Pigmentation Disorders

To the Editor:

A 42-year man presented with hollowing of the upper eyelid and skin discoloration of the left periorbital area of 10 years’ duration. He was a professional mixed martial arts fighter with a history of 2 surgeries for retinal detachment of the left eye 13 years prior to the current presentation. The patient also has macular scarring in the left eye. He denied a history of facial fracture, reconstructive surgery, or other medical conditions. His visual acuity was unknown; however, he did not require corrective glasses. He used 3 prescription ophthalmic eye drops—dorzolamide hydrochloride plus timolol maleate, 10 mL; brimonidine tartrate ophthalmic solution 0.15%, 5 mL; and latanoprost ophthalmic solution 0.005%, 125 μg/2.5 mL—in the left eye to lower intraocular pressure, as therapy for glaucoma. If left untreated, glaucoma can lead to vision loss.

Physical examination revealed periorbital hyperpigmentation on the left side; hypertrichosis and eyelash trichomegaly compared to the right side; and a deep left upper orbital sulcus compared to the right side (Figure). The patient was alert and oriented to person, place, and time. Extraocular movement was intact bilaterally, and his pupillary reflex was symmetric. No tenderness was noted over the affected area on palpation; no subcutaneous masses or lesions were observed or palpated. There was no ocular discharge, the conjunctiva was pink, and the sclera was white bilaterally.

CT113004025_fig.jpg

The differential diagnosis included professional trauma-induced orbital changes, nevus of Ota (oculomucodermal melanocytosis), prostaglandin-associated periorbitopathy (PAP), and melasma. Although the patient sustained an injury that caused retinal detachment, he never experienced an orbital bone fracture; additionally, a fracture would not explain the skin discoloration or longer eyelashes. Periorbital nevus of Ota most commonly manifests as a unilateral scleral and brown-bluish skin discoloration but does not cause hollowing of the orbital sulcus or affect the length and thickness of eyelashes. Melasma—bilateral skin hyperpigmentation that most commonly affects women—can be induced by oral contraceptives, antibiotics, heat, sun exposure, and pregnancy. It does not affect the color of the iris or the depth of the scleral sulcus, and it does not increase the length and thickness of eyelashes. Based on the clinical presentation and a review of the eye drops used, he was diagnosed with PAP due to prolonged use of latanoprost ophthalmic solution. The patient was referred to an ophthalmologist for consideration of a switch to a different class of medication.

Of the 3 eye drops used by this patient, latanoprost, a prostaglandin analog, decreases intraocular pressure and is known to cause PAP. This condition comprises a constellation of changes, including upper eyelid ptosis, deepening of the upper eyelid sulcus, involution of dermatochalasis, periorbital fat atrophy, mild enophthalmos (sunken eye), inferior scleral show, increased prominence of eyelid vessels, and tight eyelids.¹ Latanoprost most often produces these findings, but all prostaglandin ophthalmic medications can, including the dual-indication bimatoprost, which was approved by the US Food and Drug Administration to reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension but also is used to grow darker, thicker, and longer eyelashes. Clinicians who prescribe bimatoprost for this cosmetic indication should be mindful of the potential for PAP and discuss it with patients.

The prescribing information (PI) for bimatoprost (Latisse; Allergan) does not list PAP as an adverse reaction observed in the 4-month multicenter, double-blind, randomized, vehicle-controlled study of bimatoprost (as Latisse) in 278 adults.² The PI does list “periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus and eyelid ptosis” as an adverse reaction in postmarketing experience. However, according to the PI, the frequency of these adverse reactions cannot be established, as the reporting of such incidents was voluntary and the size of the treated population was uncertain.²

Prostaglandins can cause periorbitopathy by several mechanisms; one speculated cause is that this group of medications might provoke smooth muscle contraction. Prostaglandin medications also have an affinity for fat cells¹; atrophy of fat cells can lead to enophthalmos and deepening upper eyelid sulcus. In an observational study of 105 participants who were using a prostaglandin in 1 eye for longer than 1 month (the other eye was used as a control), the overall frequency of prostaglandin-associated periorbitopathy was 93.3% in the bimatoprost group, 41.4% in the latanoprost group, and 70% in the travoprost group, while the frequency of deepening of the upper eyelid sulcus was 80% in the bimatoprost group, 15.7% in the latanoprost group, and 45% in the travoprost group.³ These changes may not be as striking when a patient is using a prostaglandin ophthalmic medication in both eyes and may not be noticed even by the patient. It is prudent for the clinician to take a baseline photograph of the patient when these medications are prescribed to observe for early signs of periorbitopathy. These adverse effects may not be reversible when the medication is discontinued⁴ and have been observed as early as 4 to 6 weeks after the start of treatment.⁵

Our patient was counseled that his constellation of PAP findings potentially could be partially reversed over months or even a year or longer if the offending agent was discontinued. However, he was cautioned that cessation of latanoprost first needed to be discussed with his ophthalmologist, who would determine if there was a suitable alternative to a prostaglandin analog for him. The patient’s only concern was the aesthetic appearance of the left periorbital area. A hyaluronic acid filler or fat grafting can be considered for correction of orbital sulcus hollowing; however, we could not locate any long-term studies in which such corrective treatments were applied for PAP. Our patient continues to use latanoprost with no change in the frequency of use. There have been no further changes or progression in the physical appearance of the left eye or periorbital area. The patient has not undergone any corrective treatments.

To the Editor:

A 42-year man presented with hollowing of the upper eyelid and skin discoloration of the left periorbital area of 10 years’ duration. He was a professional mixed martial arts fighter with a history of 2 surgeries for retinal detachment of the left eye 13 years prior to the current presentation. The patient also has macular scarring in the left eye. He denied a history of facial fracture, reconstructive surgery, or other medical conditions. His visual acuity was unknown; however, he did not require corrective glasses. He used 3 prescription ophthalmic eye drops—dorzolamide hydrochloride plus timolol maleate, 10 mL; brimonidine tartrate ophthalmic solution 0.15%, 5 mL; and latanoprost ophthalmic solution 0.005%, 125 μg/2.5 mL—in the left eye to lower intraocular pressure, as therapy for glaucoma. If left untreated, glaucoma can lead to vision loss.

Physical examination revealed periorbital hyperpigmentation on the left side; hypertrichosis and eyelash trichomegaly compared to the right side; and a deep left upper orbital sulcus compared to the right side (Figure). The patient was alert and oriented to person, place, and time. Extraocular movement was intact bilaterally, and his pupillary reflex was symmetric. No tenderness was noted over the affected area on palpation; no subcutaneous masses or lesions were observed or palpated. There was no ocular discharge, the conjunctiva was pink, and the sclera was white bilaterally.

CT113004025_fig.jpg

The differential diagnosis included professional trauma-induced orbital changes, nevus of Ota (oculomucodermal melanocytosis), prostaglandin-associated periorbitopathy (PAP), and melasma. Although the patient sustained an injury that caused retinal detachment, he never experienced an orbital bone fracture; additionally, a fracture would not explain the skin discoloration or longer eyelashes. Periorbital nevus of Ota most commonly manifests as a unilateral scleral and brown-bluish skin discoloration but does not cause hollowing of the orbital sulcus or affect the length and thickness of eyelashes. Melasma—bilateral skin hyperpigmentation that most commonly affects women—can be induced by oral contraceptives, antibiotics, heat, sun exposure, and pregnancy. It does not affect the color of the iris or the depth of the scleral sulcus, and it does not increase the length and thickness of eyelashes. Based on the clinical presentation and a review of the eye drops used, he was diagnosed with PAP due to prolonged use of latanoprost ophthalmic solution. The patient was referred to an ophthalmologist for consideration of a switch to a different class of medication.

Of the 3 eye drops used by this patient, latanoprost, a prostaglandin analog, decreases intraocular pressure and is known to cause PAP. This condition comprises a constellation of changes, including upper eyelid ptosis, deepening of the upper eyelid sulcus, involution of dermatochalasis, periorbital fat atrophy, mild enophthalmos (sunken eye), inferior scleral show, increased prominence of eyelid vessels, and tight eyelids.¹ Latanoprost most often produces these findings, but all prostaglandin ophthalmic medications can, including the dual-indication bimatoprost, which was approved by the US Food and Drug Administration to reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension but also is used to grow darker, thicker, and longer eyelashes. Clinicians who prescribe bimatoprost for this cosmetic indication should be mindful of the potential for PAP and discuss it with patients.

The prescribing information (PI) for bimatoprost (Latisse; Allergan) does not list PAP as an adverse reaction observed in the 4-month multicenter, double-blind, randomized, vehicle-controlled study of bimatoprost (as Latisse) in 278 adults.² The PI does list “periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus and eyelid ptosis” as an adverse reaction in postmarketing experience. However, according to the PI, the frequency of these adverse reactions cannot be established, as the reporting of such incidents was voluntary and the size of the treated population was uncertain.²

Prostaglandins can cause periorbitopathy by several mechanisms; one speculated cause is that this group of medications might provoke smooth muscle contraction. Prostaglandin medications also have an affinity for fat cells¹; atrophy of fat cells can lead to enophthalmos and deepening upper eyelid sulcus. In an observational study of 105 participants who were using a prostaglandin in 1 eye for longer than 1 month (the other eye was used as a control), the overall frequency of prostaglandin-associated periorbitopathy was 93.3% in the bimatoprost group, 41.4% in the latanoprost group, and 70% in the travoprost group, while the frequency of deepening of the upper eyelid sulcus was 80% in the bimatoprost group, 15.7% in the latanoprost group, and 45% in the travoprost group.³ These changes may not be as striking when a patient is using a prostaglandin ophthalmic medication in both eyes and may not be noticed even by the patient. It is prudent for the clinician to take a baseline photograph of the patient when these medications are prescribed to observe for early signs of periorbitopathy. These adverse effects may not be reversible when the medication is discontinued⁴ and have been observed as early as 4 to 6 weeks after the start of treatment.⁵

Our patient was counseled that his constellation of PAP findings potentially could be partially reversed over months or even a year or longer if the offending agent was discontinued. However, he was cautioned that cessation of latanoprost first needed to be discussed with his ophthalmologist, who would determine if there was a suitable alternative to a prostaglandin analog for him. The patient’s only concern was the aesthetic appearance of the left periorbital area. A hyaluronic acid filler or fat grafting can be considered for correction of orbital sulcus hollowing; however, we could not locate any long-term studies in which such corrective treatments were applied for PAP. Our patient continues to use latanoprost with no change in the frequency of use. There have been no further changes or progression in the physical appearance of the left eye or periorbital area. The patient has not undergone any corrective treatments.

To the Editor:

A 42-year man presented with hollowing of the upper eyelid and skin discoloration of the left periorbital area of 10 years’ duration. He was a professional mixed martial arts fighter with a history of 2 surgeries for retinal detachment of the left eye 13 years prior to the current presentation. The patient also has macular scarring in the left eye. He denied a history of facial fracture, reconstructive surgery, or other medical conditions. His visual acuity was unknown; however, he did not require corrective glasses. He used 3 prescription ophthalmic eye drops—dorzolamide hydrochloride plus timolol maleate, 10 mL; brimonidine tartrate ophthalmic solution 0.15%, 5 mL; and latanoprost ophthalmic solution 0.005%, 125 μg/2.5 mL—in the left eye to lower intraocular pressure, as therapy for glaucoma. If left untreated, glaucoma can lead to vision loss.

Physical examination revealed periorbital hyperpigmentation on the left side; hypertrichosis and eyelash trichomegaly compared to the right side; and a deep left upper orbital sulcus compared to the right side (Figure). The patient was alert and oriented to person, place, and time. Extraocular movement was intact bilaterally, and his pupillary reflex was symmetric. No tenderness was noted over the affected area on palpation; no subcutaneous masses or lesions were observed or palpated. There was no ocular discharge, the conjunctiva was pink, and the sclera was white bilaterally.

CT113004025_fig.jpg

The differential diagnosis included professional trauma-induced orbital changes, nevus of Ota (oculomucodermal melanocytosis), prostaglandin-associated periorbitopathy (PAP), and melasma. Although the patient sustained an injury that caused retinal detachment, he never experienced an orbital bone fracture; additionally, a fracture would not explain the skin discoloration or longer eyelashes. Periorbital nevus of Ota most commonly manifests as a unilateral scleral and brown-bluish skin discoloration but does not cause hollowing of the orbital sulcus or affect the length and thickness of eyelashes. Melasma—bilateral skin hyperpigmentation that most commonly affects women—can be induced by oral contraceptives, antibiotics, heat, sun exposure, and pregnancy. It does not affect the color of the iris or the depth of the scleral sulcus, and it does not increase the length and thickness of eyelashes. Based on the clinical presentation and a review of the eye drops used, he was diagnosed with PAP due to prolonged use of latanoprost ophthalmic solution. The patient was referred to an ophthalmologist for consideration of a switch to a different class of medication.

Of the 3 eye drops used by this patient, latanoprost, a prostaglandin analog, decreases intraocular pressure and is known to cause PAP. This condition comprises a constellation of changes, including upper eyelid ptosis, deepening of the upper eyelid sulcus, involution of dermatochalasis, periorbital fat atrophy, mild enophthalmos (sunken eye), inferior scleral show, increased prominence of eyelid vessels, and tight eyelids.¹ Latanoprost most often produces these findings, but all prostaglandin ophthalmic medications can, including the dual-indication bimatoprost, which was approved by the US Food and Drug Administration to reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension but also is used to grow darker, thicker, and longer eyelashes. Clinicians who prescribe bimatoprost for this cosmetic indication should be mindful of the potential for PAP and discuss it with patients.

The prescribing information (PI) for bimatoprost (Latisse; Allergan) does not list PAP as an adverse reaction observed in the 4-month multicenter, double-blind, randomized, vehicle-controlled study of bimatoprost (as Latisse) in 278 adults.² The PI does list “periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus and eyelid ptosis” as an adverse reaction in postmarketing experience. However, according to the PI, the frequency of these adverse reactions cannot be established, as the reporting of such incidents was voluntary and the size of the treated population was uncertain.²

Prostaglandins can cause periorbitopathy by several mechanisms; one speculated cause is that this group of medications might provoke smooth muscle contraction. Prostaglandin medications also have an affinity for fat cells¹; atrophy of fat cells can lead to enophthalmos and deepening upper eyelid sulcus. In an observational study of 105 participants who were using a prostaglandin in 1 eye for longer than 1 month (the other eye was used as a control), the overall frequency of prostaglandin-associated periorbitopathy was 93.3% in the bimatoprost group, 41.4% in the latanoprost group, and 70% in the travoprost group, while the frequency of deepening of the upper eyelid sulcus was 80% in the bimatoprost group, 15.7% in the latanoprost group, and 45% in the travoprost group.³ These changes may not be as striking when a patient is using a prostaglandin ophthalmic medication in both eyes and may not be noticed even by the patient. It is prudent for the clinician to take a baseline photograph of the patient when these medications are prescribed to observe for early signs of periorbitopathy. These adverse effects may not be reversible when the medication is discontinued⁴ and have been observed as early as 4 to 6 weeks after the start of treatment.⁵

Our patient was counseled that his constellation of PAP findings potentially could be partially reversed over months or even a year or longer if the offending agent was discontinued. However, he was cautioned that cessation of latanoprost first needed to be discussed with his ophthalmologist, who would determine if there was a suitable alternative to a prostaglandin analog for him. The patient’s only concern was the aesthetic appearance of the left periorbital area. A hyaluronic acid filler or fat grafting can be considered for correction of orbital sulcus hollowing; however, we could not locate any long-term studies in which such corrective treatments were applied for PAP. Our patient continues to use latanoprost with no change in the frequency of use. There have been no further changes or progression in the physical appearance of the left eye or periorbital area. The patient has not undergone any corrective treatments.

To the Editor:

Vitiligo is a depigmentation disorder that results from the loss of melanocytes in the epidermis.¹ The most widely accepted pathophysiology for melanocyte destruction in vitiligo is an autoimmune process involving dysregulated cytokine production and autoreactive T-cell activation.¹ Individuals with cutaneous autoinflammatory conditions currently are vital patient populations warranting research, as their susceptibility to COVID-19 infection may differ from the general population. We previously found a small increased risk for COVID-19 infection in patients with psoriasis,² which suggests that other dermatologic conditions also may impact COVID-19 risk. The risk for COVID-19 infection in patients with vitiligo remains largely unknown. In this retrospective cohort study, we investigated the risk for COVID-19 infection in patients with vitiligo compared with those without vitiligo utilizing claims data from the COVID-19 Research Database (https://covid19researchdatabase.org/).

Claims were evaluated for patients aged 3 years and older with a vitiligo diagnosis (International Classification of Diseases, Tenth Revision [ICD-10] code L80) that was made between January 1, 2016, and January 1, 2020. Individuals without a vitiligo diagnosis during the same period were placed (4:1 ratio) in the control group and were matched with study group patients for age and sex. All comorbidity variables and vitiligo diagnoses were extracted from ICD-10 codes that were given prior to a diagnosis of COVID-19. We then constructed multivariable logistic regression models adjusting for measured confounders to evaluate if vitiligo was associated with higher risk for COVID-19 infection after January 1, 2020.

The vitiligo and nonvitiligo cohorts included 40,363 and 161,452 patients, respectively (Table 1). Logistic regression analysis with adjustment for confounding variables, including high comorbid risk factors (Table 2) revealed that patients with a diagnosis of vitiligo had significantly increased odds of COVID-19 infection compared with patients without vitiligo (adjusted odds ratio [AOR], 1.47; 95% CI, 1.37-1.57; P<.001)(Table 3). Additionally, subgroup logistic analyses for sex, age, and exclusion of patients who were HIV positive revealed that females with vitiligo had higher odds of contracting COVID-19 than males with vitiligo (Table 3).

CT113004030_Table1.jpg

Our results showed that patients with vitiligo had a higher relative risk for contracting COVID-19 than individuals without vitiligo. It has been reported that the prevalence of COVID-19 is higher among patients with autoimmune diseases compared to the general population.³ Additionally, a handful of vitiligo patients are managed with immunosuppressive agents that may further weaken their immune response.¹ Moreover, survey results from dermatologists managing vitiligo patients revealed that physicians were fairly comfortable prescribing immunosuppressants and encouraging in-office phototherapy during the COVID-19 pandemic.⁴ As a result, more patients may have been attending in-office visits for their phototherapy, which may have increased their risk for COVID-19. Although these factors play a role in ­COVID-19 infection rates, the underlying immune dysregulation in vitiligo in relation to COVID-19 remains unknown and should be further explored.

CT113004030_Table2.jpg

Our findings are limited by the use of ICD-10 codes, the inability to control for all potential confounding variables, the lack of data regarding the stage of vitiligo, and the absence of data for undiagnosed COVID-19 infections. In addition, patients with vitiligo may be more likely to seek care, potentially increasing their rates of COVID-19 testing. The inability to identify the stage of vitiligo during enrollment in the database may have altered our results, as individuals with active disease have increased levels of IFN-γ. Increased secretion of IFN-γ also potentially helps in the clearance of COVID-19 infection.¹ Future studies should investigate this relationship via planned ­COVID-19 testing, identification of vitiligo stage, and controlling for other associated comorbidities.

CT113004030_Table3.jpg

To the Editor:

Vitiligo is a depigmentation disorder that results from the loss of melanocytes in the epidermis.¹ The most widely accepted pathophysiology for melanocyte destruction in vitiligo is an autoimmune process involving dysregulated cytokine production and autoreactive T-cell activation.¹ Individuals with cutaneous autoinflammatory conditions currently are vital patient populations warranting research, as their susceptibility to COVID-19 infection may differ from the general population. We previously found a small increased risk for COVID-19 infection in patients with psoriasis,² which suggests that other dermatologic conditions also may impact COVID-19 risk. The risk for COVID-19 infection in patients with vitiligo remains largely unknown. In this retrospective cohort study, we investigated the risk for COVID-19 infection in patients with vitiligo compared with those without vitiligo utilizing claims data from the COVID-19 Research Database (https://covid19researchdatabase.org/).

Claims were evaluated for patients aged 3 years and older with a vitiligo diagnosis (International Classification of Diseases, Tenth Revision [ICD-10] code L80) that was made between January 1, 2016, and January 1, 2020. Individuals without a vitiligo diagnosis during the same period were placed (4:1 ratio) in the control group and were matched with study group patients for age and sex. All comorbidity variables and vitiligo diagnoses were extracted from ICD-10 codes that were given prior to a diagnosis of COVID-19. We then constructed multivariable logistic regression models adjusting for measured confounders to evaluate if vitiligo was associated with higher risk for COVID-19 infection after January 1, 2020.

The vitiligo and nonvitiligo cohorts included 40,363 and 161,452 patients, respectively (Table 1). Logistic regression analysis with adjustment for confounding variables, including high comorbid risk factors (Table 2) revealed that patients with a diagnosis of vitiligo had significantly increased odds of COVID-19 infection compared with patients without vitiligo (adjusted odds ratio [AOR], 1.47; 95% CI, 1.37-1.57; P<.001)(Table 3). Additionally, subgroup logistic analyses for sex, age, and exclusion of patients who were HIV positive revealed that females with vitiligo had higher odds of contracting COVID-19 than males with vitiligo (Table 3).

CT113004030_Table1.jpg

Our results showed that patients with vitiligo had a higher relative risk for contracting COVID-19 than individuals without vitiligo. It has been reported that the prevalence of COVID-19 is higher among patients with autoimmune diseases compared to the general population.³ Additionally, a handful of vitiligo patients are managed with immunosuppressive agents that may further weaken their immune response.¹ Moreover, survey results from dermatologists managing vitiligo patients revealed that physicians were fairly comfortable prescribing immunosuppressants and encouraging in-office phototherapy during the COVID-19 pandemic.⁴ As a result, more patients may have been attending in-office visits for their phototherapy, which may have increased their risk for COVID-19. Although these factors play a role in ­COVID-19 infection rates, the underlying immune dysregulation in vitiligo in relation to COVID-19 remains unknown and should be further explored.

CT113004030_Table2.jpg

Our findings are limited by the use of ICD-10 codes, the inability to control for all potential confounding variables, the lack of data regarding the stage of vitiligo, and the absence of data for undiagnosed COVID-19 infections. In addition, patients with vitiligo may be more likely to seek care, potentially increasing their rates of COVID-19 testing. The inability to identify the stage of vitiligo during enrollment in the database may have altered our results, as individuals with active disease have increased levels of IFN-γ. Increased secretion of IFN-γ also potentially helps in the clearance of COVID-19 infection.¹ Future studies should investigate this relationship via planned ­COVID-19 testing, identification of vitiligo stage, and controlling for other associated comorbidities.

CT113004030_Table3.jpg

To the Editor:

Vitiligo is a depigmentation disorder that results from the loss of melanocytes in the epidermis.¹ The most widely accepted pathophysiology for melanocyte destruction in vitiligo is an autoimmune process involving dysregulated cytokine production and autoreactive T-cell activation.¹ Individuals with cutaneous autoinflammatory conditions currently are vital patient populations warranting research, as their susceptibility to COVID-19 infection may differ from the general population. We previously found a small increased risk for COVID-19 infection in patients with psoriasis,² which suggests that other dermatologic conditions also may impact COVID-19 risk. The risk for COVID-19 infection in patients with vitiligo remains largely unknown. In this retrospective cohort study, we investigated the risk for COVID-19 infection in patients with vitiligo compared with those without vitiligo utilizing claims data from the COVID-19 Research Database (https://covid19researchdatabase.org/).

Claims were evaluated for patients aged 3 years and older with a vitiligo diagnosis (International Classification of Diseases, Tenth Revision [ICD-10] code L80) that was made between January 1, 2016, and January 1, 2020. Individuals without a vitiligo diagnosis during the same period were placed (4:1 ratio) in the control group and were matched with study group patients for age and sex. All comorbidity variables and vitiligo diagnoses were extracted from ICD-10 codes that were given prior to a diagnosis of COVID-19. We then constructed multivariable logistic regression models adjusting for measured confounders to evaluate if vitiligo was associated with higher risk for COVID-19 infection after January 1, 2020.

The vitiligo and nonvitiligo cohorts included 40,363 and 161,452 patients, respectively (Table 1). Logistic regression analysis with adjustment for confounding variables, including high comorbid risk factors (Table 2) revealed that patients with a diagnosis of vitiligo had significantly increased odds of COVID-19 infection compared with patients without vitiligo (adjusted odds ratio [AOR], 1.47; 95% CI, 1.37-1.57; P<.001)(Table 3). Additionally, subgroup logistic analyses for sex, age, and exclusion of patients who were HIV positive revealed that females with vitiligo had higher odds of contracting COVID-19 than males with vitiligo (Table 3).

CT113004030_Table1.jpg

Our results showed that patients with vitiligo had a higher relative risk for contracting COVID-19 than individuals without vitiligo. It has been reported that the prevalence of COVID-19 is higher among patients with autoimmune diseases compared to the general population.³ Additionally, a handful of vitiligo patients are managed with immunosuppressive agents that may further weaken their immune response.¹ Moreover, survey results from dermatologists managing vitiligo patients revealed that physicians were fairly comfortable prescribing immunosuppressants and encouraging in-office phototherapy during the COVID-19 pandemic.⁴ As a result, more patients may have been attending in-office visits for their phototherapy, which may have increased their risk for COVID-19. Although these factors play a role in ­COVID-19 infection rates, the underlying immune dysregulation in vitiligo in relation to COVID-19 remains unknown and should be further explored.

CT113004030_Table2.jpg

Our findings are limited by the use of ICD-10 codes, the inability to control for all potential confounding variables, the lack of data regarding the stage of vitiligo, and the absence of data for undiagnosed COVID-19 infections. In addition, patients with vitiligo may be more likely to seek care, potentially increasing their rates of COVID-19 testing. The inability to identify the stage of vitiligo during enrollment in the database may have altered our results, as individuals with active disease have increased levels of IFN-γ. Increased secretion of IFN-γ also potentially helps in the clearance of COVID-19 infection.¹ Future studies should investigate this relationship via planned ­COVID-19 testing, identification of vitiligo stage, and controlling for other associated comorbidities.

CT113004030_Table3.jpg

TOPLINE:

Infants with port-wine birthmarks (PWB) achieved near-total or total clearance with weekly pulsed dye laser (PDL) treatments in a case-series of 10 infants.

METHODOLOGY:

• Early intervention of PWB in infants can significantly improve outcomes, and some studies suggest shorter intervals between laser treatments may be more effective. While laser treatment with PDL is the gold standard, the optimal treatment interval has not been determined.
• Researchers evaluated the records of 10 infants with PWB who received weekly PDL treatments from 2022 to 2023 at a single center. Treatment was initiated when the infants were 6 months old or younger, with the median age at the first treatment being 4 weeks. Of the 10 infants, eight had Fitzpatrick skin types I-III and two had skin type IV.
• Two dermatologists assessed photographs taken before and after laser treatment, and the primary outcome was the percentage improvement of PWB.

TAKEAWAY:

• Of the 10 patients, six achieved near-total (76%-95%) clearance, and one achieved total (96%-100%) clearance of PWB at a mean of 2 months after the first treatment.
• Marked improvement (51%-75%) in PWB was observed in the remaining three patients, who achieved near-total clearance with additional treatments.
• The median duration of treatment was 2 months (range, 0.2-5.1), and a median of eight treatments (range, 2-20) were needed to achieve near total or total clearance.
• No adverse events were reported, including pigmentary changes, scarring, burns, erosions, or infections.

IN PRACTICE:

The outcomes in the case series, the authors concluded, “are compelling and warrant attention and further investigation into the possibility that this novel and decreased treatment interval of 1 week ... is associated with potential improvement in outcomes and shorter overall treatment duration.”

SOURCE:

This study was led by Shirin Bajaj, MD, of the Laser & Skin Surgery Center of New York, where the infants were treated, and was published online on April 17, 2024, in JAMA Dermatology.

LIMITATIONS:

A small sample size and the lack of a comparison arm limited the ability to draw any conclusions or make treatment recommendations based on the results.

DISCLOSURES:

The authors disclosed no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Infants with port-wine birthmarks (PWB) achieved near-total or total clearance with weekly pulsed dye laser (PDL) treatments in a case-series of 10 infants.

METHODOLOGY:

• Early intervention of PWB in infants can significantly improve outcomes, and some studies suggest shorter intervals between laser treatments may be more effective. While laser treatment with PDL is the gold standard, the optimal treatment interval has not been determined.
• Researchers evaluated the records of 10 infants with PWB who received weekly PDL treatments from 2022 to 2023 at a single center. Treatment was initiated when the infants were 6 months old or younger, with the median age at the first treatment being 4 weeks. Of the 10 infants, eight had Fitzpatrick skin types I-III and two had skin type IV.
• Two dermatologists assessed photographs taken before and after laser treatment, and the primary outcome was the percentage improvement of PWB.

TAKEAWAY:

• Of the 10 patients, six achieved near-total (76%-95%) clearance, and one achieved total (96%-100%) clearance of PWB at a mean of 2 months after the first treatment.
• Marked improvement (51%-75%) in PWB was observed in the remaining three patients, who achieved near-total clearance with additional treatments.
• The median duration of treatment was 2 months (range, 0.2-5.1), and a median of eight treatments (range, 2-20) were needed to achieve near total or total clearance.
• No adverse events were reported, including pigmentary changes, scarring, burns, erosions, or infections.

IN PRACTICE:

The outcomes in the case series, the authors concluded, “are compelling and warrant attention and further investigation into the possibility that this novel and decreased treatment interval of 1 week ... is associated with potential improvement in outcomes and shorter overall treatment duration.”

SOURCE:

This study was led by Shirin Bajaj, MD, of the Laser & Skin Surgery Center of New York, where the infants were treated, and was published online on April 17, 2024, in JAMA Dermatology.

LIMITATIONS:

A small sample size and the lack of a comparison arm limited the ability to draw any conclusions or make treatment recommendations based on the results.

DISCLOSURES:

The authors disclosed no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Infants with port-wine birthmarks (PWB) achieved near-total or total clearance with weekly pulsed dye laser (PDL) treatments in a case-series of 10 infants.

METHODOLOGY:

• Early intervention of PWB in infants can significantly improve outcomes, and some studies suggest shorter intervals between laser treatments may be more effective. While laser treatment with PDL is the gold standard, the optimal treatment interval has not been determined.
• Researchers evaluated the records of 10 infants with PWB who received weekly PDL treatments from 2022 to 2023 at a single center. Treatment was initiated when the infants were 6 months old or younger, with the median age at the first treatment being 4 weeks. Of the 10 infants, eight had Fitzpatrick skin types I-III and two had skin type IV.
• Two dermatologists assessed photographs taken before and after laser treatment, and the primary outcome was the percentage improvement of PWB.

TAKEAWAY:

• Of the 10 patients, six achieved near-total (76%-95%) clearance, and one achieved total (96%-100%) clearance of PWB at a mean of 2 months after the first treatment.
• Marked improvement (51%-75%) in PWB was observed in the remaining three patients, who achieved near-total clearance with additional treatments.
• The median duration of treatment was 2 months (range, 0.2-5.1), and a median of eight treatments (range, 2-20) were needed to achieve near total or total clearance.
• No adverse events were reported, including pigmentary changes, scarring, burns, erosions, or infections.

IN PRACTICE:

The outcomes in the case series, the authors concluded, “are compelling and warrant attention and further investigation into the possibility that this novel and decreased treatment interval of 1 week ... is associated with potential improvement in outcomes and shorter overall treatment duration.”

SOURCE:

This study was led by Shirin Bajaj, MD, of the Laser & Skin Surgery Center of New York, where the infants were treated, and was published online on April 17, 2024, in JAMA Dermatology.

LIMITATIONS:

A small sample size and the lack of a comparison arm limited the ability to draw any conclusions or make treatment recommendations based on the results.

DISCLOSURES:

The authors disclosed no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Despite a high frequency of atypical features, longitudinal melanonychia (LM) in children is associated with an exceedingly low rate of malignancy.

METHODOLOGY:

• LM — a pigmented band in the nail plate caused by increased melanin deposition — occurs in children and adults, resulting from melanocytic activation or proliferation in response to infection, systemic disease, medication, trauma, and other factors.
• Clinical features of LM in children mimic red-flag signs of subungual melanoma in adults although rarely is subungual melanoma.
• A biopsy can confirm the diagnosis, but other considerations include the scar, cost and stress of a procedure, and possibly pain or deformity.
• The researchers conducted a systematic review and meta-analysis of the prevalence of clinical and dermoscopic features in 1391 pediatric patients with LM (diagnosed at a mean age of 5-13 years) from 24 studies published between 1996 and 2023.

TAKEAWAY:

• Of 731 lesions in which a diagnosis was provided, benign nail matrix nevus accounted for 86% of cases.
• Only eight cases of subungual melanoma in situ were diagnosed, with no cases of invasive melanoma identified.
• Most lesions occurred on the fingernails (76%), particularly in the first digits (45%), and the most frequent clinical features included dark-colored bands (70%), multicolored bands (48%), broad bandwidth (41%), and pseudo-Hutchinson sign (41%).
• During a median follow-up of 1-5.5 years, 30% of lesions continued to evolve with changes in width or color, while 23% remained stable and 20% underwent spontaneous regression.

IN PRACTICE:

“In the pivotal clinical decision of whether to biopsy a child with longitudinal melanonychia, perhaps with features that would require a prompt biopsy in an adult, this study provides data to support the option of clinical monitoring,” the authors wrote.

[embed:render:related:node:261286]

SOURCE:

The meta-analysis, led by Serena Yun-Chen Tsai, MD, in the Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, was published online in Pediatric Dermatology.

LIMITATIONS:

Most studies were conducted in Asia, and data stratified by skin type were limited. Inconsistent reporting and missing critical features could affect data quality. Also, certain features displayed high heterogeneity.

DISCLOSURES:

This meta-analysis was supported by the Pediatric Dermatology Research Alliance Career Bridge Research Grant. One co-author disclosed relationships with UpToDate (author, reviewer), Skin Analytics (consultant), and DermTech (research materials).

A version of this article appeared on Medscape.com.

TOPLINE:

Despite a high frequency of atypical features, longitudinal melanonychia (LM) in children is associated with an exceedingly low rate of malignancy.

METHODOLOGY:

• LM — a pigmented band in the nail plate caused by increased melanin deposition — occurs in children and adults, resulting from melanocytic activation or proliferation in response to infection, systemic disease, medication, trauma, and other factors.
• Clinical features of LM in children mimic red-flag signs of subungual melanoma in adults although rarely is subungual melanoma.
• A biopsy can confirm the diagnosis, but other considerations include the scar, cost and stress of a procedure, and possibly pain or deformity.
• The researchers conducted a systematic review and meta-analysis of the prevalence of clinical and dermoscopic features in 1391 pediatric patients with LM (diagnosed at a mean age of 5-13 years) from 24 studies published between 1996 and 2023.

TAKEAWAY:

• Of 731 lesions in which a diagnosis was provided, benign nail matrix nevus accounted for 86% of cases.
• Only eight cases of subungual melanoma in situ were diagnosed, with no cases of invasive melanoma identified.
• Most lesions occurred on the fingernails (76%), particularly in the first digits (45%), and the most frequent clinical features included dark-colored bands (70%), multicolored bands (48%), broad bandwidth (41%), and pseudo-Hutchinson sign (41%).
• During a median follow-up of 1-5.5 years, 30% of lesions continued to evolve with changes in width or color, while 23% remained stable and 20% underwent spontaneous regression.

IN PRACTICE:

“In the pivotal clinical decision of whether to biopsy a child with longitudinal melanonychia, perhaps with features that would require a prompt biopsy in an adult, this study provides data to support the option of clinical monitoring,” the authors wrote.

[embed:render:related:node:261286]

SOURCE:

The meta-analysis, led by Serena Yun-Chen Tsai, MD, in the Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, was published online in Pediatric Dermatology.

LIMITATIONS:

Most studies were conducted in Asia, and data stratified by skin type were limited. Inconsistent reporting and missing critical features could affect data quality. Also, certain features displayed high heterogeneity.

DISCLOSURES:

This meta-analysis was supported by the Pediatric Dermatology Research Alliance Career Bridge Research Grant. One co-author disclosed relationships with UpToDate (author, reviewer), Skin Analytics (consultant), and DermTech (research materials).

A version of this article appeared on Medscape.com.

TOPLINE:

Despite a high frequency of atypical features, longitudinal melanonychia (LM) in children is associated with an exceedingly low rate of malignancy.

METHODOLOGY:

• LM — a pigmented band in the nail plate caused by increased melanin deposition — occurs in children and adults, resulting from melanocytic activation or proliferation in response to infection, systemic disease, medication, trauma, and other factors.
• Clinical features of LM in children mimic red-flag signs of subungual melanoma in adults although rarely is subungual melanoma.
• A biopsy can confirm the diagnosis, but other considerations include the scar, cost and stress of a procedure, and possibly pain or deformity.
• The researchers conducted a systematic review and meta-analysis of the prevalence of clinical and dermoscopic features in 1391 pediatric patients with LM (diagnosed at a mean age of 5-13 years) from 24 studies published between 1996 and 2023.

TAKEAWAY:

• Of 731 lesions in which a diagnosis was provided, benign nail matrix nevus accounted for 86% of cases.
• Only eight cases of subungual melanoma in situ were diagnosed, with no cases of invasive melanoma identified.
• Most lesions occurred on the fingernails (76%), particularly in the first digits (45%), and the most frequent clinical features included dark-colored bands (70%), multicolored bands (48%), broad bandwidth (41%), and pseudo-Hutchinson sign (41%).
• During a median follow-up of 1-5.5 years, 30% of lesions continued to evolve with changes in width or color, while 23% remained stable and 20% underwent spontaneous regression.

IN PRACTICE:

“In the pivotal clinical decision of whether to biopsy a child with longitudinal melanonychia, perhaps with features that would require a prompt biopsy in an adult, this study provides data to support the option of clinical monitoring,” the authors wrote.

[embed:render:related:node:261286]

SOURCE:

The meta-analysis, led by Serena Yun-Chen Tsai, MD, in the Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, was published online in Pediatric Dermatology.

LIMITATIONS:

Most studies were conducted in Asia, and data stratified by skin type were limited. Inconsistent reporting and missing critical features could affect data quality. Also, certain features displayed high heterogeneity.

DISCLOSURES:

This meta-analysis was supported by the Pediatric Dermatology Research Alliance Career Bridge Research Grant. One co-author disclosed relationships with UpToDate (author, reviewer), Skin Analytics (consultant), and DermTech (research materials).

A version of this article appeared on Medscape.com.

SAN DIEGO — In two different phase 2b trial extensions, oral treatment with Janus kinase (JAK) inhibitors showed improved skin clearance in patients with vitiligo, according to presentations at a late-breaking session at the annual meeting of the American Academy of Dermatology (AAD).

In one, the addition of narrow-band ultraviolet-B (NB-UVB) light therapy to ritlecitinib appears more effective than ritlecitinib alone. In the other study, the effectiveness of upadacitinib appears to improve over time.

Based on the ritlecitinib data, “if you have phototherapy in your office, it might be good to couple it with ritlecitinib for vitiligo patients,” said Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, who presented the findings.

However, because of the relatively small numbers in the extension study, Dr. Guttman-Yassky characterized the evidence as preliminary and in need of further investigation.

For vitiligo, the only approved JAK inhibitor is ruxolitinib, 1.5%, in a cream formulation. In June, ritlecitinib (Litfulo) was approved by the Food and Drug Administration (FDA) for alopecia areata. Phototherapy, which has been used for decades in the treatment of vitiligo, has an established efficacy and safety profile as a stand-alone vitiligo treatment. Upadacitinib has numerous indications for inflammatory diseases, such as rheumatoid arthritis, and was granted FDA approval for atopic dermatitis in 2022.
 

NB-UVB Arm Added in Ritlecitinib Extension

The ritlecitinib study population was drawn from patients with non-segmental vitiligo who initially participated in a 24-week dose-ranging period of a phase 2b trial published last year. In that study, 364 patients were randomized to doses of once-daily ritlecitinib ranging from 10 to 50 mg with or without a 4-week loading regimen. Higher doses were generally associated with greater efficacy on the primary endpoint of facial vitiligo area scoring index (F-VASI) but not with a greater risk for adverse events.

In the 24-week extension study, 187 patients received a 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib for the remaining 20 weeks. Another 43 patients were randomized to one of two arms: The same 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib or to 50-mg daily ritlecitinib without a loading dose but combined with NB-UVB delivered twice per week.

Important to interpretation of results, there was an additional twist. Patients in the randomized arm who had < 10% improvement in the total vitiligo area severity index (T-VASI) at week 12 of the extension were discontinued from the study.

The endpoints considered when comparing ritlecitinib with or without NB-UVB at the end of the extension study were F-VASI, T-VASI, patient global impression of change, and adverse events. Responses were assessed on the basis of both observed and last observation carried forward (LOCF).

Of the 43 people, who were randomized in the extension study, nine (21%) had < 10% improvement in T-VASI and were therefore discontinued from the study.

At the end of 24 weeks, both groups had a substantial response to their assigned therapy, but the addition of NB-UVB increased rates of response, although not always at a level of statistical significance, according to Dr. Guttman-Yassky.

For the percent improvement in F-VASI, specifically, the increase did not reach significance on the basis of LOCF (57.9% vs 51.5%; P = .158) but was highly significant on the basis of observed responses (69.6% vs 55.1%; P = .009). For T-VASI, differences for adjunctive NB-UVB over monotherapy did not reach significance for either observed or LOCF responses, but it was significant for observed responses in a patient global impression of change.
 

Small Numbers Limit Strength of Ritlecitinib, NB-UVB Evidence

However, Dr. Guttman-Yassky said it is important “to pay attention to the sample sizes” when noting the lack of significance.

The combination appeared safe, and there were no side effects associated with the addition of twice-weekly NB-UVB to ritlecitinib.

She acknowledged that the design of this analysis was “complicated” and that the number of randomized patients was small. She suggested the findings support the potential for benefit from the combination of a JAK inhibitor and NB-UVB, both of which have shown efficacy as monotherapy in previous studies. She indicated that a trial of this combination is reasonable while awaiting a more definitive study.

One of the questions that might be posed in a larger study is the timing of NB-UVB, such as whether it is best reserved for those with inadequate early response to a JAK inhibitor or if optimal results are achieved when a JAK inhibitor and NB-UVB are initiated simultaneously.

[embed:render:related:node:265870]

Upadacitinib Monotherapy Results

One rationale for initiating therapy with the combination of a JAK inhibitor and NB-UVB is the potential for a more rapid response, but extended results from a second phase 2b study with a different oral JAK inhibitor, upadacitinib, suggested responses on JAK inhibitor monotherapy improve steadily over time.

“The overall efficacy continued to improve without reaching a plateau at 1 year,” reported Thierry Passeron, MD, PhD, professor and chair, Department of Dermatology, Université Côte d’Azur, Nice, France. He spoke at the same AAD late-breaking session as Dr. Guttman-Yassky.

The 24-week dose-ranging data from the upadacitinib trial were previously reported at the 2023 annual meeting of the European Association of Dermatology and Venereology. In the placebo-controlled portion, which randomized 185 patients with extensive non-segmental vitiligo to 6 mg, 11 mg, or 22 mg, the two higher doses were significantly more effective than placebo.

In the extension, patients in the placebo group were randomized to 11 mg or 22 mg, while those in the higher dose groups remained on their assigned therapies.
 

F-VASI Almost Doubled in Extension Trial

From week 24 to week 52, there was nearly a doubling of the percent F-VASI reduction, climbing from 32% to 60.8% in the 11-mg group and from 38.7% to 64.9% in the 22-mg group, Dr. Passeron said. Placebo groups who were switched to active therapy at 24 weeks rapidly approached the rates of F-VASI response of those initiated on upadacitinib.

The percent reductions in T-VASI, although lower, followed the same pattern. For the 11-mg group, the reduction climbed from 16% at 24 weeks to 44.7% at 52 weeks. For the 22-mg group, the reduction climbed from 22.9% to 44.4%. Patients who were switched from placebo to 11 mg or to 22 mg also experienced improvements in T-VASI up to 52 weeks, although the level of improvement was lower than that in patients initially randomized to the higher doses of upadacitinib.

There were “no new safety signals” for upadacitinib, which is FDA-approved for multiple indications, according to Dr. Passeron. He said acne-like lesions were the most bothersome adverse event, and cases of herpes zoster were “rare.”

A version of these data was published in a British Journal of Dermatology supplement just prior to the AAD meeting.

Phase 3 vitiligo trials are planned for both ritlecitinib and upadacitinib.

Dr. Guttman-Yassky reported financial relationships with approximately 45 pharmaceutical companies, including Pfizer, which makes ritlecitinib and provided funding for the study she discussed. Dr. Passeron reported financial relationships with approximately 40 pharmaceutical companies, including AbbVie, which makes upadacitinib and provided funding for the study he discussed.

A version of this article appeared on Medscape.com.

SAN DIEGO — In two different phase 2b trial extensions, oral treatment with Janus kinase (JAK) inhibitors showed improved skin clearance in patients with vitiligo, according to presentations at a late-breaking session at the annual meeting of the American Academy of Dermatology (AAD).

In one, the addition of narrow-band ultraviolet-B (NB-UVB) light therapy to ritlecitinib appears more effective than ritlecitinib alone. In the other study, the effectiveness of upadacitinib appears to improve over time.

Based on the ritlecitinib data, “if you have phototherapy in your office, it might be good to couple it with ritlecitinib for vitiligo patients,” said Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, who presented the findings.

However, because of the relatively small numbers in the extension study, Dr. Guttman-Yassky characterized the evidence as preliminary and in need of further investigation.

For vitiligo, the only approved JAK inhibitor is ruxolitinib, 1.5%, in a cream formulation. In June, ritlecitinib (Litfulo) was approved by the Food and Drug Administration (FDA) for alopecia areata. Phototherapy, which has been used for decades in the treatment of vitiligo, has an established efficacy and safety profile as a stand-alone vitiligo treatment. Upadacitinib has numerous indications for inflammatory diseases, such as rheumatoid arthritis, and was granted FDA approval for atopic dermatitis in 2022.
 

NB-UVB Arm Added in Ritlecitinib Extension

The ritlecitinib study population was drawn from patients with non-segmental vitiligo who initially participated in a 24-week dose-ranging period of a phase 2b trial published last year. In that study, 364 patients were randomized to doses of once-daily ritlecitinib ranging from 10 to 50 mg with or without a 4-week loading regimen. Higher doses were generally associated with greater efficacy on the primary endpoint of facial vitiligo area scoring index (F-VASI) but not with a greater risk for adverse events.

In the 24-week extension study, 187 patients received a 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib for the remaining 20 weeks. Another 43 patients were randomized to one of two arms: The same 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib or to 50-mg daily ritlecitinib without a loading dose but combined with NB-UVB delivered twice per week.

Important to interpretation of results, there was an additional twist. Patients in the randomized arm who had < 10% improvement in the total vitiligo area severity index (T-VASI) at week 12 of the extension were discontinued from the study.

The endpoints considered when comparing ritlecitinib with or without NB-UVB at the end of the extension study were F-VASI, T-VASI, patient global impression of change, and adverse events. Responses were assessed on the basis of both observed and last observation carried forward (LOCF).

Of the 43 people, who were randomized in the extension study, nine (21%) had < 10% improvement in T-VASI and were therefore discontinued from the study.

At the end of 24 weeks, both groups had a substantial response to their assigned therapy, but the addition of NB-UVB increased rates of response, although not always at a level of statistical significance, according to Dr. Guttman-Yassky.

For the percent improvement in F-VASI, specifically, the increase did not reach significance on the basis of LOCF (57.9% vs 51.5%; P = .158) but was highly significant on the basis of observed responses (69.6% vs 55.1%; P = .009). For T-VASI, differences for adjunctive NB-UVB over monotherapy did not reach significance for either observed or LOCF responses, but it was significant for observed responses in a patient global impression of change.
 

Small Numbers Limit Strength of Ritlecitinib, NB-UVB Evidence

However, Dr. Guttman-Yassky said it is important “to pay attention to the sample sizes” when noting the lack of significance.

The combination appeared safe, and there were no side effects associated with the addition of twice-weekly NB-UVB to ritlecitinib.

She acknowledged that the design of this analysis was “complicated” and that the number of randomized patients was small. She suggested the findings support the potential for benefit from the combination of a JAK inhibitor and NB-UVB, both of which have shown efficacy as monotherapy in previous studies. She indicated that a trial of this combination is reasonable while awaiting a more definitive study.

One of the questions that might be posed in a larger study is the timing of NB-UVB, such as whether it is best reserved for those with inadequate early response to a JAK inhibitor or if optimal results are achieved when a JAK inhibitor and NB-UVB are initiated simultaneously.

[embed:render:related:node:265870]

Upadacitinib Monotherapy Results

One rationale for initiating therapy with the combination of a JAK inhibitor and NB-UVB is the potential for a more rapid response, but extended results from a second phase 2b study with a different oral JAK inhibitor, upadacitinib, suggested responses on JAK inhibitor monotherapy improve steadily over time.

“The overall efficacy continued to improve without reaching a plateau at 1 year,” reported Thierry Passeron, MD, PhD, professor and chair, Department of Dermatology, Université Côte d’Azur, Nice, France. He spoke at the same AAD late-breaking session as Dr. Guttman-Yassky.

The 24-week dose-ranging data from the upadacitinib trial were previously reported at the 2023 annual meeting of the European Association of Dermatology and Venereology. In the placebo-controlled portion, which randomized 185 patients with extensive non-segmental vitiligo to 6 mg, 11 mg, or 22 mg, the two higher doses were significantly more effective than placebo.

In the extension, patients in the placebo group were randomized to 11 mg or 22 mg, while those in the higher dose groups remained on their assigned therapies.
 

F-VASI Almost Doubled in Extension Trial

From week 24 to week 52, there was nearly a doubling of the percent F-VASI reduction, climbing from 32% to 60.8% in the 11-mg group and from 38.7% to 64.9% in the 22-mg group, Dr. Passeron said. Placebo groups who were switched to active therapy at 24 weeks rapidly approached the rates of F-VASI response of those initiated on upadacitinib.

The percent reductions in T-VASI, although lower, followed the same pattern. For the 11-mg group, the reduction climbed from 16% at 24 weeks to 44.7% at 52 weeks. For the 22-mg group, the reduction climbed from 22.9% to 44.4%. Patients who were switched from placebo to 11 mg or to 22 mg also experienced improvements in T-VASI up to 52 weeks, although the level of improvement was lower than that in patients initially randomized to the higher doses of upadacitinib.

There were “no new safety signals” for upadacitinib, which is FDA-approved for multiple indications, according to Dr. Passeron. He said acne-like lesions were the most bothersome adverse event, and cases of herpes zoster were “rare.”

A version of these data was published in a British Journal of Dermatology supplement just prior to the AAD meeting.

Phase 3 vitiligo trials are planned for both ritlecitinib and upadacitinib.

Dr. Guttman-Yassky reported financial relationships with approximately 45 pharmaceutical companies, including Pfizer, which makes ritlecitinib and provided funding for the study she discussed. Dr. Passeron reported financial relationships with approximately 40 pharmaceutical companies, including AbbVie, which makes upadacitinib and provided funding for the study he discussed.

A version of this article appeared on Medscape.com.

SAN DIEGO — In two different phase 2b trial extensions, oral treatment with Janus kinase (JAK) inhibitors showed improved skin clearance in patients with vitiligo, according to presentations at a late-breaking session at the annual meeting of the American Academy of Dermatology (AAD).

In one, the addition of narrow-band ultraviolet-B (NB-UVB) light therapy to ritlecitinib appears more effective than ritlecitinib alone. In the other study, the effectiveness of upadacitinib appears to improve over time.

Based on the ritlecitinib data, “if you have phototherapy in your office, it might be good to couple it with ritlecitinib for vitiligo patients,” said Emma Guttman-Yassky, MD, PhD, chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York City, who presented the findings.

However, because of the relatively small numbers in the extension study, Dr. Guttman-Yassky characterized the evidence as preliminary and in need of further investigation.

For vitiligo, the only approved JAK inhibitor is ruxolitinib, 1.5%, in a cream formulation. In June, ritlecitinib (Litfulo) was approved by the Food and Drug Administration (FDA) for alopecia areata. Phototherapy, which has been used for decades in the treatment of vitiligo, has an established efficacy and safety profile as a stand-alone vitiligo treatment. Upadacitinib has numerous indications for inflammatory diseases, such as rheumatoid arthritis, and was granted FDA approval for atopic dermatitis in 2022.
 

NB-UVB Arm Added in Ritlecitinib Extension

The ritlecitinib study population was drawn from patients with non-segmental vitiligo who initially participated in a 24-week dose-ranging period of a phase 2b trial published last year. In that study, 364 patients were randomized to doses of once-daily ritlecitinib ranging from 10 to 50 mg with or without a 4-week loading regimen. Higher doses were generally associated with greater efficacy on the primary endpoint of facial vitiligo area scoring index (F-VASI) but not with a greater risk for adverse events.

In the 24-week extension study, 187 patients received a 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib for the remaining 20 weeks. Another 43 patients were randomized to one of two arms: The same 4-week loading regimen of 200-mg ritlecitinib daily followed by 50 mg of daily ritlecitinib or to 50-mg daily ritlecitinib without a loading dose but combined with NB-UVB delivered twice per week.

Important to interpretation of results, there was an additional twist. Patients in the randomized arm who had < 10% improvement in the total vitiligo area severity index (T-VASI) at week 12 of the extension were discontinued from the study.

The endpoints considered when comparing ritlecitinib with or without NB-UVB at the end of the extension study were F-VASI, T-VASI, patient global impression of change, and adverse events. Responses were assessed on the basis of both observed and last observation carried forward (LOCF).

Of the 43 people, who were randomized in the extension study, nine (21%) had < 10% improvement in T-VASI and were therefore discontinued from the study.

At the end of 24 weeks, both groups had a substantial response to their assigned therapy, but the addition of NB-UVB increased rates of response, although not always at a level of statistical significance, according to Dr. Guttman-Yassky.

For the percent improvement in F-VASI, specifically, the increase did not reach significance on the basis of LOCF (57.9% vs 51.5%; P = .158) but was highly significant on the basis of observed responses (69.6% vs 55.1%; P = .009). For T-VASI, differences for adjunctive NB-UVB over monotherapy did not reach significance for either observed or LOCF responses, but it was significant for observed responses in a patient global impression of change.
 

Small Numbers Limit Strength of Ritlecitinib, NB-UVB Evidence

However, Dr. Guttman-Yassky said it is important “to pay attention to the sample sizes” when noting the lack of significance.

The combination appeared safe, and there were no side effects associated with the addition of twice-weekly NB-UVB to ritlecitinib.

She acknowledged that the design of this analysis was “complicated” and that the number of randomized patients was small. She suggested the findings support the potential for benefit from the combination of a JAK inhibitor and NB-UVB, both of which have shown efficacy as monotherapy in previous studies. She indicated that a trial of this combination is reasonable while awaiting a more definitive study.

One of the questions that might be posed in a larger study is the timing of NB-UVB, such as whether it is best reserved for those with inadequate early response to a JAK inhibitor or if optimal results are achieved when a JAK inhibitor and NB-UVB are initiated simultaneously.

[embed:render:related:node:265870]

Upadacitinib Monotherapy Results

One rationale for initiating therapy with the combination of a JAK inhibitor and NB-UVB is the potential for a more rapid response, but extended results from a second phase 2b study with a different oral JAK inhibitor, upadacitinib, suggested responses on JAK inhibitor monotherapy improve steadily over time.

“The overall efficacy continued to improve without reaching a plateau at 1 year,” reported Thierry Passeron, MD, PhD, professor and chair, Department of Dermatology, Université Côte d’Azur, Nice, France. He spoke at the same AAD late-breaking session as Dr. Guttman-Yassky.

The 24-week dose-ranging data from the upadacitinib trial were previously reported at the 2023 annual meeting of the European Association of Dermatology and Venereology. In the placebo-controlled portion, which randomized 185 patients with extensive non-segmental vitiligo to 6 mg, 11 mg, or 22 mg, the two higher doses were significantly more effective than placebo.

In the extension, patients in the placebo group were randomized to 11 mg or 22 mg, while those in the higher dose groups remained on their assigned therapies.
 

F-VASI Almost Doubled in Extension Trial

From week 24 to week 52, there was nearly a doubling of the percent F-VASI reduction, climbing from 32% to 60.8% in the 11-mg group and from 38.7% to 64.9% in the 22-mg group, Dr. Passeron said. Placebo groups who were switched to active therapy at 24 weeks rapidly approached the rates of F-VASI response of those initiated on upadacitinib.

The percent reductions in T-VASI, although lower, followed the same pattern. For the 11-mg group, the reduction climbed from 16% at 24 weeks to 44.7% at 52 weeks. For the 22-mg group, the reduction climbed from 22.9% to 44.4%. Patients who were switched from placebo to 11 mg or to 22 mg also experienced improvements in T-VASI up to 52 weeks, although the level of improvement was lower than that in patients initially randomized to the higher doses of upadacitinib.

There were “no new safety signals” for upadacitinib, which is FDA-approved for multiple indications, according to Dr. Passeron. He said acne-like lesions were the most bothersome adverse event, and cases of herpes zoster were “rare.”

A version of these data was published in a British Journal of Dermatology supplement just prior to the AAD meeting.

Phase 3 vitiligo trials are planned for both ritlecitinib and upadacitinib.

Dr. Guttman-Yassky reported financial relationships with approximately 45 pharmaceutical companies, including Pfizer, which makes ritlecitinib and provided funding for the study she discussed. Dr. Passeron reported financial relationships with approximately 40 pharmaceutical companies, including AbbVie, which makes upadacitinib and provided funding for the study he discussed.

A version of this article appeared on Medscape.com.

Vitiligo is a common acquired autoimmune disease that causes depigmented patches to develop throughout the skin , with descriptions dating back more than 3000 years to the earliest known Indian and Egyptian texts. Approximately 1.4% of the worldwide population has vitiligo,¹ and onset follows a bimodal age distribution with an early-onset population (mean age at onset, 10.3 years) as well as an adult-onset population (mean age at onset, 34 years).² Vitiligo manifests as well-defined, irregular, depigmented macules and patches surrounded by normal skin. The patches can vary in size from a few millimeters to several centimeters. There may be signs of inflammation, and the lesions can be itchy, but in most cases vitiligo is asymptomatic. In nonsegmental vitiligo, the depigmented patches are ymmetrical, can appear in any area of the body, and commonly progress slowly. In segmental vitiligo, the patches are unilateral, rarely cross the midline of the body, and are localized to one area. Segmental vitiligo commonly appears in childhood and progresses rapidly but stops abruptly within 6 to 12 months and remains stable, usually for life.³ Although the condition may be more apparent in patients with skin of color, vitiligo manifests at a similar rate in individuals of all races and ethnicities.⁴

Similar to most autoimmune diseases, vitiligo has a strong genetic predisposition. Although the overall prevalence of vitiligo is less than 2%, having a family history of vitiligo (ie, a first-degree relative with vitiligo) increases an individual’s risk to 6%, while concordance in identical twins is 23%.⁵ Beyond genetic predisposition, there is strong evidence that environmental exposures, such as hair dyes, contribute to risk for disease.⁶ Interestingly, vitiligo is associated with polyautoimmunity—the presence of multiple autoimmune diseases in a single patient,⁷ such as type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease, pernicious anemia, and Addison disease. Similar to vitiligo itself, polyautoimmunity likely is driven by a combination of genetic and environmental factors.⁵

We provide a brief overview of clinical trial results of Janus kinase (JAK) inhibitors for treating vitiligo and discuss the trial cohorts, with an emphasis on the impact of cohort demographic composition for individuals with skin of color. We recommend factors that investigators should consider to ensure equitable representation of individuals with skin of color in future clinical trials.

Autoimmune Pathogenesis and Treatment With JAK Inhibitors

Vitiligo is driven by autoreactive CD8⁺ T cells that target melanocytes and secrete IFN-g. Signaling of IFN-g occurs through the JAK–signal transducer and activator of transcription (JAK-STAT) pathway, leading to transcriptional changes that activate proinflammatory genes such as the chemokine CXCL10, which is required for the directed accumulation of melanocyte-specific CD8⁺ T cells at the epidermis where melanocytes reside.⁸ Once vitiligo has been initiated, the disease persists due to the presence of resident memory T cells that remain in the skin and destroy new melanocytes.^9,10

Given the central role of IFN-g signaling in the pathogenesis of vitiligo, drugs that inhibit JAK signaling are appealing to treat the disease. These JAK inhibitors bind to the kinase domain of JAK to prevent its activation, thus preventing downstream signaling events including STAT phosphorylation and its translocation to the nucleus, which ultimately stops the upregulation of inflammatory gene transcription. This process attenuates the autoimmune response in the skin and results in repigmentation of vitiligo lesions. In 2022, the US Food and Drug Administration approved the topical JAK inhibitor ruxolitinib for the treatment of vitiligo. Additional clinical trials have been initiated to test oral JAK inhibitors—ritlecitinib (ClinicalTrials.gov identifiers NCT06163326, NCT06072183, NCT05583526), povorcitinib (NCT04818346, NCT06113445, NCT06113471), and upadacitinib (NCT04927975, NCT06118411)—with strong results reported so far.¹¹

The effects of JAK inhibitors can be striking, as shown in the Figure. A patient of one of the authors (J.E.H.) used topical ruxolitinib on only the left arm for approximately 36 weeks and results were as expected—strong repigmentation of only the treated area, which is possible with JAK inhibitors. Indeed, 2 phase 3 studies—Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V1 and TRuE-V2)—showed that approximately 30% of participants in TRuE-V1 (N=330) and 30.9% of participants in TRuE-V2 (N=344) achieved at least 75% improvement over baseline in the facial vitiligo area scoring index (VASI).¹² In the oral ritlecitinib phase 2b study, 12.1% of the 187 participants on the highest tested dose of ritlecitinib (loading dose of 200 mg/d for 28 days, followed by 50 mg/d maintenance dose) achieved at least 75% improvement over baseline in the VASI at 24 weeks.¹¹ Although this rate is lower than for topical ruxolitinib, this trial required all participants to have active disease (unlike the TRuE-V trials of ruxolitinib), which likely created a higher bar for repigmentation and thus resulted in fewer participants achieving the primary outcome at the early 6-month end point. Extension of treatment through 48 weeks demonstrated continued improvement over baseline without any evidence of plateau.¹¹ Although treatment with JAK inhibitors can result in dramatic repigmentation of vitiligo patches, it falls short of providing a permanent cure, as stopping treatment results in relapse (ie, the return of depigmented lesions).

Delva_Figure.jpg

Racial Disparities in Clinical Trials

Even though vitiligo affects all skin types and races/ethnicities with similar prevalence and severity, the proportion of individuals with darker skin types enrolled in these clinical trials fails to match their representation in the population as a whole. A study examining the prevalence of vitiligo in the United States reported that Black or African American individuals represented 15.8% of vitiligo diagnoses in the United States⁴ even though they are only 12.7% of the total US population. However, Black or African American individuals comprised only 5% of the combined participants in the TRuE-V clinical trials for topical ruxolitinib¹² and 2.7% of the participants in the phase 2b study of oral ritlecitinib.¹¹ This lack of appropriate representation is not unique to JAK inhibitors or other vitiligo trials. Indeed, the US Food and Drug Administration reported that Black or African American individuals comprised only 8% of participants for all clinical trials in 2020.¹³

Efficacy Metrics Beyond Repigmentation

Disparities in quality-of-life (QOL) metrics in diseases affecting individuals with skin of color also exist. In vitiligo, the contrast between affected and unaffected skin is greater in patients with skin of color, which means that for a given VASI score, the visibility of depigmentation as well as repigmentation may be variable among patients. Additionally, there is evidence that QOL concerns vary between patients with skin of color and those with lighter skin types. Ezzedine et al¹⁴ found that QOL concerns in vitiligo patients with darker skin focused more on appearance, while concerns in vitiligo patients with lighter skin focused more on skin cancer risk. In addition to QOL differences among individuals with different skin types, there also are well-documented differences in attitudes to vitiligo among certain ethnic or cultural groups.¹⁵ For example, the Rigveda (an ancient Hindu text) indicates that individuals with vitiligo and their progeny are disqualified from marriage. Although the JAK inhibitor clinical trials for vitiligo did not appear to show differences in the degree of repigmentation among different skin types or races/ethnicities, QOL measures were not collected as a secondary end point in these studies—despite the fact that at least 1 study had documented that QOL measures were not uniform across patients when stratified by age and extent of disease.^1,11,12 This same study also presented limited data suggestive of lower QOL in patients with the darkest skin phototype.¹

Considerations for Future Clinical Trials

It is logical to assume that every clinical trialist in dermatology seeks equitable representation among a diverse set of races, ethnicities, and skin types, but achieving this goal remains elusive. Two recent publications^16,17 outlined the challenges and examined solutions to address enrollment disparities, including several barriers to diversity among clinical trial participants: awareness of the clinical trials among minority populations; easy access to clinical trial sites; reluctance to participate because of prior experiences of discrimination, even if unrelated to clinical trials; and a lack of workforce diversity among the clinical trialist teams. To overcome these barriers, a multifaceted approach is needed that requires action at the level of the patient, provider, community, and institution. Once diverse representation is achieved, investigators should consider the need for QOL metrics as a secondary outcome in their trials, which will ensure that the intended clinical effect is matched by patient expectations across different races and ethnicities based on the potential differential impact that diseases such as vitiligo can have on patients with skin of color.

Vitiligo is a common acquired autoimmune disease that causes depigmented patches to develop throughout the skin , with descriptions dating back more than 3000 years to the earliest known Indian and Egyptian texts. Approximately 1.4% of the worldwide population has vitiligo,¹ and onset follows a bimodal age distribution with an early-onset population (mean age at onset, 10.3 years) as well as an adult-onset population (mean age at onset, 34 years).² Vitiligo manifests as well-defined, irregular, depigmented macules and patches surrounded by normal skin. The patches can vary in size from a few millimeters to several centimeters. There may be signs of inflammation, and the lesions can be itchy, but in most cases vitiligo is asymptomatic. In nonsegmental vitiligo, the depigmented patches are ymmetrical, can appear in any area of the body, and commonly progress slowly. In segmental vitiligo, the patches are unilateral, rarely cross the midline of the body, and are localized to one area. Segmental vitiligo commonly appears in childhood and progresses rapidly but stops abruptly within 6 to 12 months and remains stable, usually for life.³ Although the condition may be more apparent in patients with skin of color, vitiligo manifests at a similar rate in individuals of all races and ethnicities.⁴

Similar to most autoimmune diseases, vitiligo has a strong genetic predisposition. Although the overall prevalence of vitiligo is less than 2%, having a family history of vitiligo (ie, a first-degree relative with vitiligo) increases an individual’s risk to 6%, while concordance in identical twins is 23%.⁵ Beyond genetic predisposition, there is strong evidence that environmental exposures, such as hair dyes, contribute to risk for disease.⁶ Interestingly, vitiligo is associated with polyautoimmunity—the presence of multiple autoimmune diseases in a single patient,⁷ such as type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease, pernicious anemia, and Addison disease. Similar to vitiligo itself, polyautoimmunity likely is driven by a combination of genetic and environmental factors.⁵

We provide a brief overview of clinical trial results of Janus kinase (JAK) inhibitors for treating vitiligo and discuss the trial cohorts, with an emphasis on the impact of cohort demographic composition for individuals with skin of color. We recommend factors that investigators should consider to ensure equitable representation of individuals with skin of color in future clinical trials.

Autoimmune Pathogenesis and Treatment With JAK Inhibitors

Vitiligo is driven by autoreactive CD8⁺ T cells that target melanocytes and secrete IFN-g. Signaling of IFN-g occurs through the JAK–signal transducer and activator of transcription (JAK-STAT) pathway, leading to transcriptional changes that activate proinflammatory genes such as the chemokine CXCL10, which is required for the directed accumulation of melanocyte-specific CD8⁺ T cells at the epidermis where melanocytes reside.⁸ Once vitiligo has been initiated, the disease persists due to the presence of resident memory T cells that remain in the skin and destroy new melanocytes.^9,10

Given the central role of IFN-g signaling in the pathogenesis of vitiligo, drugs that inhibit JAK signaling are appealing to treat the disease. These JAK inhibitors bind to the kinase domain of JAK to prevent its activation, thus preventing downstream signaling events including STAT phosphorylation and its translocation to the nucleus, which ultimately stops the upregulation of inflammatory gene transcription. This process attenuates the autoimmune response in the skin and results in repigmentation of vitiligo lesions. In 2022, the US Food and Drug Administration approved the topical JAK inhibitor ruxolitinib for the treatment of vitiligo. Additional clinical trials have been initiated to test oral JAK inhibitors—ritlecitinib (ClinicalTrials.gov identifiers NCT06163326, NCT06072183, NCT05583526), povorcitinib (NCT04818346, NCT06113445, NCT06113471), and upadacitinib (NCT04927975, NCT06118411)—with strong results reported so far.¹¹

The effects of JAK inhibitors can be striking, as shown in the Figure. A patient of one of the authors (J.E.H.) used topical ruxolitinib on only the left arm for approximately 36 weeks and results were as expected—strong repigmentation of only the treated area, which is possible with JAK inhibitors. Indeed, 2 phase 3 studies—Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V1 and TRuE-V2)—showed that approximately 30% of participants in TRuE-V1 (N=330) and 30.9% of participants in TRuE-V2 (N=344) achieved at least 75% improvement over baseline in the facial vitiligo area scoring index (VASI).¹² In the oral ritlecitinib phase 2b study, 12.1% of the 187 participants on the highest tested dose of ritlecitinib (loading dose of 200 mg/d for 28 days, followed by 50 mg/d maintenance dose) achieved at least 75% improvement over baseline in the VASI at 24 weeks.¹¹ Although this rate is lower than for topical ruxolitinib, this trial required all participants to have active disease (unlike the TRuE-V trials of ruxolitinib), which likely created a higher bar for repigmentation and thus resulted in fewer participants achieving the primary outcome at the early 6-month end point. Extension of treatment through 48 weeks demonstrated continued improvement over baseline without any evidence of plateau.¹¹ Although treatment with JAK inhibitors can result in dramatic repigmentation of vitiligo patches, it falls short of providing a permanent cure, as stopping treatment results in relapse (ie, the return of depigmented lesions).

Delva_Figure.jpg

Racial Disparities in Clinical Trials

Even though vitiligo affects all skin types and races/ethnicities with similar prevalence and severity, the proportion of individuals with darker skin types enrolled in these clinical trials fails to match their representation in the population as a whole. A study examining the prevalence of vitiligo in the United States reported that Black or African American individuals represented 15.8% of vitiligo diagnoses in the United States⁴ even though they are only 12.7% of the total US population. However, Black or African American individuals comprised only 5% of the combined participants in the TRuE-V clinical trials for topical ruxolitinib¹² and 2.7% of the participants in the phase 2b study of oral ritlecitinib.¹¹ This lack of appropriate representation is not unique to JAK inhibitors or other vitiligo trials. Indeed, the US Food and Drug Administration reported that Black or African American individuals comprised only 8% of participants for all clinical trials in 2020.¹³

Efficacy Metrics Beyond Repigmentation

Disparities in quality-of-life (QOL) metrics in diseases affecting individuals with skin of color also exist. In vitiligo, the contrast between affected and unaffected skin is greater in patients with skin of color, which means that for a given VASI score, the visibility of depigmentation as well as repigmentation may be variable among patients. Additionally, there is evidence that QOL concerns vary between patients with skin of color and those with lighter skin types. Ezzedine et al¹⁴ found that QOL concerns in vitiligo patients with darker skin focused more on appearance, while concerns in vitiligo patients with lighter skin focused more on skin cancer risk. In addition to QOL differences among individuals with different skin types, there also are well-documented differences in attitudes to vitiligo among certain ethnic or cultural groups.¹⁵ For example, the Rigveda (an ancient Hindu text) indicates that individuals with vitiligo and their progeny are disqualified from marriage. Although the JAK inhibitor clinical trials for vitiligo did not appear to show differences in the degree of repigmentation among different skin types or races/ethnicities, QOL measures were not collected as a secondary end point in these studies—despite the fact that at least 1 study had documented that QOL measures were not uniform across patients when stratified by age and extent of disease.^1,11,12 This same study also presented limited data suggestive of lower QOL in patients with the darkest skin phototype.¹

Considerations for Future Clinical Trials

It is logical to assume that every clinical trialist in dermatology seeks equitable representation among a diverse set of races, ethnicities, and skin types, but achieving this goal remains elusive. Two recent publications^16,17 outlined the challenges and examined solutions to address enrollment disparities, including several barriers to diversity among clinical trial participants: awareness of the clinical trials among minority populations; easy access to clinical trial sites; reluctance to participate because of prior experiences of discrimination, even if unrelated to clinical trials; and a lack of workforce diversity among the clinical trialist teams. To overcome these barriers, a multifaceted approach is needed that requires action at the level of the patient, provider, community, and institution. Once diverse representation is achieved, investigators should consider the need for QOL metrics as a secondary outcome in their trials, which will ensure that the intended clinical effect is matched by patient expectations across different races and ethnicities based on the potential differential impact that diseases such as vitiligo can have on patients with skin of color.

Vitiligo is a common acquired autoimmune disease that causes depigmented patches to develop throughout the skin , with descriptions dating back more than 3000 years to the earliest known Indian and Egyptian texts. Approximately 1.4% of the worldwide population has vitiligo,¹ and onset follows a bimodal age distribution with an early-onset population (mean age at onset, 10.3 years) as well as an adult-onset population (mean age at onset, 34 years).² Vitiligo manifests as well-defined, irregular, depigmented macules and patches surrounded by normal skin. The patches can vary in size from a few millimeters to several centimeters. There may be signs of inflammation, and the lesions can be itchy, but in most cases vitiligo is asymptomatic. In nonsegmental vitiligo, the depigmented patches are ymmetrical, can appear in any area of the body, and commonly progress slowly. In segmental vitiligo, the patches are unilateral, rarely cross the midline of the body, and are localized to one area. Segmental vitiligo commonly appears in childhood and progresses rapidly but stops abruptly within 6 to 12 months and remains stable, usually for life.³ Although the condition may be more apparent in patients with skin of color, vitiligo manifests at a similar rate in individuals of all races and ethnicities.⁴

Similar to most autoimmune diseases, vitiligo has a strong genetic predisposition. Although the overall prevalence of vitiligo is less than 2%, having a family history of vitiligo (ie, a first-degree relative with vitiligo) increases an individual’s risk to 6%, while concordance in identical twins is 23%.⁵ Beyond genetic predisposition, there is strong evidence that environmental exposures, such as hair dyes, contribute to risk for disease.⁶ Interestingly, vitiligo is associated with polyautoimmunity—the presence of multiple autoimmune diseases in a single patient,⁷ such as type 1 diabetes mellitus, rheumatoid arthritis, autoimmune thyroid disease, pernicious anemia, and Addison disease. Similar to vitiligo itself, polyautoimmunity likely is driven by a combination of genetic and environmental factors.⁵

We provide a brief overview of clinical trial results of Janus kinase (JAK) inhibitors for treating vitiligo and discuss the trial cohorts, with an emphasis on the impact of cohort demographic composition for individuals with skin of color. We recommend factors that investigators should consider to ensure equitable representation of individuals with skin of color in future clinical trials.

Autoimmune Pathogenesis and Treatment With JAK Inhibitors

Vitiligo is driven by autoreactive CD8⁺ T cells that target melanocytes and secrete IFN-g. Signaling of IFN-g occurs through the JAK–signal transducer and activator of transcription (JAK-STAT) pathway, leading to transcriptional changes that activate proinflammatory genes such as the chemokine CXCL10, which is required for the directed accumulation of melanocyte-specific CD8⁺ T cells at the epidermis where melanocytes reside.⁸ Once vitiligo has been initiated, the disease persists due to the presence of resident memory T cells that remain in the skin and destroy new melanocytes.^9,10

Given the central role of IFN-g signaling in the pathogenesis of vitiligo, drugs that inhibit JAK signaling are appealing to treat the disease. These JAK inhibitors bind to the kinase domain of JAK to prevent its activation, thus preventing downstream signaling events including STAT phosphorylation and its translocation to the nucleus, which ultimately stops the upregulation of inflammatory gene transcription. This process attenuates the autoimmune response in the skin and results in repigmentation of vitiligo lesions. In 2022, the US Food and Drug Administration approved the topical JAK inhibitor ruxolitinib for the treatment of vitiligo. Additional clinical trials have been initiated to test oral JAK inhibitors—ritlecitinib (ClinicalTrials.gov identifiers NCT06163326, NCT06072183, NCT05583526), povorcitinib (NCT04818346, NCT06113445, NCT06113471), and upadacitinib (NCT04927975, NCT06118411)—with strong results reported so far.¹¹

The effects of JAK inhibitors can be striking, as shown in the Figure. A patient of one of the authors (J.E.H.) used topical ruxolitinib on only the left arm for approximately 36 weeks and results were as expected—strong repigmentation of only the treated area, which is possible with JAK inhibitors. Indeed, 2 phase 3 studies—Topical Ruxolitinib Evaluation in Vitiligo (TRuE-V1 and TRuE-V2)—showed that approximately 30% of participants in TRuE-V1 (N=330) and 30.9% of participants in TRuE-V2 (N=344) achieved at least 75% improvement over baseline in the facial vitiligo area scoring index (VASI).¹² In the oral ritlecitinib phase 2b study, 12.1% of the 187 participants on the highest tested dose of ritlecitinib (loading dose of 200 mg/d for 28 days, followed by 50 mg/d maintenance dose) achieved at least 75% improvement over baseline in the VASI at 24 weeks.¹¹ Although this rate is lower than for topical ruxolitinib, this trial required all participants to have active disease (unlike the TRuE-V trials of ruxolitinib), which likely created a higher bar for repigmentation and thus resulted in fewer participants achieving the primary outcome at the early 6-month end point. Extension of treatment through 48 weeks demonstrated continued improvement over baseline without any evidence of plateau.¹¹ Although treatment with JAK inhibitors can result in dramatic repigmentation of vitiligo patches, it falls short of providing a permanent cure, as stopping treatment results in relapse (ie, the return of depigmented lesions).

Delva_Figure.jpg

Racial Disparities in Clinical Trials

Even though vitiligo affects all skin types and races/ethnicities with similar prevalence and severity, the proportion of individuals with darker skin types enrolled in these clinical trials fails to match their representation in the population as a whole. A study examining the prevalence of vitiligo in the United States reported that Black or African American individuals represented 15.8% of vitiligo diagnoses in the United States⁴ even though they are only 12.7% of the total US population. However, Black or African American individuals comprised only 5% of the combined participants in the TRuE-V clinical trials for topical ruxolitinib¹² and 2.7% of the participants in the phase 2b study of oral ritlecitinib.¹¹ This lack of appropriate representation is not unique to JAK inhibitors or other vitiligo trials. Indeed, the US Food and Drug Administration reported that Black or African American individuals comprised only 8% of participants for all clinical trials in 2020.¹³

Efficacy Metrics Beyond Repigmentation

Disparities in quality-of-life (QOL) metrics in diseases affecting individuals with skin of color also exist. In vitiligo, the contrast between affected and unaffected skin is greater in patients with skin of color, which means that for a given VASI score, the visibility of depigmentation as well as repigmentation may be variable among patients. Additionally, there is evidence that QOL concerns vary between patients with skin of color and those with lighter skin types. Ezzedine et al¹⁴ found that QOL concerns in vitiligo patients with darker skin focused more on appearance, while concerns in vitiligo patients with lighter skin focused more on skin cancer risk. In addition to QOL differences among individuals with different skin types, there also are well-documented differences in attitudes to vitiligo among certain ethnic or cultural groups.¹⁵ For example, the Rigveda (an ancient Hindu text) indicates that individuals with vitiligo and their progeny are disqualified from marriage. Although the JAK inhibitor clinical trials for vitiligo did not appear to show differences in the degree of repigmentation among different skin types or races/ethnicities, QOL measures were not collected as a secondary end point in these studies—despite the fact that at least 1 study had documented that QOL measures were not uniform across patients when stratified by age and extent of disease.^1,11,12 This same study also presented limited data suggestive of lower QOL in patients with the darkest skin phototype.¹

Considerations for Future Clinical Trials

It is logical to assume that every clinical trialist in dermatology seeks equitable representation among a diverse set of races, ethnicities, and skin types, but achieving this goal remains elusive. Two recent publications^16,17 outlined the challenges and examined solutions to address enrollment disparities, including several barriers to diversity among clinical trial participants: awareness of the clinical trials among minority populations; easy access to clinical trial sites; reluctance to participate because of prior experiences of discrimination, even if unrelated to clinical trials; and a lack of workforce diversity among the clinical trialist teams. To overcome these barriers, a multifaceted approach is needed that requires action at the level of the patient, provider, community, and institution. Once diverse representation is achieved, investigators should consider the need for QOL metrics as a secondary outcome in their trials, which will ensure that the intended clinical effect is matched by patient expectations across different races and ethnicities based on the potential differential impact that diseases such as vitiligo can have on patients with skin of color.

TOPLINE:

Topical calcineurin inhibitors (TCIs), topical corticosteroids (TCSs), and topical Janus kinase (JAK) inhibitors are supported as mainstay treatments in new expert recommendations on the use of topical therapeutics in children, adolescents, and young adults with vitiligo.

METHODOLOGY:

• While half of all vitiligo cases manifest within the initial two decades of life, no guidelines specifically address the management of vitiligo in children, adolescents, and young adults with vitiligo.
• A protocol was established to formulate consensus recommendations addressing questions related to pediatric vitiligo.
• Overall, 50 articles on topical corticosteroids and/or topical calcineurin inhibitors, five on topical Janus kinase inhibitors, and two each on pseudocatalase and microdermabrasion were included.
• The participants recorded their agreement levels with the formulated statements, using a 5-point Likert scale.

TAKEAWAY:

• TCIs, TCSs, JAK inhibitors, and phototherapy, specifically narrowband ultraviolet (UV)-B light therapy, are mainstay treatments; the combination of UV-B light and topical therapy may enhance initial repigmentation.
• Long-term monitoring for skin cancers is advised, and short outdoor UV exposure is suggested for pediatric patients.
• TCIs, such as tacrolimus and pimecrolimus, are recommended as first-line therapy, particularly on the face, applied twice daily for ≥ 3 months; continued use for 6-12 additional months is recommended if repigmentation is observed.
• The choice of TCS class depends on the site and planned usage duration. Short-term use or overlap with TCIs is recommended because of the risk for atrophy with long-term TCS use. Class 5-6 agents are another option.
• For areas with thin skin, TCSs can be considered second-line treatments.
• Topical JAK inhibitors, specifically topical 1.5% ruxolitinib cream, are recommended for patients aged ≥ 12 years, as first- or second-line therapy. Limitation to 10% body surface area is recommended to minimize systemic absorption. Limited evidence exists for children aged < 12 years.

IN PRACTICE:

“Effective therapy requires a focus on long-term therapeutic interventions to maximize the local gain and retention of pigmentation with a trial period of twice-weekly application. Counseling should include discussion of the chronicity of vitiligo and the need for long-term care,” the authors wrote.

[embed:render:related:node:266785]

LIMITATIONS:

Some of the recommendations were opinion-based because of the scarcity of evidence-based literature.

SOURCE:

The consensus statement was published on March 13 in JAMA Dermatology.

DISCLOSURES:

This work was supported by grants from Vitiligo Research Foundation and Incyte Pharmaceuticals. The majority of authors disclosed financial relationships outside this work; several reported no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Topical calcineurin inhibitors (TCIs), topical corticosteroids (TCSs), and topical Janus kinase (JAK) inhibitors are supported as mainstay treatments in new expert recommendations on the use of topical therapeutics in children, adolescents, and young adults with vitiligo.

METHODOLOGY:

• While half of all vitiligo cases manifest within the initial two decades of life, no guidelines specifically address the management of vitiligo in children, adolescents, and young adults with vitiligo.
• A protocol was established to formulate consensus recommendations addressing questions related to pediatric vitiligo.
• Overall, 50 articles on topical corticosteroids and/or topical calcineurin inhibitors, five on topical Janus kinase inhibitors, and two each on pseudocatalase and microdermabrasion were included.
• The participants recorded their agreement levels with the formulated statements, using a 5-point Likert scale.

TAKEAWAY:

• TCIs, TCSs, JAK inhibitors, and phototherapy, specifically narrowband ultraviolet (UV)-B light therapy, are mainstay treatments; the combination of UV-B light and topical therapy may enhance initial repigmentation.
• Long-term monitoring for skin cancers is advised, and short outdoor UV exposure is suggested for pediatric patients.
• TCIs, such as tacrolimus and pimecrolimus, are recommended as first-line therapy, particularly on the face, applied twice daily for ≥ 3 months; continued use for 6-12 additional months is recommended if repigmentation is observed.
• The choice of TCS class depends on the site and planned usage duration. Short-term use or overlap with TCIs is recommended because of the risk for atrophy with long-term TCS use. Class 5-6 agents are another option.
• For areas with thin skin, TCSs can be considered second-line treatments.
• Topical JAK inhibitors, specifically topical 1.5% ruxolitinib cream, are recommended for patients aged ≥ 12 years, as first- or second-line therapy. Limitation to 10% body surface area is recommended to minimize systemic absorption. Limited evidence exists for children aged < 12 years.

IN PRACTICE:

“Effective therapy requires a focus on long-term therapeutic interventions to maximize the local gain and retention of pigmentation with a trial period of twice-weekly application. Counseling should include discussion of the chronicity of vitiligo and the need for long-term care,” the authors wrote.

[embed:render:related:node:266785]

LIMITATIONS:

Some of the recommendations were opinion-based because of the scarcity of evidence-based literature.

SOURCE:

The consensus statement was published on March 13 in JAMA Dermatology.

DISCLOSURES:

This work was supported by grants from Vitiligo Research Foundation and Incyte Pharmaceuticals. The majority of authors disclosed financial relationships outside this work; several reported no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Topical calcineurin inhibitors (TCIs), topical corticosteroids (TCSs), and topical Janus kinase (JAK) inhibitors are supported as mainstay treatments in new expert recommendations on the use of topical therapeutics in children, adolescents, and young adults with vitiligo.

METHODOLOGY:

• While half of all vitiligo cases manifest within the initial two decades of life, no guidelines specifically address the management of vitiligo in children, adolescents, and young adults with vitiligo.
• A protocol was established to formulate consensus recommendations addressing questions related to pediatric vitiligo.
• Overall, 50 articles on topical corticosteroids and/or topical calcineurin inhibitors, five on topical Janus kinase inhibitors, and two each on pseudocatalase and microdermabrasion were included.
• The participants recorded their agreement levels with the formulated statements, using a 5-point Likert scale.

TAKEAWAY:

• TCIs, TCSs, JAK inhibitors, and phototherapy, specifically narrowband ultraviolet (UV)-B light therapy, are mainstay treatments; the combination of UV-B light and topical therapy may enhance initial repigmentation.
• Long-term monitoring for skin cancers is advised, and short outdoor UV exposure is suggested for pediatric patients.
• TCIs, such as tacrolimus and pimecrolimus, are recommended as first-line therapy, particularly on the face, applied twice daily for ≥ 3 months; continued use for 6-12 additional months is recommended if repigmentation is observed.
• The choice of TCS class depends on the site and planned usage duration. Short-term use or overlap with TCIs is recommended because of the risk for atrophy with long-term TCS use. Class 5-6 agents are another option.
• For areas with thin skin, TCSs can be considered second-line treatments.
• Topical JAK inhibitors, specifically topical 1.5% ruxolitinib cream, are recommended for patients aged ≥ 12 years, as first- or second-line therapy. Limitation to 10% body surface area is recommended to minimize systemic absorption. Limited evidence exists for children aged < 12 years.

IN PRACTICE:

“Effective therapy requires a focus on long-term therapeutic interventions to maximize the local gain and retention of pigmentation with a trial period of twice-weekly application. Counseling should include discussion of the chronicity of vitiligo and the need for long-term care,” the authors wrote.

[embed:render:related:node:266785]

LIMITATIONS:

Some of the recommendations were opinion-based because of the scarcity of evidence-based literature.

SOURCE:

The consensus statement was published on March 13 in JAMA Dermatology.

DISCLOSURES:

This work was supported by grants from Vitiligo Research Foundation and Incyte Pharmaceuticals. The majority of authors disclosed financial relationships outside this work; several reported no disclosures.

A version of this article appeared on Medscape.com.

Ashley Winter, MD, remembers the first time she Googled the skin condition lichen sclerosus. Most of the websites listed the autoimmune condition as a rare disease.

In the realm of genital health, some conditions remain shrouded in silence and consequently are more likely to go undercounted and underdiagnosed, said Dr. Winter, a urologist based in Los Angeles.

“I truly believe that we just miss the diagnosis a vast majority of the time because there isn’t enough training on [detecting] it,” said Dr. Winter.

Lichen sclerosus primarily affects the skin in the genital and anal regions. Estimates of the disease range between 1 in 300 and 1 in 1000 people, according to the US National Institutes of Health. The condition also more commonly occurs among women, and symptoms include hypopigmentation, itching, pain, changes in skin appearance, and skin atrophy.

“Most cases [affect the] genital [area] only, so often patients don’t bring it up because they don’t want to be examined,” said Sarah Lonowski, MD, assistant professor of dermatology and codirector of the Multidisciplinary Autoimmune Skin Disease/Derm-Rheum Program at the University of Nebraska–Lincoln. “It’s a sensitive area, it’s an uncomfortable area to have examined, so it comes with a lot of emotional burden,” for patients, Dr. Lonowski said.

Receiving a lichen sclerosis diagnosis can take 5 years or longer, in part because the condition’s symptoms can lead clinicians to first make a diagnosis of a yeast infection or bacterial vaginosis, according to Christina Kraus, MD, assistant professor of dermatology at UCI Health in Irvine, California.

“There is still limited information on this condition in medical education, and it is not uncommon for clinicians who are not in dermatology or gynecology to be unfamiliar with this diagnosis,” Dr. Kraus said.

Because no medical tests are available to confirm lichen sclerosus, clinicians diagnose the condition based on the skin’s appearance and symptoms. In some cases, a skin biopsy may help differentiate it from similar rashes that occur in the genital area.

Prepubescent children and postmenopausal women are most likely to develop genital lichen sclerosis, so pediatricians and primary care physicians may be the first to see possible cases, Dr. Lonowski said.

Patients “may not mention it unless they’re asked,” Dr. Lonowski said, adding clinicians can inquire with patients about genital health, examine bothersome areas, “and refer if you’re not sure.”

Clinicians may also miss the condition during physical exams if they do not examine the vulvar skin, she said. The exact cause also remains elusive, but researchers believe genetic and hormonal factors, as well as an overactive immune response, may contribute to development of the condition.
 

Watch Out for Presentation

While lichen sclerosus more frequently occurs in women, men are also affected by the condition. Benjamin N. Breyer, MD, professor and chair of urology at the University of California San Francisco, said lichen sclerosus is one of the most common skin conditions he treats in his male patients.

“Advanced cases can cause urethral narrowing, which is a condition I treat commonly,” said Dr. Breyer. “Lichen sclerosus is often an underrecognized cause of pain or tearing with erections and sex in men.”

Similar to women, lichen sclerosus presents as white color changes on the skin. For men, the condition can also result in fusion of the shaft skin to the head of the penis and burying or concealment of the penis, Dr. Breyer said.

“This leads to challenges with intimacy and urination and can have extensive impacts on quality of life,” said Dr. Breyer.

For women, the skin changes often extend to the perianal area and can cause scarring, said Dr. Kraus.

“Early scarring may present as adherence of the labia minora to the labia majora or inability to fully retract the clitoral hood from the clitoris,” said Dr. Kraus.

In both men and women, lichen sclerosus and another autoimmune condition known as morphea, characterized by skin hardening and discoloration, often present together, said Dr. Lonowski.

“If you have a patient with known morphea, it’s important to ask about genital symptoms,” said Dr. Lonowski. “The association between the two is fairly strong.”

Circumcision is often the first step to help prevent chronic inflammation among male patients, said Dr. Breyer. Because lichen sclerosus is associated with an increased risk for penile cancer, “it is important to biopsy suspicious lesions,” Dr. Breyer added.

Increasing awareness of lichen sclerosus is crucial for early detection and timely intervention, said Dr. Lonowski. The first-line treatment of genital lichen sclerosus is strong topical steroid ointments to reduce inflammation. Clinicians might prescribe this treatment for use twice daily for 2-3 months and then assesses the patient on their response.

“It is fairly responsive to treatment in most cases,” said Dr. Lonowski.

Once symptoms have improved, Dr. Lonowski transitions patients to a maintenance regimen, which might include using the same steroid but only three times a week, switching to a topical with a less potent steroid dosage, or using a combination of a topical steroid and a nonsteroidal anti-inflammatory cream. Despite the prolonged use of the drug, she said patients with lichen sclerosus usually do not present with side effects like discoloration or thinning of skin.

“You may achieve control or remission, but we don’t stop treatment completely because we know the natural history of the disease is to have flares and recurrence.”

If left untreated, the condition can lead to atrophy, scarring, and distortion of the genital anatomy and, in some cases, develop into squamous cell carcinoma.

“The fact that you can do a topical cream intervention and prevent cancer is huge,” said Dr. Winter.

She said open discussions surrounding genital health led by primary care providers can destigmatize conditions like lichen sclerosus and promote early detection and management.

“We need to foster an environment where individuals feel comfortable discussing their symptoms openly,” Dr. Winter said. “Increased awareness can pave the way for early detection, which is crucial for managing the condition effectively.”

The experts included in the story reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Ashley Winter, MD, remembers the first time she Googled the skin condition lichen sclerosus. Most of the websites listed the autoimmune condition as a rare disease.

In the realm of genital health, some conditions remain shrouded in silence and consequently are more likely to go undercounted and underdiagnosed, said Dr. Winter, a urologist based in Los Angeles.

“I truly believe that we just miss the diagnosis a vast majority of the time because there isn’t enough training on [detecting] it,” said Dr. Winter.

Lichen sclerosus primarily affects the skin in the genital and anal regions. Estimates of the disease range between 1 in 300 and 1 in 1000 people, according to the US National Institutes of Health. The condition also more commonly occurs among women, and symptoms include hypopigmentation, itching, pain, changes in skin appearance, and skin atrophy.

“Most cases [affect the] genital [area] only, so often patients don’t bring it up because they don’t want to be examined,” said Sarah Lonowski, MD, assistant professor of dermatology and codirector of the Multidisciplinary Autoimmune Skin Disease/Derm-Rheum Program at the University of Nebraska–Lincoln. “It’s a sensitive area, it’s an uncomfortable area to have examined, so it comes with a lot of emotional burden,” for patients, Dr. Lonowski said.

Receiving a lichen sclerosis diagnosis can take 5 years or longer, in part because the condition’s symptoms can lead clinicians to first make a diagnosis of a yeast infection or bacterial vaginosis, according to Christina Kraus, MD, assistant professor of dermatology at UCI Health in Irvine, California.

“There is still limited information on this condition in medical education, and it is not uncommon for clinicians who are not in dermatology or gynecology to be unfamiliar with this diagnosis,” Dr. Kraus said.

Because no medical tests are available to confirm lichen sclerosus, clinicians diagnose the condition based on the skin’s appearance and symptoms. In some cases, a skin biopsy may help differentiate it from similar rashes that occur in the genital area.

Prepubescent children and postmenopausal women are most likely to develop genital lichen sclerosis, so pediatricians and primary care physicians may be the first to see possible cases, Dr. Lonowski said.

Patients “may not mention it unless they’re asked,” Dr. Lonowski said, adding clinicians can inquire with patients about genital health, examine bothersome areas, “and refer if you’re not sure.”

Clinicians may also miss the condition during physical exams if they do not examine the vulvar skin, she said. The exact cause also remains elusive, but researchers believe genetic and hormonal factors, as well as an overactive immune response, may contribute to development of the condition.
 

Watch Out for Presentation

While lichen sclerosus more frequently occurs in women, men are also affected by the condition. Benjamin N. Breyer, MD, professor and chair of urology at the University of California San Francisco, said lichen sclerosus is one of the most common skin conditions he treats in his male patients.

“Advanced cases can cause urethral narrowing, which is a condition I treat commonly,” said Dr. Breyer. “Lichen sclerosus is often an underrecognized cause of pain or tearing with erections and sex in men.”

Similar to women, lichen sclerosus presents as white color changes on the skin. For men, the condition can also result in fusion of the shaft skin to the head of the penis and burying or concealment of the penis, Dr. Breyer said.

“This leads to challenges with intimacy and urination and can have extensive impacts on quality of life,” said Dr. Breyer.

For women, the skin changes often extend to the perianal area and can cause scarring, said Dr. Kraus.

“Early scarring may present as adherence of the labia minora to the labia majora or inability to fully retract the clitoral hood from the clitoris,” said Dr. Kraus.

In both men and women, lichen sclerosus and another autoimmune condition known as morphea, characterized by skin hardening and discoloration, often present together, said Dr. Lonowski.

“If you have a patient with known morphea, it’s important to ask about genital symptoms,” said Dr. Lonowski. “The association between the two is fairly strong.”

Circumcision is often the first step to help prevent chronic inflammation among male patients, said Dr. Breyer. Because lichen sclerosus is associated with an increased risk for penile cancer, “it is important to biopsy suspicious lesions,” Dr. Breyer added.

Increasing awareness of lichen sclerosus is crucial for early detection and timely intervention, said Dr. Lonowski. The first-line treatment of genital lichen sclerosus is strong topical steroid ointments to reduce inflammation. Clinicians might prescribe this treatment for use twice daily for 2-3 months and then assesses the patient on their response.

“It is fairly responsive to treatment in most cases,” said Dr. Lonowski.

Once symptoms have improved, Dr. Lonowski transitions patients to a maintenance regimen, which might include using the same steroid but only three times a week, switching to a topical with a less potent steroid dosage, or using a combination of a topical steroid and a nonsteroidal anti-inflammatory cream. Despite the prolonged use of the drug, she said patients with lichen sclerosus usually do not present with side effects like discoloration or thinning of skin.

“You may achieve control or remission, but we don’t stop treatment completely because we know the natural history of the disease is to have flares and recurrence.”

If left untreated, the condition can lead to atrophy, scarring, and distortion of the genital anatomy and, in some cases, develop into squamous cell carcinoma.

“The fact that you can do a topical cream intervention and prevent cancer is huge,” said Dr. Winter.

She said open discussions surrounding genital health led by primary care providers can destigmatize conditions like lichen sclerosus and promote early detection and management.

“We need to foster an environment where individuals feel comfortable discussing their symptoms openly,” Dr. Winter said. “Increased awareness can pave the way for early detection, which is crucial for managing the condition effectively.”

The experts included in the story reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Ashley Winter, MD, remembers the first time she Googled the skin condition lichen sclerosus. Most of the websites listed the autoimmune condition as a rare disease.

In the realm of genital health, some conditions remain shrouded in silence and consequently are more likely to go undercounted and underdiagnosed, said Dr. Winter, a urologist based in Los Angeles.

“I truly believe that we just miss the diagnosis a vast majority of the time because there isn’t enough training on [detecting] it,” said Dr. Winter.

Lichen sclerosus primarily affects the skin in the genital and anal regions. Estimates of the disease range between 1 in 300 and 1 in 1000 people, according to the US National Institutes of Health. The condition also more commonly occurs among women, and symptoms include hypopigmentation, itching, pain, changes in skin appearance, and skin atrophy.

“Most cases [affect the] genital [area] only, so often patients don’t bring it up because they don’t want to be examined,” said Sarah Lonowski, MD, assistant professor of dermatology and codirector of the Multidisciplinary Autoimmune Skin Disease/Derm-Rheum Program at the University of Nebraska–Lincoln. “It’s a sensitive area, it’s an uncomfortable area to have examined, so it comes with a lot of emotional burden,” for patients, Dr. Lonowski said.

Receiving a lichen sclerosis diagnosis can take 5 years or longer, in part because the condition’s symptoms can lead clinicians to first make a diagnosis of a yeast infection or bacterial vaginosis, according to Christina Kraus, MD, assistant professor of dermatology at UCI Health in Irvine, California.

“There is still limited information on this condition in medical education, and it is not uncommon for clinicians who are not in dermatology or gynecology to be unfamiliar with this diagnosis,” Dr. Kraus said.

Because no medical tests are available to confirm lichen sclerosus, clinicians diagnose the condition based on the skin’s appearance and symptoms. In some cases, a skin biopsy may help differentiate it from similar rashes that occur in the genital area.

Prepubescent children and postmenopausal women are most likely to develop genital lichen sclerosis, so pediatricians and primary care physicians may be the first to see possible cases, Dr. Lonowski said.

Patients “may not mention it unless they’re asked,” Dr. Lonowski said, adding clinicians can inquire with patients about genital health, examine bothersome areas, “and refer if you’re not sure.”

Clinicians may also miss the condition during physical exams if they do not examine the vulvar skin, she said. The exact cause also remains elusive, but researchers believe genetic and hormonal factors, as well as an overactive immune response, may contribute to development of the condition.
 

Watch Out for Presentation

While lichen sclerosus more frequently occurs in women, men are also affected by the condition. Benjamin N. Breyer, MD, professor and chair of urology at the University of California San Francisco, said lichen sclerosus is one of the most common skin conditions he treats in his male patients.

“Advanced cases can cause urethral narrowing, which is a condition I treat commonly,” said Dr. Breyer. “Lichen sclerosus is often an underrecognized cause of pain or tearing with erections and sex in men.”

Similar to women, lichen sclerosus presents as white color changes on the skin. For men, the condition can also result in fusion of the shaft skin to the head of the penis and burying or concealment of the penis, Dr. Breyer said.

“This leads to challenges with intimacy and urination and can have extensive impacts on quality of life,” said Dr. Breyer.

For women, the skin changes often extend to the perianal area and can cause scarring, said Dr. Kraus.

“Early scarring may present as adherence of the labia minora to the labia majora or inability to fully retract the clitoral hood from the clitoris,” said Dr. Kraus.

In both men and women, lichen sclerosus and another autoimmune condition known as morphea, characterized by skin hardening and discoloration, often present together, said Dr. Lonowski.

“If you have a patient with known morphea, it’s important to ask about genital symptoms,” said Dr. Lonowski. “The association between the two is fairly strong.”

Circumcision is often the first step to help prevent chronic inflammation among male patients, said Dr. Breyer. Because lichen sclerosus is associated with an increased risk for penile cancer, “it is important to biopsy suspicious lesions,” Dr. Breyer added.

Increasing awareness of lichen sclerosus is crucial for early detection and timely intervention, said Dr. Lonowski. The first-line treatment of genital lichen sclerosus is strong topical steroid ointments to reduce inflammation. Clinicians might prescribe this treatment for use twice daily for 2-3 months and then assesses the patient on their response.

“It is fairly responsive to treatment in most cases,” said Dr. Lonowski.

Once symptoms have improved, Dr. Lonowski transitions patients to a maintenance regimen, which might include using the same steroid but only three times a week, switching to a topical with a less potent steroid dosage, or using a combination of a topical steroid and a nonsteroidal anti-inflammatory cream. Despite the prolonged use of the drug, she said patients with lichen sclerosus usually do not present with side effects like discoloration or thinning of skin.

“You may achieve control or remission, but we don’t stop treatment completely because we know the natural history of the disease is to have flares and recurrence.”

If left untreated, the condition can lead to atrophy, scarring, and distortion of the genital anatomy and, in some cases, develop into squamous cell carcinoma.

“The fact that you can do a topical cream intervention and prevent cancer is huge,” said Dr. Winter.

She said open discussions surrounding genital health led by primary care providers can destigmatize conditions like lichen sclerosus and promote early detection and management.

“We need to foster an environment where individuals feel comfortable discussing their symptoms openly,” Dr. Winter said. “Increased awareness can pave the way for early detection, which is crucial for managing the condition effectively.”

The experts included in the story reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

For active-duty service members, dermatologic conditions are among the most common presenting concerns, comprising 15% to 75% of wartime outpatient visits.¹ In general, there are unique considerations when caring for active-duty service members, including meeting designated active-duty retention and hierarchical standards.² We present a hypothetical case: An active-duty military patient presents to a new dermatologist for cosmetic enhancement of facial skin dyspigmentation. The patient will be leaving soon for deployment and will not be able to follow up for 9 months. How should the dermatologist treat a patient who cannot follow up for so long?

The therapeutic modalities offered can be impacted by forthcoming deployments³ that may result in delayed time to administer repeat treatments or follow-up. The patient may have high expectations for a single appointment for a condition that requires prolonged treatment courses. Because there often is no reliable mechanism for patients to obtain refills during deployment, any medications prescribed would need to be provided in advance for the entire deployment duration, which often is 6 to 9 months. Additionally, treatment monitoring or modifications are severely limited, especially in the context of treatment nonresponse or adverse reactions. Considering the unique limitations of this patient population, both military and civilian physicians are faced with a need to maximize beneficence and autonomy while balancing nonmaleficence and justice.

One possible option is to decline to treat until the patient can follow up after returning from deployment. However, denying a request for an active treatable indication for which the patient desires treatment compromises patient autonomy and beneficence. Further, treatment should be provided to patients equitably to maintain justice. Although there may be a role for discussing active monitoring with nonintervention with the patient, denying treatment can negatively impact their physical and mental health and may be harmful. However, the patient should know and fully understand the risks and benefits of nonintervention with limited follow-up, including suboptimal outcomes or adverse events.

Another possibility for the management of this case may be conducting a one-time laser or light-based therapy or a one-time superficial- to medium-depth chemical peel before the patient leaves on deployment. Often, a series of laser- or light-based treatments is required to maximize outcomes for dyspigmentation. Without follow-up and with possible deployment to an environment with high UV exposure, the patient may experience disease exacerbation or other adverse effects. Treatment of those adverse effects may be delayed, as further intervention is not possible during deployment. Lower initial laser settings may be safer but may not be highly effective initially. More rigorous treatment upon return from deployment may be considered. Similar to laser therapies, chemical peels usually require several treatments for optimal outcomes. Without follow-up and with potential deployment to remote environments, there is a risk for adverse events that outweighs the minimal benefit of a single treatment. Therefore, either intervention may violate the principle of nonmaleficence.

A more reasonable approach may be initiating topical therapy and following up via telemedicine evaluation. Topical therapy often is the least-invasive approach and carries a reduced risk for adverse effects. Triple-combination therapy with topical retinoids, hydroquinone, and topical steroids is a common first-line approach.⁴ Because this approach is patient dependent, therapy can be more easily modulated or halted in the context of undesired results. Additionally, if internet connectivity is available, an asynchronous telemedicine approach could be utilized during deployment to monitor and advise changes as necessary, provided the regulatory framework allows for it.⁵

Although there is no uniformly correct approach in a scenario of limited patient follow-up, the last solution may be most ethically favorable: to begin therapy with milder and safer therapies (topical) and defer higher-intensity regimens until the patient returns from deployment. This allows some treatment initiation to preserve justice, beneficence, and patient autonomy. Associated virtual follow-up via telemedicine also allows avoidance of nonmaleficence in this context.

For active-duty service members, dermatologic conditions are among the most common presenting concerns, comprising 15% to 75% of wartime outpatient visits.¹ In general, there are unique considerations when caring for active-duty service members, including meeting designated active-duty retention and hierarchical standards.² We present a hypothetical case: An active-duty military patient presents to a new dermatologist for cosmetic enhancement of facial skin dyspigmentation. The patient will be leaving soon for deployment and will not be able to follow up for 9 months. How should the dermatologist treat a patient who cannot follow up for so long?

The therapeutic modalities offered can be impacted by forthcoming deployments³ that may result in delayed time to administer repeat treatments or follow-up. The patient may have high expectations for a single appointment for a condition that requires prolonged treatment courses. Because there often is no reliable mechanism for patients to obtain refills during deployment, any medications prescribed would need to be provided in advance for the entire deployment duration, which often is 6 to 9 months. Additionally, treatment monitoring or modifications are severely limited, especially in the context of treatment nonresponse or adverse reactions. Considering the unique limitations of this patient population, both military and civilian physicians are faced with a need to maximize beneficence and autonomy while balancing nonmaleficence and justice.

One possible option is to decline to treat until the patient can follow up after returning from deployment. However, denying a request for an active treatable indication for which the patient desires treatment compromises patient autonomy and beneficence. Further, treatment should be provided to patients equitably to maintain justice. Although there may be a role for discussing active monitoring with nonintervention with the patient, denying treatment can negatively impact their physical and mental health and may be harmful. However, the patient should know and fully understand the risks and benefits of nonintervention with limited follow-up, including suboptimal outcomes or adverse events.

Another possibility for the management of this case may be conducting a one-time laser or light-based therapy or a one-time superficial- to medium-depth chemical peel before the patient leaves on deployment. Often, a series of laser- or light-based treatments is required to maximize outcomes for dyspigmentation. Without follow-up and with possible deployment to an environment with high UV exposure, the patient may experience disease exacerbation or other adverse effects. Treatment of those adverse effects may be delayed, as further intervention is not possible during deployment. Lower initial laser settings may be safer but may not be highly effective initially. More rigorous treatment upon return from deployment may be considered. Similar to laser therapies, chemical peels usually require several treatments for optimal outcomes. Without follow-up and with potential deployment to remote environments, there is a risk for adverse events that outweighs the minimal benefit of a single treatment. Therefore, either intervention may violate the principle of nonmaleficence.

A more reasonable approach may be initiating topical therapy and following up via telemedicine evaluation. Topical therapy often is the least-invasive approach and carries a reduced risk for adverse effects. Triple-combination therapy with topical retinoids, hydroquinone, and topical steroids is a common first-line approach.⁴ Because this approach is patient dependent, therapy can be more easily modulated or halted in the context of undesired results. Additionally, if internet connectivity is available, an asynchronous telemedicine approach could be utilized during deployment to monitor and advise changes as necessary, provided the regulatory framework allows for it.⁵

Although there is no uniformly correct approach in a scenario of limited patient follow-up, the last solution may be most ethically favorable: to begin therapy with milder and safer therapies (topical) and defer higher-intensity regimens until the patient returns from deployment. This allows some treatment initiation to preserve justice, beneficence, and patient autonomy. Associated virtual follow-up via telemedicine also allows avoidance of nonmaleficence in this context.

For active-duty service members, dermatologic conditions are among the most common presenting concerns, comprising 15% to 75% of wartime outpatient visits.¹ In general, there are unique considerations when caring for active-duty service members, including meeting designated active-duty retention and hierarchical standards.² We present a hypothetical case: An active-duty military patient presents to a new dermatologist for cosmetic enhancement of facial skin dyspigmentation. The patient will be leaving soon for deployment and will not be able to follow up for 9 months. How should the dermatologist treat a patient who cannot follow up for so long?

The therapeutic modalities offered can be impacted by forthcoming deployments³ that may result in delayed time to administer repeat treatments or follow-up. The patient may have high expectations for a single appointment for a condition that requires prolonged treatment courses. Because there often is no reliable mechanism for patients to obtain refills during deployment, any medications prescribed would need to be provided in advance for the entire deployment duration, which often is 6 to 9 months. Additionally, treatment monitoring or modifications are severely limited, especially in the context of treatment nonresponse or adverse reactions. Considering the unique limitations of this patient population, both military and civilian physicians are faced with a need to maximize beneficence and autonomy while balancing nonmaleficence and justice.

One possible option is to decline to treat until the patient can follow up after returning from deployment. However, denying a request for an active treatable indication for which the patient desires treatment compromises patient autonomy and beneficence. Further, treatment should be provided to patients equitably to maintain justice. Although there may be a role for discussing active monitoring with nonintervention with the patient, denying treatment can negatively impact their physical and mental health and may be harmful. However, the patient should know and fully understand the risks and benefits of nonintervention with limited follow-up, including suboptimal outcomes or adverse events.

Another possibility for the management of this case may be conducting a one-time laser or light-based therapy or a one-time superficial- to medium-depth chemical peel before the patient leaves on deployment. Often, a series of laser- or light-based treatments is required to maximize outcomes for dyspigmentation. Without follow-up and with possible deployment to an environment with high UV exposure, the patient may experience disease exacerbation or other adverse effects. Treatment of those adverse effects may be delayed, as further intervention is not possible during deployment. Lower initial laser settings may be safer but may not be highly effective initially. More rigorous treatment upon return from deployment may be considered. Similar to laser therapies, chemical peels usually require several treatments for optimal outcomes. Without follow-up and with potential deployment to remote environments, there is a risk for adverse events that outweighs the minimal benefit of a single treatment. Therefore, either intervention may violate the principle of nonmaleficence.

A more reasonable approach may be initiating topical therapy and following up via telemedicine evaluation. Topical therapy often is the least-invasive approach and carries a reduced risk for adverse effects. Triple-combination therapy with topical retinoids, hydroquinone, and topical steroids is a common first-line approach.⁴ Because this approach is patient dependent, therapy can be more easily modulated or halted in the context of undesired results. Additionally, if internet connectivity is available, an asynchronous telemedicine approach could be utilized during deployment to monitor and advise changes as necessary, provided the regulatory framework allows for it.⁵

Although there is no uniformly correct approach in a scenario of limited patient follow-up, the last solution may be most ethically favorable: to begin therapy with milder and safer therapies (topical) and defer higher-intensity regimens until the patient returns from deployment. This allows some treatment initiation to preserve justice, beneficence, and patient autonomy. Associated virtual follow-up via telemedicine also allows avoidance of nonmaleficence in this context.

This patient showed no evidence of recurrence in the scar where the melanoma was excised, and had no enlarged lymph nodes on palpation. His complete blood count and liver function tests were normal. A positron emission tomography (PET) scan was ordered by Dr. Nasser that revealed hypermetabolic right paratracheal, right hilar, and subcarinal lymph nodes, highly suspicious for malignant lymph nodes. The patient was referred to oncology for metastatic melanoma treatment and has been doing well on ipilimumab and nivolumab.

166695_eyebrow_web.jpg

Vitiligo is an autoimmune condition characterized by the progressive destruction of melanocytes resulting in hypopigmentation or depigmentation of the skin. Vitiligo has been associated with cutaneous melanoma. Patients with melanoma can present with hypopigmentation around the primary lesion and/or bilateral symmetrical lesions similar to vitiligo. Melanoma-associated leukoderma occurs in a portion of patients with melanoma and is correlated with a favorable prognosis. Additionally, leukoderma has been described as a side effect of melanoma treatment itself. However, cases such as this one have also been reported of vitiligo-like depigmentation presenting prior to the diagnosis of metastatic melanoma.

Melanoma, like vitiligo, is considered highly immunogenic, and cytotoxic T lymphocytes (CTLs) can recognize antigens in melanoma. Furthermore, studies have shown a vitiligo-like halo around melanoma tumors, likely caused by T-cell recruitment, and this may lead to tumor destruction, but rarely total clearance. It seems that the CTL infiltrate in both diseases is similar, but regulatory T cells are decreased in vitiligo, whereas they are present in melanomas and may contribute to the immunosuppressive tumor microenvironment found at the margin of these lesions.

Leukoderma is also associated with melanoma immunotherapy which may be described as drug-induced leukoderma. Additionally, the frequency of recognition of melanoma cells by CTLs leading to hypopigmentation appears to be higher in those with metastatic disease. High immune infiltrate with CTLs and interferon-gamma (IFN-gamma) expression by type 1 T helper cells is associated with favorable prognosis. Immunotherapy with checkpoint inhibitors has shown promise in treatment augmentation for melanoma, but not all patients fully respond to therapy. Nonetheless, development of leukoderma with these treatments has been significantly associated with good therapeutic response. Depigmentation of hair and retinal epithelium has also been reported. However, drug-induced leukoderma and vitiligo seem to have clinical and biological differences, including family history of disease and serum chemokine levels. Vaccines are in production to aid in the treatment of melanoma, but researchers must first identify the appropriate antigen(s) to include.

BiluMartin_Donna_FLORIDA_web.jpg

Conversely, vitiligo-like depigmentation has been reported as a harbinger of metastatic melanoma. Patients with previous excision of primary melanoma have presented months or years later with depigmentation and, upon further evaluation, have been diagnosed with metastatic melanoma. The prevalence of depigmentation in melanoma patients is about 3%-6%, and is estimated to be 7-10 times more common in those with melanoma than in the general population. In most cases, hypopigmentation follows the diagnosis of melanoma, with an average of 4.8 years after the initial diagnosis and 1-2 years after lymph node or distant metastases. It is unclear whether hypopigmentation occurs before or after the growth of metastatic lesions, but this clinical finding in a patient with previous melanoma may serve as an important clue to conduct further investigation for metastasis.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Natalie Y. Nasser, MD, Kaiser Permanente Riverside Medical Center; Riverside, California. The column was edited by Donna Bilu Martin, MD.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Cerci FB et al. Cutis. 2017 Jun;99(6):E1-E2. PMID: 28686764.

Cho EA et al. Ann Dermatol. 2009 May;21(2):178-181.

Failla CM et al. Int J Mol Sci. 2019 Nov 15;20(22):5731.

This patient showed no evidence of recurrence in the scar where the melanoma was excised, and had no enlarged lymph nodes on palpation. His complete blood count and liver function tests were normal. A positron emission tomography (PET) scan was ordered by Dr. Nasser that revealed hypermetabolic right paratracheal, right hilar, and subcarinal lymph nodes, highly suspicious for malignant lymph nodes. The patient was referred to oncology for metastatic melanoma treatment and has been doing well on ipilimumab and nivolumab.

166695_eyebrow_web.jpg

Vitiligo is an autoimmune condition characterized by the progressive destruction of melanocytes resulting in hypopigmentation or depigmentation of the skin. Vitiligo has been associated with cutaneous melanoma. Patients with melanoma can present with hypopigmentation around the primary lesion and/or bilateral symmetrical lesions similar to vitiligo. Melanoma-associated leukoderma occurs in a portion of patients with melanoma and is correlated with a favorable prognosis. Additionally, leukoderma has been described as a side effect of melanoma treatment itself. However, cases such as this one have also been reported of vitiligo-like depigmentation presenting prior to the diagnosis of metastatic melanoma.

Melanoma, like vitiligo, is considered highly immunogenic, and cytotoxic T lymphocytes (CTLs) can recognize antigens in melanoma. Furthermore, studies have shown a vitiligo-like halo around melanoma tumors, likely caused by T-cell recruitment, and this may lead to tumor destruction, but rarely total clearance. It seems that the CTL infiltrate in both diseases is similar, but regulatory T cells are decreased in vitiligo, whereas they are present in melanomas and may contribute to the immunosuppressive tumor microenvironment found at the margin of these lesions.

Leukoderma is also associated with melanoma immunotherapy which may be described as drug-induced leukoderma. Additionally, the frequency of recognition of melanoma cells by CTLs leading to hypopigmentation appears to be higher in those with metastatic disease. High immune infiltrate with CTLs and interferon-gamma (IFN-gamma) expression by type 1 T helper cells is associated with favorable prognosis. Immunotherapy with checkpoint inhibitors has shown promise in treatment augmentation for melanoma, but not all patients fully respond to therapy. Nonetheless, development of leukoderma with these treatments has been significantly associated with good therapeutic response. Depigmentation of hair and retinal epithelium has also been reported. However, drug-induced leukoderma and vitiligo seem to have clinical and biological differences, including family history of disease and serum chemokine levels. Vaccines are in production to aid in the treatment of melanoma, but researchers must first identify the appropriate antigen(s) to include.

BiluMartin_Donna_FLORIDA_web.jpg

Conversely, vitiligo-like depigmentation has been reported as a harbinger of metastatic melanoma. Patients with previous excision of primary melanoma have presented months or years later with depigmentation and, upon further evaluation, have been diagnosed with metastatic melanoma. The prevalence of depigmentation in melanoma patients is about 3%-6%, and is estimated to be 7-10 times more common in those with melanoma than in the general population. In most cases, hypopigmentation follows the diagnosis of melanoma, with an average of 4.8 years after the initial diagnosis and 1-2 years after lymph node or distant metastases. It is unclear whether hypopigmentation occurs before or after the growth of metastatic lesions, but this clinical finding in a patient with previous melanoma may serve as an important clue to conduct further investigation for metastasis.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Natalie Y. Nasser, MD, Kaiser Permanente Riverside Medical Center; Riverside, California. The column was edited by Donna Bilu Martin, MD.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Cerci FB et al. Cutis. 2017 Jun;99(6):E1-E2. PMID: 28686764.

Cho EA et al. Ann Dermatol. 2009 May;21(2):178-181.

Failla CM et al. Int J Mol Sci. 2019 Nov 15;20(22):5731.

This patient showed no evidence of recurrence in the scar where the melanoma was excised, and had no enlarged lymph nodes on palpation. His complete blood count and liver function tests were normal. A positron emission tomography (PET) scan was ordered by Dr. Nasser that revealed hypermetabolic right paratracheal, right hilar, and subcarinal lymph nodes, highly suspicious for malignant lymph nodes. The patient was referred to oncology for metastatic melanoma treatment and has been doing well on ipilimumab and nivolumab.

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Vitiligo is an autoimmune condition characterized by the progressive destruction of melanocytes resulting in hypopigmentation or depigmentation of the skin. Vitiligo has been associated with cutaneous melanoma. Patients with melanoma can present with hypopigmentation around the primary lesion and/or bilateral symmetrical lesions similar to vitiligo. Melanoma-associated leukoderma occurs in a portion of patients with melanoma and is correlated with a favorable prognosis. Additionally, leukoderma has been described as a side effect of melanoma treatment itself. However, cases such as this one have also been reported of vitiligo-like depigmentation presenting prior to the diagnosis of metastatic melanoma.

Melanoma, like vitiligo, is considered highly immunogenic, and cytotoxic T lymphocytes (CTLs) can recognize antigens in melanoma. Furthermore, studies have shown a vitiligo-like halo around melanoma tumors, likely caused by T-cell recruitment, and this may lead to tumor destruction, but rarely total clearance. It seems that the CTL infiltrate in both diseases is similar, but regulatory T cells are decreased in vitiligo, whereas they are present in melanomas and may contribute to the immunosuppressive tumor microenvironment found at the margin of these lesions.

Leukoderma is also associated with melanoma immunotherapy which may be described as drug-induced leukoderma. Additionally, the frequency of recognition of melanoma cells by CTLs leading to hypopigmentation appears to be higher in those with metastatic disease. High immune infiltrate with CTLs and interferon-gamma (IFN-gamma) expression by type 1 T helper cells is associated with favorable prognosis. Immunotherapy with checkpoint inhibitors has shown promise in treatment augmentation for melanoma, but not all patients fully respond to therapy. Nonetheless, development of leukoderma with these treatments has been significantly associated with good therapeutic response. Depigmentation of hair and retinal epithelium has also been reported. However, drug-induced leukoderma and vitiligo seem to have clinical and biological differences, including family history of disease and serum chemokine levels. Vaccines are in production to aid in the treatment of melanoma, but researchers must first identify the appropriate antigen(s) to include.

BiluMartin_Donna_FLORIDA_web.jpg

Conversely, vitiligo-like depigmentation has been reported as a harbinger of metastatic melanoma. Patients with previous excision of primary melanoma have presented months or years later with depigmentation and, upon further evaluation, have been diagnosed with metastatic melanoma. The prevalence of depigmentation in melanoma patients is about 3%-6%, and is estimated to be 7-10 times more common in those with melanoma than in the general population. In most cases, hypopigmentation follows the diagnosis of melanoma, with an average of 4.8 years after the initial diagnosis and 1-2 years after lymph node or distant metastases. It is unclear whether hypopigmentation occurs before or after the growth of metastatic lesions, but this clinical finding in a patient with previous melanoma may serve as an important clue to conduct further investigation for metastasis.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida, and Natalie Y. Nasser, MD, Kaiser Permanente Riverside Medical Center; Riverside, California. The column was edited by Donna Bilu Martin, MD.
 

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Florida More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to dermnews@mdedge.com.

References

Cerci FB et al. Cutis. 2017 Jun;99(6):E1-E2. PMID: 28686764.

Cho EA et al. Ann Dermatol. 2009 May;21(2):178-181.

Failla CM et al. Int J Mol Sci. 2019 Nov 15;20(22):5731.