaken for periductal mastitis, a benign mass with microcalcification, or inflammatory carcinoma. Lastly, due to pain, erythema, pruritus, small vesicles, and crusting, it may be confused for herpes simplex virus.¹

Furuncular myiasis typically is diagnosed based on clinical presentation, especially in endemic regions. In nonendemic areas, the patient’s history may reveal recent travel or predisposition to myiasis. In cases where there is uncertainty, dermoscopy may be used to identify the maggot in the lesion, or ultrasonography can be used to confirm myiasis through the detection of larval movement.⁸ Dermoscopy will reveal a furuncular lesion with a central opening surrounded by dilated blood vessels and a yellowish structure with black barblike spines.⁹ Within the dermis is a fibrous cystic sinus tract containing the dipteran larva. Laboratory studies typically are unremarkable. In chronic cases, a complete blood cell count and other laboratory tests may show systemic inflammation, peripheral eosinophilia, and elevated IgE.¹⁰ Biopsies of furuncular myiasis are not necessary for diagnosis. Histopathology reveals an ulcerated epidermis with or without hyperkeratosis and an inflammatory infiltrate composed of lymphocytes and neutrophils with eosinophils, fibroblasts, histiocytes, basophils, mast cells, plasma cells, and Langerhans cells within the dermis and subcutis.¹¹

There are various approaches to treating furuncular myiasis, with the goal of complete removal of the larva and prevention of secondary infection. One treatment option is to apply a toxic substance to the larva, effectively killing it. Another approach is to force the larva to emerge via localized hypoxia, which can be done by occluding the punctum of the lesion for at least 24 hours. A complication of this method is suffocation of the larva without migration, leading to incomplete extraction and secondary infection.¹ A third method is to surgically remove the larva, which allows for debridement of necrotic tissue surrounding the lesion if present.¹² Ultrasonography also can be used therapeutically to aid in the removal of the larvae. The last method is to inject lidocaine into the base of the lesion, forcing the larva out of the punctum via fluid pressure.¹³ Oral treatments such as ivermectin are not recommended because they can result in the death of larvae within the lesion, leading to an inflammatory response.⁸

Furuncular myiasis is a form of cutaneous larvae infestation not commonly seen in individuals who do not live or travel in endemic, tropical, and subtropical regions. Diagnosis is based on clinical presentation, with imaging and laboratory studies available to supplement in unclear or atypical manifestations. Treatment involves complete removal of the larva, typically through forced evacuation via hypoxia or through surgical removal. Most cases resolve without notable scarring or other sequelae; however, in those who do have complications, the most common is secondary bacterial infection. Our patient’s absence of notable travel history and frequent environmental exposure in Michigan led us to believe the organism was from a domestic source. Our case underlines the importance of a thorough history and clinical examination of furuncular lesions including the use of dermoscopy to yield an appropriate diagnosis and treatment plan.

To the Editor:

Cutaneous myiasis is a skin infestation with dipterous larvae that feed on the host’s tissue and cause a wide range of manifestations depending on the location of infestation. Cutaneous myiasis, which includes furuncular, wound, and migratory types, is the most common clinical form of this condition.¹ It is endemic to tropical and subtropical areas and is not common in the United States, thus it can pose a diagnostic challenge when presenting in nonendemic areas. We present the case of a woman from Michigan who acquired furuncular myiasis without travel history to a tropical or subtropical locale.

A 72-year-old woman presented to our clinic with a chief concern of a burning, pruritic, migratory skin lesion on the left arm of approximately 1 week’s duration. She had a medical history of squamous cell carcinoma, keratoacanthoma, and multiple tick bites. She reported that the lesion started on the distal aspect of the left arm as an eraser-sized, perfectly round, raised bruise with a dark pepperlike bump in the center. The lesion then spread proximally over the course of 1 week, creating 3 more identical lesions. As one lesion resolved, a new lesion appeared approximately 2 to 4 cm proximal to the preceding lesion. The patient had traveled to England, Scotland, and Ireland 2 months prior but otherwise denied leaving the state of Michigan. She reported frequent exposure to gardens, meadows, and wetlands in search of milkweed and monarch butterfly larvae that she raises in northeast Michigan. She denied any recent illness or associated systemic symptoms. Initial evaluation by a primary care physician resulted in a diagnosis of a furuncle or tick bite; she completed a 10-day course of amoxicillin and a methylprednisolone dose pack without improvement.

Physical examination revealed a 1-cm, firm, violaceous nodule with a small distinct central punctum and surrounding erythema on the proximal aspect of the left arm. Dermoscopy revealed a pulsating motion and expulsion of serosanguineous fluid from the central punctum (Figure 1). Further inspection of the patient’s left arm exposed several noninflammatory puncta distal to the primary lesion spaced at 2- to 4-cm intervals.

Gross examination of a 6-mm punch biopsy from the primary inflammatory nodule uncovered a small, motile, gray-white larval organism in the inferior portion of the specimen (Figure 2). Histopathology revealed superficial and deep eosinophil-rich inflammation, fibrosis, and hemorrhage. There was a complex wedge-shaped organism with extensive internal muscle bounded by a thin cuticle bearing rows of chitinous hooklets located at one side within the deep dermis (Figure 3). The findings were consistent with a diagnosis of cutaneous myiasis. No further treatment was required, as the organism was completely excised with the biopsy.

The most common causative agents of furuncular myiasis obtained from travelers returning from Mexico and Central and South America are Dermatobia hominis and Cordylobia anthropophaga. Cases of furuncular myiasis acquired in the United States without recent foreign travel are rare. Most of these cases are caused by larvae of the Cuterebra species (also known as the rabbit botfly or rodent botfly).² In a 2003 literature review by Safdar et al³ on 56 cases of furuncular myiasis in the United States, the median age of patients was 14 years, 87% of cases occurred in August and September, and most involved exposure in rural or suburban settings; 53% of cases presented in the northeastern United States.

Furuncular myiasis occurs when the organism’s ova are deposited on the skin of a human host by the parent organism or a mosquito vector. The heat of the skin causes the eggs to hatch and the dipteran larvae must penetrate the skin within 20 days.¹ Signs of infection typically are seen 6 to 10 days after infestation.³ The larvae then feed on human tissue and burrow deep in the dermis, forming an erythematous furunculoid nodule containing one or multiple maggots. After 5 to 10 weeks, the adult larvae drop to the ground, where they mature into adult organisms in the soil.¹

The most reported symptoms of furuncular myiasis include pruritus, pain, and movement sensation, typically occurring suddenly at night.⁴ The most common presentation is a furunclelike lesion that exudes serosanguineous or purulent fluid,¹ but there have been reports of vesicular, bullous, pustular, erosive, ecchymotic, and ulcerative lesions.⁵Dermatobia hominis usually presents on an exposed site, such as the scalp, face, and extremities. It may present with paroxysmal episodes of lancinating pain. Over time, the lesion usually heals without a scar, though hyperpigmentation and scarring can occur. The most reported complication is secondary bacterial infection.⁴ Local lymphadenopathy or systemic symptoms should raise concern for infection. Staphylococcus aureus and group B Streptococcus have been cultured from lesions.^6,7

The differential diagnosis for myiasis should include furuncle, insect bite, insect prurigo, pyoderma, inflamed cyst, and tungiasis. Myiasis also can present similarly to severe soft tissue infections or cellulitis. If located on the breasts, it can be mistaken for periductal mastitis, a benign mass with microcalcification, or inflammatory carcinoma. Lastly, due to pain, erythema, pruritus, small vesicles, and crusting, it may be confused for herpes simplex virus.¹

Furuncular myiasis typically is diagnosed based on clinical presentation, especially in endemic regions. In nonendemic areas, the patient’s history may reveal recent travel or predisposition to myiasis. In cases where there is uncertainty, dermoscopy may be used to identify the maggot in the lesion, or ultrasonography can be used to confirm myiasis through the detection of larval movement.⁸ Dermoscopy will reveal a furuncular lesion with a central opening surrounded by dilated blood vessels and a yellowish structure with black barblike spines.⁹ Within the dermis is a fibrous cystic sinus tract containing the dipteran larva. Laboratory studies typically are unremarkable. In chronic cases, a complete blood cell count and other laboratory tests may show systemic inflammation, peripheral eosinophilia, and elevated IgE.¹⁰ Biopsies of furuncular myiasis are not necessary for diagnosis. Histopathology reveals an ulcerated epidermis with or without hyperkeratosis and an inflammatory infiltrate composed of lymphocytes and neutrophils with eosinophils, fibroblasts, histiocytes, basophils, mast cells, plasma cells, and Langerhans cells within the dermis and subcutis.¹¹

There are various approaches to treating furuncular myiasis, with the goal of complete removal of the larva and prevention of secondary infection. One treatment option is to apply a toxic substance to the larva, effectively killing it. Another approach is to force the larva to emerge via localized hypoxia, which can be done by occluding the punctum of the lesion for at least 24 hours. A complication of this method is suffocation of the larva without migration, leading to incomplete extraction and secondary infection.¹ A third method is to surgically remove the larva, which allows for debridement of necrotic tissue surrounding the lesion if present.¹² Ultrasonography also can be used therapeutically to aid in the removal of the larvae. The last method is to inject lidocaine into the base of the lesion, forcing the larva out of the punctum via fluid pressure.¹³ Oral treatments such as ivermectin are not recommended because they can result in the death of larvae within the lesion, leading to an inflammatory response.⁸

Furuncular myiasis is a form of cutaneous larvae infestation not commonly seen in individuals who do not live or travel in endemic, tropical, and subtropical regions. Diagnosis is based on clinical presentation, with imaging and laboratory studies available to supplement in unclear or atypical manifestations. Treatment involves complete removal of the larva, typically through forced evacuation via hypoxia or through surgical removal. Most cases resolve without notable scarring or other sequelae; however, in those who do have complications, the most common is secondary bacterial infection. Our patient’s absence of notable travel history and frequent environmental exposure in Michigan led us to believe the organism was from a domestic source. Our case underlines the importance of a thorough history and clinical examination of furuncular lesions including the use of dermoscopy to yield an appropriate diagnosis and treatment plan.

To the Editor:

Cutaneous myiasis is a skin infestation with dipterous larvae that feed on the host’s tissue and cause a wide range of manifestations depending on the location of infestation. Cutaneous myiasis, which includes furuncular, wound, and migratory types, is the most common clinical form of this condition.¹ It is endemic to tropical and subtropical areas and is not common in the United States, thus it can pose a diagnostic challenge when presenting in nonendemic areas. We present the case of a woman from Michigan who acquired furuncular myiasis without travel history to a tropical or subtropical locale.

A 72-year-old woman presented to our clinic with a chief concern of a burning, pruritic, migratory skin lesion on the left arm of approximately 1 week’s duration. She had a medical history of squamous cell carcinoma, keratoacanthoma, and multiple tick bites. She reported that the lesion started on the distal aspect of the left arm as an eraser-sized, perfectly round, raised bruise with a dark pepperlike bump in the center. The lesion then spread proximally over the course of 1 week, creating 3 more identical lesions. As one lesion resolved, a new lesion appeared approximately 2 to 4 cm proximal to the preceding lesion. The patient had traveled to England, Scotland, and Ireland 2 months prior but otherwise denied leaving the state of Michigan. She reported frequent exposure to gardens, meadows, and wetlands in search of milkweed and monarch butterfly larvae that she raises in northeast Michigan. She denied any recent illness or associated systemic symptoms. Initial evaluation by a primary care physician resulted in a diagnosis of a furuncle or tick bite; she completed a 10-day course of amoxicillin and a methylprednisolone dose pack without improvement.

Physical examination revealed a 1-cm, firm, violaceous nodule with a small distinct central punctum and surrounding erythema on the proximal aspect of the left arm. Dermoscopy revealed a pulsating motion and expulsion of serosanguineous fluid from the central punctum (Figure 1). Further inspection of the patient’s left arm exposed several noninflammatory puncta distal to the primary lesion spaced at 2- to 4-cm intervals.

Gross examination of a 6-mm punch biopsy from the primary inflammatory nodule uncovered a small, motile, gray-white larval organism in the inferior portion of the specimen (Figure 2). Histopathology revealed superficial and deep eosinophil-rich inflammation, fibrosis, and hemorrhage. There was a complex wedge-shaped organism with extensive internal muscle bounded by a thin cuticle bearing rows of chitinous hooklets located at one side within the deep dermis (Figure 3). The findings were consistent with a diagnosis of cutaneous myiasis. No further treatment was required, as the organism was completely excised with the biopsy.

The most common causative agents of furuncular myiasis obtained from travelers returning from Mexico and Central and South America are Dermatobia hominis and Cordylobia anthropophaga. Cases of furuncular myiasis acquired in the United States without recent foreign travel are rare. Most of these cases are caused by larvae of the Cuterebra species (also known as the rabbit botfly or rodent botfly).² In a 2003 literature review by Safdar et al³ on 56 cases of furuncular myiasis in the United States, the median age of patients was 14 years, 87% of cases occurred in August and September, and most involved exposure in rural or suburban settings; 53% of cases presented in the northeastern United States.

Furuncular myiasis occurs when the organism’s ova are deposited on the skin of a human host by the parent organism or a mosquito vector. The heat of the skin causes the eggs to hatch and the dipteran larvae must penetrate the skin within 20 days.¹ Signs of infection typically are seen 6 to 10 days after infestation.³ The larvae then feed on human tissue and burrow deep in the dermis, forming an erythematous furunculoid nodule containing one or multiple maggots. After 5 to 10 weeks, the adult larvae drop to the ground, where they mature into adult organisms in the soil.¹

The most reported symptoms of furuncular myiasis include pruritus, pain, and movement sensation, typically occurring suddenly at night.⁴ The most common presentation is a furunclelike lesion that exudes serosanguineous or purulent fluid,¹ but there have been reports of vesicular, bullous, pustular, erosive, ecchymotic, and ulcerative lesions.⁵Dermatobia hominis usually presents on an exposed site, such as the scalp, face, and extremities. It may present with paroxysmal episodes of lancinating pain. Over time, the lesion usually heals without a scar, though hyperpigmentation and scarring can occur. The most reported complication is secondary bacterial infection.⁴ Local lymphadenopathy or systemic symptoms should raise concern for infection. Staphylococcus aureus and group B Streptococcus have been cultured from lesions.^6,7

The differential diagnosis for myiasis should include furuncle, insect bite, insect prurigo, pyoderma, inflamed cyst, and tungiasis. Myiasis also can present similarly to severe soft tissue infections or cellulitis. If located on the breasts, it can be mistaken for periductal mastitis, a benign mass with microcalcification, or inflammatory carcinoma. Lastly, due to pain, erythema, pruritus, small vesicles, and crusting, it may be confused for herpes simplex virus.¹

Furuncular myiasis typically is diagnosed based on clinical presentation, especially in endemic regions. In nonendemic areas, the patient’s history may reveal recent travel or predisposition to myiasis. In cases where there is uncertainty, dermoscopy may be used to identify the maggot in the lesion, or ultrasonography can be used to confirm myiasis through the detection of larval movement.⁸ Dermoscopy will reveal a furuncular lesion with a central opening surrounded by dilated blood vessels and a yellowish structure with black barblike spines.⁹ Within the dermis is a fibrous cystic sinus tract containing the dipteran larva. Laboratory studies typically are unremarkable. In chronic cases, a complete blood cell count and other laboratory tests may show systemic inflammation, peripheral eosinophilia, and elevated IgE.¹⁰ Biopsies of furuncular myiasis are not necessary for diagnosis. Histopathology reveals an ulcerated epidermis with or without hyperkeratosis and an inflammatory infiltrate composed of lymphocytes and neutrophils with eosinophils, fibroblasts, histiocytes, basophils, mast cells, plasma cells, and Langerhans cells within the dermis and subcutis.¹¹

There are various approaches to treating furuncular myiasis, with the goal of complete removal of the larva and prevention of secondary infection. One treatment option is to apply a toxic substance to the larva, effectively killing it. Another approach is to force the larva to emerge via localized hypoxia, which can be done by occluding the punctum of the lesion for at least 24 hours. A complication of this method is suffocation of the larva without migration, leading to incomplete extraction and secondary infection.¹ A third method is to surgically remove the larva, which allows for debridement of necrotic tissue surrounding the lesion if present.¹² Ultrasonography also can be used therapeutically to aid in the removal of the larvae. The last method is to inject lidocaine into the base of the lesion, forcing the larva out of the punctum via fluid pressure.¹³ Oral treatments such as ivermectin are not recommended because they can result in the death of larvae within the lesion, leading to an inflammatory response.⁸

Furuncular myiasis is a form of cutaneous larvae infestation not commonly seen in individuals who do not live or travel in endemic, tropical, and subtropical regions. Diagnosis is based on clinical presentation, with imaging and laboratory studies available to supplement in unclear or atypical manifestations. Treatment involves complete removal of the larva, typically through forced evacuation via hypoxia or through surgical removal. Most cases resolve without notable scarring or other sequelae; however, in those who do have complications, the most common is secondary bacterial infection. Our patient’s absence of notable travel history and frequent environmental exposure in Michigan led us to believe the organism was from a domestic source. Our case underlines the importance of a thorough history and clinical examination of furuncular lesions including the use of dermoscopy to yield an appropriate diagnosis and treatment plan.

To the Editor:

Ultra-late melanoma recurrence represents a minority of cases in which the quiescent period lasts longer than 15 years, and epidemiologic studies have reported recurrence rates of 6% to 10% during the ultra-late period.¹ Even more uncommon are cases that span many decades (eg, >30 years), but all are useful in understanding the cellular behavior leading to the reactivation of fully excised melanomas. Few cases have been reported in which recurrence occurs more than 35 years after the original diagnosis of melanoma. Unfortunately, mechanisms underlying this long stable quiescence and subsequent reactivation are poorly understood, which is why it is important to identify and document cases. We present a case of local recurrence of cutaneous melanoma on the patient’s lower back after a 49-year disease-free period.

A 78-year-old White woman presented to a private dermatology office for a full-body skin examination. She had a medical history of a cutaneous melanoma that had been removed on the lower back 49 years prior; Parkinson disease of 10 years’ duration; and an enlarged thyroid nodule with decreased thyrotropin and hyperthyroidism, atrial fibrillation, mitral valve prolapse, osteoarthritis in the knees, and actinic keratoses, all of which were chronic conditions lasting years to decades. She was taking several medications for these medical conditions. Her surgical history included a hysterectomy, hip replacement, hernia repair, cardioversion, and tonsillectomy in childhood. Her family medical history included breast cancer in her paternal grandmother and aunt; hypertension in her father; and sarcoma in her mother at 78 years of age, which initially was identified in the sacrum and metastasized to the lungs causing death. No family history of melanoma or other skin cancers was reported. Prior to the original diagnosis of melanoma at 29 years of age, she had no history of skin cancer or any other medical condition other than acne. The patient did report spending a great deal of time in the sun during high school.

The patient reported developing the original cutaneous melanoma during her second pregnancy at 29 years of age and recalled that it was excised with wide margins. There had been a mole on her back that was present for years but changed in size during pregnancy, prompting the original visit to the primary care physician for evaluation. Remarkably, the original pathology report was obtained from the patient and revealed a specimen consisting of a 3.7×1.7-cm skin ellipse averaging 0.7 cm in thickness. In the center of the specimen was a 0.6-cm, round, raised, pigmented lesion that revealed moderately frequent mitoses on microscopic evaluation. It was determined by the pathologist to be a malignant tumor, and the report stated that the surgical margins appeared clear.

Physical examination at the current presentation 49 years later revealed an even-bordered 2-mm black macule that was located approximately 1 cm from the original melanoma excision scar line (Figure). A biopsy was performed and sent to a dermatopathologist. Microscopic evaluation revealed nests, islands, and sheets of atypical epithelioid melanocytes extending through the dermis between collagen bundles. The melanocytes varied in size and shape with moderate nuclear pleomorphism present. Scattered mitotic figures and necrotic melanocytes were present, which most likely represented cutaneous satellite metastases of melanoma. Subsequent chest radiography, full-body positron emission tomography, and standard laboratory blood tests were unremarkable except for an enlarged right thyroid gland and moderate cardiomegaly. The patient was sent to a surgical oncologist for excision with wide surgical margins, and she elected not to have a sentinel lymph node biopsy. At follow-up 3, 6, 12, and 24 months later, there were no signs of recurrence based on direct clinical examination. The patient subsequently was lost to follow-up.

Recurrence rates of melanoma vary by stage and age at diagnosis, but prior studies have reported a recurrence rate of approximately 6% after 10 or more years following the initial diagnosis.² Ultra-late recurrences of approximately 4 decades or more are extremely rare. A PubMed search of articles indexed for MEDLINE using the terms melanoma and ultra-late recurrence revealed 4 reported cases with a quiescent period of 38 or more years.^3-6 All cases were metastatic melanomas in women; spanned 38, 40, 41, and 45 years from the initial melanoma diagnosis to recurrence; and all of the recurrences except one were regional or distal metastatic lesions (eg, lymph node, brain). In one case, both the original and recurrent lesions occurred on the left elbow.⁶ The original lesions occurred on the legs, elbow, and back of the neck, and there were no notable concomitant medical conditions. The patients were aged 72, 73, 73, and 84 years at recurrence.^3-6 However, generalizations from these cases are limited given the potential for selection bias (eg, men may be less likely to visit a clinic for follow-up and nevi examination) and the likelihood that many cases of ultra-late melanoma recurrence are unrecognized or unreported.

More recently, genomic analyses on melanoma lesions occurring 30 years apart confirmed that the second lesion was indeed a recurrence, although with numerous additional mutations.⁷ The specific mechanisms underlying the dormancy and subsequent reemergence of metastatic lesions are unclear, but there may be aberrations in the skin beyond histopathologic margins that represent an early phase of disease that are histologically unrecognizable and may lay dormant for many years before reemerging in response to external or immunologic changes.⁸ Alternatively, recurrences may be associated with lymphatic or hematogenous emboli, or there may be a tendency for melanomas to metastasize to inflamed or scarred tissue representing a tropism of the malignant melanocytes.⁹

It also is worth highlighting the concomitant diagnosis of Parkinson disease in our patient. In recent years, Parkinson disease has been linked to melanoma in both epidemiologic and genetic studies. For example, one large-scale study found a 50% increased risk for developing Parkinson disease in patients with melanoma (and vice versa), and this finding has been replicated in other studies.¹⁰ Moreover, patients with Parkinson disease have a 2-fold increase in their risk for developing melanoma, demonstrating that it is a bidirectional pathway. Not surprisingly, associations between melanin and neuromelanin pathways have been identified as a potential link between these diseases, and scientists are in the process of understanding the genetic components of both.¹⁰ It is unknown if specific genetic mutations contributed to both diseases in our case, but follow-up genetic testing on the recurrent melanoma specimen currently is being pursued.

The 49-year quiescent period in our case of recurrent cutaneous malignant melanoma potentially represents the longest ultra-late recurrence of melanoma in the literature to date based on a review of indexed publications. Moreover, it is relatively unique compared to other similar cases in that the recurrence was within a centimeter of the original excisional scar. Most metastases occur in locoregional lymph nodes or the lungs³; therefore, it is unusual to find one so close to the original lesion, especially one that occurred decades later. Factors associated with ultra-late recurrences are unknown, primarily because of the rarity of these cases as well as the biases and other factors that limit existing studies. However, genetic sequencing may provide information regarding these factors and related processes. Genetic sequencing specifically points to a small cell group remaining after excision of the primary tumor, which mutates while proliferating. Low antigenicity and tolerance to immunity during the quiescent period may explain the long duration of dormancy.⁶ More recently, there have been efforts to identify immunohistochemical signatures that may predict late recurrences, though the data are preliminary in nature.¹¹

Given the latency period and location of the recurrence, our case demonstrates that even fully excised melanomas may recur locally many decades later, hence patients should be aware of the importance of a lifetime of vigilance after being diagnosed with melanoma.

To the Editor:

Ultra-late melanoma recurrence represents a minority of cases in which the quiescent period lasts longer than 15 years, and epidemiologic studies have reported recurrence rates of 6% to 10% during the ultra-late period.¹ Even more uncommon are cases that span many decades (eg, >30 years), but all are useful in understanding the cellular behavior leading to the reactivation of fully excised melanomas. Few cases have been reported in which recurrence occurs more than 35 years after the original diagnosis of melanoma. Unfortunately, mechanisms underlying this long stable quiescence and subsequent reactivation are poorly understood, which is why it is important to identify and document cases. We present a case of local recurrence of cutaneous melanoma on the patient’s lower back after a 49-year disease-free period.

A 78-year-old White woman presented to a private dermatology office for a full-body skin examination. She had a medical history of a cutaneous melanoma that had been removed on the lower back 49 years prior; Parkinson disease of 10 years’ duration; and an enlarged thyroid nodule with decreased thyrotropin and hyperthyroidism, atrial fibrillation, mitral valve prolapse, osteoarthritis in the knees, and actinic keratoses, all of which were chronic conditions lasting years to decades. She was taking several medications for these medical conditions. Her surgical history included a hysterectomy, hip replacement, hernia repair, cardioversion, and tonsillectomy in childhood. Her family medical history included breast cancer in her paternal grandmother and aunt; hypertension in her father; and sarcoma in her mother at 78 years of age, which initially was identified in the sacrum and metastasized to the lungs causing death. No family history of melanoma or other skin cancers was reported. Prior to the original diagnosis of melanoma at 29 years of age, she had no history of skin cancer or any other medical condition other than acne. The patient did report spending a great deal of time in the sun during high school.

The patient reported developing the original cutaneous melanoma during her second pregnancy at 29 years of age and recalled that it was excised with wide margins. There had been a mole on her back that was present for years but changed in size during pregnancy, prompting the original visit to the primary care physician for evaluation. Remarkably, the original pathology report was obtained from the patient and revealed a specimen consisting of a 3.7×1.7-cm skin ellipse averaging 0.7 cm in thickness. In the center of the specimen was a 0.6-cm, round, raised, pigmented lesion that revealed moderately frequent mitoses on microscopic evaluation. It was determined by the pathologist to be a malignant tumor, and the report stated that the surgical margins appeared clear.

Physical examination at the current presentation 49 years later revealed an even-bordered 2-mm black macule that was located approximately 1 cm from the original melanoma excision scar line (Figure). A biopsy was performed and sent to a dermatopathologist. Microscopic evaluation revealed nests, islands, and sheets of atypical epithelioid melanocytes extending through the dermis between collagen bundles. The melanocytes varied in size and shape with moderate nuclear pleomorphism present. Scattered mitotic figures and necrotic melanocytes were present, which most likely represented cutaneous satellite metastases of melanoma. Subsequent chest radiography, full-body positron emission tomography, and standard laboratory blood tests were unremarkable except for an enlarged right thyroid gland and moderate cardiomegaly. The patient was sent to a surgical oncologist for excision with wide surgical margins, and she elected not to have a sentinel lymph node biopsy. At follow-up 3, 6, 12, and 24 months later, there were no signs of recurrence based on direct clinical examination. The patient subsequently was lost to follow-up.

Recurrence rates of melanoma vary by stage and age at diagnosis, but prior studies have reported a recurrence rate of approximately 6% after 10 or more years following the initial diagnosis.² Ultra-late recurrences of approximately 4 decades or more are extremely rare. A PubMed search of articles indexed for MEDLINE using the terms melanoma and ultra-late recurrence revealed 4 reported cases with a quiescent period of 38 or more years.^3-6 All cases were metastatic melanomas in women; spanned 38, 40, 41, and 45 years from the initial melanoma diagnosis to recurrence; and all of the recurrences except one were regional or distal metastatic lesions (eg, lymph node, brain). In one case, both the original and recurrent lesions occurred on the left elbow.⁶ The original lesions occurred on the legs, elbow, and back of the neck, and there were no notable concomitant medical conditions. The patients were aged 72, 73, 73, and 84 years at recurrence.^3-6 However, generalizations from these cases are limited given the potential for selection bias (eg, men may be less likely to visit a clinic for follow-up and nevi examination) and the likelihood that many cases of ultra-late melanoma recurrence are unrecognized or unreported.

More recently, genomic analyses on melanoma lesions occurring 30 years apart confirmed that the second lesion was indeed a recurrence, although with numerous additional mutations.⁷ The specific mechanisms underlying the dormancy and subsequent reemergence of metastatic lesions are unclear, but there may be aberrations in the skin beyond histopathologic margins that represent an early phase of disease that are histologically unrecognizable and may lay dormant for many years before reemerging in response to external or immunologic changes.⁸ Alternatively, recurrences may be associated with lymphatic or hematogenous emboli, or there may be a tendency for melanomas to metastasize to inflamed or scarred tissue representing a tropism of the malignant melanocytes.⁹

It also is worth highlighting the concomitant diagnosis of Parkinson disease in our patient. In recent years, Parkinson disease has been linked to melanoma in both epidemiologic and genetic studies. For example, one large-scale study found a 50% increased risk for developing Parkinson disease in patients with melanoma (and vice versa), and this finding has been replicated in other studies.¹⁰ Moreover, patients with Parkinson disease have a 2-fold increase in their risk for developing melanoma, demonstrating that it is a bidirectional pathway. Not surprisingly, associations between melanin and neuromelanin pathways have been identified as a potential link between these diseases, and scientists are in the process of understanding the genetic components of both.¹⁰ It is unknown if specific genetic mutations contributed to both diseases in our case, but follow-up genetic testing on the recurrent melanoma specimen currently is being pursued.

The 49-year quiescent period in our case of recurrent cutaneous malignant melanoma potentially represents the longest ultra-late recurrence of melanoma in the literature to date based on a review of indexed publications. Moreover, it is relatively unique compared to other similar cases in that the recurrence was within a centimeter of the original excisional scar. Most metastases occur in locoregional lymph nodes or the lungs³; therefore, it is unusual to find one so close to the original lesion, especially one that occurred decades later. Factors associated with ultra-late recurrences are unknown, primarily because of the rarity of these cases as well as the biases and other factors that limit existing studies. However, genetic sequencing may provide information regarding these factors and related processes. Genetic sequencing specifically points to a small cell group remaining after excision of the primary tumor, which mutates while proliferating. Low antigenicity and tolerance to immunity during the quiescent period may explain the long duration of dormancy.⁶ More recently, there have been efforts to identify immunohistochemical signatures that may predict late recurrences, though the data are preliminary in nature.¹¹

Given the latency period and location of the recurrence, our case demonstrates that even fully excised melanomas may recur locally many decades later, hence patients should be aware of the importance of a lifetime of vigilance after being diagnosed with melanoma.

To the Editor:

Ultra-late melanoma recurrence represents a minority of cases in which the quiescent period lasts longer than 15 years, and epidemiologic studies have reported recurrence rates of 6% to 10% during the ultra-late period.¹ Even more uncommon are cases that span many decades (eg, >30 years), but all are useful in understanding the cellular behavior leading to the reactivation of fully excised melanomas. Few cases have been reported in which recurrence occurs more than 35 years after the original diagnosis of melanoma. Unfortunately, mechanisms underlying this long stable quiescence and subsequent reactivation are poorly understood, which is why it is important to identify and document cases. We present a case of local recurrence of cutaneous melanoma on the patient’s lower back after a 49-year disease-free period.

A 78-year-old White woman presented to a private dermatology office for a full-body skin examination. She had a medical history of a cutaneous melanoma that had been removed on the lower back 49 years prior; Parkinson disease of 10 years’ duration; and an enlarged thyroid nodule with decreased thyrotropin and hyperthyroidism, atrial fibrillation, mitral valve prolapse, osteoarthritis in the knees, and actinic keratoses, all of which were chronic conditions lasting years to decades. She was taking several medications for these medical conditions. Her surgical history included a hysterectomy, hip replacement, hernia repair, cardioversion, and tonsillectomy in childhood. Her family medical history included breast cancer in her paternal grandmother and aunt; hypertension in her father; and sarcoma in her mother at 78 years of age, which initially was identified in the sacrum and metastasized to the lungs causing death. No family history of melanoma or other skin cancers was reported. Prior to the original diagnosis of melanoma at 29 years of age, she had no history of skin cancer or any other medical condition other than acne. The patient did report spending a great deal of time in the sun during high school.

The patient reported developing the original cutaneous melanoma during her second pregnancy at 29 years of age and recalled that it was excised with wide margins. There had been a mole on her back that was present for years but changed in size during pregnancy, prompting the original visit to the primary care physician for evaluation. Remarkably, the original pathology report was obtained from the patient and revealed a specimen consisting of a 3.7×1.7-cm skin ellipse averaging 0.7 cm in thickness. In the center of the specimen was a 0.6-cm, round, raised, pigmented lesion that revealed moderately frequent mitoses on microscopic evaluation. It was determined by the pathologist to be a malignant tumor, and the report stated that the surgical margins appeared clear.

Physical examination at the current presentation 49 years later revealed an even-bordered 2-mm black macule that was located approximately 1 cm from the original melanoma excision scar line (Figure). A biopsy was performed and sent to a dermatopathologist. Microscopic evaluation revealed nests, islands, and sheets of atypical epithelioid melanocytes extending through the dermis between collagen bundles. The melanocytes varied in size and shape with moderate nuclear pleomorphism present. Scattered mitotic figures and necrotic melanocytes were present, which most likely represented cutaneous satellite metastases of melanoma. Subsequent chest radiography, full-body positron emission tomography, and standard laboratory blood tests were unremarkable except for an enlarged right thyroid gland and moderate cardiomegaly. The patient was sent to a surgical oncologist for excision with wide surgical margins, and she elected not to have a sentinel lymph node biopsy. At follow-up 3, 6, 12, and 24 months later, there were no signs of recurrence based on direct clinical examination. The patient subsequently was lost to follow-up.

Recurrence rates of melanoma vary by stage and age at diagnosis, but prior studies have reported a recurrence rate of approximately 6% after 10 or more years following the initial diagnosis.² Ultra-late recurrences of approximately 4 decades or more are extremely rare. A PubMed search of articles indexed for MEDLINE using the terms melanoma and ultra-late recurrence revealed 4 reported cases with a quiescent period of 38 or more years.^3-6 All cases were metastatic melanomas in women; spanned 38, 40, 41, and 45 years from the initial melanoma diagnosis to recurrence; and all of the recurrences except one were regional or distal metastatic lesions (eg, lymph node, brain). In one case, both the original and recurrent lesions occurred on the left elbow.⁶ The original lesions occurred on the legs, elbow, and back of the neck, and there were no notable concomitant medical conditions. The patients were aged 72, 73, 73, and 84 years at recurrence.^3-6 However, generalizations from these cases are limited given the potential for selection bias (eg, men may be less likely to visit a clinic for follow-up and nevi examination) and the likelihood that many cases of ultra-late melanoma recurrence are unrecognized or unreported.

More recently, genomic analyses on melanoma lesions occurring 30 years apart confirmed that the second lesion was indeed a recurrence, although with numerous additional mutations.⁷ The specific mechanisms underlying the dormancy and subsequent reemergence of metastatic lesions are unclear, but there may be aberrations in the skin beyond histopathologic margins that represent an early phase of disease that are histologically unrecognizable and may lay dormant for many years before reemerging in response to external or immunologic changes.⁸ Alternatively, recurrences may be associated with lymphatic or hematogenous emboli, or there may be a tendency for melanomas to metastasize to inflamed or scarred tissue representing a tropism of the malignant melanocytes.⁹

It also is worth highlighting the concomitant diagnosis of Parkinson disease in our patient. In recent years, Parkinson disease has been linked to melanoma in both epidemiologic and genetic studies. For example, one large-scale study found a 50% increased risk for developing Parkinson disease in patients with melanoma (and vice versa), and this finding has been replicated in other studies.¹⁰ Moreover, patients with Parkinson disease have a 2-fold increase in their risk for developing melanoma, demonstrating that it is a bidirectional pathway. Not surprisingly, associations between melanin and neuromelanin pathways have been identified as a potential link between these diseases, and scientists are in the process of understanding the genetic components of both.¹⁰ It is unknown if specific genetic mutations contributed to both diseases in our case, but follow-up genetic testing on the recurrent melanoma specimen currently is being pursued.

The 49-year quiescent period in our case of recurrent cutaneous malignant melanoma potentially represents the longest ultra-late recurrence of melanoma in the literature to date based on a review of indexed publications. Moreover, it is relatively unique compared to other similar cases in that the recurrence was within a centimeter of the original excisional scar. Most metastases occur in locoregional lymph nodes or the lungs³; therefore, it is unusual to find one so close to the original lesion, especially one that occurred decades later. Factors associated with ultra-late recurrences are unknown, primarily because of the rarity of these cases as well as the biases and other factors that limit existing studies. However, genetic sequencing may provide information regarding these factors and related processes. Genetic sequencing specifically points to a small cell group remaining after excision of the primary tumor, which mutates while proliferating. Low antigenicity and tolerance to immunity during the quiescent period may explain the long duration of dormancy.⁶ More recently, there have been efforts to identify immunohistochemical signatures that may predict late recurrences, though the data are preliminary in nature.¹¹

Given the latency period and location of the recurrence, our case demonstrates that even fully excised melanomas may recur locally many decades later, hence patients should be aware of the importance of a lifetime of vigilance after being diagnosed with melanoma.

To the Editor:

Nail abnormalities associated with SARS-CoV-2 infection that have been reported in the medical literature include nail psoriasis,¹ Beau lines,² onychomadesis,³ heterogeneous red-white discoloration of the nail bed,⁴ transverse orange nail lesions,³ and the red half‐moon nail sign.^3,5 It has been hypothesized that these nail findings may be an indication of microvascular injury to the distal subungual arcade of the digit or may be indicative of a procoagulant state.^5,6 Currently, there is limited knowledge of the effect of COVID-19 vaccines on nail changes. We report a patient who presented with transverse leukonychia (Mees lines) and Beau lines shortly after each dose of the Pfizer-BioNTech COVID-19 messenger RNA vaccine was administered (with a total of 2 doses administered on presentation).

A 64-year-old woman with a history of rheumatoid arthritis presented with peeling of the fingernails and proximal white discoloration of several fingernails of 2 months’ duration. The patient first noticed whitening of the nails 3 weeks after she recevied the first dose of the COVID-19 vaccine. Five days after receiving the second, she presented to the dermatology clinic and exhibited transverse leukonychia in most fingernails (Figure 1).

Six weeks following the second dose of the COVID-19 vaccine, the patient returned to the dermatology clinic with Beau lines on the second and third fingernails on the right hand (Figure 2A). Subtle erythema of the proximal nail folds and distal fingers was observed in both hands. The patient also exhibited mild onychorrhexis of the left thumbnail and mottled red-brown discoloration of the third finger on the left hand (Figure 2B). Splinter hemorrhages and melanonychia of several fingernails also were observed. Our patient denied any known history of infection with SARS-CoV-2, which was confirmed by a negative COVID-19 polymerase chain reaction test result. She also denied fevers, chills, nausea, and vomiting, she and reported feeling generally well in the context of these postvaccination nail changes.

She reported no trauma or worsening of rheumatoid arthritis before or after COVID-19 vaccination. She was seronegative for rheumatoid arthritis and was being treated with hydroxychloroquine for the last year and methotrexate for the last 2 years. After each dose of the vaccine, methotrexate was withheld for 1 week and then resumed.

Subsequent follow-up examinations revealed the migration and resolution of transverse leukonychia and Beau lines. There also was interval improvement of the splinter hemorrhages. At 17 weeks following the second vaccine dose, all transverse leukonychia and Beau lines had resolved (Figure 3). The patient’s melanonychia remained unchanged.

Laboratory evaluations drawn 1 month following the first dose of the COVID-19 vaccine, including comprehensive metabolic panel; erythrocyte sedimentation rate; C-reactive protein; and vitamin B₁₂, ferritin, and iron levels were within reference range. The complete blood cell count only showed a mildly decreased white blood cell count (3.55×10³/µL [reference range, 4.16–9.95×10³/µL]) and mildly elevated mean corpuscular volume (101.9 fL [reference range, 79.3–98.6 fL), both near the patient’s baseline values prior to vaccination.

Documented cutaneous manifestations of SARS‐CoV‐2 infection have included perniolike lesions (known as COVID toes) and vesicular, urticarial, petechial, livedoid, or retiform purpura eruptions. Less frequently, nail findings in patients infected with COVID-19 have been reported, including Beau lines,² onychomadesis,³ transverse leukonychia,^3,7 and the red half‐moon nail sign.^3,5 Single or multiple nails may be affected. Although the pathogenesis of nail manifestations related to COVID-19 remains unclear, complement-mediated microvascular injury and thrombosis as well as the procoagulant state, which have been associated with COVID-19, may offer possible explanations.^5,6 The presence of microvascular abnormalities was observed in a nail fold video capillaroscopy study of the nails of 82 patients with COVID-19, revealing pericapillary edema, capillary ectasia, sludge flow, meandering capillaries and microvascular derangement, and low capillary density.⁸

Our patient exhibited transverse leukonychia of the fingernails, which is thought to result from abnormal keratinization of the nail plate due to systemic disorders that induce a temporary dysfunction of nail growth.⁹ Fernandez-Nieto et al⁷ reported transverse leukonychia in a patient with COVID-19 that was hypothesized to be due to a transitory nail matrix injury.

Beau lines and onychomadesis, which represent nail matrix arrest, commonly are seen with systemic drug treatments such as chemotherapy and in infectious diseases that precipitate systemic illness, such as hand, foot, and mouth disease. Although histologic examination was not performed in our patient due to cosmetic concerns, we believe that inflammation induced by the vaccine response also can trigger nail abnormalities such as transverse leukonychia and Beau lines. Both SARS-CoV-2 infections and the COVID-19 messenger RNA vaccines can induce systemic inflammation largely due a T_H1-dominant response, and they also can trigger other inflammatory conditions. Reports of lichen planus and psoriasis triggered by vaccination—the hepatitis B vaccine,¹⁰ influenza vaccine,¹¹ and even COVID-19 vaccines^1,12—have been reported. Beau lines have been observed to spontaneously resolve in a self-limiting manner in asymptomatic patients with COVID-19.

Interestingly, our patient only showed 2 nails with Beau lines. We hypothesize that the immune response triggered by vaccination was more subdued than that caused by SARS-CoV-2 infection. Additionally, our patient was already being treated with immunosuppressants, which may have been associated with a reduced immune response despite being withheld right before vaccination. One may debate whether the nail abnormalities observed in our patient constituted an isolated finding from COVID-19 vaccination or were caused by reactivation of rheumatoid arthritis. We favor the former, as the rheumatoid arthritis remained stable before and after COVID-19 vaccination. Laboratory evaluations and physical examination revealed no evidence of flares, and our patient was otherwise healthy. Although the splinter hemorrhages also improved, it is difficult to comment as to whether they were caused by the vaccine or had existed prior to vaccination. However, we believe the melanonychia observed in the nails was unrelated to the vaccine and was likely a chronic manifestation due to long-term hydroxychloroquine and/or methotrexate use.

Given accelerated global vaccination efforts to control the COVID-19 pandemic, more cases of adverse nail manifestations associated with COVID-19 vaccines are expected. Dermatologists should be aware of and use the reported nail findings to educate patients and reassure them that ungual abnormalities are potential adverse effects of COVID-19 vaccines, but they should not discourage vaccination because they usually are temporary and self-resolving.

To the Editor:

Nail abnormalities associated with SARS-CoV-2 infection that have been reported in the medical literature include nail psoriasis,¹ Beau lines,² onychomadesis,³ heterogeneous red-white discoloration of the nail bed,⁴ transverse orange nail lesions,³ and the red half‐moon nail sign.^3,5 It has been hypothesized that these nail findings may be an indication of microvascular injury to the distal subungual arcade of the digit or may be indicative of a procoagulant state.^5,6 Currently, there is limited knowledge of the effect of COVID-19 vaccines on nail changes. We report a patient who presented with transverse leukonychia (Mees lines) and Beau lines shortly after each dose of the Pfizer-BioNTech COVID-19 messenger RNA vaccine was administered (with a total of 2 doses administered on presentation).

A 64-year-old woman with a history of rheumatoid arthritis presented with peeling of the fingernails and proximal white discoloration of several fingernails of 2 months’ duration. The patient first noticed whitening of the nails 3 weeks after she recevied the first dose of the COVID-19 vaccine. Five days after receiving the second, she presented to the dermatology clinic and exhibited transverse leukonychia in most fingernails (Figure 1).

Six weeks following the second dose of the COVID-19 vaccine, the patient returned to the dermatology clinic with Beau lines on the second and third fingernails on the right hand (Figure 2A). Subtle erythema of the proximal nail folds and distal fingers was observed in both hands. The patient also exhibited mild onychorrhexis of the left thumbnail and mottled red-brown discoloration of the third finger on the left hand (Figure 2B). Splinter hemorrhages and melanonychia of several fingernails also were observed. Our patient denied any known history of infection with SARS-CoV-2, which was confirmed by a negative COVID-19 polymerase chain reaction test result. She also denied fevers, chills, nausea, and vomiting, she and reported feeling generally well in the context of these postvaccination nail changes.

She reported no trauma or worsening of rheumatoid arthritis before or after COVID-19 vaccination. She was seronegative for rheumatoid arthritis and was being treated with hydroxychloroquine for the last year and methotrexate for the last 2 years. After each dose of the vaccine, methotrexate was withheld for 1 week and then resumed.

Subsequent follow-up examinations revealed the migration and resolution of transverse leukonychia and Beau lines. There also was interval improvement of the splinter hemorrhages. At 17 weeks following the second vaccine dose, all transverse leukonychia and Beau lines had resolved (Figure 3). The patient’s melanonychia remained unchanged.

Laboratory evaluations drawn 1 month following the first dose of the COVID-19 vaccine, including comprehensive metabolic panel; erythrocyte sedimentation rate; C-reactive protein; and vitamin B₁₂, ferritin, and iron levels were within reference range. The complete blood cell count only showed a mildly decreased white blood cell count (3.55×10³/µL [reference range, 4.16–9.95×10³/µL]) and mildly elevated mean corpuscular volume (101.9 fL [reference range, 79.3–98.6 fL), both near the patient’s baseline values prior to vaccination.

Documented cutaneous manifestations of SARS‐CoV‐2 infection have included perniolike lesions (known as COVID toes) and vesicular, urticarial, petechial, livedoid, or retiform purpura eruptions. Less frequently, nail findings in patients infected with COVID-19 have been reported, including Beau lines,² onychomadesis,³ transverse leukonychia,^3,7 and the red half‐moon nail sign.^3,5 Single or multiple nails may be affected. Although the pathogenesis of nail manifestations related to COVID-19 remains unclear, complement-mediated microvascular injury and thrombosis as well as the procoagulant state, which have been associated with COVID-19, may offer possible explanations.^5,6 The presence of microvascular abnormalities was observed in a nail fold video capillaroscopy study of the nails of 82 patients with COVID-19, revealing pericapillary edema, capillary ectasia, sludge flow, meandering capillaries and microvascular derangement, and low capillary density.⁸

Our patient exhibited transverse leukonychia of the fingernails, which is thought to result from abnormal keratinization of the nail plate due to systemic disorders that induce a temporary dysfunction of nail growth.⁹ Fernandez-Nieto et al⁷ reported transverse leukonychia in a patient with COVID-19 that was hypothesized to be due to a transitory nail matrix injury.

Beau lines and onychomadesis, which represent nail matrix arrest, commonly are seen with systemic drug treatments such as chemotherapy and in infectious diseases that precipitate systemic illness, such as hand, foot, and mouth disease. Although histologic examination was not performed in our patient due to cosmetic concerns, we believe that inflammation induced by the vaccine response also can trigger nail abnormalities such as transverse leukonychia and Beau lines. Both SARS-CoV-2 infections and the COVID-19 messenger RNA vaccines can induce systemic inflammation largely due a T_H1-dominant response, and they also can trigger other inflammatory conditions. Reports of lichen planus and psoriasis triggered by vaccination—the hepatitis B vaccine,¹⁰ influenza vaccine,¹¹ and even COVID-19 vaccines^1,12—have been reported. Beau lines have been observed to spontaneously resolve in a self-limiting manner in asymptomatic patients with COVID-19.

Interestingly, our patient only showed 2 nails with Beau lines. We hypothesize that the immune response triggered by vaccination was more subdued than that caused by SARS-CoV-2 infection. Additionally, our patient was already being treated with immunosuppressants, which may have been associated with a reduced immune response despite being withheld right before vaccination. One may debate whether the nail abnormalities observed in our patient constituted an isolated finding from COVID-19 vaccination or were caused by reactivation of rheumatoid arthritis. We favor the former, as the rheumatoid arthritis remained stable before and after COVID-19 vaccination. Laboratory evaluations and physical examination revealed no evidence of flares, and our patient was otherwise healthy. Although the splinter hemorrhages also improved, it is difficult to comment as to whether they were caused by the vaccine or had existed prior to vaccination. However, we believe the melanonychia observed in the nails was unrelated to the vaccine and was likely a chronic manifestation due to long-term hydroxychloroquine and/or methotrexate use.

Given accelerated global vaccination efforts to control the COVID-19 pandemic, more cases of adverse nail manifestations associated with COVID-19 vaccines are expected. Dermatologists should be aware of and use the reported nail findings to educate patients and reassure them that ungual abnormalities are potential adverse effects of COVID-19 vaccines, but they should not discourage vaccination because they usually are temporary and self-resolving.

To the Editor:

Nail abnormalities associated with SARS-CoV-2 infection that have been reported in the medical literature include nail psoriasis,¹ Beau lines,² onychomadesis,³ heterogeneous red-white discoloration of the nail bed,⁴ transverse orange nail lesions,³ and the red half‐moon nail sign.^3,5 It has been hypothesized that these nail findings may be an indication of microvascular injury to the distal subungual arcade of the digit or may be indicative of a procoagulant state.^5,6 Currently, there is limited knowledge of the effect of COVID-19 vaccines on nail changes. We report a patient who presented with transverse leukonychia (Mees lines) and Beau lines shortly after each dose of the Pfizer-BioNTech COVID-19 messenger RNA vaccine was administered (with a total of 2 doses administered on presentation).

A 64-year-old woman with a history of rheumatoid arthritis presented with peeling of the fingernails and proximal white discoloration of several fingernails of 2 months’ duration. The patient first noticed whitening of the nails 3 weeks after she recevied the first dose of the COVID-19 vaccine. Five days after receiving the second, she presented to the dermatology clinic and exhibited transverse leukonychia in most fingernails (Figure 1).

Six weeks following the second dose of the COVID-19 vaccine, the patient returned to the dermatology clinic with Beau lines on the second and third fingernails on the right hand (Figure 2A). Subtle erythema of the proximal nail folds and distal fingers was observed in both hands. The patient also exhibited mild onychorrhexis of the left thumbnail and mottled red-brown discoloration of the third finger on the left hand (Figure 2B). Splinter hemorrhages and melanonychia of several fingernails also were observed. Our patient denied any known history of infection with SARS-CoV-2, which was confirmed by a negative COVID-19 polymerase chain reaction test result. She also denied fevers, chills, nausea, and vomiting, she and reported feeling generally well in the context of these postvaccination nail changes.

She reported no trauma or worsening of rheumatoid arthritis before or after COVID-19 vaccination. She was seronegative for rheumatoid arthritis and was being treated with hydroxychloroquine for the last year and methotrexate for the last 2 years. After each dose of the vaccine, methotrexate was withheld for 1 week and then resumed.

Subsequent follow-up examinations revealed the migration and resolution of transverse leukonychia and Beau lines. There also was interval improvement of the splinter hemorrhages. At 17 weeks following the second vaccine dose, all transverse leukonychia and Beau lines had resolved (Figure 3). The patient’s melanonychia remained unchanged.

Laboratory evaluations drawn 1 month following the first dose of the COVID-19 vaccine, including comprehensive metabolic panel; erythrocyte sedimentation rate; C-reactive protein; and vitamin B₁₂, ferritin, and iron levels were within reference range. The complete blood cell count only showed a mildly decreased white blood cell count (3.55×10³/µL [reference range, 4.16–9.95×10³/µL]) and mildly elevated mean corpuscular volume (101.9 fL [reference range, 79.3–98.6 fL), both near the patient’s baseline values prior to vaccination.

Documented cutaneous manifestations of SARS‐CoV‐2 infection have included perniolike lesions (known as COVID toes) and vesicular, urticarial, petechial, livedoid, or retiform purpura eruptions. Less frequently, nail findings in patients infected with COVID-19 have been reported, including Beau lines,² onychomadesis,³ transverse leukonychia,^3,7 and the red half‐moon nail sign.^3,5 Single or multiple nails may be affected. Although the pathogenesis of nail manifestations related to COVID-19 remains unclear, complement-mediated microvascular injury and thrombosis as well as the procoagulant state, which have been associated with COVID-19, may offer possible explanations.^5,6 The presence of microvascular abnormalities was observed in a nail fold video capillaroscopy study of the nails of 82 patients with COVID-19, revealing pericapillary edema, capillary ectasia, sludge flow, meandering capillaries and microvascular derangement, and low capillary density.⁸

Our patient exhibited transverse leukonychia of the fingernails, which is thought to result from abnormal keratinization of the nail plate due to systemic disorders that induce a temporary dysfunction of nail growth.⁹ Fernandez-Nieto et al⁷ reported transverse leukonychia in a patient with COVID-19 that was hypothesized to be due to a transitory nail matrix injury.

Beau lines and onychomadesis, which represent nail matrix arrest, commonly are seen with systemic drug treatments such as chemotherapy and in infectious diseases that precipitate systemic illness, such as hand, foot, and mouth disease. Although histologic examination was not performed in our patient due to cosmetic concerns, we believe that inflammation induced by the vaccine response also can trigger nail abnormalities such as transverse leukonychia and Beau lines. Both SARS-CoV-2 infections and the COVID-19 messenger RNA vaccines can induce systemic inflammation largely due a T_H1-dominant response, and they also can trigger other inflammatory conditions. Reports of lichen planus and psoriasis triggered by vaccination—the hepatitis B vaccine,¹⁰ influenza vaccine,¹¹ and even COVID-19 vaccines^1,12—have been reported. Beau lines have been observed to spontaneously resolve in a self-limiting manner in asymptomatic patients with COVID-19.

Interestingly, our patient only showed 2 nails with Beau lines. We hypothesize that the immune response triggered by vaccination was more subdued than that caused by SARS-CoV-2 infection. Additionally, our patient was already being treated with immunosuppressants, which may have been associated with a reduced immune response despite being withheld right before vaccination. One may debate whether the nail abnormalities observed in our patient constituted an isolated finding from COVID-19 vaccination or were caused by reactivation of rheumatoid arthritis. We favor the former, as the rheumatoid arthritis remained stable before and after COVID-19 vaccination. Laboratory evaluations and physical examination revealed no evidence of flares, and our patient was otherwise healthy. Although the splinter hemorrhages also improved, it is difficult to comment as to whether they were caused by the vaccine or had existed prior to vaccination. However, we believe the melanonychia observed in the nails was unrelated to the vaccine and was likely a chronic manifestation due to long-term hydroxychloroquine and/or methotrexate use.

Given accelerated global vaccination efforts to control the COVID-19 pandemic, more cases of adverse nail manifestations associated with COVID-19 vaccines are expected. Dermatologists should be aware of and use the reported nail findings to educate patients and reassure them that ungual abnormalities are potential adverse effects of COVID-19 vaccines, but they should not discourage vaccination because they usually are temporary and self-resolving.

To the Editor:

The itch-scratch cycle refers to the sequence created when a pruritic skin condition leads to scratching and skin barrier disruption, ultimately facilitating secondary skin changes and neural activation that prolongs pruritus. In patients with pruritic conditions, the itch-scratch cycle often can run unrestrained, with patients unaware of their scratching habits. Understanding what drives a patient to scratch, such as the pleasure gained from scratching, may be beneficial for dermatologists combating a patient’s scratching habits. The earliest documented attempts to understand the mechanism of an itch were made in Greece around the fifth century, but the pathophysiology of this sensation still is not fully understood. The Latin term pruritus refers to itching, irritation, or sexual excitement, while the Greek term knêsmos and related words also denote itch in an irritating or pleasurable sense.¹ This paradoxical duality of irritation and pleasure is a phenomenon all too well understood by those affected with pruritic symptoms.

Although there are many measured characteristics of an itch, the pleasure granted from scratching an itch rarely is addressed. Understanding the factors influencing the pleasurability of scratching could help improve management and outcomes of patients’ pruritic conditions.

Pruritus is associated with a wide array of etiologies including dermatologic, infectious, metabolic, and autoimmune, but unanimously it evokes a strong desire to scratch. Scratching an itch often yields temporary relief from the irritation by dispensing a complex sensory concoction between pleasure and pain.² The neurobiology behind this pleasure phenomenon is inconclusive. Some hypotheses point to how scratching-induced pleasure may be derived from the deactivation or inhibition of the unpleasant sensation of an itch in the central nervous system, the stimulation of the reward signals in the C-fiber system in the peripheral nervous system, the release of pruritis-inhibiting prostaglandin D2, or a combination of these pathways. Levels of sensation and pleasure induced from itch attenuation by scratching even vary based on anatomic location. One study demonstrated that, when compared to the forearms, the ankles and back perceived baseline induced itch most intensely, but no significant difference in perceived itch intensity was found between the ankles and back. Additionally, scratching an itchy back or ankle notably induced more pleasure when compared to the forearms, but there was no significant difference in scratching pleasurability between the ankle and back.³

Although there are adequate questionnaires and scales (eg, ItchyQoL,⁴ Skindex-16, Skindex-29) to quantify the severity of pruritus and its effects on a patient’s quality of life, these measurements do not assess the pleasure yielded from scratching, the impact of scratch pleasure on the patient experience, or the effect of scratch pleasure on the disease state.⁴ It appears that there are inadequate assessment tools to define factors associated with the pleasurability of scratching. A PubMed search of articles indexed for MEDLINE using the terms scratching pleasure scale and pruritus pleasure questionnaire yielded scarce results measuring patient perspectives on scratching-associated pleasure. A pertinent study performed by O’Neill et al⁵ compared the differences in itch characteristics between patients with psoriasis and those with atopic dermatitis using a web-based questionnaire featuring a numerical pleasure scale (ranging from −5 [highly unpleasurable] to +5 [highly pleasurable]) on an 11-point Likert scale. The questionnaire sought to measure the effects of scratching during a typical episode of itch within the past 2 weeks. Scratching was found pleasurable in both groups of patients.⁵ Another web-based questionnaire that characterized pleasurability in scratching a typical episode of itch in individuals with atopic dermatitis using a −5 to +5 Likert scale (−5 [highly unpleasurable] to +5 [highly pleasurable]) found that most participants perceived scratching as pleasurable and that there was a positive correlation between itch intensity and scratch pleasurability.⁶ Both of these studies quantified that scratching an itch is pleasurable, a correlation that may not come as a surprise. This direct correlation suggests that a more detailed analysis of this scratch pleasure could be beneficial in the management of pruritic conditions.

Treating the underlying cause of an itch is key to inhibiting the sensation; in some cases, anti-itch medications must be used. Current medications have limited effects on itch relief, but an expanding understanding of itch pathophysiology through clinical and laboratory research in the fields of dermatology, immunology, and neurology is paving the way for promising new therapeutic medications.^7-11 In a review of the literature, Sanders and Akiyama¹² elucidated the influence of stress and anxiety in scratching an itch and the way in which both pharmacologic and nonpharmacologic (ie, psychological and educational interventions) may be used to help break the itch-scratch cycle. Possible techniques include habit-reversal training, relaxation therapy, and cognitive behavioral therapy.¹³ Understanding patient perspectives on the pleasure yielded from scratching an itch and the disease factors that influence this pleasure seeking are paramount to reducing patient scratching. In understanding the pleasurability of scratching in pruritic conditions, the itch-scratch cycle and its accompanying deleterious effects (eg, stress, anxiety, pain, infection, secondary skin changes) can be broken.

The pleasure yielded from scratching an itch is a component of patient scratching habits that should be analyzed and quantified to reduce itch in pruritic conditions, mitigate damaging consequences of scratching, and improve the quality of life of patients with pruritic conditions. Furthermore, this understanding may help guide clinicians in management, such as counseling patients on the itch-scratch cycle and deciding which forthcoming medications could ameliorate a patient’s pruritic symptoms.

To the Editor:

The itch-scratch cycle refers to the sequence created when a pruritic skin condition leads to scratching and skin barrier disruption, ultimately facilitating secondary skin changes and neural activation that prolongs pruritus. In patients with pruritic conditions, the itch-scratch cycle often can run unrestrained, with patients unaware of their scratching habits. Understanding what drives a patient to scratch, such as the pleasure gained from scratching, may be beneficial for dermatologists combating a patient’s scratching habits. The earliest documented attempts to understand the mechanism of an itch were made in Greece around the fifth century, but the pathophysiology of this sensation still is not fully understood. The Latin term pruritus refers to itching, irritation, or sexual excitement, while the Greek term knêsmos and related words also denote itch in an irritating or pleasurable sense.¹ This paradoxical duality of irritation and pleasure is a phenomenon all too well understood by those affected with pruritic symptoms.

Although there are many measured characteristics of an itch, the pleasure granted from scratching an itch rarely is addressed. Understanding the factors influencing the pleasurability of scratching could help improve management and outcomes of patients’ pruritic conditions.

Pruritus is associated with a wide array of etiologies including dermatologic, infectious, metabolic, and autoimmune, but unanimously it evokes a strong desire to scratch. Scratching an itch often yields temporary relief from the irritation by dispensing a complex sensory concoction between pleasure and pain.² The neurobiology behind this pleasure phenomenon is inconclusive. Some hypotheses point to how scratching-induced pleasure may be derived from the deactivation or inhibition of the unpleasant sensation of an itch in the central nervous system, the stimulation of the reward signals in the C-fiber system in the peripheral nervous system, the release of pruritis-inhibiting prostaglandin D2, or a combination of these pathways. Levels of sensation and pleasure induced from itch attenuation by scratching even vary based on anatomic location. One study demonstrated that, when compared to the forearms, the ankles and back perceived baseline induced itch most intensely, but no significant difference in perceived itch intensity was found between the ankles and back. Additionally, scratching an itchy back or ankle notably induced more pleasure when compared to the forearms, but there was no significant difference in scratching pleasurability between the ankle and back.³

Although there are adequate questionnaires and scales (eg, ItchyQoL,⁴ Skindex-16, Skindex-29) to quantify the severity of pruritus and its effects on a patient’s quality of life, these measurements do not assess the pleasure yielded from scratching, the impact of scratch pleasure on the patient experience, or the effect of scratch pleasure on the disease state.⁴ It appears that there are inadequate assessment tools to define factors associated with the pleasurability of scratching. A PubMed search of articles indexed for MEDLINE using the terms scratching pleasure scale and pruritus pleasure questionnaire yielded scarce results measuring patient perspectives on scratching-associated pleasure. A pertinent study performed by O’Neill et al⁵ compared the differences in itch characteristics between patients with psoriasis and those with atopic dermatitis using a web-based questionnaire featuring a numerical pleasure scale (ranging from −5 [highly unpleasurable] to +5 [highly pleasurable]) on an 11-point Likert scale. The questionnaire sought to measure the effects of scratching during a typical episode of itch within the past 2 weeks. Scratching was found pleasurable in both groups of patients.⁵ Another web-based questionnaire that characterized pleasurability in scratching a typical episode of itch in individuals with atopic dermatitis using a −5 to +5 Likert scale (−5 [highly unpleasurable] to +5 [highly pleasurable]) found that most participants perceived scratching as pleasurable and that there was a positive correlation between itch intensity and scratch pleasurability.⁶ Both of these studies quantified that scratching an itch is pleasurable, a correlation that may not come as a surprise. This direct correlation suggests that a more detailed analysis of this scratch pleasure could be beneficial in the management of pruritic conditions.

Treating the underlying cause of an itch is key to inhibiting the sensation; in some cases, anti-itch medications must be used. Current medications have limited effects on itch relief, but an expanding understanding of itch pathophysiology through clinical and laboratory research in the fields of dermatology, immunology, and neurology is paving the way for promising new therapeutic medications.^7-11 In a review of the literature, Sanders and Akiyama¹² elucidated the influence of stress and anxiety in scratching an itch and the way in which both pharmacologic and nonpharmacologic (ie, psychological and educational interventions) may be used to help break the itch-scratch cycle. Possible techniques include habit-reversal training, relaxation therapy, and cognitive behavioral therapy.¹³ Understanding patient perspectives on the pleasure yielded from scratching an itch and the disease factors that influence this pleasure seeking are paramount to reducing patient scratching. In understanding the pleasurability of scratching in pruritic conditions, the itch-scratch cycle and its accompanying deleterious effects (eg, stress, anxiety, pain, infection, secondary skin changes) can be broken.

The pleasure yielded from scratching an itch is a component of patient scratching habits that should be analyzed and quantified to reduce itch in pruritic conditions, mitigate damaging consequences of scratching, and improve the quality of life of patients with pruritic conditions. Furthermore, this understanding may help guide clinicians in management, such as counseling patients on the itch-scratch cycle and deciding which forthcoming medications could ameliorate a patient’s pruritic symptoms.

To the Editor:

The itch-scratch cycle refers to the sequence created when a pruritic skin condition leads to scratching and skin barrier disruption, ultimately facilitating secondary skin changes and neural activation that prolongs pruritus. In patients with pruritic conditions, the itch-scratch cycle often can run unrestrained, with patients unaware of their scratching habits. Understanding what drives a patient to scratch, such as the pleasure gained from scratching, may be beneficial for dermatologists combating a patient’s scratching habits. The earliest documented attempts to understand the mechanism of an itch were made in Greece around the fifth century, but the pathophysiology of this sensation still is not fully understood. The Latin term pruritus refers to itching, irritation, or sexual excitement, while the Greek term knêsmos and related words also denote itch in an irritating or pleasurable sense.¹ This paradoxical duality of irritation and pleasure is a phenomenon all too well understood by those affected with pruritic symptoms.

Although there are many measured characteristics of an itch, the pleasure granted from scratching an itch rarely is addressed. Understanding the factors influencing the pleasurability of scratching could help improve management and outcomes of patients’ pruritic conditions.

Pruritus is associated with a wide array of etiologies including dermatologic, infectious, metabolic, and autoimmune, but unanimously it evokes a strong desire to scratch. Scratching an itch often yields temporary relief from the irritation by dispensing a complex sensory concoction between pleasure and pain.² The neurobiology behind this pleasure phenomenon is inconclusive. Some hypotheses point to how scratching-induced pleasure may be derived from the deactivation or inhibition of the unpleasant sensation of an itch in the central nervous system, the stimulation of the reward signals in the C-fiber system in the peripheral nervous system, the release of pruritis-inhibiting prostaglandin D2, or a combination of these pathways. Levels of sensation and pleasure induced from itch attenuation by scratching even vary based on anatomic location. One study demonstrated that, when compared to the forearms, the ankles and back perceived baseline induced itch most intensely, but no significant difference in perceived itch intensity was found between the ankles and back. Additionally, scratching an itchy back or ankle notably induced more pleasure when compared to the forearms, but there was no significant difference in scratching pleasurability between the ankle and back.³

Although there are adequate questionnaires and scales (eg, ItchyQoL,⁴ Skindex-16, Skindex-29) to quantify the severity of pruritus and its effects on a patient’s quality of life, these measurements do not assess the pleasure yielded from scratching, the impact of scratch pleasure on the patient experience, or the effect of scratch pleasure on the disease state.⁴ It appears that there are inadequate assessment tools to define factors associated with the pleasurability of scratching. A PubMed search of articles indexed for MEDLINE using the terms scratching pleasure scale and pruritus pleasure questionnaire yielded scarce results measuring patient perspectives on scratching-associated pleasure. A pertinent study performed by O’Neill et al⁵ compared the differences in itch characteristics between patients with psoriasis and those with atopic dermatitis using a web-based questionnaire featuring a numerical pleasure scale (ranging from −5 [highly unpleasurable] to +5 [highly pleasurable]) on an 11-point Likert scale. The questionnaire sought to measure the effects of scratching during a typical episode of itch within the past 2 weeks. Scratching was found pleasurable in both groups of patients.⁵ Another web-based questionnaire that characterized pleasurability in scratching a typical episode of itch in individuals with atopic dermatitis using a −5 to +5 Likert scale (−5 [highly unpleasurable] to +5 [highly pleasurable]) found that most participants perceived scratching as pleasurable and that there was a positive correlation between itch intensity and scratch pleasurability.⁶ Both of these studies quantified that scratching an itch is pleasurable, a correlation that may not come as a surprise. This direct correlation suggests that a more detailed analysis of this scratch pleasure could be beneficial in the management of pruritic conditions.

Treating the underlying cause of an itch is key to inhibiting the sensation; in some cases, anti-itch medications must be used. Current medications have limited effects on itch relief, but an expanding understanding of itch pathophysiology through clinical and laboratory research in the fields of dermatology, immunology, and neurology is paving the way for promising new therapeutic medications.^7-11 In a review of the literature, Sanders and Akiyama¹² elucidated the influence of stress and anxiety in scratching an itch and the way in which both pharmacologic and nonpharmacologic (ie, psychological and educational interventions) may be used to help break the itch-scratch cycle. Possible techniques include habit-reversal training, relaxation therapy, and cognitive behavioral therapy.¹³ Understanding patient perspectives on the pleasure yielded from scratching an itch and the disease factors that influence this pleasure seeking are paramount to reducing patient scratching. In understanding the pleasurability of scratching in pruritic conditions, the itch-scratch cycle and its accompanying deleterious effects (eg, stress, anxiety, pain, infection, secondary skin changes) can be broken.

The pleasure yielded from scratching an itch is a component of patient scratching habits that should be analyzed and quantified to reduce itch in pruritic conditions, mitigate damaging consequences of scratching, and improve the quality of life of patients with pruritic conditions. Furthermore, this understanding may help guide clinicians in management, such as counseling patients on the itch-scratch cycle and deciding which forthcoming medications could ameliorate a patient’s pruritic symptoms.

To the Editor:

Dermatofibromas (also known as fibrous histiocytomas) are benign fibrous nodules that most often arise as solitary lesions on the lower extremities. Multiple eruptive dermatofibromas (MEDFs) are uncommon and have been defined as more than 15 in number¹ or 5 to 8 dermatofibromas appearing within 4 months.² They have been reported in association with a number of conditions of immune dysregulation such as systemic lupus erythematosus, Sjögren syndrome, HIV infection, and leukemia.³ Multiple eruptive dermatofibromas also have been described in patients with Down syndrome (DS).^4-7 We report a case of MEDFs in a patient with DS and review the literature on the association between MEDFs and DS.

A 38-year-old woman with DS, hidradenitis suppurativa, and hypothyroidism presented with multiple cutaneous lesions developing over the last year. The lesions continued to increase in number but were otherwise asymptomatic. Physical examination revealed approximately 20 rubbery, pink-tan papules measuring less than 1 cm in diameter that were scattered along the trunk (Figure, A), arms, and legs (Figure, B).

The patient had no known history of immunosuppression or rheumatologic disease and was otherwise healthy. Basic laboratory tests including a complete blood cell count and antinuclear antibody titer were within reference range. The lesions were clinically consistent with dermatofibromas, but due to their increasing number within a short period of time, a biopsy of a representative lesion was performed to confirm the diagnosis.

The exact incidence of MEDFs is unknown, but they are rare, with one review finding only 50 cases reported from 1960 to 2002.⁸ They are increasingly recognized as a sign of potential immune dysregulation. Approximately 56% to 70% of cases are seen in patients with an underlying disease state; 80% are immune mediated.^8,9 Interestingly, DS has long been associated with notable immune dysfunction,^10,11 with evidence suggesting that trisomy 21 may result in widespread changes in gene expression that can lead to interferon activation.¹²

A PubMed search of articles indexed for MEDLINE using the terms dermatofibroma and Down, dermatofibroma and Down syndrome, eruptive dermatofibroma and Down syndrome, and multiple dermatofibroma and Down syndrome revealed 6 cases of MEDFs in patients with DS that have been reported since 2005.^4-7 An additional report by Honda et al¹³ described a patient with DS who developed 7 dermatofibromas, but no time frame of development was specified. We reviewed the characteristics of 8 patients with DS with MEDFs, which included our patient (Table). The average age at time of presentation was 39 years (median age, 40 years). Six patients (75%) were female and 2 (25%) were male. Dermatofibromas were reported to appear over the course of months to years. Comorbidities included psoriatic arthritis (treated with methotrexate),⁶ thyroid disorders (ie, Graves disease),⁶ hypercholesterolemia,⁶ hidradenitis suppurativa, long-standing mild lymphopenia (1.4×10⁹/L [reference range, 1.5−4.0×10⁹/L]),⁴ and acute megakaryoblastic leukemia¹³ treated 15 years before the appearance of dermatofibromas.

Many dermatologic conditions have been reported at increased rates in individuals with DS, including seborrheic dermatitis, alopecia areata, syringomas, elastosis perforans serpiginosa, cutis marmorata, xerosis, and palmoplantar hyperkeratosis.^14,15 Although drawing conclusions about associations between MEDFs and DS is limited by our small sample size, we have reported this case and reviewed existing cases of MEDFs in DS to highlight a potential association that may be underrecognized or underreported. More evidence is needed to determine the strength of the association between MEDFs and DS, but dermatologists should be aware that MEDFs may be an additional skin finding associated with DS that is related to the syndrome’s immune dysregulation.

To the Editor:

Dermatofibromas (also known as fibrous histiocytomas) are benign fibrous nodules that most often arise as solitary lesions on the lower extremities. Multiple eruptive dermatofibromas (MEDFs) are uncommon and have been defined as more than 15 in number¹ or 5 to 8 dermatofibromas appearing within 4 months.² They have been reported in association with a number of conditions of immune dysregulation such as systemic lupus erythematosus, Sjögren syndrome, HIV infection, and leukemia.³ Multiple eruptive dermatofibromas also have been described in patients with Down syndrome (DS).^4-7 We report a case of MEDFs in a patient with DS and review the literature on the association between MEDFs and DS.

A 38-year-old woman with DS, hidradenitis suppurativa, and hypothyroidism presented with multiple cutaneous lesions developing over the last year. The lesions continued to increase in number but were otherwise asymptomatic. Physical examination revealed approximately 20 rubbery, pink-tan papules measuring less than 1 cm in diameter that were scattered along the trunk (Figure, A), arms, and legs (Figure, B).

The patient had no known history of immunosuppression or rheumatologic disease and was otherwise healthy. Basic laboratory tests including a complete blood cell count and antinuclear antibody titer were within reference range. The lesions were clinically consistent with dermatofibromas, but due to their increasing number within a short period of time, a biopsy of a representative lesion was performed to confirm the diagnosis.

The exact incidence of MEDFs is unknown, but they are rare, with one review finding only 50 cases reported from 1960 to 2002.⁸ They are increasingly recognized as a sign of potential immune dysregulation. Approximately 56% to 70% of cases are seen in patients with an underlying disease state; 80% are immune mediated.^8,9 Interestingly, DS has long been associated with notable immune dysfunction,^10,11 with evidence suggesting that trisomy 21 may result in widespread changes in gene expression that can lead to interferon activation.¹²

A PubMed search of articles indexed for MEDLINE using the terms dermatofibroma and Down, dermatofibroma and Down syndrome, eruptive dermatofibroma and Down syndrome, and multiple dermatofibroma and Down syndrome revealed 6 cases of MEDFs in patients with DS that have been reported since 2005.^4-7 An additional report by Honda et al¹³ described a patient with DS who developed 7 dermatofibromas, but no time frame of development was specified. We reviewed the characteristics of 8 patients with DS with MEDFs, which included our patient (Table). The average age at time of presentation was 39 years (median age, 40 years). Six patients (75%) were female and 2 (25%) were male. Dermatofibromas were reported to appear over the course of months to years. Comorbidities included psoriatic arthritis (treated with methotrexate),⁶ thyroid disorders (ie, Graves disease),⁶ hypercholesterolemia,⁶ hidradenitis suppurativa, long-standing mild lymphopenia (1.4×10⁹/L [reference range, 1.5−4.0×10⁹/L]),⁴ and acute megakaryoblastic leukemia¹³ treated 15 years before the appearance of dermatofibromas.

Many dermatologic conditions have been reported at increased rates in individuals with DS, including seborrheic dermatitis, alopecia areata, syringomas, elastosis perforans serpiginosa, cutis marmorata, xerosis, and palmoplantar hyperkeratosis.^14,15 Although drawing conclusions about associations between MEDFs and DS is limited by our small sample size, we have reported this case and reviewed existing cases of MEDFs in DS to highlight a potential association that may be underrecognized or underreported. More evidence is needed to determine the strength of the association between MEDFs and DS, but dermatologists should be aware that MEDFs may be an additional skin finding associated with DS that is related to the syndrome’s immune dysregulation.

To the Editor:

Dermatofibromas (also known as fibrous histiocytomas) are benign fibrous nodules that most often arise as solitary lesions on the lower extremities. Multiple eruptive dermatofibromas (MEDFs) are uncommon and have been defined as more than 15 in number¹ or 5 to 8 dermatofibromas appearing within 4 months.² They have been reported in association with a number of conditions of immune dysregulation such as systemic lupus erythematosus, Sjögren syndrome, HIV infection, and leukemia.³ Multiple eruptive dermatofibromas also have been described in patients with Down syndrome (DS).^4-7 We report a case of MEDFs in a patient with DS and review the literature on the association between MEDFs and DS.

A 38-year-old woman with DS, hidradenitis suppurativa, and hypothyroidism presented with multiple cutaneous lesions developing over the last year. The lesions continued to increase in number but were otherwise asymptomatic. Physical examination revealed approximately 20 rubbery, pink-tan papules measuring less than 1 cm in diameter that were scattered along the trunk (Figure, A), arms, and legs (Figure, B).

The patient had no known history of immunosuppression or rheumatologic disease and was otherwise healthy. Basic laboratory tests including a complete blood cell count and antinuclear antibody titer were within reference range. The lesions were clinically consistent with dermatofibromas, but due to their increasing number within a short period of time, a biopsy of a representative lesion was performed to confirm the diagnosis.

The exact incidence of MEDFs is unknown, but they are rare, with one review finding only 50 cases reported from 1960 to 2002.⁸ They are increasingly recognized as a sign of potential immune dysregulation. Approximately 56% to 70% of cases are seen in patients with an underlying disease state; 80% are immune mediated.^8,9 Interestingly, DS has long been associated with notable immune dysfunction,^10,11 with evidence suggesting that trisomy 21 may result in widespread changes in gene expression that can lead to interferon activation.¹²

A PubMed search of articles indexed for MEDLINE using the terms dermatofibroma and Down, dermatofibroma and Down syndrome, eruptive dermatofibroma and Down syndrome, and multiple dermatofibroma and Down syndrome revealed 6 cases of MEDFs in patients with DS that have been reported since 2005.^4-7 An additional report by Honda et al¹³ described a patient with DS who developed 7 dermatofibromas, but no time frame of development was specified. We reviewed the characteristics of 8 patients with DS with MEDFs, which included our patient (Table). The average age at time of presentation was 39 years (median age, 40 years). Six patients (75%) were female and 2 (25%) were male. Dermatofibromas were reported to appear over the course of months to years. Comorbidities included psoriatic arthritis (treated with methotrexate),⁶ thyroid disorders (ie, Graves disease),⁶ hypercholesterolemia,⁶ hidradenitis suppurativa, long-standing mild lymphopenia (1.4×10⁹/L [reference range, 1.5−4.0×10⁹/L]),⁴ and acute megakaryoblastic leukemia¹³ treated 15 years before the appearance of dermatofibromas.

Many dermatologic conditions have been reported at increased rates in individuals with DS, including seborrheic dermatitis, alopecia areata, syringomas, elastosis perforans serpiginosa, cutis marmorata, xerosis, and palmoplantar hyperkeratosis.^14,15 Although drawing conclusions about associations between MEDFs and DS is limited by our small sample size, we have reported this case and reviewed existing cases of MEDFs in DS to highlight a potential association that may be underrecognized or underreported. More evidence is needed to determine the strength of the association between MEDFs and DS, but dermatologists should be aware that MEDFs may be an additional skin finding associated with DS that is related to the syndrome’s immune dysregulation.

The sun protection factor (SPF) value indicates to consumers the level of protection that a given sunscreen formulation provides against erythemally effective UV radiation (UVR). ¹ In vivo SPF testing, the gold standard for determining SPF, yields highly variable results and can harm human test participants. ² In vitro SPF testing methodologies have been under development for years but none have (yet) replaced the in vivo test required by national and international regulatory agencies.

Recent European studies have shown strong data to support a highly standardized in vitro method,¹ now under development by the International Organization for Standardization (ISO)—potentially to serve as a new SPF determination standard.^1,3 Academia and industry should follow this example and actively take steps to develop and validate a suitable replacement for in vivo SPF testing.

In Vivo SPF Testing

The in vivo SPF test involves comparing doses of UVR necessary to induce erythema in human participants with and without sunscreen applied.² Although this method has long been the standard for SPF determination, it is associated with the following major disadvantages:

• Cost: The in vivo test is expensive.
• Variability: Results of the test are subject to high interlaboratory variability due to the inherent subjectivity of identifying erythema, the variable skin types of human participants, and other laboratory-dependent factors.² A study found that the average coefficient of variation for SPF values obtained from 3 or 4 laboratories to be 20%—with values exceeding 50% in some cases. With that level of variability, the same sunscreen may be labeled SPF 30, SPF 50, or SPF 50+, thereby posing a health risk to consumers who rely on the accuracy of such claims. In fact, Miksa et al² concluded that “the largest obstacle to a reliable SPF assessment for consumer health is the in vivo SPF test itself.”
• Ethical concerns: Human participants are intentionally exposed to harmful UVR until sunburn is achieved. For that reason, there have been calls to abandon the practice of in vivo testing.¹

Alternatives to In Vivo SPF Testing

There has been international interest in developing in silico and in vitro alternatives to the in vivo SPF test. These options are attractive because they are relatively inexpensive; avoid exposing human participants to harmful UVR; and have the potential to be more accurate and more reproducible than in vivo tests.

In Vitro Protocols—Many such in vitro tests exist; all generally involve applying a layer of sunscreen to an artificial substrate, exposing it to UVR from a solar simulator, and measuring the UVR transmittance through the product and film by spectrophotometry.¹ Prior shortcomings of this method have included suboptimal reproducibility, lack of data on substrate and product properties, and lack of demonstrated equivalency to in vivo SPF testing.⁴

In Silico Protocols—These tests use data on the UV spectra of sunscreen filters, physical characteristics of sunscreen films on skin, and the unique photoinstability of filters to calculate expected UVR transmittance and SPF of sunscreens based on their ingredients.⁵ Reports have shown high correlation with in vivo values. Results are not subject to random error; reproducibility is theoretically perfect.⁵

Regulatory Agencies and In Vitro Testing

In the United States, sunscreens are regulated as over-the-counter drugs. In vivo testing is the only US Food and Drug Administration (FDA)–approved method for determining SPF for labeling purposes.¹ In a 2007 Proposed Rule and a 2011 Final Rule, the FDA stated that in vitro SPF tests were an inadequate alternative to in vivo tests because of their shortcomings.^4,6

Acknowledging the potential benefits of in vitro testing, the FDA wrote that it would consider in vitro alternatives if equivalency to the in vivo test could be proved.⁶ The agency has not published an official stance on in vitro SPF testing since those statements in 2007 and 2011. Of note, the FDA deems in vitro testing sufficient for making claims of broad-spectrum coverage.⁴

In contrast to the regulatory scenario in the United States, Europe regulates sunscreens as cosmetics, and the European Union (EU) has banned animal testing of cosmetics,⁷ which poses a problem for the development of new sunscreens. It is not surprising, therefore, that in 2006 the European Commission (the executive arm of the EU) published a mandate that in vitro SPF testing methods be actively developed due to ethical concerns associated with in vivo methods.⁸ In 2017, the International Organization for Standardization released specific validation criteria for proposed in vitro tests to facilitate the eventual approval of such methods.¹

Progress of In Vitro Methods

In recent years, advances in in vitro SPF testing methods have addressed shortcomings noted previously by the FDA, which has led to notably improved reproducibility of results and correlation with in vivo values, in large part due to strict standardization of protocols,¹ such as tight temperature control of samples, a multisubstrate approach, robotic product application to ensure even distribution, and pre-irradiation of sunscreen samples.

With these improvements, a 2018 study demonstrated an in vitro SPF testing methodology that exceeded published ISO validation criteria for emulsion-type products.¹ This method was found to have low interlaboratory variability and high correlation with in vivo SPF values (Pearson r=0.88). Importantly, the authors noted that the consistency and reliability of in vitro SPF testing requires broad institution of a single unified method.¹

The method described in the 2018 study¹ has been accepted by the ISO Technical Committee and is undergoing further development³; it is expected to be approved by the European Committee for Standardization. After approval, adoption by member nations of the EU will require individual action, representing the next regulatory hurdle for in vitro SPF testing in Europe.

Final Thoughts and Future Steps

Recent data confirm the potential viability of in vitro testing as a primary method of determining SPF values.¹ Although ISO has moved forward with development of this method, the FDA has been quiet on in vitro SPF testing since 2011.⁴ The agency has, however, acknowledged the disadvantages of in vivo broad-spectrum testing, including exposure of human participants to harmful UVR and poor interlaboratory reproducibility.⁶

Given the technical developments and substantial potential benefits of in vitro testing, we believe that it is time for the FDA to revisit this matter. We propose that the FDA take 2 steps toward in vitro testing. First, publish specific validation criteria that would be deemed necessary for approval of such a test, similar to what ISO published in 2017. Second, thoroughly assess new data supporting the viability of available in vitro testing to determine if the FDA’s stated position that in vitro testing is inadequate remains true.

Although these 2 steps will be important to the process, adoption of an in vitro standard will require more than statements from the FDA. Additional funding should be allocated to researchers who are studying in vitro methodologies, and companies that profit from the multibillion-dollar sunscreen industry should be encouraged to invest in the development of more accurate and more ethical alternatives to in vivo SPF testing.

In vitro SPF testing is inexpensive, avoids the moral quandary of intentionally sunburning human participants, and is more reliable than in vivo testing. It is time for the FDA to facilitate the efforts of academia and industry in taking concrete steps toward approval of an in vitro alternative to in vivo SPF testing.

The sun protection factor (SPF) value indicates to consumers the level of protection that a given sunscreen formulation provides against erythemally effective UV radiation (UVR). ¹ In vivo SPF testing, the gold standard for determining SPF, yields highly variable results and can harm human test participants. ² In vitro SPF testing methodologies have been under development for years but none have (yet) replaced the in vivo test required by national and international regulatory agencies.

Recent European studies have shown strong data to support a highly standardized in vitro method,¹ now under development by the International Organization for Standardization (ISO)—potentially to serve as a new SPF determination standard.^1,3 Academia and industry should follow this example and actively take steps to develop and validate a suitable replacement for in vivo SPF testing.

In Vivo SPF Testing

The in vivo SPF test involves comparing doses of UVR necessary to induce erythema in human participants with and without sunscreen applied.² Although this method has long been the standard for SPF determination, it is associated with the following major disadvantages:

• Cost: The in vivo test is expensive.
• Variability: Results of the test are subject to high interlaboratory variability due to the inherent subjectivity of identifying erythema, the variable skin types of human participants, and other laboratory-dependent factors.² A study found that the average coefficient of variation for SPF values obtained from 3 or 4 laboratories to be 20%—with values exceeding 50% in some cases. With that level of variability, the same sunscreen may be labeled SPF 30, SPF 50, or SPF 50+, thereby posing a health risk to consumers who rely on the accuracy of such claims. In fact, Miksa et al² concluded that “the largest obstacle to a reliable SPF assessment for consumer health is the in vivo SPF test itself.”
• Ethical concerns: Human participants are intentionally exposed to harmful UVR until sunburn is achieved. For that reason, there have been calls to abandon the practice of in vivo testing.¹

Alternatives to In Vivo SPF Testing

There has been international interest in developing in silico and in vitro alternatives to the in vivo SPF test. These options are attractive because they are relatively inexpensive; avoid exposing human participants to harmful UVR; and have the potential to be more accurate and more reproducible than in vivo tests.

In Vitro Protocols—Many such in vitro tests exist; all generally involve applying a layer of sunscreen to an artificial substrate, exposing it to UVR from a solar simulator, and measuring the UVR transmittance through the product and film by spectrophotometry.¹ Prior shortcomings of this method have included suboptimal reproducibility, lack of data on substrate and product properties, and lack of demonstrated equivalency to in vivo SPF testing.⁴

In Silico Protocols—These tests use data on the UV spectra of sunscreen filters, physical characteristics of sunscreen films on skin, and the unique photoinstability of filters to calculate expected UVR transmittance and SPF of sunscreens based on their ingredients.⁵ Reports have shown high correlation with in vivo values. Results are not subject to random error; reproducibility is theoretically perfect.⁵

Regulatory Agencies and In Vitro Testing

In the United States, sunscreens are regulated as over-the-counter drugs. In vivo testing is the only US Food and Drug Administration (FDA)–approved method for determining SPF for labeling purposes.¹ In a 2007 Proposed Rule and a 2011 Final Rule, the FDA stated that in vitro SPF tests were an inadequate alternative to in vivo tests because of their shortcomings.^4,6

Acknowledging the potential benefits of in vitro testing, the FDA wrote that it would consider in vitro alternatives if equivalency to the in vivo test could be proved.⁶ The agency has not published an official stance on in vitro SPF testing since those statements in 2007 and 2011. Of note, the FDA deems in vitro testing sufficient for making claims of broad-spectrum coverage.⁴

In contrast to the regulatory scenario in the United States, Europe regulates sunscreens as cosmetics, and the European Union (EU) has banned animal testing of cosmetics,⁷ which poses a problem for the development of new sunscreens. It is not surprising, therefore, that in 2006 the European Commission (the executive arm of the EU) published a mandate that in vitro SPF testing methods be actively developed due to ethical concerns associated with in vivo methods.⁸ In 2017, the International Organization for Standardization released specific validation criteria for proposed in vitro tests to facilitate the eventual approval of such methods.¹

Progress of In Vitro Methods

In recent years, advances in in vitro SPF testing methods have addressed shortcomings noted previously by the FDA, which has led to notably improved reproducibility of results and correlation with in vivo values, in large part due to strict standardization of protocols,¹ such as tight temperature control of samples, a multisubstrate approach, robotic product application to ensure even distribution, and pre-irradiation of sunscreen samples.

With these improvements, a 2018 study demonstrated an in vitro SPF testing methodology that exceeded published ISO validation criteria for emulsion-type products.¹ This method was found to have low interlaboratory variability and high correlation with in vivo SPF values (Pearson r=0.88). Importantly, the authors noted that the consistency and reliability of in vitro SPF testing requires broad institution of a single unified method.¹

The method described in the 2018 study¹ has been accepted by the ISO Technical Committee and is undergoing further development³; it is expected to be approved by the European Committee for Standardization. After approval, adoption by member nations of the EU will require individual action, representing the next regulatory hurdle for in vitro SPF testing in Europe.

Final Thoughts and Future Steps

Recent data confirm the potential viability of in vitro testing as a primary method of determining SPF values.¹ Although ISO has moved forward with development of this method, the FDA has been quiet on in vitro SPF testing since 2011.⁴ The agency has, however, acknowledged the disadvantages of in vivo broad-spectrum testing, including exposure of human participants to harmful UVR and poor interlaboratory reproducibility.⁶

Given the technical developments and substantial potential benefits of in vitro testing, we believe that it is time for the FDA to revisit this matter. We propose that the FDA take 2 steps toward in vitro testing. First, publish specific validation criteria that would be deemed necessary for approval of such a test, similar to what ISO published in 2017. Second, thoroughly assess new data supporting the viability of available in vitro testing to determine if the FDA’s stated position that in vitro testing is inadequate remains true.

Although these 2 steps will be important to the process, adoption of an in vitro standard will require more than statements from the FDA. Additional funding should be allocated to researchers who are studying in vitro methodologies, and companies that profit from the multibillion-dollar sunscreen industry should be encouraged to invest in the development of more accurate and more ethical alternatives to in vivo SPF testing.

In vitro SPF testing is inexpensive, avoids the moral quandary of intentionally sunburning human participants, and is more reliable than in vivo testing. It is time for the FDA to facilitate the efforts of academia and industry in taking concrete steps toward approval of an in vitro alternative to in vivo SPF testing.

The sun protection factor (SPF) value indicates to consumers the level of protection that a given sunscreen formulation provides against erythemally effective UV radiation (UVR). ¹ In vivo SPF testing, the gold standard for determining SPF, yields highly variable results and can harm human test participants. ² In vitro SPF testing methodologies have been under development for years but none have (yet) replaced the in vivo test required by national and international regulatory agencies.

Recent European studies have shown strong data to support a highly standardized in vitro method,¹ now under development by the International Organization for Standardization (ISO)—potentially to serve as a new SPF determination standard.^1,3 Academia and industry should follow this example and actively take steps to develop and validate a suitable replacement for in vivo SPF testing.

In Vivo SPF Testing

The in vivo SPF test involves comparing doses of UVR necessary to induce erythema in human participants with and without sunscreen applied.² Although this method has long been the standard for SPF determination, it is associated with the following major disadvantages:

• Cost: The in vivo test is expensive.
• Variability: Results of the test are subject to high interlaboratory variability due to the inherent subjectivity of identifying erythema, the variable skin types of human participants, and other laboratory-dependent factors.² A study found that the average coefficient of variation for SPF values obtained from 3 or 4 laboratories to be 20%—with values exceeding 50% in some cases. With that level of variability, the same sunscreen may be labeled SPF 30, SPF 50, or SPF 50+, thereby posing a health risk to consumers who rely on the accuracy of such claims. In fact, Miksa et al² concluded that “the largest obstacle to a reliable SPF assessment for consumer health is the in vivo SPF test itself.”
• Ethical concerns: Human participants are intentionally exposed to harmful UVR until sunburn is achieved. For that reason, there have been calls to abandon the practice of in vivo testing.¹

Alternatives to In Vivo SPF Testing

There has been international interest in developing in silico and in vitro alternatives to the in vivo SPF test. These options are attractive because they are relatively inexpensive; avoid exposing human participants to harmful UVR; and have the potential to be more accurate and more reproducible than in vivo tests.

In Vitro Protocols—Many such in vitro tests exist; all generally involve applying a layer of sunscreen to an artificial substrate, exposing it to UVR from a solar simulator, and measuring the UVR transmittance through the product and film by spectrophotometry.¹ Prior shortcomings of this method have included suboptimal reproducibility, lack of data on substrate and product properties, and lack of demonstrated equivalency to in vivo SPF testing.⁴

In Silico Protocols—These tests use data on the UV spectra of sunscreen filters, physical characteristics of sunscreen films on skin, and the unique photoinstability of filters to calculate expected UVR transmittance and SPF of sunscreens based on their ingredients.⁵ Reports have shown high correlation with in vivo values. Results are not subject to random error; reproducibility is theoretically perfect.⁵

Regulatory Agencies and In Vitro Testing

In the United States, sunscreens are regulated as over-the-counter drugs. In vivo testing is the only US Food and Drug Administration (FDA)–approved method for determining SPF for labeling purposes.¹ In a 2007 Proposed Rule and a 2011 Final Rule, the FDA stated that in vitro SPF tests were an inadequate alternative to in vivo tests because of their shortcomings.^4,6

Acknowledging the potential benefits of in vitro testing, the FDA wrote that it would consider in vitro alternatives if equivalency to the in vivo test could be proved.⁶ The agency has not published an official stance on in vitro SPF testing since those statements in 2007 and 2011. Of note, the FDA deems in vitro testing sufficient for making claims of broad-spectrum coverage.⁴

In contrast to the regulatory scenario in the United States, Europe regulates sunscreens as cosmetics, and the European Union (EU) has banned animal testing of cosmetics,⁷ which poses a problem for the development of new sunscreens. It is not surprising, therefore, that in 2006 the European Commission (the executive arm of the EU) published a mandate that in vitro SPF testing methods be actively developed due to ethical concerns associated with in vivo methods.⁸ In 2017, the International Organization for Standardization released specific validation criteria for proposed in vitro tests to facilitate the eventual approval of such methods.¹

Progress of In Vitro Methods

In recent years, advances in in vitro SPF testing methods have addressed shortcomings noted previously by the FDA, which has led to notably improved reproducibility of results and correlation with in vivo values, in large part due to strict standardization of protocols,¹ such as tight temperature control of samples, a multisubstrate approach, robotic product application to ensure even distribution, and pre-irradiation of sunscreen samples.

With these improvements, a 2018 study demonstrated an in vitro SPF testing methodology that exceeded published ISO validation criteria for emulsion-type products.¹ This method was found to have low interlaboratory variability and high correlation with in vivo SPF values (Pearson r=0.88). Importantly, the authors noted that the consistency and reliability of in vitro SPF testing requires broad institution of a single unified method.¹

The method described in the 2018 study¹ has been accepted by the ISO Technical Committee and is undergoing further development³; it is expected to be approved by the European Committee for Standardization. After approval, adoption by member nations of the EU will require individual action, representing the next regulatory hurdle for in vitro SPF testing in Europe.

Final Thoughts and Future Steps

Recent data confirm the potential viability of in vitro testing as a primary method of determining SPF values.¹ Although ISO has moved forward with development of this method, the FDA has been quiet on in vitro SPF testing since 2011.⁴ The agency has, however, acknowledged the disadvantages of in vivo broad-spectrum testing, including exposure of human participants to harmful UVR and poor interlaboratory reproducibility.⁶

Given the technical developments and substantial potential benefits of in vitro testing, we believe that it is time for the FDA to revisit this matter. We propose that the FDA take 2 steps toward in vitro testing. First, publish specific validation criteria that would be deemed necessary for approval of such a test, similar to what ISO published in 2017. Second, thoroughly assess new data supporting the viability of available in vitro testing to determine if the FDA’s stated position that in vitro testing is inadequate remains true.

Although these 2 steps will be important to the process, adoption of an in vitro standard will require more than statements from the FDA. Additional funding should be allocated to researchers who are studying in vitro methodologies, and companies that profit from the multibillion-dollar sunscreen industry should be encouraged to invest in the development of more accurate and more ethical alternatives to in vivo SPF testing.

In vitro SPF testing is inexpensive, avoids the moral quandary of intentionally sunburning human participants, and is more reliable than in vivo testing. It is time for the FDA to facilitate the efforts of academia and industry in taking concrete steps toward approval of an in vitro alternative to in vivo SPF testing.

To the Editor:

There is increasing evidence supporting the use of the human papillomavirus (HPV) vaccine in the treatment of recalcitrant common warts.¹ We describe a potential complication associated with HPV vaccine treatment of warts that would be of interest to dermatologists.

A 70-year-old woman presented with a plantar wart measuring 6 mm in diameter at the base of the right hallux of 5 years’ duration. Prior failed therapies for wart removal included multiple paring treatments, cryotherapy, and topical salicylic acid 40% to 60%. The patient had no notable comorbidities; no history of gout; and no known risk factors for gout, such as hypertension, renal insufficiency, diuretic use, obesity, family history, or trauma.

Prior reports cited effective treatment of recalcitrant warts with recombinant HPV vaccines, both intralesionally¹ and intramuscularly.^2,3 With this knowledge in mind, we administered an intralesional injection with 0.1-mL recombinant HPV 9-valent vaccine to the patient’s plantar wart. Gradual erythema and swelling of the right first metatarsophalangeal joint developed over the next 7 days. Synovial fluid analysis demonstrated negatively birefringent crystals. The patient commenced treatment with colchicine and indomethacin and improved over the next 5 days. The wart resolved 3 months later and required no further treatment.

Prophylactic quadrivalent HPV vaccines have shown efficacy in treating HPV-associated precancerous and cancerous lesions.⁴ Case reports have suggested that HPV vaccines may be an effective treatment option for recalcitrant warts,^1-3,5 especially in cases that do not respond to traditional treatment. It is possible that the mechanism of wart treatment involves overlap in the antigenic epitopes of the HPV types targeted by the vaccine vs the HPV types responsible for causing warts.² Papillomaviruslike particles, based on the L1 capsid protein, can induce a specific CD8⁺ activation signal, leading to a vaccine-induced cytotoxic T-cell response that targets the wart cells with HPV-like antigens.⁶ The HPV vaccine contains aluminium, which has been shown to activate NLRP3 inflammasome,⁵ which may trigger gout by increasing monosodium urate crystal deposition via IL-1β production.⁷ This may lead to an increased risk for gout flares, an adverse effect of the HPV vaccine. This finding is supported by other studies of aluminium-containing vaccines that show an association with gout.⁶ It is noted that these vaccines are mostly delivered intramuscularly or subcutaneously in some cases.

We reported a case of gout triggered by intralesional HPV vaccine treatment of warts. It is unclear whether the gout was induced by the vaccine itself or whether it was due to trauma caused by the intralesional injection near the joint space. Based on our findings, we recommend that patients receiving intralesional injections for wart treatment be advised of this potential adverse effect, especially if they have risk factors for gout or have a history of gout.

To the Editor:

There is increasing evidence supporting the use of the human papillomavirus (HPV) vaccine in the treatment of recalcitrant common warts.¹ We describe a potential complication associated with HPV vaccine treatment of warts that would be of interest to dermatologists.

A 70-year-old woman presented with a plantar wart measuring 6 mm in diameter at the base of the right hallux of 5 years’ duration. Prior failed therapies for wart removal included multiple paring treatments, cryotherapy, and topical salicylic acid 40% to 60%. The patient had no notable comorbidities; no history of gout; and no known risk factors for gout, such as hypertension, renal insufficiency, diuretic use, obesity, family history, or trauma.

Prior reports cited effective treatment of recalcitrant warts with recombinant HPV vaccines, both intralesionally¹ and intramuscularly.^2,3 With this knowledge in mind, we administered an intralesional injection with 0.1-mL recombinant HPV 9-valent vaccine to the patient’s plantar wart. Gradual erythema and swelling of the right first metatarsophalangeal joint developed over the next 7 days. Synovial fluid analysis demonstrated negatively birefringent crystals. The patient commenced treatment with colchicine and indomethacin and improved over the next 5 days. The wart resolved 3 months later and required no further treatment.

Prophylactic quadrivalent HPV vaccines have shown efficacy in treating HPV-associated precancerous and cancerous lesions.⁴ Case reports have suggested that HPV vaccines may be an effective treatment option for recalcitrant warts,^1-3,5 especially in cases that do not respond to traditional treatment. It is possible that the mechanism of wart treatment involves overlap in the antigenic epitopes of the HPV types targeted by the vaccine vs the HPV types responsible for causing warts.² Papillomaviruslike particles, based on the L1 capsid protein, can induce a specific CD8⁺ activation signal, leading to a vaccine-induced cytotoxic T-cell response that targets the wart cells with HPV-like antigens.⁶ The HPV vaccine contains aluminium, which has been shown to activate NLRP3 inflammasome,⁵ which may trigger gout by increasing monosodium urate crystal deposition via IL-1β production.⁷ This may lead to an increased risk for gout flares, an adverse effect of the HPV vaccine. This finding is supported by other studies of aluminium-containing vaccines that show an association with gout.⁶ It is noted that these vaccines are mostly delivered intramuscularly or subcutaneously in some cases.

We reported a case of gout triggered by intralesional HPV vaccine treatment of warts. It is unclear whether the gout was induced by the vaccine itself or whether it was due to trauma caused by the intralesional injection near the joint space. Based on our findings, we recommend that patients receiving intralesional injections for wart treatment be advised of this potential adverse effect, especially if they have risk factors for gout or have a history of gout.

To the Editor:

There is increasing evidence supporting the use of the human papillomavirus (HPV) vaccine in the treatment of recalcitrant common warts.¹ We describe a potential complication associated with HPV vaccine treatment of warts that would be of interest to dermatologists.

A 70-year-old woman presented with a plantar wart measuring 6 mm in diameter at the base of the right hallux of 5 years’ duration. Prior failed therapies for wart removal included multiple paring treatments, cryotherapy, and topical salicylic acid 40% to 60%. The patient had no notable comorbidities; no history of gout; and no known risk factors for gout, such as hypertension, renal insufficiency, diuretic use, obesity, family history, or trauma.

Prior reports cited effective treatment of recalcitrant warts with recombinant HPV vaccines, both intralesionally¹ and intramuscularly.^2,3 With this knowledge in mind, we administered an intralesional injection with 0.1-mL recombinant HPV 9-valent vaccine to the patient’s plantar wart. Gradual erythema and swelling of the right first metatarsophalangeal joint developed over the next 7 days. Synovial fluid analysis demonstrated negatively birefringent crystals. The patient commenced treatment with colchicine and indomethacin and improved over the next 5 days. The wart resolved 3 months later and required no further treatment.

Prophylactic quadrivalent HPV vaccines have shown efficacy in treating HPV-associated precancerous and cancerous lesions.⁴ Case reports have suggested that HPV vaccines may be an effective treatment option for recalcitrant warts,^1-3,5 especially in cases that do not respond to traditional treatment. It is possible that the mechanism of wart treatment involves overlap in the antigenic epitopes of the HPV types targeted by the vaccine vs the HPV types responsible for causing warts.² Papillomaviruslike particles, based on the L1 capsid protein, can induce a specific CD8⁺ activation signal, leading to a vaccine-induced cytotoxic T-cell response that targets the wart cells with HPV-like antigens.⁶ The HPV vaccine contains aluminium, which has been shown to activate NLRP3 inflammasome,⁵ which may trigger gout by increasing monosodium urate crystal deposition via IL-1β production.⁷ This may lead to an increased risk for gout flares, an adverse effect of the HPV vaccine. This finding is supported by other studies of aluminium-containing vaccines that show an association with gout.⁶ It is noted that these vaccines are mostly delivered intramuscularly or subcutaneously in some cases.

We reported a case of gout triggered by intralesional HPV vaccine treatment of warts. It is unclear whether the gout was induced by the vaccine itself or whether it was due to trauma caused by the intralesional injection near the joint space. Based on our findings, we recommend that patients receiving intralesional injections for wart treatment be advised of this potential adverse effect, especially if they have risk factors for gout or have a history of gout.

To the Editor:

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

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

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

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

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

To the Editor:

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

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

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

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

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

To the Editor:

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

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

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

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

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

To the Editor:

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by the formation of antihemidesmosomal antibodies, resulting in tense bullae concentrated on the extremities and trunk that often are preceded by a pruritic urticarial phase.¹ A rare complication of BP is the subsequent development of acquired hemophilia A. We report a case of BP with associated factor VIII–neutralizing antibodies in a patient who improved with prednisone and rituximab therapy.

A 78-year-old woman presented with red-orange pruritic plaques on the right heel that spread to involve the arms and legs, abdomen, and trunk with new-onset bullae over the course of 2 weeks (Figure 1). Dermatology was consulted, and a diagnosis of BP was confirmed via biopsy and direct immunofluorescence.

Despite treatment with prednisone 40 mg/d and clobetasol ointment 0.05%, she continued to develop extensive cutaneous bullae and new hemorrhagic bullae on the buccal mucosae (Figure 2), necessitating hospital admission. She clinically improved after prednisone was increased to 60 mg/d and mycophenolate mofetil 500 mg twice daily was added; however, she returned 8 days after discharge from the hospital with altered mental status, new-onset hematomas of the abdomen and right leg, and a hemoglobin level of 5.8 g/dL (reference range, 14.0–17.5 g/dL). Activated prothrombin time was prolonged without correction on mixing studies, raising concern for coagulation factor inhibition. Factor VIII activity was diminished to 9% and then 1% three days later. Mycophenolate mofetil was discontinued, and the patient was acutely stabilized with blood transfusions, intravenous immunoglobulin, tranexamic acid, and aminocaproic acid. Rituximab was initiated at 1000 mg and then administered again 2 weeks later. At 7-week follow-up, coagulation studies normalized, and there was no evidence of blistering dermatosis on examination.

Bullous pemphigoid generally is seen in patients older than 60 years, and the incidence increases with age. The disease course follows formation of IgG antibodies against BP180 or BP230, leading to localized activation of the complement cascade at the basement membrane zone.¹ Medications, vaccinations, UV radiation, and burns have been implicated in disease induction.²

Identification of antihemidesmosomal antibodies on lesional biopsy via direct immunofluorescence is the gold standard for diagnosis, though indirect antibodies measured via enzyme-linked immunosorbent assay may provide information regarding disease severity.¹ Patients with milder disease may be treated with topical corticosteroids, doxycycline, and nicotinamide; however, severe disease requires treatment with systemic glucocorticoids and steroid-sparing agents.³ Rituximab initially was approved by the US Food and Drug Administration for the treatment of pemphigus vulgaris, and mounting evidence for the use of rituximab in BP is promising. Although data are limited to retrospective studies, rituximab has shown notable remission rates and steroid-sparing effects in those with moderate to severe BP.⁴

Acquired hemophilia A (AHA) is caused by the production of IgG autoantibodies, which block physiologic interactions between factor VIII and factor IX, phospholipids, and von Willebrand factor.⁵ Acquired hemophilia A often is diagnosed by prolonged activated prothrombin time and decreased factor VIII activity after a previously unaffected patient develops severe bleeding. Treatment involves re-establishing hemostasis and the use of corticosteroids and immunosuppressive agents to diminish autoantibody production.⁴

Bullous pemphigoid–associated AHA likely is due to antigenic similarity between BP180 and factor VIII, leading to concomitant neutralization of factor VIII with the production of BP-associated autoantibodies.⁵ Bullous pemphigoid–associated AHA has been reported with manifestations of bleeding concurrent with or after the development of dermatologic disease. Rituximab use has been reported with clinical efficacy in several cases, including our patient.⁶ Continued hematologic monitoring is recommended, as recurrences are common within the first 2 years.⁵

To the Editor:

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by the formation of antihemidesmosomal antibodies, resulting in tense bullae concentrated on the extremities and trunk that often are preceded by a pruritic urticarial phase.¹ A rare complication of BP is the subsequent development of acquired hemophilia A. We report a case of BP with associated factor VIII–neutralizing antibodies in a patient who improved with prednisone and rituximab therapy.

A 78-year-old woman presented with red-orange pruritic plaques on the right heel that spread to involve the arms and legs, abdomen, and trunk with new-onset bullae over the course of 2 weeks (Figure 1). Dermatology was consulted, and a diagnosis of BP was confirmed via biopsy and direct immunofluorescence.

Despite treatment with prednisone 40 mg/d and clobetasol ointment 0.05%, she continued to develop extensive cutaneous bullae and new hemorrhagic bullae on the buccal mucosae (Figure 2), necessitating hospital admission. She clinically improved after prednisone was increased to 60 mg/d and mycophenolate mofetil 500 mg twice daily was added; however, she returned 8 days after discharge from the hospital with altered mental status, new-onset hematomas of the abdomen and right leg, and a hemoglobin level of 5.8 g/dL (reference range, 14.0–17.5 g/dL). Activated prothrombin time was prolonged without correction on mixing studies, raising concern for coagulation factor inhibition. Factor VIII activity was diminished to 9% and then 1% three days later. Mycophenolate mofetil was discontinued, and the patient was acutely stabilized with blood transfusions, intravenous immunoglobulin, tranexamic acid, and aminocaproic acid. Rituximab was initiated at 1000 mg and then administered again 2 weeks later. At 7-week follow-up, coagulation studies normalized, and there was no evidence of blistering dermatosis on examination.

Bullous pemphigoid generally is seen in patients older than 60 years, and the incidence increases with age. The disease course follows formation of IgG antibodies against BP180 or BP230, leading to localized activation of the complement cascade at the basement membrane zone.¹ Medications, vaccinations, UV radiation, and burns have been implicated in disease induction.²

Identification of antihemidesmosomal antibodies on lesional biopsy via direct immunofluorescence is the gold standard for diagnosis, though indirect antibodies measured via enzyme-linked immunosorbent assay may provide information regarding disease severity.¹ Patients with milder disease may be treated with topical corticosteroids, doxycycline, and nicotinamide; however, severe disease requires treatment with systemic glucocorticoids and steroid-sparing agents.³ Rituximab initially was approved by the US Food and Drug Administration for the treatment of pemphigus vulgaris, and mounting evidence for the use of rituximab in BP is promising. Although data are limited to retrospective studies, rituximab has shown notable remission rates and steroid-sparing effects in those with moderate to severe BP.⁴

Acquired hemophilia A (AHA) is caused by the production of IgG autoantibodies, which block physiologic interactions between factor VIII and factor IX, phospholipids, and von Willebrand factor.⁵ Acquired hemophilia A often is diagnosed by prolonged activated prothrombin time and decreased factor VIII activity after a previously unaffected patient develops severe bleeding. Treatment involves re-establishing hemostasis and the use of corticosteroids and immunosuppressive agents to diminish autoantibody production.⁴

Bullous pemphigoid–associated AHA likely is due to antigenic similarity between BP180 and factor VIII, leading to concomitant neutralization of factor VIII with the production of BP-associated autoantibodies.⁵ Bullous pemphigoid–associated AHA has been reported with manifestations of bleeding concurrent with or after the development of dermatologic disease. Rituximab use has been reported with clinical efficacy in several cases, including our patient.⁶ Continued hematologic monitoring is recommended, as recurrences are common within the first 2 years.⁵

To the Editor:

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by the formation of antihemidesmosomal antibodies, resulting in tense bullae concentrated on the extremities and trunk that often are preceded by a pruritic urticarial phase.¹ A rare complication of BP is the subsequent development of acquired hemophilia A. We report a case of BP with associated factor VIII–neutralizing antibodies in a patient who improved with prednisone and rituximab therapy.

A 78-year-old woman presented with red-orange pruritic plaques on the right heel that spread to involve the arms and legs, abdomen, and trunk with new-onset bullae over the course of 2 weeks (Figure 1). Dermatology was consulted, and a diagnosis of BP was confirmed via biopsy and direct immunofluorescence.

Despite treatment with prednisone 40 mg/d and clobetasol ointment 0.05%, she continued to develop extensive cutaneous bullae and new hemorrhagic bullae on the buccal mucosae (Figure 2), necessitating hospital admission. She clinically improved after prednisone was increased to 60 mg/d and mycophenolate mofetil 500 mg twice daily was added; however, she returned 8 days after discharge from the hospital with altered mental status, new-onset hematomas of the abdomen and right leg, and a hemoglobin level of 5.8 g/dL (reference range, 14.0–17.5 g/dL). Activated prothrombin time was prolonged without correction on mixing studies, raising concern for coagulation factor inhibition. Factor VIII activity was diminished to 9% and then 1% three days later. Mycophenolate mofetil was discontinued, and the patient was acutely stabilized with blood transfusions, intravenous immunoglobulin, tranexamic acid, and aminocaproic acid. Rituximab was initiated at 1000 mg and then administered again 2 weeks later. At 7-week follow-up, coagulation studies normalized, and there was no evidence of blistering dermatosis on examination.

Bullous pemphigoid generally is seen in patients older than 60 years, and the incidence increases with age. The disease course follows formation of IgG antibodies against BP180 or BP230, leading to localized activation of the complement cascade at the basement membrane zone.¹ Medications, vaccinations, UV radiation, and burns have been implicated in disease induction.²

Identification of antihemidesmosomal antibodies on lesional biopsy via direct immunofluorescence is the gold standard for diagnosis, though indirect antibodies measured via enzyme-linked immunosorbent assay may provide information regarding disease severity.¹ Patients with milder disease may be treated with topical corticosteroids, doxycycline, and nicotinamide; however, severe disease requires treatment with systemic glucocorticoids and steroid-sparing agents.³ Rituximab initially was approved by the US Food and Drug Administration for the treatment of pemphigus vulgaris, and mounting evidence for the use of rituximab in BP is promising. Although data are limited to retrospective studies, rituximab has shown notable remission rates and steroid-sparing effects in those with moderate to severe BP.⁴

Acquired hemophilia A (AHA) is caused by the production of IgG autoantibodies, which block physiologic interactions between factor VIII and factor IX, phospholipids, and von Willebrand factor.⁵ Acquired hemophilia A often is diagnosed by prolonged activated prothrombin time and decreased factor VIII activity after a previously unaffected patient develops severe bleeding. Treatment involves re-establishing hemostasis and the use of corticosteroids and immunosuppressive agents to diminish autoantibody production.⁴

Bullous pemphigoid–associated AHA likely is due to antigenic similarity between BP180 and factor VIII, leading to concomitant neutralization of factor VIII with the production of BP-associated autoantibodies.⁵ Bullous pemphigoid–associated AHA has been reported with manifestations of bleeding concurrent with or after the development of dermatologic disease. Rituximab use has been reported with clinical efficacy in several cases, including our patient.⁶ Continued hematologic monitoring is recommended, as recurrences are common within the first 2 years.⁵

To the Editor:

Peristomal pyoderma gangrenosum (PPG) is a rare entity first described in 1984.¹ Lesions usually begin as pustules that coalesce into an erythematous skin ulceration that contains purulent material. The lesion appears on the skin that surrounds an abdominal stoma. Peristomal pyoderma gangrenosum typically is associated with Crohn disease and ulcerative colitis, cancer, blood dyscrasia, diabetes mellitus, and hepatitis.² We describe a case of PPG following an ileostomy in a patient with colon cancer and a related history of Crohn disease.

A 32-year-old woman presented to a dermatology office with a spontaneously painful, 3.2-cm ulceration that was extremely tender to palpation, located immediately adjacent to the site of an ileostomy (Figure). The patient had a history of refractory constipation that failed to respond to standard conservative measures 4 years prior. She underwent a colonoscopy, which revealed a 6.5-cm, irregularly shaped, exophytic mass in the rectosigmoid portion of the colon. Histopathologic examination of several biopsies confirmed the diagnosis of moderately well-differentiated adenocarcinoma, and additional evaluation determined the cancer to be stage IIB. She had a medical history of pancolonic Crohn disease since high school that was treated with periodic infusions of infliximab at the standard dose of 5 mg/kg. Colon cancer treatment consisted of preoperative radiotherapy, complete colectomy with ileoanal anastomosis, and creation of a J-pouch and formation of a temporary ileostomy, along with postoperative capecitabine chemotherapy.

The ileostomy eventually was reversed, and the patient did well for 3 years. When the patient developed severe abdominal pain, the J-pouch was examined and found to be remarkably involved with Crohn disease. However, during the colonoscopy, the J-pouch was inadvertently punctured, leading to the formation of a large pelvic abscess. The latter necessitated diversion of stool, and the patient had the original ileostomy recreated.

Prior to presentation to dermatology, various consultants suspected the ulceration was possibly a deep fungal infection, cutaneous Crohn disease, a factitious ulceration, or acute allergic contact dermatitis related to some element of ostomy care. However, dermatologic consultation suggested that the troublesome lesion was classic PPG and recommended administration of a tumor necrosis factor (TNF) α–blocking agent and concomitant intralesional injections of dilute triamcinolone acetonide.

The patient was treated with subcutaneous adalimumab 40 mg once weekly, and received near weekly subcutaneous injections of triamcinolone acetonide 10 mg/mL. After 2 months, the discomfort subsided, and the ulceration gradually resolved into a depressed scar. Eighteen months later, the scar was barely perceptible as a minimally erythematous depression. Adalimumab ultimately was discontinued, as the residual J-pouch was removed, and the biologic drug was associated with extensive alopecia areata–like hair loss. There has been no recurrence of PPG in the 40 months since clinical resolution.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum, which is characterized by chronic, persistent, or recurrent painful ulceration(s) close to an abdominal stoma. In total, fewer than 100 cases of PPG have been reported thus far in the readily available medical literature.³ Inflammatory bowel disease (IBD) is the most frequently diagnosed systemic condition associated with PPG, though other associated conditions include diverticular disease, abdominal malignancy, and neurologic dysfunction. Approximately 2% to 4.3% of all patients who have stoma creation surgery related to underlying IBD develop PPG. It is estimated that the yearly incidence rate of PPG in all abdominal stomas is quite low (approximately 0.6%).⁴

Peristomal pyoderma gangrenosum can occur at any age, but it tends to predominate in young to middle-aged adults, with a slight female predilection. The etiology and pathogenesis of PPG are largely unknown, though studies have shown that an abnormal immune response may be critical to its development. Risk factors for PPG are not well defined but potentially include autoimmune disorders, a high body mass index, and females or African Americans with IBD.⁴ Because PPG does not have characteristic histopathologic features, it is a diagnosis of exclusion that is based on the clinical examination and histologic findings that rule out other potential disorders.

There are 4 types of PPG based on the clinical and histopathologic characteristics: ulcerative, pustular, bullous, and vegetative. Peristomal pyoderma gangrenosum tends to be either ulcerative or vegetative, with ulcerative being by far the predominant type. The onset of PPG is quite variable, occurring a few weeks to several years after stoma formation.⁵ Ulcer size can range from less than 3 cm to 30 cm.⁴ Lesions begin as deep painful nodules or as superficial hemorrhagic pustules, either idiopathic or following ostensibly minimal trauma. Subsequently, they become necrotic and form an ulceration. The ulcers can be single or multiple lesions, typically with erythematous raised borders and purulent discharge. The ulcers are extremely painful and rapidly progressive. After the ulcers heal, they often leave a characteristic weblike atrophic scar that can break down further following any form of irritation or trauma.⁵

A prompt diagnosis of PPG is important. A diagnosis of PPG should be considered when dealing with a noninfectious ulcer surrounding a stoma in patients with IBD or other autoimmune conditions.⁶ Because PPG is a rare skin disorder, it is likely to be missed and lead to unnecessary diagnostic workup and a delay in proper therapy. In our patient, a diagnosis of PPG was overlooked for other infectious and autoimmune causes. The diagnostic evaluation of a patient with PPG is based on 3 principles: (1) ruling out other causes of a peristomal ulcer, such as an abscess, contact dermatitis, or wound infection; (2) determining whether there is an underlying intestinal bowel disease in the stoma; and (3) identifying associated systemic disorders such as vasculitis, erythema nodosum, or similar processes.⁴ The differential diagnosis depends on the type and stage of PPG and can include malignancy, vasculitis, extraintestinal IBD, infectious disease, and insect bites. A review of the history of the ulcer is helpful in ruling out other diseases, and a colonoscopy or ileoscopy can identify if patients have an underlying active IBD. Swabs for smear and both bacterial and fungal cultures should be taken from the exudate and directly from the ulcer base. Biopsy of the ulcer also helps to exclude alternative diagnoses.⁶

The primary goals of treating PPG include to reduce pain and the risk for secondary infection, increase pouch adherence, and decrease purulent exudate.⁷ Although there is not one well-defined optimal therapeutic intervention, there are a variety of effective approaches that may be considered and used. In mild cases, management methods such as dressings, topical agents, or intralesional steroids may be capable of controlling the disease. Daily wound care is important. Moisture-retentive dressings can control pain, induce collagen formation, promote angiogenesis, and prevent contamination. Cleaning the wound with sterile saline and applying an anti-infective agent also may be effective. Application of ultrapotent topical steroids and tacrolimus ointment 0.3% can be used in patients without concomitant secondary infection. In patients who are in remission, human platelet-derived growth factor may be used. Intralesional injections of dilute triamcinolone acetonide or cyclosporine solution also can be helpful. Cyclosporin A was used as a systemic monotherapy to treat a 48-year-old man and 50-year-old woman with the idiopathic form of PPG. After 3 months of treatment, PPG had completely resolved and there were no major side effects.⁸ Other potential topical therapies that control inflammation and promote wound healing include benzoyl peroxide, chlormethine (topical alkylating agent and nitrogen mustard that has anti-inflammatory properties), nicotine, and 5-aminosalicylic acid. If an ulcer becomes infected, empiric antibiotic therapy should be given immediately and adjusted based on culture and sensitivity results.⁴

Systemic therapy should be considered in patients who do not respond to topical or local interventions, have a rapid and severe course, or have an active underlying bowel disease. Oral prednisone (1 mg/kg/d) has proved to be one of the most successful drugs used to treat PPG. Treatment should be continued until complete lesion healing, and low-dose maintenance therapy should be administered in recurrent cases. Intravenous corticosteroid therapy—hydrocortisone 100 mg 4 times daily or pulse therapy with intravenous methylprednisolone 1 g/d)—can be used for up to 5 days and may be effective. Oral minocycline 100 mg twice daily may be helpful as an adjunctive therapy to corticosteroids. When corticosteroids fail, oral cyclosporine 3 to 5 mg/kg/d often is prescribed. Studies have shown that patients demonstrate clinical improvement within 3 weeks of cyclosporine initiation, and it has been shown further to be more effective than either azathioprine or methotrexate.^4,8

Infliximab, a chimeric antibody that binds both circulating and tissue-bound TNF-α, has been shown to effectively treat PPG. A clinical trial conducted by Brooklyn et al⁹ found that 46% of patients (6/13) treated with infliximab responded compared with only 6% in a placebo control group (1/17). Although infliximab may result in sepsis, the benefits far outweigh the risks, especially for patients with steroid-refractory PPG.⁴ Adalimumab is a human monoclonal IgG1 antibody to TNF-α that neutralizes its function by blocking the interaction between the molecule and its receptor. Many clinical studies have shown that adalimumab induces and maintains a clinical response in patients with active Crohn disease. The biologic proved to be effective in our patient, but it is associated with potential side effects that should be monitored including injection-site reactions, pruritus, leukopenia, urticaria, and rare instances of alopecia.¹⁰ Etanercept is another potentially effective biologic agent.⁷ Plasma exchange, immunoglobulin infusion, and interferon-alfa therapy also can be used in refractory PPG cases, though data on these treatments are very limited.⁴

Unlike routine pyoderma gangrenosum—for which surgical intervention is contraindicated—surgical intervention may be appropriate for the peristomal variant. Surgical treatment options include stoma revision and/or relocation; however, both of these procedures are accompanied by failure rates ranging from 40% to 100%.⁵ Removal of a diseased intestinal segment, especially one with active IBD, may result in healing of the skin lesion. In our patient, removal of the residual and diseased J-pouch was part of the management plan. However,it generally is recommended that any surgical intervention be accompanied by medical therapy including oral metronidazole 500 mg/d and concomitant administration of an immunosuppressant.^1,3

Because PPG tends to recur, long-term maintenance therapy should always be considered. Pain reduction, anemia correction, proper nutrition, and management of associated and underlying diseases should be performed. Meticulous care of the stoma and prevention of leaks also should be emphasized. Overall, if PPG is detected and diagnosed early as well as treated appropriately and aggressively, the patient likely will have a good prognosis.⁴

To the Editor:

Peristomal pyoderma gangrenosum (PPG) is a rare entity first described in 1984.¹ Lesions usually begin as pustules that coalesce into an erythematous skin ulceration that contains purulent material. The lesion appears on the skin that surrounds an abdominal stoma. Peristomal pyoderma gangrenosum typically is associated with Crohn disease and ulcerative colitis, cancer, blood dyscrasia, diabetes mellitus, and hepatitis.² We describe a case of PPG following an ileostomy in a patient with colon cancer and a related history of Crohn disease.

A 32-year-old woman presented to a dermatology office with a spontaneously painful, 3.2-cm ulceration that was extremely tender to palpation, located immediately adjacent to the site of an ileostomy (Figure). The patient had a history of refractory constipation that failed to respond to standard conservative measures 4 years prior. She underwent a colonoscopy, which revealed a 6.5-cm, irregularly shaped, exophytic mass in the rectosigmoid portion of the colon. Histopathologic examination of several biopsies confirmed the diagnosis of moderately well-differentiated adenocarcinoma, and additional evaluation determined the cancer to be stage IIB. She had a medical history of pancolonic Crohn disease since high school that was treated with periodic infusions of infliximab at the standard dose of 5 mg/kg. Colon cancer treatment consisted of preoperative radiotherapy, complete colectomy with ileoanal anastomosis, and creation of a J-pouch and formation of a temporary ileostomy, along with postoperative capecitabine chemotherapy.

The ileostomy eventually was reversed, and the patient did well for 3 years. When the patient developed severe abdominal pain, the J-pouch was examined and found to be remarkably involved with Crohn disease. However, during the colonoscopy, the J-pouch was inadvertently punctured, leading to the formation of a large pelvic abscess. The latter necessitated diversion of stool, and the patient had the original ileostomy recreated.

Prior to presentation to dermatology, various consultants suspected the ulceration was possibly a deep fungal infection, cutaneous Crohn disease, a factitious ulceration, or acute allergic contact dermatitis related to some element of ostomy care. However, dermatologic consultation suggested that the troublesome lesion was classic PPG and recommended administration of a tumor necrosis factor (TNF) α–blocking agent and concomitant intralesional injections of dilute triamcinolone acetonide.

The patient was treated with subcutaneous adalimumab 40 mg once weekly, and received near weekly subcutaneous injections of triamcinolone acetonide 10 mg/mL. After 2 months, the discomfort subsided, and the ulceration gradually resolved into a depressed scar. Eighteen months later, the scar was barely perceptible as a minimally erythematous depression. Adalimumab ultimately was discontinued, as the residual J-pouch was removed, and the biologic drug was associated with extensive alopecia areata–like hair loss. There has been no recurrence of PPG in the 40 months since clinical resolution.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum, which is characterized by chronic, persistent, or recurrent painful ulceration(s) close to an abdominal stoma. In total, fewer than 100 cases of PPG have been reported thus far in the readily available medical literature.³ Inflammatory bowel disease (IBD) is the most frequently diagnosed systemic condition associated with PPG, though other associated conditions include diverticular disease, abdominal malignancy, and neurologic dysfunction. Approximately 2% to 4.3% of all patients who have stoma creation surgery related to underlying IBD develop PPG. It is estimated that the yearly incidence rate of PPG in all abdominal stomas is quite low (approximately 0.6%).⁴

Peristomal pyoderma gangrenosum can occur at any age, but it tends to predominate in young to middle-aged adults, with a slight female predilection. The etiology and pathogenesis of PPG are largely unknown, though studies have shown that an abnormal immune response may be critical to its development. Risk factors for PPG are not well defined but potentially include autoimmune disorders, a high body mass index, and females or African Americans with IBD.⁴ Because PPG does not have characteristic histopathologic features, it is a diagnosis of exclusion that is based on the clinical examination and histologic findings that rule out other potential disorders.

There are 4 types of PPG based on the clinical and histopathologic characteristics: ulcerative, pustular, bullous, and vegetative. Peristomal pyoderma gangrenosum tends to be either ulcerative or vegetative, with ulcerative being by far the predominant type. The onset of PPG is quite variable, occurring a few weeks to several years after stoma formation.⁵ Ulcer size can range from less than 3 cm to 30 cm.⁴ Lesions begin as deep painful nodules or as superficial hemorrhagic pustules, either idiopathic or following ostensibly minimal trauma. Subsequently, they become necrotic and form an ulceration. The ulcers can be single or multiple lesions, typically with erythematous raised borders and purulent discharge. The ulcers are extremely painful and rapidly progressive. After the ulcers heal, they often leave a characteristic weblike atrophic scar that can break down further following any form of irritation or trauma.⁵

A prompt diagnosis of PPG is important. A diagnosis of PPG should be considered when dealing with a noninfectious ulcer surrounding a stoma in patients with IBD or other autoimmune conditions.⁶ Because PPG is a rare skin disorder, it is likely to be missed and lead to unnecessary diagnostic workup and a delay in proper therapy. In our patient, a diagnosis of PPG was overlooked for other infectious and autoimmune causes. The diagnostic evaluation of a patient with PPG is based on 3 principles: (1) ruling out other causes of a peristomal ulcer, such as an abscess, contact dermatitis, or wound infection; (2) determining whether there is an underlying intestinal bowel disease in the stoma; and (3) identifying associated systemic disorders such as vasculitis, erythema nodosum, or similar processes.⁴ The differential diagnosis depends on the type and stage of PPG and can include malignancy, vasculitis, extraintestinal IBD, infectious disease, and insect bites. A review of the history of the ulcer is helpful in ruling out other diseases, and a colonoscopy or ileoscopy can identify if patients have an underlying active IBD. Swabs for smear and both bacterial and fungal cultures should be taken from the exudate and directly from the ulcer base. Biopsy of the ulcer also helps to exclude alternative diagnoses.⁶

The primary goals of treating PPG include to reduce pain and the risk for secondary infection, increase pouch adherence, and decrease purulent exudate.⁷ Although there is not one well-defined optimal therapeutic intervention, there are a variety of effective approaches that may be considered and used. In mild cases, management methods such as dressings, topical agents, or intralesional steroids may be capable of controlling the disease. Daily wound care is important. Moisture-retentive dressings can control pain, induce collagen formation, promote angiogenesis, and prevent contamination. Cleaning the wound with sterile saline and applying an anti-infective agent also may be effective. Application of ultrapotent topical steroids and tacrolimus ointment 0.3% can be used in patients without concomitant secondary infection. In patients who are in remission, human platelet-derived growth factor may be used. Intralesional injections of dilute triamcinolone acetonide or cyclosporine solution also can be helpful. Cyclosporin A was used as a systemic monotherapy to treat a 48-year-old man and 50-year-old woman with the idiopathic form of PPG. After 3 months of treatment, PPG had completely resolved and there were no major side effects.⁸ Other potential topical therapies that control inflammation and promote wound healing include benzoyl peroxide, chlormethine (topical alkylating agent and nitrogen mustard that has anti-inflammatory properties), nicotine, and 5-aminosalicylic acid. If an ulcer becomes infected, empiric antibiotic therapy should be given immediately and adjusted based on culture and sensitivity results.⁴

Systemic therapy should be considered in patients who do not respond to topical or local interventions, have a rapid and severe course, or have an active underlying bowel disease. Oral prednisone (1 mg/kg/d) has proved to be one of the most successful drugs used to treat PPG. Treatment should be continued until complete lesion healing, and low-dose maintenance therapy should be administered in recurrent cases. Intravenous corticosteroid therapy—hydrocortisone 100 mg 4 times daily or pulse therapy with intravenous methylprednisolone 1 g/d)—can be used for up to 5 days and may be effective. Oral minocycline 100 mg twice daily may be helpful as an adjunctive therapy to corticosteroids. When corticosteroids fail, oral cyclosporine 3 to 5 mg/kg/d often is prescribed. Studies have shown that patients demonstrate clinical improvement within 3 weeks of cyclosporine initiation, and it has been shown further to be more effective than either azathioprine or methotrexate.^4,8

Infliximab, a chimeric antibody that binds both circulating and tissue-bound TNF-α, has been shown to effectively treat PPG. A clinical trial conducted by Brooklyn et al⁹ found that 46% of patients (6/13) treated with infliximab responded compared with only 6% in a placebo control group (1/17). Although infliximab may result in sepsis, the benefits far outweigh the risks, especially for patients with steroid-refractory PPG.⁴ Adalimumab is a human monoclonal IgG1 antibody to TNF-α that neutralizes its function by blocking the interaction between the molecule and its receptor. Many clinical studies have shown that adalimumab induces and maintains a clinical response in patients with active Crohn disease. The biologic proved to be effective in our patient, but it is associated with potential side effects that should be monitored including injection-site reactions, pruritus, leukopenia, urticaria, and rare instances of alopecia.¹⁰ Etanercept is another potentially effective biologic agent.⁷ Plasma exchange, immunoglobulin infusion, and interferon-alfa therapy also can be used in refractory PPG cases, though data on these treatments are very limited.⁴

Unlike routine pyoderma gangrenosum—for which surgical intervention is contraindicated—surgical intervention may be appropriate for the peristomal variant. Surgical treatment options include stoma revision and/or relocation; however, both of these procedures are accompanied by failure rates ranging from 40% to 100%.⁵ Removal of a diseased intestinal segment, especially one with active IBD, may result in healing of the skin lesion. In our patient, removal of the residual and diseased J-pouch was part of the management plan. However,it generally is recommended that any surgical intervention be accompanied by medical therapy including oral metronidazole 500 mg/d and concomitant administration of an immunosuppressant.^1,3

Because PPG tends to recur, long-term maintenance therapy should always be considered. Pain reduction, anemia correction, proper nutrition, and management of associated and underlying diseases should be performed. Meticulous care of the stoma and prevention of leaks also should be emphasized. Overall, if PPG is detected and diagnosed early as well as treated appropriately and aggressively, the patient likely will have a good prognosis.⁴

To the Editor:

Peristomal pyoderma gangrenosum (PPG) is a rare entity first described in 1984.¹ Lesions usually begin as pustules that coalesce into an erythematous skin ulceration that contains purulent material. The lesion appears on the skin that surrounds an abdominal stoma. Peristomal pyoderma gangrenosum typically is associated with Crohn disease and ulcerative colitis, cancer, blood dyscrasia, diabetes mellitus, and hepatitis.² We describe a case of PPG following an ileostomy in a patient with colon cancer and a related history of Crohn disease.

A 32-year-old woman presented to a dermatology office with a spontaneously painful, 3.2-cm ulceration that was extremely tender to palpation, located immediately adjacent to the site of an ileostomy (Figure). The patient had a history of refractory constipation that failed to respond to standard conservative measures 4 years prior. She underwent a colonoscopy, which revealed a 6.5-cm, irregularly shaped, exophytic mass in the rectosigmoid portion of the colon. Histopathologic examination of several biopsies confirmed the diagnosis of moderately well-differentiated adenocarcinoma, and additional evaluation determined the cancer to be stage IIB. She had a medical history of pancolonic Crohn disease since high school that was treated with periodic infusions of infliximab at the standard dose of 5 mg/kg. Colon cancer treatment consisted of preoperative radiotherapy, complete colectomy with ileoanal anastomosis, and creation of a J-pouch and formation of a temporary ileostomy, along with postoperative capecitabine chemotherapy.

The ileostomy eventually was reversed, and the patient did well for 3 years. When the patient developed severe abdominal pain, the J-pouch was examined and found to be remarkably involved with Crohn disease. However, during the colonoscopy, the J-pouch was inadvertently punctured, leading to the formation of a large pelvic abscess. The latter necessitated diversion of stool, and the patient had the original ileostomy recreated.

Prior to presentation to dermatology, various consultants suspected the ulceration was possibly a deep fungal infection, cutaneous Crohn disease, a factitious ulceration, or acute allergic contact dermatitis related to some element of ostomy care. However, dermatologic consultation suggested that the troublesome lesion was classic PPG and recommended administration of a tumor necrosis factor (TNF) α–blocking agent and concomitant intralesional injections of dilute triamcinolone acetonide.

The patient was treated with subcutaneous adalimumab 40 mg once weekly, and received near weekly subcutaneous injections of triamcinolone acetonide 10 mg/mL. After 2 months, the discomfort subsided, and the ulceration gradually resolved into a depressed scar. Eighteen months later, the scar was barely perceptible as a minimally erythematous depression. Adalimumab ultimately was discontinued, as the residual J-pouch was removed, and the biologic drug was associated with extensive alopecia areata–like hair loss. There has been no recurrence of PPG in the 40 months since clinical resolution.

Peristomal pyoderma gangrenosum is an uncommon subtype of pyoderma gangrenosum, which is characterized by chronic, persistent, or recurrent painful ulceration(s) close to an abdominal stoma. In total, fewer than 100 cases of PPG have been reported thus far in the readily available medical literature.³ Inflammatory bowel disease (IBD) is the most frequently diagnosed systemic condition associated with PPG, though other associated conditions include diverticular disease, abdominal malignancy, and neurologic dysfunction. Approximately 2% to 4.3% of all patients who have stoma creation surgery related to underlying IBD develop PPG. It is estimated that the yearly incidence rate of PPG in all abdominal stomas is quite low (approximately 0.6%).⁴

Peristomal pyoderma gangrenosum can occur at any age, but it tends to predominate in young to middle-aged adults, with a slight female predilection. The etiology and pathogenesis of PPG are largely unknown, though studies have shown that an abnormal immune response may be critical to its development. Risk factors for PPG are not well defined but potentially include autoimmune disorders, a high body mass index, and females or African Americans with IBD.⁴ Because PPG does not have characteristic histopathologic features, it is a diagnosis of exclusion that is based on the clinical examination and histologic findings that rule out other potential disorders.

There are 4 types of PPG based on the clinical and histopathologic characteristics: ulcerative, pustular, bullous, and vegetative. Peristomal pyoderma gangrenosum tends to be either ulcerative or vegetative, with ulcerative being by far the predominant type. The onset of PPG is quite variable, occurring a few weeks to several years after stoma formation.⁵ Ulcer size can range from less than 3 cm to 30 cm.⁴ Lesions begin as deep painful nodules or as superficial hemorrhagic pustules, either idiopathic or following ostensibly minimal trauma. Subsequently, they become necrotic and form an ulceration. The ulcers can be single or multiple lesions, typically with erythematous raised borders and purulent discharge. The ulcers are extremely painful and rapidly progressive. After the ulcers heal, they often leave a characteristic weblike atrophic scar that can break down further following any form of irritation or trauma.⁵

A prompt diagnosis of PPG is important. A diagnosis of PPG should be considered when dealing with a noninfectious ulcer surrounding a stoma in patients with IBD or other autoimmune conditions.⁶ Because PPG is a rare skin disorder, it is likely to be missed and lead to unnecessary diagnostic workup and a delay in proper therapy. In our patient, a diagnosis of PPG was overlooked for other infectious and autoimmune causes. The diagnostic evaluation of a patient with PPG is based on 3 principles: (1) ruling out other causes of a peristomal ulcer, such as an abscess, contact dermatitis, or wound infection; (2) determining whether there is an underlying intestinal bowel disease in the stoma; and (3) identifying associated systemic disorders such as vasculitis, erythema nodosum, or similar processes.⁴ The differential diagnosis depends on the type and stage of PPG and can include malignancy, vasculitis, extraintestinal IBD, infectious disease, and insect bites. A review of the history of the ulcer is helpful in ruling out other diseases, and a colonoscopy or ileoscopy can identify if patients have an underlying active IBD. Swabs for smear and both bacterial and fungal cultures should be taken from the exudate and directly from the ulcer base. Biopsy of the ulcer also helps to exclude alternative diagnoses.⁶

The primary goals of treating PPG include to reduce pain and the risk for secondary infection, increase pouch adherence, and decrease purulent exudate.⁷ Although there is not one well-defined optimal therapeutic intervention, there are a variety of effective approaches that may be considered and used. In mild cases, management methods such as dressings, topical agents, or intralesional steroids may be capable of controlling the disease. Daily wound care is important. Moisture-retentive dressings can control pain, induce collagen formation, promote angiogenesis, and prevent contamination. Cleaning the wound with sterile saline and applying an anti-infective agent also may be effective. Application of ultrapotent topical steroids and tacrolimus ointment 0.3% can be used in patients without concomitant secondary infection. In patients who are in remission, human platelet-derived growth factor may be used. Intralesional injections of dilute triamcinolone acetonide or cyclosporine solution also can be helpful. Cyclosporin A was used as a systemic monotherapy to treat a 48-year-old man and 50-year-old woman with the idiopathic form of PPG. After 3 months of treatment, PPG had completely resolved and there were no major side effects.⁸ Other potential topical therapies that control inflammation and promote wound healing include benzoyl peroxide, chlormethine (topical alkylating agent and nitrogen mustard that has anti-inflammatory properties), nicotine, and 5-aminosalicylic acid. If an ulcer becomes infected, empiric antibiotic therapy should be given immediately and adjusted based on culture and sensitivity results.⁴

Systemic therapy should be considered in patients who do not respond to topical or local interventions, have a rapid and severe course, or have an active underlying bowel disease. Oral prednisone (1 mg/kg/d) has proved to be one of the most successful drugs used to treat PPG. Treatment should be continued until complete lesion healing, and low-dose maintenance therapy should be administered in recurrent cases. Intravenous corticosteroid therapy—hydrocortisone 100 mg 4 times daily or pulse therapy with intravenous methylprednisolone 1 g/d)—can be used for up to 5 days and may be effective. Oral minocycline 100 mg twice daily may be helpful as an adjunctive therapy to corticosteroids. When corticosteroids fail, oral cyclosporine 3 to 5 mg/kg/d often is prescribed. Studies have shown that patients demonstrate clinical improvement within 3 weeks of cyclosporine initiation, and it has been shown further to be more effective than either azathioprine or methotrexate.^4,8

Infliximab, a chimeric antibody that binds both circulating and tissue-bound TNF-α, has been shown to effectively treat PPG. A clinical trial conducted by Brooklyn et al⁹ found that 46% of patients (6/13) treated with infliximab responded compared with only 6% in a placebo control group (1/17). Although infliximab may result in sepsis, the benefits far outweigh the risks, especially for patients with steroid-refractory PPG.⁴ Adalimumab is a human monoclonal IgG1 antibody to TNF-α that neutralizes its function by blocking the interaction between the molecule and its receptor. Many clinical studies have shown that adalimumab induces and maintains a clinical response in patients with active Crohn disease. The biologic proved to be effective in our patient, but it is associated with potential side effects that should be monitored including injection-site reactions, pruritus, leukopenia, urticaria, and rare instances of alopecia.¹⁰ Etanercept is another potentially effective biologic agent.⁷ Plasma exchange, immunoglobulin infusion, and interferon-alfa therapy also can be used in refractory PPG cases, though data on these treatments are very limited.⁴

Unlike routine pyoderma gangrenosum—for which surgical intervention is contraindicated—surgical intervention may be appropriate for the peristomal variant. Surgical treatment options include stoma revision and/or relocation; however, both of these procedures are accompanied by failure rates ranging from 40% to 100%.⁵ Removal of a diseased intestinal segment, especially one with active IBD, may result in healing of the skin lesion. In our patient, removal of the residual and diseased J-pouch was part of the management plan. However,it generally is recommended that any surgical intervention be accompanied by medical therapy including oral metronidazole 500 mg/d and concomitant administration of an immunosuppressant.^1,3

Because PPG tends to recur, long-term maintenance therapy should always be considered. Pain reduction, anemia correction, proper nutrition, and management of associated and underlying diseases should be performed. Meticulous care of the stoma and prevention of leaks also should be emphasized. Overall, if PPG is detected and diagnosed early as well as treated appropriately and aggressively, the patient likely will have a good prognosis.⁴