Case Letter

To the Editor:

Segmental neurofibromatosis, or neurofibromatosis type 5 (NF5), is a rare subtype of neurofibromatosis type 1 (NF1)(also known as von Recklinghausen disease). Phenotypic manifestations of NF5 include café-au-lait macules, neurofibromas, or both in 1 or more adjacent dermatomes. In contrast to the systemic features of NF1, the dermatomal distribution of NF5 demonstrates mosaicism due to a spontaneous postzygotic mutation in the neurofibromin 1 gene, NF1. We describe an atypical presentation of NF5 with bilateral features on the upper extremities.

A 74-year-old woman presented with soft pink- to flesh-colored growths on the left dorsal forearm and hand that were observed incidentally during a Mohs procedure for treatment of a basal cell carcinoma on the upper cutaneous lip. The patient reported that the lesions initially appeared on the left dorsal hand at approximately 16 years of age and had since spread proximally up to the mid dorsal forearm over the course of her lifetime. She denied any pain but claimed the affected area could be itchy. The lesions did not interfere with her daily activities, but they negatively impacted her social life due to their cosmetic appearance as well as her fear that they could be contagious. She denied any family history of NF1.

Physical examination revealed innumerable soft, pink- to flesh-colored cutaneous nodules ranging from 3 to 9 mm in diameter clustered uniformly on the left dorsal hand and lower forearm within the C6, C7, and C8 dermatomal regions (Figure, A). A singular brown patch measuring 20 mm in diameter also was observed on the right dorsal hand within the C6 dermatome, which the patient reported had been present since birth (Figure, B). The nodules and pigmented patch were clinically diagnosed as cutaneous neurofibromas on the left arm and a café-au-lait macule on the right arm, each manifesting within the C6 dermatome on separate upper extremities. Lisch nodules, axillary freckling, and acoustic schwannomas were not observed. Because of the dermatomal distribution of the lesions and lack of family history of NF1, a diagnosis of bilateral NF5 was made. The patient stated she had declined treatment of the neurofibromas from her referring general dermatologist due to possible risk for recurrence.

Segmental neurofibromatosis was first described in 1931 by Gammel,¹ and in 1982, segmental neurofibromatosis was classified as NF5 by Riccardi.² After Tinschert et al³ later demonstrated NF5 to be a somatic mutation of NF1,³ Ruggieri and Huson⁴ proposed the term mosaic neurofibromatosis 1 in 2001.

While the prevalence of NF1 is 1 in 3000 individuals,⁵ NF5 is rare with an occurrence of 1 in 40,000.⁶ In NF5, a spontaneous NF1 gene mutation occurs on chromosome 17 in a dividing cell after conception.⁷ Individuals with NF5 are born mosaic with 2 genotypes—one normal and one abnormal—for the NF1 gene.⁸ This contrasts with the autosomal-dominant and systemic characteristics of NF1, which has the NF1 gene mutation in all cells. Patients with NF5 generally are not expected to have affected offspring because the spontaneous mutation usually arises in somatic cells; however, a postzygotic mutation in the gonadal region could potentially affect germline cells, resulting in vertical transmission, with documented cases of offspring with systemic NF1.⁴ Because of the risk for malignancy with systemic neurofibromatosis, early diagnosis with genetic counseling is imperative in patients with both NF1 and NF5.

Neurofibromatosis type 5 is a clinical diagnosis based on the presence of neurofibromas and/or café-au-lait macules in a dermatomal distribution. The clinical presentation depends on when and where the NF1 gene mutation occurs in utero as cells multiply, differentiate, and migrate.⁸ Earlier mutations result in a broader manifestation of NF5 in comparison to late mutations, which have more localized features. An NF1 gene mutation causes a loss of function of neurofibromin, a tumor suppressor protein, in Schwann cells and fibroblasts.⁸ This produces neurofibromas and café-au-lait macules, respectively.⁸

A large literature review on segmental neurofibromatosis by Garcia-Romero et al⁶ identified 320 individuals who did not meet full inclusion criteria for NF1 between 1977 and 2012. Overall, 76% of cases were unilaterally distributed. The investigators identified 157 individual case reports in which the most to least common presentation was pigmentary changes only, neurofibromas only, mixed pigmentary changes with neurofibromas, and plexiform neurofibromas only; however, many of these cases were children who may have later developed both neurofibromas and pigmentary changes during puberty.⁶ Additional features of NF5 may include freckling, Lisch nodules, optic gliomas, malignant peripheral nerve sheath tumors, skeletal abnormalities, precocious puberty, vascular malformations, hypertension, seizures, and/or learning difficulties based on the affected anatomy.

Segmental neurofibromatosis, or NF5, is a rare subtype of NF1. Our case demonstrates an unusual bilateral distribution of NF5 with cutaneous neurofibromas and a café-au-lait macule on the upper extremities. Awareness of variations of neurofibromatosis and their genetic implications is essential in establishing earlier clinical diagnoses in cases with subtle manifestations.

To the Editor:

Segmental neurofibromatosis, or neurofibromatosis type 5 (NF5), is a rare subtype of neurofibromatosis type 1 (NF1)(also known as von Recklinghausen disease). Phenotypic manifestations of NF5 include café-au-lait macules, neurofibromas, or both in 1 or more adjacent dermatomes. In contrast to the systemic features of NF1, the dermatomal distribution of NF5 demonstrates mosaicism due to a spontaneous postzygotic mutation in the neurofibromin 1 gene, NF1. We describe an atypical presentation of NF5 with bilateral features on the upper extremities.

A 74-year-old woman presented with soft pink- to flesh-colored growths on the left dorsal forearm and hand that were observed incidentally during a Mohs procedure for treatment of a basal cell carcinoma on the upper cutaneous lip. The patient reported that the lesions initially appeared on the left dorsal hand at approximately 16 years of age and had since spread proximally up to the mid dorsal forearm over the course of her lifetime. She denied any pain but claimed the affected area could be itchy. The lesions did not interfere with her daily activities, but they negatively impacted her social life due to their cosmetic appearance as well as her fear that they could be contagious. She denied any family history of NF1.

Physical examination revealed innumerable soft, pink- to flesh-colored cutaneous nodules ranging from 3 to 9 mm in diameter clustered uniformly on the left dorsal hand and lower forearm within the C6, C7, and C8 dermatomal regions (Figure, A). A singular brown patch measuring 20 mm in diameter also was observed on the right dorsal hand within the C6 dermatome, which the patient reported had been present since birth (Figure, B). The nodules and pigmented patch were clinically diagnosed as cutaneous neurofibromas on the left arm and a café-au-lait macule on the right arm, each manifesting within the C6 dermatome on separate upper extremities. Lisch nodules, axillary freckling, and acoustic schwannomas were not observed. Because of the dermatomal distribution of the lesions and lack of family history of NF1, a diagnosis of bilateral NF5 was made. The patient stated she had declined treatment of the neurofibromas from her referring general dermatologist due to possible risk for recurrence.

Segmental neurofibromatosis was first described in 1931 by Gammel,¹ and in 1982, segmental neurofibromatosis was classified as NF5 by Riccardi.² After Tinschert et al³ later demonstrated NF5 to be a somatic mutation of NF1,³ Ruggieri and Huson⁴ proposed the term mosaic neurofibromatosis 1 in 2001.

While the prevalence of NF1 is 1 in 3000 individuals,⁵ NF5 is rare with an occurrence of 1 in 40,000.⁶ In NF5, a spontaneous NF1 gene mutation occurs on chromosome 17 in a dividing cell after conception.⁷ Individuals with NF5 are born mosaic with 2 genotypes—one normal and one abnormal—for the NF1 gene.⁸ This contrasts with the autosomal-dominant and systemic characteristics of NF1, which has the NF1 gene mutation in all cells. Patients with NF5 generally are not expected to have affected offspring because the spontaneous mutation usually arises in somatic cells; however, a postzygotic mutation in the gonadal region could potentially affect germline cells, resulting in vertical transmission, with documented cases of offspring with systemic NF1.⁴ Because of the risk for malignancy with systemic neurofibromatosis, early diagnosis with genetic counseling is imperative in patients with both NF1 and NF5.

Neurofibromatosis type 5 is a clinical diagnosis based on the presence of neurofibromas and/or café-au-lait macules in a dermatomal distribution. The clinical presentation depends on when and where the NF1 gene mutation occurs in utero as cells multiply, differentiate, and migrate.⁸ Earlier mutations result in a broader manifestation of NF5 in comparison to late mutations, which have more localized features. An NF1 gene mutation causes a loss of function of neurofibromin, a tumor suppressor protein, in Schwann cells and fibroblasts.⁸ This produces neurofibromas and café-au-lait macules, respectively.⁸

A large literature review on segmental neurofibromatosis by Garcia-Romero et al⁶ identified 320 individuals who did not meet full inclusion criteria for NF1 between 1977 and 2012. Overall, 76% of cases were unilaterally distributed. The investigators identified 157 individual case reports in which the most to least common presentation was pigmentary changes only, neurofibromas only, mixed pigmentary changes with neurofibromas, and plexiform neurofibromas only; however, many of these cases were children who may have later developed both neurofibromas and pigmentary changes during puberty.⁶ Additional features of NF5 may include freckling, Lisch nodules, optic gliomas, malignant peripheral nerve sheath tumors, skeletal abnormalities, precocious puberty, vascular malformations, hypertension, seizures, and/or learning difficulties based on the affected anatomy.

Segmental neurofibromatosis, or NF5, is a rare subtype of NF1. Our case demonstrates an unusual bilateral distribution of NF5 with cutaneous neurofibromas and a café-au-lait macule on the upper extremities. Awareness of variations of neurofibromatosis and their genetic implications is essential in establishing earlier clinical diagnoses in cases with subtle manifestations.

To the Editor:

Segmental neurofibromatosis, or neurofibromatosis type 5 (NF5), is a rare subtype of neurofibromatosis type 1 (NF1)(also known as von Recklinghausen disease). Phenotypic manifestations of NF5 include café-au-lait macules, neurofibromas, or both in 1 or more adjacent dermatomes. In contrast to the systemic features of NF1, the dermatomal distribution of NF5 demonstrates mosaicism due to a spontaneous postzygotic mutation in the neurofibromin 1 gene, NF1. We describe an atypical presentation of NF5 with bilateral features on the upper extremities.

A 74-year-old woman presented with soft pink- to flesh-colored growths on the left dorsal forearm and hand that were observed incidentally during a Mohs procedure for treatment of a basal cell carcinoma on the upper cutaneous lip. The patient reported that the lesions initially appeared on the left dorsal hand at approximately 16 years of age and had since spread proximally up to the mid dorsal forearm over the course of her lifetime. She denied any pain but claimed the affected area could be itchy. The lesions did not interfere with her daily activities, but they negatively impacted her social life due to their cosmetic appearance as well as her fear that they could be contagious. She denied any family history of NF1.

Physical examination revealed innumerable soft, pink- to flesh-colored cutaneous nodules ranging from 3 to 9 mm in diameter clustered uniformly on the left dorsal hand and lower forearm within the C6, C7, and C8 dermatomal regions (Figure, A). A singular brown patch measuring 20 mm in diameter also was observed on the right dorsal hand within the C6 dermatome, which the patient reported had been present since birth (Figure, B). The nodules and pigmented patch were clinically diagnosed as cutaneous neurofibromas on the left arm and a café-au-lait macule on the right arm, each manifesting within the C6 dermatome on separate upper extremities. Lisch nodules, axillary freckling, and acoustic schwannomas were not observed. Because of the dermatomal distribution of the lesions and lack of family history of NF1, a diagnosis of bilateral NF5 was made. The patient stated she had declined treatment of the neurofibromas from her referring general dermatologist due to possible risk for recurrence.

Segmental neurofibromatosis was first described in 1931 by Gammel,¹ and in 1982, segmental neurofibromatosis was classified as NF5 by Riccardi.² After Tinschert et al³ later demonstrated NF5 to be a somatic mutation of NF1,³ Ruggieri and Huson⁴ proposed the term mosaic neurofibromatosis 1 in 2001.

While the prevalence of NF1 is 1 in 3000 individuals,⁵ NF5 is rare with an occurrence of 1 in 40,000.⁶ In NF5, a spontaneous NF1 gene mutation occurs on chromosome 17 in a dividing cell after conception.⁷ Individuals with NF5 are born mosaic with 2 genotypes—one normal and one abnormal—for the NF1 gene.⁸ This contrasts with the autosomal-dominant and systemic characteristics of NF1, which has the NF1 gene mutation in all cells. Patients with NF5 generally are not expected to have affected offspring because the spontaneous mutation usually arises in somatic cells; however, a postzygotic mutation in the gonadal region could potentially affect germline cells, resulting in vertical transmission, with documented cases of offspring with systemic NF1.⁴ Because of the risk for malignancy with systemic neurofibromatosis, early diagnosis with genetic counseling is imperative in patients with both NF1 and NF5.

Neurofibromatosis type 5 is a clinical diagnosis based on the presence of neurofibromas and/or café-au-lait macules in a dermatomal distribution. The clinical presentation depends on when and where the NF1 gene mutation occurs in utero as cells multiply, differentiate, and migrate.⁸ Earlier mutations result in a broader manifestation of NF5 in comparison to late mutations, which have more localized features. An NF1 gene mutation causes a loss of function of neurofibromin, a tumor suppressor protein, in Schwann cells and fibroblasts.⁸ This produces neurofibromas and café-au-lait macules, respectively.⁸

A large literature review on segmental neurofibromatosis by Garcia-Romero et al⁶ identified 320 individuals who did not meet full inclusion criteria for NF1 between 1977 and 2012. Overall, 76% of cases were unilaterally distributed. The investigators identified 157 individual case reports in which the most to least common presentation was pigmentary changes only, neurofibromas only, mixed pigmentary changes with neurofibromas, and plexiform neurofibromas only; however, many of these cases were children who may have later developed both neurofibromas and pigmentary changes during puberty.⁶ Additional features of NF5 may include freckling, Lisch nodules, optic gliomas, malignant peripheral nerve sheath tumors, skeletal abnormalities, precocious puberty, vascular malformations, hypertension, seizures, and/or learning difficulties based on the affected anatomy.

Segmental neurofibromatosis, or NF5, is a rare subtype of NF1. Our case demonstrates an unusual bilateral distribution of NF5 with cutaneous neurofibromas and a café-au-lait macule on the upper extremities. Awareness of variations of neurofibromatosis and their genetic implications is essential in establishing earlier clinical diagnoses in cases with subtle manifestations.

To the Editor:

Vedolizumab is an innovative monoclonal antibody targeted against the α4β7 integrin that is approved for treatment of moderate to severe ulcerative colitis and Crohn disease refractory to standard treatment.¹ Vedolizumab is thought to be gut specific, blocking integrins specific to T lymphocytes destined for the gastrointestinal tract and their interaction with endothelial cells, thereby modulating the adaptive immune system in the gut without systemic immunosuppression.² It generally is well tolerated, and acne rarely has been reported as an adverse event.^3,4 We present a case of acne fulminans without systemic symptoms (AF-WOSS) as a severe side effect of vedolizumab that responded very well to systemic steroids and oral isotretinoin in addition to the discontinuation of treatment.

A 46-year-old obese man presented to our dermatology clinic with a chief complaint of rapidly progressive tender skin lesions. The patient had a long-standing history of severe fistulating and stricturing Crohn disease status post–bowel resection with ileostomy and had recently started treatment with vedolizumab after failing treatment with infliximab, adalimumab, certolizumab pegol, ustekinumab, and methotrexate. Several weeks after beginning infusions of vedolizumab, the patient began to develop many erythematous papules and pustules on the face, chest (Figure 1), and buttocks that rapidly progressed into painful and coalescing nodules and cysts over the next several months. He was prescribed benzoyl peroxide wash 10% as well as several weeks of oral doxycycline 100 mg twice daily with no improvement. The patient denied any other new medications or triggers, fever, chills, bone pain, headache, fatigue, or myalgia. The skin involvement continued to worsen with successive vedolizumab infusions over a period of 8 weeks, which ultimately resulted in cessation of vedolizumab.

Physical examination revealed large, tender, pink, erythematous, and indurated plaques that were heavily studded with pink papules, pustules, and nodules on the cheeks (Figure 2), central chest, and buttocks. A punch biopsy of a pustule on the cheek showed ruptured suppurative folliculitis. The patient subsequently was diagnosed with AF-WOSS.

The patient then completed a 7-day course of sulfamethoxazole-trimethoprim followed by a 10-day course of amoxicillin-clavulanic acid, neither of which led to improvement of the lesions. He then was started on an oral prednisone taper (1 mg/kg starting dose) that ultimately totaled 14 weeks in length due to his frequent flares any time prednisone was decreased below 40 mg daily. After 3 weeks on the oral prednisone, the patient was started on 0.3 mg/kg of concomitant oral isotretinoin every other day, which slowly was increased as tolerated until he reached a goal dose of roughly 150 mg/kg, which resolved the acneform papules and pustules and allowed for successful tapering off the prednisone.

Many studies have been published regarding the safety and side-effect profile of vedolizumab, but most do not report acne as an adverse event.^3-5 A German cohort study by Baumgart et al³ reported acne as a side effect in 15 of 212 (7.1%) patients but did not classify the severity. Another case report noted nodulocystic acne in a patient receiving vedolizumab for treatment of inflammatory bowel disease; however, this patient responded well to the use of a tetracycline antibiotic and was able to continue therapy with vedolizumab.⁵ Our patient demonstrated a severe and uncommon case of acne classified as AF-WOSS following initiation of therapy with vedolizumab, which required treatment with systemic steroids plus oral isotretinoin and resulted in cessation of vedolizumab.

As new therapies emerge, it is important to document new or severe adverse effects so providers can choose an appropriate therapy and adequately counsel patients regarding the side effects. Although vedolizumab was thought to have gut-specific action, there is new evidence to suggest that the principal ligand of the α4β7 integrin, mucosal addressin cell adhesion molecule-1, is not only expressed on gut endothelial cells but also on fibroblasts and melanomas, which may provide insight into the observed extraintestinal side effects of vedolizumab.⁶

To the Editor:

Vedolizumab is an innovative monoclonal antibody targeted against the α4β7 integrin that is approved for treatment of moderate to severe ulcerative colitis and Crohn disease refractory to standard treatment.¹ Vedolizumab is thought to be gut specific, blocking integrins specific to T lymphocytes destined for the gastrointestinal tract and their interaction with endothelial cells, thereby modulating the adaptive immune system in the gut without systemic immunosuppression.² It generally is well tolerated, and acne rarely has been reported as an adverse event.^3,4 We present a case of acne fulminans without systemic symptoms (AF-WOSS) as a severe side effect of vedolizumab that responded very well to systemic steroids and oral isotretinoin in addition to the discontinuation of treatment.

A 46-year-old obese man presented to our dermatology clinic with a chief complaint of rapidly progressive tender skin lesions. The patient had a long-standing history of severe fistulating and stricturing Crohn disease status post–bowel resection with ileostomy and had recently started treatment with vedolizumab after failing treatment with infliximab, adalimumab, certolizumab pegol, ustekinumab, and methotrexate. Several weeks after beginning infusions of vedolizumab, the patient began to develop many erythematous papules and pustules on the face, chest (Figure 1), and buttocks that rapidly progressed into painful and coalescing nodules and cysts over the next several months. He was prescribed benzoyl peroxide wash 10% as well as several weeks of oral doxycycline 100 mg twice daily with no improvement. The patient denied any other new medications or triggers, fever, chills, bone pain, headache, fatigue, or myalgia. The skin involvement continued to worsen with successive vedolizumab infusions over a period of 8 weeks, which ultimately resulted in cessation of vedolizumab.

Physical examination revealed large, tender, pink, erythematous, and indurated plaques that were heavily studded with pink papules, pustules, and nodules on the cheeks (Figure 2), central chest, and buttocks. A punch biopsy of a pustule on the cheek showed ruptured suppurative folliculitis. The patient subsequently was diagnosed with AF-WOSS.

The patient then completed a 7-day course of sulfamethoxazole-trimethoprim followed by a 10-day course of amoxicillin-clavulanic acid, neither of which led to improvement of the lesions. He then was started on an oral prednisone taper (1 mg/kg starting dose) that ultimately totaled 14 weeks in length due to his frequent flares any time prednisone was decreased below 40 mg daily. After 3 weeks on the oral prednisone, the patient was started on 0.3 mg/kg of concomitant oral isotretinoin every other day, which slowly was increased as tolerated until he reached a goal dose of roughly 150 mg/kg, which resolved the acneform papules and pustules and allowed for successful tapering off the prednisone.

Many studies have been published regarding the safety and side-effect profile of vedolizumab, but most do not report acne as an adverse event.^3-5 A German cohort study by Baumgart et al³ reported acne as a side effect in 15 of 212 (7.1%) patients but did not classify the severity. Another case report noted nodulocystic acne in a patient receiving vedolizumab for treatment of inflammatory bowel disease; however, this patient responded well to the use of a tetracycline antibiotic and was able to continue therapy with vedolizumab.⁵ Our patient demonstrated a severe and uncommon case of acne classified as AF-WOSS following initiation of therapy with vedolizumab, which required treatment with systemic steroids plus oral isotretinoin and resulted in cessation of vedolizumab.

As new therapies emerge, it is important to document new or severe adverse effects so providers can choose an appropriate therapy and adequately counsel patients regarding the side effects. Although vedolizumab was thought to have gut-specific action, there is new evidence to suggest that the principal ligand of the α4β7 integrin, mucosal addressin cell adhesion molecule-1, is not only expressed on gut endothelial cells but also on fibroblasts and melanomas, which may provide insight into the observed extraintestinal side effects of vedolizumab.⁶

To the Editor:

Vedolizumab is an innovative monoclonal antibody targeted against the α4β7 integrin that is approved for treatment of moderate to severe ulcerative colitis and Crohn disease refractory to standard treatment.¹ Vedolizumab is thought to be gut specific, blocking integrins specific to T lymphocytes destined for the gastrointestinal tract and their interaction with endothelial cells, thereby modulating the adaptive immune system in the gut without systemic immunosuppression.² It generally is well tolerated, and acne rarely has been reported as an adverse event.^3,4 We present a case of acne fulminans without systemic symptoms (AF-WOSS) as a severe side effect of vedolizumab that responded very well to systemic steroids and oral isotretinoin in addition to the discontinuation of treatment.

A 46-year-old obese man presented to our dermatology clinic with a chief complaint of rapidly progressive tender skin lesions. The patient had a long-standing history of severe fistulating and stricturing Crohn disease status post–bowel resection with ileostomy and had recently started treatment with vedolizumab after failing treatment with infliximab, adalimumab, certolizumab pegol, ustekinumab, and methotrexate. Several weeks after beginning infusions of vedolizumab, the patient began to develop many erythematous papules and pustules on the face, chest (Figure 1), and buttocks that rapidly progressed into painful and coalescing nodules and cysts over the next several months. He was prescribed benzoyl peroxide wash 10% as well as several weeks of oral doxycycline 100 mg twice daily with no improvement. The patient denied any other new medications or triggers, fever, chills, bone pain, headache, fatigue, or myalgia. The skin involvement continued to worsen with successive vedolizumab infusions over a period of 8 weeks, which ultimately resulted in cessation of vedolizumab.

Physical examination revealed large, tender, pink, erythematous, and indurated plaques that were heavily studded with pink papules, pustules, and nodules on the cheeks (Figure 2), central chest, and buttocks. A punch biopsy of a pustule on the cheek showed ruptured suppurative folliculitis. The patient subsequently was diagnosed with AF-WOSS.

The patient then completed a 7-day course of sulfamethoxazole-trimethoprim followed by a 10-day course of amoxicillin-clavulanic acid, neither of which led to improvement of the lesions. He then was started on an oral prednisone taper (1 mg/kg starting dose) that ultimately totaled 14 weeks in length due to his frequent flares any time prednisone was decreased below 40 mg daily. After 3 weeks on the oral prednisone, the patient was started on 0.3 mg/kg of concomitant oral isotretinoin every other day, which slowly was increased as tolerated until he reached a goal dose of roughly 150 mg/kg, which resolved the acneform papules and pustules and allowed for successful tapering off the prednisone.

Many studies have been published regarding the safety and side-effect profile of vedolizumab, but most do not report acne as an adverse event.^3-5 A German cohort study by Baumgart et al³ reported acne as a side effect in 15 of 212 (7.1%) patients but did not classify the severity. Another case report noted nodulocystic acne in a patient receiving vedolizumab for treatment of inflammatory bowel disease; however, this patient responded well to the use of a tetracycline antibiotic and was able to continue therapy with vedolizumab.⁵ Our patient demonstrated a severe and uncommon case of acne classified as AF-WOSS following initiation of therapy with vedolizumab, which required treatment with systemic steroids plus oral isotretinoin and resulted in cessation of vedolizumab.

As new therapies emerge, it is important to document new or severe adverse effects so providers can choose an appropriate therapy and adequately counsel patients regarding the side effects. Although vedolizumab was thought to have gut-specific action, there is new evidence to suggest that the principal ligand of the α4β7 integrin, mucosal addressin cell adhesion molecule-1, is not only expressed on gut endothelial cells but also on fibroblasts and melanomas, which may provide insight into the observed extraintestinal side effects of vedolizumab.⁶

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.