Pigmentation Disorders

MADRID – Repigmentation in patients with vitiligo documented at 24 weeks continued to increase up to 1 year, in a randomized clinical trial of ruxolitinib cream for the treatment of vitiligo, Amit G. Pandya, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“I have been waiting 30 years for the first clinical trial for vitiligo. I know many of you dermatologists have been waiting for something for vitiligo, so I’m happy to present the results of the first randomized, placebo-controlled, double-blind, prospective trial of a topical agent in history for vitiligo,” said Dr. Pandya, who was clearly overjoyed to present the final results of the 52-week trial.

Ruxolitinib is a Janus kinase (JAK) 1 and 2 inhibitor. Topical ruxolitinib is under study for vitiligo because this chronic autoimmune disease targeting melanocytes is now recognized as being driven by signaling through the JAK 1/2 pathways.

The interim 24-week results of the phase 2 trial, presented earlier in the year at the World Congress of Dermatology in Milan, showed significant repigmentation with ruxolitinib cream. Dr. Pandya’s key message at EADV 2019 was that continued treatment out to a year brought substantial further improvement, and with a benign safety profile indistinguishable from vehicle control.

“We see a tremendous difference between 6 months and 1 year,” said Dr. Pandya, professor of dermatology at the University of Texas, Dallas. “For the first time, we dare talk about F-VASI75 [Facial Vitiligo Area Scoring Index] and F-VASI90 responses. We don’t usually tell patients that they can get 75% or 90% of their color back, and yet the week-52 F-VASI75 rate was 51.5%, up from 30.3% at week 24. And the F-VASI90 response was 33.3%, versus 12.1% at week 24.”

F-VASI is measured using the patient’s hand, which is typically equivalent to about 1% of body surface area. The mean baseline F-VASI was 1.26% in this study of 157 mostly middle-aged adults with longstanding vitiligo of a mean 14-year duration. That’s fairly severe vitiligo, since the total face occupies only about 4% of total body surface area.

The primary study endpoint was achievement of greater than 50% repigmentation in the F-VASI, or an F-VASI50 response. Under double-blind conditions at 52 weeks in the group randomized to 1.5% ruxolitinib cream twice a day, the highest dose used in the trial, the F-VASI50 rate was 57.6%. That’s up from a week-24 F-VASI50 of 45.5%, and a week-34 response rate of 51.5%.

A key secondary endpoint was T-VASI50, reflecting the total body response.

“Patients don’t just want their face to be better, they want their chest, arms, elbows, knees, hands, and feet to be better,” the dermatologist commented.

The week-52 T-VASI50 rate was 36.4%, up substantially from 12.1% at week 24. And that week-52 T-VASI50 rate probably underestimates the full potential benefit. That’s because a safety-based study rule prohibited patients from applying the cream to more than 20% of their body surface area. Adverse effects reported for oral ruxolitinib, approved for treatment of myelofibrosis, polycythemia vera, and acute graft-versus-host disease, include thrombocytopenia and anemia.

“In this early study we didn’t want to take a chance of systemic absorption with serum levels that would potentially affect the bone marrow,” Dr. Pandya explained.

He noted that 57 study participants had a baseline T-VASI greater than 20% of their body surface area and thus weren’t able to treat all of their disease. In the 100 patients with a vitiligo-involved total body surface area of 20% or less, however, the week-52 T-VASI50 reached 45%, compared with 20% at week 24.

Another prespecified secondary endpoint was the proportion of patients who received a facial physician’s global assessment of clear or almost clear. About 21% of patients in the highest-dose group achieved this milestone at 52 weeks.

A phase 3, randomized, controlled trial of ruxolitinib cream is ongoing and should be completed next year. Dr. Pandya reported receiving research funding from and serving as a consultant to Incyte, the study sponsor. He has similar financial relationships with Pfizer, Aclaris Therapeutics, and the Immune Tolerance Network.

[email protected]

MADRID – Repigmentation in patients with vitiligo documented at 24 weeks continued to increase up to 1 year, in a randomized clinical trial of ruxolitinib cream for the treatment of vitiligo, Amit G. Pandya, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“I have been waiting 30 years for the first clinical trial for vitiligo. I know many of you dermatologists have been waiting for something for vitiligo, so I’m happy to present the results of the first randomized, placebo-controlled, double-blind, prospective trial of a topical agent in history for vitiligo,” said Dr. Pandya, who was clearly overjoyed to present the final results of the 52-week trial.

Ruxolitinib is a Janus kinase (JAK) 1 and 2 inhibitor. Topical ruxolitinib is under study for vitiligo because this chronic autoimmune disease targeting melanocytes is now recognized as being driven by signaling through the JAK 1/2 pathways.

The interim 24-week results of the phase 2 trial, presented earlier in the year at the World Congress of Dermatology in Milan, showed significant repigmentation with ruxolitinib cream. Dr. Pandya’s key message at EADV 2019 was that continued treatment out to a year brought substantial further improvement, and with a benign safety profile indistinguishable from vehicle control.

“We see a tremendous difference between 6 months and 1 year,” said Dr. Pandya, professor of dermatology at the University of Texas, Dallas. “For the first time, we dare talk about F-VASI75 [Facial Vitiligo Area Scoring Index] and F-VASI90 responses. We don’t usually tell patients that they can get 75% or 90% of their color back, and yet the week-52 F-VASI75 rate was 51.5%, up from 30.3% at week 24. And the F-VASI90 response was 33.3%, versus 12.1% at week 24.”

F-VASI is measured using the patient’s hand, which is typically equivalent to about 1% of body surface area. The mean baseline F-VASI was 1.26% in this study of 157 mostly middle-aged adults with longstanding vitiligo of a mean 14-year duration. That’s fairly severe vitiligo, since the total face occupies only about 4% of total body surface area.

The primary study endpoint was achievement of greater than 50% repigmentation in the F-VASI, or an F-VASI50 response. Under double-blind conditions at 52 weeks in the group randomized to 1.5% ruxolitinib cream twice a day, the highest dose used in the trial, the F-VASI50 rate was 57.6%. That’s up from a week-24 F-VASI50 of 45.5%, and a week-34 response rate of 51.5%.

A key secondary endpoint was T-VASI50, reflecting the total body response.

“Patients don’t just want their face to be better, they want their chest, arms, elbows, knees, hands, and feet to be better,” the dermatologist commented.

The week-52 T-VASI50 rate was 36.4%, up substantially from 12.1% at week 24. And that week-52 T-VASI50 rate probably underestimates the full potential benefit. That’s because a safety-based study rule prohibited patients from applying the cream to more than 20% of their body surface area. Adverse effects reported for oral ruxolitinib, approved for treatment of myelofibrosis, polycythemia vera, and acute graft-versus-host disease, include thrombocytopenia and anemia.

“In this early study we didn’t want to take a chance of systemic absorption with serum levels that would potentially affect the bone marrow,” Dr. Pandya explained.

He noted that 57 study participants had a baseline T-VASI greater than 20% of their body surface area and thus weren’t able to treat all of their disease. In the 100 patients with a vitiligo-involved total body surface area of 20% or less, however, the week-52 T-VASI50 reached 45%, compared with 20% at week 24.

Another prespecified secondary endpoint was the proportion of patients who received a facial physician’s global assessment of clear or almost clear. About 21% of patients in the highest-dose group achieved this milestone at 52 weeks.

A phase 3, randomized, controlled trial of ruxolitinib cream is ongoing and should be completed next year. Dr. Pandya reported receiving research funding from and serving as a consultant to Incyte, the study sponsor. He has similar financial relationships with Pfizer, Aclaris Therapeutics, and the Immune Tolerance Network.

[email protected]

MADRID – Repigmentation in patients with vitiligo documented at 24 weeks continued to increase up to 1 year, in a randomized clinical trial of ruxolitinib cream for the treatment of vitiligo, Amit G. Pandya, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

“I have been waiting 30 years for the first clinical trial for vitiligo. I know many of you dermatologists have been waiting for something for vitiligo, so I’m happy to present the results of the first randomized, placebo-controlled, double-blind, prospective trial of a topical agent in history for vitiligo,” said Dr. Pandya, who was clearly overjoyed to present the final results of the 52-week trial.

Ruxolitinib is a Janus kinase (JAK) 1 and 2 inhibitor. Topical ruxolitinib is under study for vitiligo because this chronic autoimmune disease targeting melanocytes is now recognized as being driven by signaling through the JAK 1/2 pathways.

The interim 24-week results of the phase 2 trial, presented earlier in the year at the World Congress of Dermatology in Milan, showed significant repigmentation with ruxolitinib cream. Dr. Pandya’s key message at EADV 2019 was that continued treatment out to a year brought substantial further improvement, and with a benign safety profile indistinguishable from vehicle control.

“We see a tremendous difference between 6 months and 1 year,” said Dr. Pandya, professor of dermatology at the University of Texas, Dallas. “For the first time, we dare talk about F-VASI75 [Facial Vitiligo Area Scoring Index] and F-VASI90 responses. We don’t usually tell patients that they can get 75% or 90% of their color back, and yet the week-52 F-VASI75 rate was 51.5%, up from 30.3% at week 24. And the F-VASI90 response was 33.3%, versus 12.1% at week 24.”

F-VASI is measured using the patient’s hand, which is typically equivalent to about 1% of body surface area. The mean baseline F-VASI was 1.26% in this study of 157 mostly middle-aged adults with longstanding vitiligo of a mean 14-year duration. That’s fairly severe vitiligo, since the total face occupies only about 4% of total body surface area.

The primary study endpoint was achievement of greater than 50% repigmentation in the F-VASI, or an F-VASI50 response. Under double-blind conditions at 52 weeks in the group randomized to 1.5% ruxolitinib cream twice a day, the highest dose used in the trial, the F-VASI50 rate was 57.6%. That’s up from a week-24 F-VASI50 of 45.5%, and a week-34 response rate of 51.5%.

A key secondary endpoint was T-VASI50, reflecting the total body response.

“Patients don’t just want their face to be better, they want their chest, arms, elbows, knees, hands, and feet to be better,” the dermatologist commented.

The week-52 T-VASI50 rate was 36.4%, up substantially from 12.1% at week 24. And that week-52 T-VASI50 rate probably underestimates the full potential benefit. That’s because a safety-based study rule prohibited patients from applying the cream to more than 20% of their body surface area. Adverse effects reported for oral ruxolitinib, approved for treatment of myelofibrosis, polycythemia vera, and acute graft-versus-host disease, include thrombocytopenia and anemia.

“In this early study we didn’t want to take a chance of systemic absorption with serum levels that would potentially affect the bone marrow,” Dr. Pandya explained.

He noted that 57 study participants had a baseline T-VASI greater than 20% of their body surface area and thus weren’t able to treat all of their disease. In the 100 patients with a vitiligo-involved total body surface area of 20% or less, however, the week-52 T-VASI50 reached 45%, compared with 20% at week 24.

Another prespecified secondary endpoint was the proportion of patients who received a facial physician’s global assessment of clear or almost clear. About 21% of patients in the highest-dose group achieved this milestone at 52 weeks.

A phase 3, randomized, controlled trial of ruxolitinib cream is ongoing and should be completed next year. Dr. Pandya reported receiving research funding from and serving as a consultant to Incyte, the study sponsor. He has similar financial relationships with Pfizer, Aclaris Therapeutics, and the Immune Tolerance Network.

[email protected]

The Diagnosis: Bleomycin-Induced Flagellate Hyperpigmentation 

Histopathology of the affected skin demonstrated a slight increase in collagen bundle thickness, a chronic dermal perivascular inflammation, and associated pigment incontinence with dermal melanophages compared to unaffected skin (Figure). CD34 was faintly decreased, and dermal mucin increased in affected skin. This postinflammatory pigmentary alteration with subtle dermal sclerosis had persisted unchanged for more than 5 years after cessation of bleomycin therapy. Topical hydroquinone, physical blocker photoprotection, and laser modalities such as the Q-switched alexandrite (755-nm)/Nd:YAG (1064-nm) and ablative CO₂ resurfacing lasers were attempted with minimal overall impact on cosmesis. 

Bleomycin is a chemotherapeutic antibiotic that has been commonly used to treat Hodgkin lymphoma, germ cell tumors, and recurrent malignant pleural effusions.¹ The drug is inactivated in most tissues by the enzyme bleomycin hydrolase. This enzyme is not present in skin and lung tissue; as a result, these organs are the most common sites of bleomycin toxicity.¹ There are a variety of cutaneous effects associated with bleomycin including alopecia, hyperpigmentation, acral erythema, Raynaud phenomenon, and nail dystrophy.² Flagellate hyperpigmentation is a less common cutaneous toxicity. It is an unusual eruption that appears as whiplike linear streaks on the upper chest and back, limbs, and flanks.³ This cutaneous manifestation was once thought to be specific to bleomycin use; however, it also has been described in dermatomyositis, adult-onset Still disease, and after the ingestion of uncooked or undercooked shiitake mushrooms.⁴ Flagellate hyperpigmentation also was once thought to be dose dependent; however, it has been described in even very small doses.⁵ The eruption has been described as independent of the route of drug administration, appearing with intravenous, subcutaneous, and intramuscular bleomycin.² The association of bleomycin and flagellate hyperpigmentation has been reported since 1970; however, it is less commonly seen in clinical practice with the declining use of bleomycin.¹  

The exact mechanism for the hyperpigmentation is unknown. It has been proposed that the linear lesions are related to areas of pruritus and subsequent excoriations.¹ Dermatographism may be present to a limited extent, but it is unlikely to be a chief cause of flagellate hyperpigmentation, as linear streaks have been reported in the absence of trauma. It also has been proposed that bleomycin has a direct toxic effect on the melanocytes, which stimulates increased melanin secretion.² The hyperpigmentation also may be due to pigmentary incontinence secondary to inflammation.⁵ Histopathologic findings usually are varied and nonspecific.² There may be a deep perivascular lymphocytic infiltrate, which is nonspecific but can be associated with drug-induced pathology.⁴ Bleomycin also is used to induce localized scleroderma in mouse-model research⁶ and has been reported to cause localized scleroderma at an infusion site or after an intralesional injection,^7,8 which is not typically reported in flagellate erythema, but bleomycin's sclerosing effects may have played a role in the visible and sclerosing atrophy noted in our patient. Yamamoto et al⁹ reported a similar case of dermal sclerosis induced by bleomycin.  

Flagellate hyperpigmentation typically lasts for up to 6 months.³ Patients with cutaneous manifestations from bleomycin therapy usually respond to steroid therapy and discontinuation of the drug. Bleomycin re-exposure should be avoided, as it may cause extension or widespread recurrence of flagellate hyperpigmentation.³ Postinflammatory pigment alteration may persist in patients with darker skin types and in patients with dramatic inciting inflammation.  

Atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents with 1 or more sharply demarcated depressed patches. There is some debate whether it is a distinct entity or a primary atrophic morphea.¹⁰ Linear atrophoderma of Moulin has a similar morphology with hyperpigmented depressions and "cliff-drop" borders, but these lesions follow the lines of Blaschko.¹¹ Linear morphea initially can present as a linear erythematous streak but more commonly appears as a plaque-type morphea lesion that forms a scarlike band.¹² Erythema dyschromicum perstans is an ashy dermatosis characterized by gray or blue-brown macules seen in Fitzpatrick skin types III through V and typically is chronic and progressive.¹³  

The Diagnosis: Bleomycin-Induced Flagellate Hyperpigmentation 

Histopathology of the affected skin demonstrated a slight increase in collagen bundle thickness, a chronic dermal perivascular inflammation, and associated pigment incontinence with dermal melanophages compared to unaffected skin (Figure). CD34 was faintly decreased, and dermal mucin increased in affected skin. This postinflammatory pigmentary alteration with subtle dermal sclerosis had persisted unchanged for more than 5 years after cessation of bleomycin therapy. Topical hydroquinone, physical blocker photoprotection, and laser modalities such as the Q-switched alexandrite (755-nm)/Nd:YAG (1064-nm) and ablative CO₂ resurfacing lasers were attempted with minimal overall impact on cosmesis. 

Bleomycin is a chemotherapeutic antibiotic that has been commonly used to treat Hodgkin lymphoma, germ cell tumors, and recurrent malignant pleural effusions.¹ The drug is inactivated in most tissues by the enzyme bleomycin hydrolase. This enzyme is not present in skin and lung tissue; as a result, these organs are the most common sites of bleomycin toxicity.¹ There are a variety of cutaneous effects associated with bleomycin including alopecia, hyperpigmentation, acral erythema, Raynaud phenomenon, and nail dystrophy.² Flagellate hyperpigmentation is a less common cutaneous toxicity. It is an unusual eruption that appears as whiplike linear streaks on the upper chest and back, limbs, and flanks.³ This cutaneous manifestation was once thought to be specific to bleomycin use; however, it also has been described in dermatomyositis, adult-onset Still disease, and after the ingestion of uncooked or undercooked shiitake mushrooms.⁴ Flagellate hyperpigmentation also was once thought to be dose dependent; however, it has been described in even very small doses.⁵ The eruption has been described as independent of the route of drug administration, appearing with intravenous, subcutaneous, and intramuscular bleomycin.² The association of bleomycin and flagellate hyperpigmentation has been reported since 1970; however, it is less commonly seen in clinical practice with the declining use of bleomycin.¹  

The exact mechanism for the hyperpigmentation is unknown. It has been proposed that the linear lesions are related to areas of pruritus and subsequent excoriations.¹ Dermatographism may be present to a limited extent, but it is unlikely to be a chief cause of flagellate hyperpigmentation, as linear streaks have been reported in the absence of trauma. It also has been proposed that bleomycin has a direct toxic effect on the melanocytes, which stimulates increased melanin secretion.² The hyperpigmentation also may be due to pigmentary incontinence secondary to inflammation.⁵ Histopathologic findings usually are varied and nonspecific.² There may be a deep perivascular lymphocytic infiltrate, which is nonspecific but can be associated with drug-induced pathology.⁴ Bleomycin also is used to induce localized scleroderma in mouse-model research⁶ and has been reported to cause localized scleroderma at an infusion site or after an intralesional injection,^7,8 which is not typically reported in flagellate erythema, but bleomycin's sclerosing effects may have played a role in the visible and sclerosing atrophy noted in our patient. Yamamoto et al⁹ reported a similar case of dermal sclerosis induced by bleomycin.  

Flagellate hyperpigmentation typically lasts for up to 6 months.³ Patients with cutaneous manifestations from bleomycin therapy usually respond to steroid therapy and discontinuation of the drug. Bleomycin re-exposure should be avoided, as it may cause extension or widespread recurrence of flagellate hyperpigmentation.³ Postinflammatory pigment alteration may persist in patients with darker skin types and in patients with dramatic inciting inflammation.  

Atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents with 1 or more sharply demarcated depressed patches. There is some debate whether it is a distinct entity or a primary atrophic morphea.¹⁰ Linear atrophoderma of Moulin has a similar morphology with hyperpigmented depressions and "cliff-drop" borders, but these lesions follow the lines of Blaschko.¹¹ Linear morphea initially can present as a linear erythematous streak but more commonly appears as a plaque-type morphea lesion that forms a scarlike band.¹² Erythema dyschromicum perstans is an ashy dermatosis characterized by gray or blue-brown macules seen in Fitzpatrick skin types III through V and typically is chronic and progressive.¹³  

The Diagnosis: Bleomycin-Induced Flagellate Hyperpigmentation 

Histopathology of the affected skin demonstrated a slight increase in collagen bundle thickness, a chronic dermal perivascular inflammation, and associated pigment incontinence with dermal melanophages compared to unaffected skin (Figure). CD34 was faintly decreased, and dermal mucin increased in affected skin. This postinflammatory pigmentary alteration with subtle dermal sclerosis had persisted unchanged for more than 5 years after cessation of bleomycin therapy. Topical hydroquinone, physical blocker photoprotection, and laser modalities such as the Q-switched alexandrite (755-nm)/Nd:YAG (1064-nm) and ablative CO₂ resurfacing lasers were attempted with minimal overall impact on cosmesis. 

Bleomycin is a chemotherapeutic antibiotic that has been commonly used to treat Hodgkin lymphoma, germ cell tumors, and recurrent malignant pleural effusions.¹ The drug is inactivated in most tissues by the enzyme bleomycin hydrolase. This enzyme is not present in skin and lung tissue; as a result, these organs are the most common sites of bleomycin toxicity.¹ There are a variety of cutaneous effects associated with bleomycin including alopecia, hyperpigmentation, acral erythema, Raynaud phenomenon, and nail dystrophy.² Flagellate hyperpigmentation is a less common cutaneous toxicity. It is an unusual eruption that appears as whiplike linear streaks on the upper chest and back, limbs, and flanks.³ This cutaneous manifestation was once thought to be specific to bleomycin use; however, it also has been described in dermatomyositis, adult-onset Still disease, and after the ingestion of uncooked or undercooked shiitake mushrooms.⁴ Flagellate hyperpigmentation also was once thought to be dose dependent; however, it has been described in even very small doses.⁵ The eruption has been described as independent of the route of drug administration, appearing with intravenous, subcutaneous, and intramuscular bleomycin.² The association of bleomycin and flagellate hyperpigmentation has been reported since 1970; however, it is less commonly seen in clinical practice with the declining use of bleomycin.¹  

The exact mechanism for the hyperpigmentation is unknown. It has been proposed that the linear lesions are related to areas of pruritus and subsequent excoriations.¹ Dermatographism may be present to a limited extent, but it is unlikely to be a chief cause of flagellate hyperpigmentation, as linear streaks have been reported in the absence of trauma. It also has been proposed that bleomycin has a direct toxic effect on the melanocytes, which stimulates increased melanin secretion.² The hyperpigmentation also may be due to pigmentary incontinence secondary to inflammation.⁵ Histopathologic findings usually are varied and nonspecific.² There may be a deep perivascular lymphocytic infiltrate, which is nonspecific but can be associated with drug-induced pathology.⁴ Bleomycin also is used to induce localized scleroderma in mouse-model research⁶ and has been reported to cause localized scleroderma at an infusion site or after an intralesional injection,^7,8 which is not typically reported in flagellate erythema, but bleomycin's sclerosing effects may have played a role in the visible and sclerosing atrophy noted in our patient. Yamamoto et al⁹ reported a similar case of dermal sclerosis induced by bleomycin.  

Flagellate hyperpigmentation typically lasts for up to 6 months.³ Patients with cutaneous manifestations from bleomycin therapy usually respond to steroid therapy and discontinuation of the drug. Bleomycin re-exposure should be avoided, as it may cause extension or widespread recurrence of flagellate hyperpigmentation.³ Postinflammatory pigment alteration may persist in patients with darker skin types and in patients with dramatic inciting inflammation.  

Atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents with 1 or more sharply demarcated depressed patches. There is some debate whether it is a distinct entity or a primary atrophic morphea.¹⁰ Linear atrophoderma of Moulin has a similar morphology with hyperpigmented depressions and "cliff-drop" borders, but these lesions follow the lines of Blaschko.¹¹ Linear morphea initially can present as a linear erythematous streak but more commonly appears as a plaque-type morphea lesion that forms a scarlike band.¹² Erythema dyschromicum perstans is an ashy dermatosis characterized by gray or blue-brown macules seen in Fitzpatrick skin types III through V and typically is chronic and progressive.¹³  

To the Editor:

Hyperkeratosis lenticularis perstans (HLP), or Flegel disease, is a rare keratinization disorder characterized by asymptomatic, red-brown, 1- to 5-mm papules with irregular horny scales commonly seen on the dorsal feet and lower legs.¹ Hyperkeratosis lenticularis perstans is notorious for being difficult to treat. Various treatment options, including 5-fluorouracil, topical and oral retinoids, vitamin D₃ derivatives, psoralen plus UVA therapy, and dermabrasion, have been explored but none have proven to be consistently effective.

A woman in her 50s presented with an asymptomatic eruption on the legs and thighs that had been present for the last 20 years. She had been misdiagnosed by multiple outside providers with atopic dermatitis and was treated with topical steroids without considerable improvement. Upon initial presentation to our clinic , physical examination revealed a woman with Fitzpatrick skin type II with multiple hyperpigmented, red-brown, 2- to 6-mm papules on the extensor surfaces of the lower legs and upper thighs (Figure, A). A 3-mm punch biopsy of a lesion on the right upper thigh revealed hyperkeratosis and parakeratosis with basal layer degeneration and a perivascular lymphocytic infiltrate. The clinical and histopathologic findings were consistent with HLP.

The patient was started on treatment with 5-fluorouracil cream on the right leg and tazarotene cream 0.1% on the left leg to determine which agent would work best. After 9 weeks of treatment, slight improvement was observed on both legs, but the lesions were still erythematous (Figure, B). Treatment was continued, and after 14 weeks complete resolution of the lesions was noted on both legs; however, postinflammatory hyperpigmentation (PIH) was observed on the left leg, which had been treated with tazarotene (Figure, C). The patient was lost to follow-up prior to treatment of the PIH.

In PIH, there is either abnormal production or distribution of melanin pigment in the epidermis and/or dermis. Several mechanisms for PIH have been suggested. One potential mechanism is disruption of the basal cell layer due to dermal lymphocytic inflammation, causing melanin to be released and trapped by macrophages present in the dermal papillae. Another possible mechanism is epidermal hypermelanosis, in which the release and oxidation of arachidonic acid to prostaglandins and leukotrienes alters immune cells and melanocytes, causing an increase in melanin and increased transfer of melanin to keratinocytes in the surrounding epidermis.⁴

Treatment of PIH can be a difficult and prolonged process, especially when a dermal rather than epidermal melanosis is observed. Topical retinoids, topical hydroquinone, azelaic acid, corticosteroids, tretinoin cream, glycolic acid, and trichloroacetic acid have been shown to be effective in treating epidermal PIH. Tazarotene is a synthetic retinoid that has been proven to be an effective treatment of PIH³; however, in our patient the PIH progressed with treatment. One plausible explanation is that irritation caused by the medication led to further PIH.^2,5

It is uncommon for tazarotene to cause PIH. Hyperpigmentation is listed as an adverse effect observed during the postmarketing experience according to one manufacturer⁶ and the US Food and Drug Administration; however, details about prior incidents of hyperpigmentation have not been reported in the literature. Our case is unique because both treatments showed considerable improvement in HLP, but more PIH was observed on the tazarotene-treated leg.

To the Editor:

Hyperkeratosis lenticularis perstans (HLP), or Flegel disease, is a rare keratinization disorder characterized by asymptomatic, red-brown, 1- to 5-mm papules with irregular horny scales commonly seen on the dorsal feet and lower legs.¹ Hyperkeratosis lenticularis perstans is notorious for being difficult to treat. Various treatment options, including 5-fluorouracil, topical and oral retinoids, vitamin D₃ derivatives, psoralen plus UVA therapy, and dermabrasion, have been explored but none have proven to be consistently effective.

A woman in her 50s presented with an asymptomatic eruption on the legs and thighs that had been present for the last 20 years. She had been misdiagnosed by multiple outside providers with atopic dermatitis and was treated with topical steroids without considerable improvement. Upon initial presentation to our clinic , physical examination revealed a woman with Fitzpatrick skin type II with multiple hyperpigmented, red-brown, 2- to 6-mm papules on the extensor surfaces of the lower legs and upper thighs (Figure, A). A 3-mm punch biopsy of a lesion on the right upper thigh revealed hyperkeratosis and parakeratosis with basal layer degeneration and a perivascular lymphocytic infiltrate. The clinical and histopathologic findings were consistent with HLP.

The patient was started on treatment with 5-fluorouracil cream on the right leg and tazarotene cream 0.1% on the left leg to determine which agent would work best. After 9 weeks of treatment, slight improvement was observed on both legs, but the lesions were still erythematous (Figure, B). Treatment was continued, and after 14 weeks complete resolution of the lesions was noted on both legs; however, postinflammatory hyperpigmentation (PIH) was observed on the left leg, which had been treated with tazarotene (Figure, C). The patient was lost to follow-up prior to treatment of the PIH.

In PIH, there is either abnormal production or distribution of melanin pigment in the epidermis and/or dermis. Several mechanisms for PIH have been suggested. One potential mechanism is disruption of the basal cell layer due to dermal lymphocytic inflammation, causing melanin to be released and trapped by macrophages present in the dermal papillae. Another possible mechanism is epidermal hypermelanosis, in which the release and oxidation of arachidonic acid to prostaglandins and leukotrienes alters immune cells and melanocytes, causing an increase in melanin and increased transfer of melanin to keratinocytes in the surrounding epidermis.⁴

Treatment of PIH can be a difficult and prolonged process, especially when a dermal rather than epidermal melanosis is observed. Topical retinoids, topical hydroquinone, azelaic acid, corticosteroids, tretinoin cream, glycolic acid, and trichloroacetic acid have been shown to be effective in treating epidermal PIH. Tazarotene is a synthetic retinoid that has been proven to be an effective treatment of PIH³; however, in our patient the PIH progressed with treatment. One plausible explanation is that irritation caused by the medication led to further PIH.^2,5

It is uncommon for tazarotene to cause PIH. Hyperpigmentation is listed as an adverse effect observed during the postmarketing experience according to one manufacturer⁶ and the US Food and Drug Administration; however, details about prior incidents of hyperpigmentation have not been reported in the literature. Our case is unique because both treatments showed considerable improvement in HLP, but more PIH was observed on the tazarotene-treated leg.

To the Editor:

Hyperkeratosis lenticularis perstans (HLP), or Flegel disease, is a rare keratinization disorder characterized by asymptomatic, red-brown, 1- to 5-mm papules with irregular horny scales commonly seen on the dorsal feet and lower legs.¹ Hyperkeratosis lenticularis perstans is notorious for being difficult to treat. Various treatment options, including 5-fluorouracil, topical and oral retinoids, vitamin D₃ derivatives, psoralen plus UVA therapy, and dermabrasion, have been explored but none have proven to be consistently effective.

A woman in her 50s presented with an asymptomatic eruption on the legs and thighs that had been present for the last 20 years. She had been misdiagnosed by multiple outside providers with atopic dermatitis and was treated with topical steroids without considerable improvement. Upon initial presentation to our clinic , physical examination revealed a woman with Fitzpatrick skin type II with multiple hyperpigmented, red-brown, 2- to 6-mm papules on the extensor surfaces of the lower legs and upper thighs (Figure, A). A 3-mm punch biopsy of a lesion on the right upper thigh revealed hyperkeratosis and parakeratosis with basal layer degeneration and a perivascular lymphocytic infiltrate. The clinical and histopathologic findings were consistent with HLP.

The patient was started on treatment with 5-fluorouracil cream on the right leg and tazarotene cream 0.1% on the left leg to determine which agent would work best. After 9 weeks of treatment, slight improvement was observed on both legs, but the lesions were still erythematous (Figure, B). Treatment was continued, and after 14 weeks complete resolution of the lesions was noted on both legs; however, postinflammatory hyperpigmentation (PIH) was observed on the left leg, which had been treated with tazarotene (Figure, C). The patient was lost to follow-up prior to treatment of the PIH.

In PIH, there is either abnormal production or distribution of melanin pigment in the epidermis and/or dermis. Several mechanisms for PIH have been suggested. One potential mechanism is disruption of the basal cell layer due to dermal lymphocytic inflammation, causing melanin to be released and trapped by macrophages present in the dermal papillae. Another possible mechanism is epidermal hypermelanosis, in which the release and oxidation of arachidonic acid to prostaglandins and leukotrienes alters immune cells and melanocytes, causing an increase in melanin and increased transfer of melanin to keratinocytes in the surrounding epidermis.⁴

Treatment of PIH can be a difficult and prolonged process, especially when a dermal rather than epidermal melanosis is observed. Topical retinoids, topical hydroquinone, azelaic acid, corticosteroids, tretinoin cream, glycolic acid, and trichloroacetic acid have been shown to be effective in treating epidermal PIH. Tazarotene is a synthetic retinoid that has been proven to be an effective treatment of PIH³; however, in our patient the PIH progressed with treatment. One plausible explanation is that irritation caused by the medication led to further PIH.^2,5

It is uncommon for tazarotene to cause PIH. Hyperpigmentation is listed as an adverse effect observed during the postmarketing experience according to one manufacturer⁶ and the US Food and Drug Administration; however, details about prior incidents of hyperpigmentation have not been reported in the literature. Our case is unique because both treatments showed considerable improvement in HLP, but more PIH was observed on the tazarotene-treated leg.

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

The Diagnosis: Phacomatosis Cesioflammea  

Phacomatosis pigmentovascularis (PPV) encompasses a group of diseases that have a vascular nevus coupled with a pigmented nevus.¹ It is divided into 5 types: Type I is defined by the presence of a vascular malformation and epidermal nevus; type II by a vascular malformation and dermal melanosis with or without nevus anemicus; type III by a vascular malformation and nevus spilus with or without nevus anemicus; type IV by a vascular malformation, dermal melanosis, and nevus spilus with or without nevus anemicus; and type V as cutis marmorata telangiectatica congenita and dermal melanosis.¹  

Happle² proposed a descriptive classification system in 2005 that eliminated type I PPV because neither linear epidermal nevus nor Becker nevus are derived from pigmentary cells. An appended "a" denotes a subtype with isolated cutaneous findings, while "b" is associated with extracutaneous manifestations. Phacomatosis cesioflammea (type IIa/b) refers to blue-hued dermal melanocytosis and nevus flammeus. Phacomatosis spilorosea (type IIIa/b) refers to nevus spilus and rose-colored nevus flammeus. Phacomatosis cesiomarmorata (type Va/b) refers to dermal melanocytosis and cutis marmorata telangiectasia congenita. The last group (type IVa/b) is unclassifiable phacomatosis pigmentovascularis.^2,3  

Phacomatosis pigmentovascularis can be isolated to the skin or have associated extracutaneous findings, including ocular melanocytosis, seizures, or cognitive delay due to intracerebral vascular malformations. Patients also can develop limb and soft-tissue overgrowth.⁴ Phacomatosis pigmentovascularis has been found to be associated with mutations in the GNA11 and GNAQ genes. The theory behind PPV is twin spotting, resulting from a somatic mutation that leads to mosaic proliferation of 2 different cell lines.⁵ Phacomatosis pigmentovascularis can occur in isolation or can demonstrate the phenotype of Sturge-Weber syndrome or Klippel-Trenaunay syndrome. In Sturge-Weber syndrome, capillary malformations involve the face and underlying leptomeninges and cerebral cortex. Glaucoma and epilepsy also may be present. In Klippel-Trenaunay syndrome, capillary malformations involve the extremities (usually the legs) in association with varicose veins, soft-tissue hypertrophy, and skeletal overgrowth.^6-9 Tuberous sclerosis is an autosomal-dominant neurocutaneous disease in which patients develop hamartomas throughout the body, including the brain, skin, eyes, kidneys, heart, and lungs. Cutaneous manifestations include facial angiofibromas, ungual fibromas, hypomelanotic macules (ash leaf spots, confetti-like lesions), shagreen patches or connective tissue hamartomas, and fibrous plaques on the forehead. Tuberous sclerosis does not include vascular malformations.¹⁰  

Our patient was diagnosed with PPV type IIb, or phacomatosis cesioflammea. He had a large port-wine stain involving the right upper arm, back (Figure, A), and chest (Figure, B) with involvement of the bilateral conjunctivae (Figure, C). Our case is unique because our patient did not have dermal melanocytosis, only ocular melanocytosis.  

Once underlying neurologic and vascular anomalies have been ruled out, port-wine stains can be treated cosmetically. Pulsed dye laser is the gold standard therapy for capillary malformations, especially when instituted early. Follow-up with ophthalmology is advised to monitor ocular involvement. Shields et al¹¹ suggested dilated fundoscopy for patients with port-wine stains because choroidal pigmentation often is the only ocular change seen. Ocular melanocytosis can progress to pigmented glaucoma or choroidal melanoma. 

NEW YORK – Progress in understanding the sequence of events that drives vitiligo is not only behind highly promising new options for treatment, but also might be leading to a strategy that will prevent the inevitable relapse that occurs after treatment is stopped, according to an update at the American Academy of Dermatology summer meeting.

MarijaRadovic/Getty Images

Recently, trial results with a Janus kinase (JAK) pathway inhibitor have shown promise for treatment of vitiligo, but the ultimate fix for this recurring autoimmune disease might be elimination of resident-memory T cells, according to John Harris, MD, PhD, of the department of dermatology at the University of Massachusetts, Worcester.

In a murine vitiligo model, targeting interleukin-15, a cytokine thought to be essential for maintaining memory T cells, produced rapid and durable repigmentation without apparent adverse effects in a series of studies sufficiently promising that clinical trials are now being actively planned, Dr. Harris said. The ongoing work to eliminate resident-memory T cells to prevent relapse of vitiligo comes at the end of other recent advances that have provided major insights into the pathophysiology of vitiligo.

As outlined by Dr. Harris, vitiligo involves an autoimmune sequence that includes up-regulation of interferon-gamma, activation of the JAK signaling pathway, and mobilization of the cytokine CXCl10, all of which are part of the sequence of events culminating in activation of T cells that attack the melanocyte. The process can be stopped when any of these events are targeted, according to the experimental studies. These findings have already been translated into new drug development.

“There are now three ongoing clinical trials with JAK inhibitors. This is a tremendous advance in a disease for which there have been no clinical trials for decades,” Dr. Harris said. He cited highly positive data with the JAK inhibitor ruxolitinib, which were reported just weeks earlier at the World Congress of Dermatology, to confirm that this principle of intervention is viable.

However, relapse after discontinuation of ruxolitinib, like other treatments for vitiligo, is high. The observation that relapses typically occur in the exact spot where skin lesions occurred previously created the framework of a new potential wave of advances, according to Dr. Harris, director of the Vitiligo Clinic and Research Center at the University of Massachusetts, Worcester.

These advances involve progress in understanding the role of resident-memory T cells in driving autoimmune disease relapse.

In principle, memory-resident T cells are left behind in order to stimulate a rapid immune response in the event of a recurrence of a virus or another pathogen. According to work performed in animal models of vitiligo, they also appear to play a critical role in reactivation of this autoimmune disease, Dr. Harris said.

This role was not surprising, but the potential breakthrough in vitiligo surrounds evidence that the cytokine IL-15 is essential to the creation and maintenance of these memory cells. Evidence suggests vitiligo in animal models does not recur in the absence of IL-15, making it a potential target for treatment.

Initially, there was concern that inhibition of IL-15 would have off-target effects, but this concern has diminished with antibodies designed to inhibit IL-15 signaling in the animal model.

“It turns out that autoreactive cells are much more dependent on the cytokine than other T cells,” he said.

In the animal model, repigmentation has occurred more rapidly with anti-IL-15 therapy than with any other treatment tested to date, but more importantly, these mice then appear to be protected from vitiligo recurrence for extended periods, Dr. Harris noted.

Studies conducted with human tissue have provided strong evidence that the same mechanisms are in play. There are now several approaches to blocking IL-15 signaling, including a monoclonal antibody targeted at the IL-15 receptor, in development. This latter approach is now the focus of a company formed by Dr. Harris.

It is not yet clear if one approach to the inhibition of IL-15 will be superior to another, but Dr. Harris is highly optimistic that this will be a viable approach to control of vitiligo. Noting that good results have been achieved in experimental models by skin injections, thereby avoiding systemic exposure, he is also optimistic that this approach will be well tolerated.

“Based on these data, we are expecting clinical trials soon,” he said.

Dr. Harris reported serving as a consultant and/or investigator for multiple pharmaceutical companies including Aclaris Therapeutics, Celgene, EMD Serono, Genzyme, Incyte, and Janssen Biotech.

NEW YORK – Progress in understanding the sequence of events that drives vitiligo is not only behind highly promising new options for treatment, but also might be leading to a strategy that will prevent the inevitable relapse that occurs after treatment is stopped, according to an update at the American Academy of Dermatology summer meeting.

MarijaRadovic/Getty Images

Recently, trial results with a Janus kinase (JAK) pathway inhibitor have shown promise for treatment of vitiligo, but the ultimate fix for this recurring autoimmune disease might be elimination of resident-memory T cells, according to John Harris, MD, PhD, of the department of dermatology at the University of Massachusetts, Worcester.

In a murine vitiligo model, targeting interleukin-15, a cytokine thought to be essential for maintaining memory T cells, produced rapid and durable repigmentation without apparent adverse effects in a series of studies sufficiently promising that clinical trials are now being actively planned, Dr. Harris said. The ongoing work to eliminate resident-memory T cells to prevent relapse of vitiligo comes at the end of other recent advances that have provided major insights into the pathophysiology of vitiligo.

As outlined by Dr. Harris, vitiligo involves an autoimmune sequence that includes up-regulation of interferon-gamma, activation of the JAK signaling pathway, and mobilization of the cytokine CXCl10, all of which are part of the sequence of events culminating in activation of T cells that attack the melanocyte. The process can be stopped when any of these events are targeted, according to the experimental studies. These findings have already been translated into new drug development.

“There are now three ongoing clinical trials with JAK inhibitors. This is a tremendous advance in a disease for which there have been no clinical trials for decades,” Dr. Harris said. He cited highly positive data with the JAK inhibitor ruxolitinib, which were reported just weeks earlier at the World Congress of Dermatology, to confirm that this principle of intervention is viable.

However, relapse after discontinuation of ruxolitinib, like other treatments for vitiligo, is high. The observation that relapses typically occur in the exact spot where skin lesions occurred previously created the framework of a new potential wave of advances, according to Dr. Harris, director of the Vitiligo Clinic and Research Center at the University of Massachusetts, Worcester.

These advances involve progress in understanding the role of resident-memory T cells in driving autoimmune disease relapse.

In principle, memory-resident T cells are left behind in order to stimulate a rapid immune response in the event of a recurrence of a virus or another pathogen. According to work performed in animal models of vitiligo, they also appear to play a critical role in reactivation of this autoimmune disease, Dr. Harris said.

This role was not surprising, but the potential breakthrough in vitiligo surrounds evidence that the cytokine IL-15 is essential to the creation and maintenance of these memory cells. Evidence suggests vitiligo in animal models does not recur in the absence of IL-15, making it a potential target for treatment.

Initially, there was concern that inhibition of IL-15 would have off-target effects, but this concern has diminished with antibodies designed to inhibit IL-15 signaling in the animal model.

“It turns out that autoreactive cells are much more dependent on the cytokine than other T cells,” he said.

In the animal model, repigmentation has occurred more rapidly with anti-IL-15 therapy than with any other treatment tested to date, but more importantly, these mice then appear to be protected from vitiligo recurrence for extended periods, Dr. Harris noted.

Studies conducted with human tissue have provided strong evidence that the same mechanisms are in play. There are now several approaches to blocking IL-15 signaling, including a monoclonal antibody targeted at the IL-15 receptor, in development. This latter approach is now the focus of a company formed by Dr. Harris.

It is not yet clear if one approach to the inhibition of IL-15 will be superior to another, but Dr. Harris is highly optimistic that this will be a viable approach to control of vitiligo. Noting that good results have been achieved in experimental models by skin injections, thereby avoiding systemic exposure, he is also optimistic that this approach will be well tolerated.

“Based on these data, we are expecting clinical trials soon,” he said.

Dr. Harris reported serving as a consultant and/or investigator for multiple pharmaceutical companies including Aclaris Therapeutics, Celgene, EMD Serono, Genzyme, Incyte, and Janssen Biotech.

NEW YORK – Progress in understanding the sequence of events that drives vitiligo is not only behind highly promising new options for treatment, but also might be leading to a strategy that will prevent the inevitable relapse that occurs after treatment is stopped, according to an update at the American Academy of Dermatology summer meeting.

MarijaRadovic/Getty Images

Recently, trial results with a Janus kinase (JAK) pathway inhibitor have shown promise for treatment of vitiligo, but the ultimate fix for this recurring autoimmune disease might be elimination of resident-memory T cells, according to John Harris, MD, PhD, of the department of dermatology at the University of Massachusetts, Worcester.

In a murine vitiligo model, targeting interleukin-15, a cytokine thought to be essential for maintaining memory T cells, produced rapid and durable repigmentation without apparent adverse effects in a series of studies sufficiently promising that clinical trials are now being actively planned, Dr. Harris said. The ongoing work to eliminate resident-memory T cells to prevent relapse of vitiligo comes at the end of other recent advances that have provided major insights into the pathophysiology of vitiligo.

As outlined by Dr. Harris, vitiligo involves an autoimmune sequence that includes up-regulation of interferon-gamma, activation of the JAK signaling pathway, and mobilization of the cytokine CXCl10, all of which are part of the sequence of events culminating in activation of T cells that attack the melanocyte. The process can be stopped when any of these events are targeted, according to the experimental studies. These findings have already been translated into new drug development.

“There are now three ongoing clinical trials with JAK inhibitors. This is a tremendous advance in a disease for which there have been no clinical trials for decades,” Dr. Harris said. He cited highly positive data with the JAK inhibitor ruxolitinib, which were reported just weeks earlier at the World Congress of Dermatology, to confirm that this principle of intervention is viable.

However, relapse after discontinuation of ruxolitinib, like other treatments for vitiligo, is high. The observation that relapses typically occur in the exact spot where skin lesions occurred previously created the framework of a new potential wave of advances, according to Dr. Harris, director of the Vitiligo Clinic and Research Center at the University of Massachusetts, Worcester.

These advances involve progress in understanding the role of resident-memory T cells in driving autoimmune disease relapse.

In principle, memory-resident T cells are left behind in order to stimulate a rapid immune response in the event of a recurrence of a virus or another pathogen. According to work performed in animal models of vitiligo, they also appear to play a critical role in reactivation of this autoimmune disease, Dr. Harris said.

This role was not surprising, but the potential breakthrough in vitiligo surrounds evidence that the cytokine IL-15 is essential to the creation and maintenance of these memory cells. Evidence suggests vitiligo in animal models does not recur in the absence of IL-15, making it a potential target for treatment.

Initially, there was concern that inhibition of IL-15 would have off-target effects, but this concern has diminished with antibodies designed to inhibit IL-15 signaling in the animal model.

“It turns out that autoreactive cells are much more dependent on the cytokine than other T cells,” he said.

In the animal model, repigmentation has occurred more rapidly with anti-IL-15 therapy than with any other treatment tested to date, but more importantly, these mice then appear to be protected from vitiligo recurrence for extended periods, Dr. Harris noted.

Studies conducted with human tissue have provided strong evidence that the same mechanisms are in play. There are now several approaches to blocking IL-15 signaling, including a monoclonal antibody targeted at the IL-15 receptor, in development. This latter approach is now the focus of a company formed by Dr. Harris.

It is not yet clear if one approach to the inhibition of IL-15 will be superior to another, but Dr. Harris is highly optimistic that this will be a viable approach to control of vitiligo. Noting that good results have been achieved in experimental models by skin injections, thereby avoiding systemic exposure, he is also optimistic that this approach will be well tolerated.

“Based on these data, we are expecting clinical trials soon,” he said.

Dr. Harris reported serving as a consultant and/or investigator for multiple pharmaceutical companies including Aclaris Therapeutics, Celgene, EMD Serono, Genzyme, Incyte, and Janssen Biotech.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Long, dark, and thick eyelashes have been a focal point of society’s perception of beauty for thousands of years,¹ and the use of makeup products such as mascaras, eyeliners, and eye shadows has further increased the perception of attractiveness of the eyes.² Many eyelash enhancement methods have been developed or in some instances have been serendipitously discovered. Bimatoprost ophthalmic solution 0.03% originally was developed as an eye drop that was approved by the US Food and Drug Association (FDA) in 2001 for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. An unexpected side effect of this product was eyelash hypertrichosis.^3,4 As a result, the FDA approved bimatoprost ophthalmic solution 0.03% as an eyelash solution with an eyelid applicator for treatment of eyelash hypotrichosis in 2008.⁵

Because all follicular development occurs during embryogenesis, the number of eyelash follicles does not increase over time.⁶ Bitmatoprost eyelash solution works by prolonging the anagen (growth) phase of the eyelashes and stimulating the transition from the telogen (dormant) phase to the anagen phase. It also has been shown to increase the hair bulb diameter of follicles undergoing the anagen phase, resulting in thicker eyelashes.⁷ Although many patients have enjoyed this unexpected indication, prostaglandin (PG) analogues such as bimatoprost and latanoprost have a well-documented history of ocular side effects when applied directly to the eye. The most common adverse reactions include eye pruritus, conjunctival hyperemia, and eyelid pigmentation.³ The product safety information indicates that eyelid pigmentation typically is reversible.^3,5 Iris pigmentation is perhaps the least desirable side effect of PG analogues and was first noted in latanoprost studies on primates.⁸ The underlying mechanism appears to be due to an increase in melanogenesis that results in an increase in melanin granules without concomitant proliferation of melanocytes, cellular atypia, or evidence of inflammatory reaction. Unfortunately, this pigmentation typically is permanent.^3,5,9

Studies have shown that iris hyperpigmentation can occur when bimatoprost eye drops are applied to the eyes for the treatment of glaucoma and ocular hypertension, but reports associated with bimatoprost eyelash solution are rare.^3,4,10 We report a case of iris hyperpigmentation following cosmetic use of bimatoprost eyelash solution.

An otherwise healthy 63-year-old woman presented to our clinic for an annual skin examination. She noted that she had worsening dark pigmentation of the bilateral irises. The patient did not have any personal or family history of melanoma or ocular nevi, and there were no associated symptoms of eye tearing, pruritus, burning, or discharge. No prior surgical procedures had been performed on or around the eyes, and the patient never used contact lenses. She had been intermittently using bimatoprost eyelash solution prescribed by an outside physician for approximately 3 years to enhance her eyelashes. Although she never applied the product directly into her eyes, she noted that she often was unmethodical in application of the product and that runoff from the product may have occasionally leaked into the eyes. Physical examination revealed bilateral blue irises with ink spot–like, grayish black patches encircling the bilateral pupils (Figure).

There have been several studies of iris hyperpigmentation with use of PG analogues in the treatment of glaucoma. In a phase 3 clinical trial of the safety and efficacy of latanoprost for treatment of ocular hypertension, it was noted that 24 (12%) of 198 patients experienced iris hyperpigmentation and that patients with heterogeneous pigmentation (ie, hazel irises and mixed coloring) were at an increased risk.¹¹ Other studies also have shown an increased risk of iris hyperpigmentation due to heterogeneous phenotype¹² as well as older age.¹³

Reports of bimatoprost eye drops used for treatment of glaucoma have shown a high incidence of iris hyperpigmentation with long-term use. A prospective study conducted in 2012 investigated the adverse events of bimatoprost eye drops in 52 Japanese patients with glaucoma or ocular hypertension. Clinical photographs of the irises, eyelids, and eyelashes were taken at baseline and after 6 months of treatment. It was noted that 50% (26/52) of participants experienced iris hyperpigmentation upon completion of treatment.¹⁰

In our patient, bimatoprost eyelash solution was applied to the top eyelid margins using an applicator; our patient did not use the eye drop formulation, which is directed for use in ocular hypertension or glaucoma. A PubMed search of articles indexed for MEDLINE using the terms bimatoprost and iris hyperpigmentation yielded no published peer-reviewed studies or case reports of iris hyperpigmentation caused by bimatoprost eyelash solution for treatment of eyelid hypotrichosis, which makes this case report novel. With that said, the package insert states iris hyperpigmentation as a side effect in the prescribing information for both a bimatoprost eye drop formulation used to treat ocular hypertension³ as well as a formulation for topical application on the eyelids/eyelashes.⁵ A 2014 retrospective review of long-term safety with bimatoprost eyelash solution for eyelash hypotrichosis reported 4 instances (0.7%) of documented adverse events after 12 months of use in 585 patients, including dry eye, eyelid erythema, ocular pruritus, and low ocular pressure. Iris hyperpigmentation was not reported.¹⁴

The method of bimatoprost application likely is a determining factor in the number of reported adverse events. Studies with similar treatment periods have demonstrated more adverse events associated with bimatoprost eye drops vs eyelash solution.^15,16 When bimatoprost is used in the eye drop formulation for treatment of glaucoma, iris hyperpigmentation has been estimated to occur in 1.5%⁴ to 50%⁹ of cases. To our knowledge, there are no documented cases when bimatoprost eyelash solution is applied with a dermal applicator for treatment of eyelash hypotrichosis.^15,17 These results may be explained using an ocular splash test. In one study using lissamine green dye, decreased delivery of bimatoprost eyelash solution with the dermal applicator was noted vs eye drop application. Additionally, it has been demonstrated that approximately 5% (based on weight) of a one-drop dose of bimatoprost eyelash solution applied to the dermal applicator is actually delivered to the patient.¹⁸ The rest of the solution remains on the applicator.

It is important that patients use bimatoprost eyelash solution as instructed in the prescribing information (eg, clean the face, remove makeup and contact lenses prior to applying the product). The eyelid should not be rinsed after application, which limits the possibility of the bimatoprost solution from contacting or pooling in the eye. One drop of bimatoprost eyelash solution should be applied to the applicator supplied by the manufacturer and distributed evenly along the skin of the upper eyelid margin at the base of the eyelashes. It is important to blot any excess solution runoff outside the upper eyelid margin.⁵ Of note, our patient admitted to not always doing this step, which may have contributed to her susceptibility to this rare side effect.

Prostaglandin analogues have been observed to cause iris hyperpigmentation when applied directly to the eye for use in the treatment of glaucoma.¹⁹ Theoretically, the same side-effect profile should apply in their use as a dermal application on the eyelids. For this reason, one manufacturer includes iris hyperpigmentation as an adverse side effect in the prescribing information.⁵ It is important for physicians who prescribe bimatoprost eyelash solution to inform patients of this rare yet possible side effect and to instruct patients on proper application to minimize hyperpigmentation.

Our literature review did not demonstrate previous cases of iris hyperpigmentation associated with bimatoprost eyelash solution. One study suggested that 2 patients experienced hypopigmentation; however, this was not clinically significant and was not consistent with the proposed iris pigmentation thought to be caused by bimatoprost eyelash solution.²⁰

Potential future applications and off-label uses of bimatoprost include treatment of eyelash hypotrichosis on the lower eyelid margin and eyebrow hypertrichosis, as well as androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring.²¹ Currently, investigational studies are looking at bimatoprost ophthalmic solution 0.03% for chemotherapy-induced eyelash hypotrichosis with positive results.²² In the future, bimatoprost may be used for other off-label and possibly FDA-approved uses.

To the Editor:

Erlotinib is a small-molecule selective tyrosine kinase inhibitor that functions by blocking the intracellular portion of the epidermal growth factor receptor (EGFR)^1,2; EGFR normally is expressed in the basal layer of the epidermis, sweat glands, and hair follicles, and is overexpressed in some cancers.^1,3 Normal activation of EGFR leads to signal transduction through the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell survival and proliferation.^4,5 Erlotinib-induced inhibition of EGFR prevents tyrosine kinase phosphorylation and aims to decrease cell proliferation in these tumors.

Erlotinib is indicated as once-daily oral monotherapy for the treatment of advanced-stage non–small cell lung cancer (NSCLCA) and in combination with gemcitabine for treatment of advanced-stage pancreatic cancer.¹ A number of cutaneous side effects have been reported, including acneform eruption, xerosis, paronychia, and pruritus.⁶ Other tyrosine kinase inhibitors, which also decrease signal transduction through the MAPK pathway, have some overlapping side effects; among these are vemurafenib, a selective BRAF inhibitor, and sorafenib, a multikinase inhibitor.^7,8

A 70-year-old man with NSCLCA presented with eruptive nevi and darkening of existing nevi 3 months after starting monotherapy with erlotinib. Physical examination demonstrated the simultaneous appearance of scattered acneform papules and pustules; diffuse xerosis; and numerous dark brown to black nevi on the trunk, arms, and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1).

A review of the patient’s treatment timeline revealed that all other chemotherapeutic medications had been discontinued a minimum of 5 weeks before starting erlotinib. A complete cutaneous examination performed in our office after completion of these chemotherapeutic agents and prior to initiation of erlotinib was unremarkable for abnormally dark or eruptive nevi.

Since starting erlotinib treatment, the patient underwent 10 biopsies of clinically suspicious dark nevi performed by a dermatologist in our office. Two of these were diagnosed as melanoma in situ and one as an atypical nevus. A temporal association of the darkening and eruptive nevi with erlotinib treatment was established; however, because erlotinib was essential to his NSCLCA treatment, he continued erlotinib with frequent complete cutaneous examinations.

A number of cutaneous side effects have been described during treatment with erlotinib, the most common being acneform eruption.⁶ The incidence and severity of acneform eruptions have been positively correlated to survival in patients with NSCLCA.^3,5,6 Other common side effects include xerosis, paronychia, and pruritus.^1,5,6 Less common side effects include periungual pyogenic granulomas and hair growth abnormalities.¹

Eruptive nevi previously were reported in a patient who was treated with erlotinib.¹ Other tyrosine kinase inhibitors that also decrease signal transduction through the MAPK pathway, including sorafenib and vemurafenib, have been reported to cause eruptive nevi. There are 7 reports of eruptive nevi with sorafenib and 5 reports with vemurafenib.^7-9 Development of nevi were noted within a few months of initiating treatment with these medications.⁷

A PubMed search of articles indexed for MEDLINE using the terms erlotinib and melanoma and erlotinib and nevi yielded no prior reports of darkening of existing nevi or the development of melanoma during treatment with erlotinib. However, vemurafenib has been reported to cause dysplastic nevi, melanomas, and darkening of existing nevi, in addition to eruptive nevi.^8-10 The side effects of vemurafenib have been ascribed to a paradoxical upregulation of MAPK in BRAF wild-type cells. This effect has been well documented and demonstrated in vivo.^8,10 Perhaps erlotinib has a similar potential to paradoxically upregulate the MAPK pathway, thus stimulating cellular proliferation and survival.

Another tyrosine kinase receptor, c-KIT, is found on the cell membrane of melanocytes along with EGFR.^11,12 The c-KIT receptor also activates the MAPK pathway and is critical to the development, migration, and survival of melanocytes.^11,13 Stimulation of the c-KIT tyrosine kinase receptor also can induce melanocyte proliferation and melanogenesis.¹¹ The c-KIT receptor is encoded by the KIT gene (KIT proto-oncogene receptor tyrosine kinase). Mutations in this gene are associated with melanocytic disorders. Inherited KIT mutation leading to c-KIT receptor deficiency is associated with piebaldism. Acquired activating KIT mutations increasing c-KIT expression are associated with acral and mucosal melanomas as well as melanomas in chronically sun-damaged skin.¹³

We hypothesized that erlotinib-induced inhibition of the MAPK pathway could lead to a reactive increase in expression of c-KIT and thus stimulate melanocyte proliferation and pigment production. Similar feedback upregulation of an MAPK pathway stimulating receptor during downstream MAPK inhibition has been demonstrated in colon adenocarcinoma; in this setting, BRAF inhibitors blocking the MAPK pathway leads to upregulation of EGFR.­¹⁴ In our patient, c-KIT immunostaining revealed a mild to moderate increase in intensity (ie, the darkness of the staining) in nevi and melanomas during treatment with erlotinib compared to nevi biopsied before erlotinib treatment (Figure 2). The increased intensity of c-KIT immunostaining was further confirmed via semiquantitative digital image analysis. Using this method, a darkened nevus biopsied during treatment with erlotinib demonstrated 43.16% of cells (N=31,451) had very strong c-KIT staining, while a nevus biopsied before treatment with erlotinib demonstrated only 3.32% of cells (N=7507) with very strong c-KIT staining. Increased expression of c-KIT, possibly reactive to downstream inhibition the MAPK pathway from erlotinib, could be implicated in our case of eruptive nevi. 

To the Editor:

Erlotinib is a small-molecule selective tyrosine kinase inhibitor that functions by blocking the intracellular portion of the epidermal growth factor receptor (EGFR)^1,2; EGFR normally is expressed in the basal layer of the epidermis, sweat glands, and hair follicles, and is overexpressed in some cancers.^1,3 Normal activation of EGFR leads to signal transduction through the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell survival and proliferation.^4,5 Erlotinib-induced inhibition of EGFR prevents tyrosine kinase phosphorylation and aims to decrease cell proliferation in these tumors.

Erlotinib is indicated as once-daily oral monotherapy for the treatment of advanced-stage non–small cell lung cancer (NSCLCA) and in combination with gemcitabine for treatment of advanced-stage pancreatic cancer.¹ A number of cutaneous side effects have been reported, including acneform eruption, xerosis, paronychia, and pruritus.⁶ Other tyrosine kinase inhibitors, which also decrease signal transduction through the MAPK pathway, have some overlapping side effects; among these are vemurafenib, a selective BRAF inhibitor, and sorafenib, a multikinase inhibitor.^7,8

A 70-year-old man with NSCLCA presented with eruptive nevi and darkening of existing nevi 3 months after starting monotherapy with erlotinib. Physical examination demonstrated the simultaneous appearance of scattered acneform papules and pustules; diffuse xerosis; and numerous dark brown to black nevi on the trunk, arms, and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1).

A review of the patient’s treatment timeline revealed that all other chemotherapeutic medications had been discontinued a minimum of 5 weeks before starting erlotinib. A complete cutaneous examination performed in our office after completion of these chemotherapeutic agents and prior to initiation of erlotinib was unremarkable for abnormally dark or eruptive nevi.

Since starting erlotinib treatment, the patient underwent 10 biopsies of clinically suspicious dark nevi performed by a dermatologist in our office. Two of these were diagnosed as melanoma in situ and one as an atypical nevus. A temporal association of the darkening and eruptive nevi with erlotinib treatment was established; however, because erlotinib was essential to his NSCLCA treatment, he continued erlotinib with frequent complete cutaneous examinations.

A number of cutaneous side effects have been described during treatment with erlotinib, the most common being acneform eruption.⁶ The incidence and severity of acneform eruptions have been positively correlated to survival in patients with NSCLCA.^3,5,6 Other common side effects include xerosis, paronychia, and pruritus.^1,5,6 Less common side effects include periungual pyogenic granulomas and hair growth abnormalities.¹

Eruptive nevi previously were reported in a patient who was treated with erlotinib.¹ Other tyrosine kinase inhibitors that also decrease signal transduction through the MAPK pathway, including sorafenib and vemurafenib, have been reported to cause eruptive nevi. There are 7 reports of eruptive nevi with sorafenib and 5 reports with vemurafenib.^7-9 Development of nevi were noted within a few months of initiating treatment with these medications.⁷

A PubMed search of articles indexed for MEDLINE using the terms erlotinib and melanoma and erlotinib and nevi yielded no prior reports of darkening of existing nevi or the development of melanoma during treatment with erlotinib. However, vemurafenib has been reported to cause dysplastic nevi, melanomas, and darkening of existing nevi, in addition to eruptive nevi.^8-10 The side effects of vemurafenib have been ascribed to a paradoxical upregulation of MAPK in BRAF wild-type cells. This effect has been well documented and demonstrated in vivo.^8,10 Perhaps erlotinib has a similar potential to paradoxically upregulate the MAPK pathway, thus stimulating cellular proliferation and survival.

Another tyrosine kinase receptor, c-KIT, is found on the cell membrane of melanocytes along with EGFR.^11,12 The c-KIT receptor also activates the MAPK pathway and is critical to the development, migration, and survival of melanocytes.^11,13 Stimulation of the c-KIT tyrosine kinase receptor also can induce melanocyte proliferation and melanogenesis.¹¹ The c-KIT receptor is encoded by the KIT gene (KIT proto-oncogene receptor tyrosine kinase). Mutations in this gene are associated with melanocytic disorders. Inherited KIT mutation leading to c-KIT receptor deficiency is associated with piebaldism. Acquired activating KIT mutations increasing c-KIT expression are associated with acral and mucosal melanomas as well as melanomas in chronically sun-damaged skin.¹³

We hypothesized that erlotinib-induced inhibition of the MAPK pathway could lead to a reactive increase in expression of c-KIT and thus stimulate melanocyte proliferation and pigment production. Similar feedback upregulation of an MAPK pathway stimulating receptor during downstream MAPK inhibition has been demonstrated in colon adenocarcinoma; in this setting, BRAF inhibitors blocking the MAPK pathway leads to upregulation of EGFR.­¹⁴ In our patient, c-KIT immunostaining revealed a mild to moderate increase in intensity (ie, the darkness of the staining) in nevi and melanomas during treatment with erlotinib compared to nevi biopsied before erlotinib treatment (Figure 2). The increased intensity of c-KIT immunostaining was further confirmed via semiquantitative digital image analysis. Using this method, a darkened nevus biopsied during treatment with erlotinib demonstrated 43.16% of cells (N=31,451) had very strong c-KIT staining, while a nevus biopsied before treatment with erlotinib demonstrated only 3.32% of cells (N=7507) with very strong c-KIT staining. Increased expression of c-KIT, possibly reactive to downstream inhibition the MAPK pathway from erlotinib, could be implicated in our case of eruptive nevi. 

To the Editor:

Erlotinib is a small-molecule selective tyrosine kinase inhibitor that functions by blocking the intracellular portion of the epidermal growth factor receptor (EGFR)^1,2; EGFR normally is expressed in the basal layer of the epidermis, sweat glands, and hair follicles, and is overexpressed in some cancers.^1,3 Normal activation of EGFR leads to signal transduction through the mitogen-activated protein kinase (MAPK) signaling pathway, which stimulates cell survival and proliferation.^4,5 Erlotinib-induced inhibition of EGFR prevents tyrosine kinase phosphorylation and aims to decrease cell proliferation in these tumors.

Erlotinib is indicated as once-daily oral monotherapy for the treatment of advanced-stage non–small cell lung cancer (NSCLCA) and in combination with gemcitabine for treatment of advanced-stage pancreatic cancer.¹ A number of cutaneous side effects have been reported, including acneform eruption, xerosis, paronychia, and pruritus.⁶ Other tyrosine kinase inhibitors, which also decrease signal transduction through the MAPK pathway, have some overlapping side effects; among these are vemurafenib, a selective BRAF inhibitor, and sorafenib, a multikinase inhibitor.^7,8

A 70-year-old man with NSCLCA presented with eruptive nevi and darkening of existing nevi 3 months after starting monotherapy with erlotinib. Physical examination demonstrated the simultaneous appearance of scattered acneform papules and pustules; diffuse xerosis; and numerous dark brown to black nevi on the trunk, arms, and legs. Compared to prior clinical photographs taken in our office, darkening of existing medium brown nevi was noted, and new nevi developed in areas where no prior nevi had been visible (Figure 1).

A review of the patient’s treatment timeline revealed that all other chemotherapeutic medications had been discontinued a minimum of 5 weeks before starting erlotinib. A complete cutaneous examination performed in our office after completion of these chemotherapeutic agents and prior to initiation of erlotinib was unremarkable for abnormally dark or eruptive nevi.

Since starting erlotinib treatment, the patient underwent 10 biopsies of clinically suspicious dark nevi performed by a dermatologist in our office. Two of these were diagnosed as melanoma in situ and one as an atypical nevus. A temporal association of the darkening and eruptive nevi with erlotinib treatment was established; however, because erlotinib was essential to his NSCLCA treatment, he continued erlotinib with frequent complete cutaneous examinations.

A number of cutaneous side effects have been described during treatment with erlotinib, the most common being acneform eruption.⁶ The incidence and severity of acneform eruptions have been positively correlated to survival in patients with NSCLCA.^3,5,6 Other common side effects include xerosis, paronychia, and pruritus.^1,5,6 Less common side effects include periungual pyogenic granulomas and hair growth abnormalities.¹

Eruptive nevi previously were reported in a patient who was treated with erlotinib.¹ Other tyrosine kinase inhibitors that also decrease signal transduction through the MAPK pathway, including sorafenib and vemurafenib, have been reported to cause eruptive nevi. There are 7 reports of eruptive nevi with sorafenib and 5 reports with vemurafenib.^7-9 Development of nevi were noted within a few months of initiating treatment with these medications.⁷

A PubMed search of articles indexed for MEDLINE using the terms erlotinib and melanoma and erlotinib and nevi yielded no prior reports of darkening of existing nevi or the development of melanoma during treatment with erlotinib. However, vemurafenib has been reported to cause dysplastic nevi, melanomas, and darkening of existing nevi, in addition to eruptive nevi.^8-10 The side effects of vemurafenib have been ascribed to a paradoxical upregulation of MAPK in BRAF wild-type cells. This effect has been well documented and demonstrated in vivo.^8,10 Perhaps erlotinib has a similar potential to paradoxically upregulate the MAPK pathway, thus stimulating cellular proliferation and survival.

Another tyrosine kinase receptor, c-KIT, is found on the cell membrane of melanocytes along with EGFR.^11,12 The c-KIT receptor also activates the MAPK pathway and is critical to the development, migration, and survival of melanocytes.^11,13 Stimulation of the c-KIT tyrosine kinase receptor also can induce melanocyte proliferation and melanogenesis.¹¹ The c-KIT receptor is encoded by the KIT gene (KIT proto-oncogene receptor tyrosine kinase). Mutations in this gene are associated with melanocytic disorders. Inherited KIT mutation leading to c-KIT receptor deficiency is associated with piebaldism. Acquired activating KIT mutations increasing c-KIT expression are associated with acral and mucosal melanomas as well as melanomas in chronically sun-damaged skin.¹³

We hypothesized that erlotinib-induced inhibition of the MAPK pathway could lead to a reactive increase in expression of c-KIT and thus stimulate melanocyte proliferation and pigment production. Similar feedback upregulation of an MAPK pathway stimulating receptor during downstream MAPK inhibition has been demonstrated in colon adenocarcinoma; in this setting, BRAF inhibitors blocking the MAPK pathway leads to upregulation of EGFR.­¹⁴ In our patient, c-KIT immunostaining revealed a mild to moderate increase in intensity (ie, the darkness of the staining) in nevi and melanomas during treatment with erlotinib compared to nevi biopsied before erlotinib treatment (Figure 2). The increased intensity of c-KIT immunostaining was further confirmed via semiquantitative digital image analysis. Using this method, a darkened nevus biopsied during treatment with erlotinib demonstrated 43.16% of cells (N=31,451) had very strong c-KIT staining, while a nevus biopsied before treatment with erlotinib demonstrated only 3.32% of cells (N=7507) with very strong c-KIT staining. Increased expression of c-KIT, possibly reactive to downstream inhibition the MAPK pathway from erlotinib, could be implicated in our case of eruptive nevi. 

MILAN – Targeting the Janus kinase (JAK) 1 and 2 pathways in vitiligo resulted in significant reduction of facial depigmentation after 24 weeks of treatment, in a phase 2b trial of topical ruxolitinib cream.

Kari Oakes/MDedge News

With all four doses of ruxolitinib in the cream formulation evaluated, significantly more patients with vitiligo had at least 50% facial repigmentation, compared with vehicle alone, said David Rosmarin, MD, speaking in a late-breaking abstracts session at the World Congress of Dermatology.

The highest response rate was seen with a higher dose: Among patients receiving ruxolitinib cream 1.5% once daily, 50% met the 50% clearing mark at 24 weeks, as did 45.5% of those with twice-daily 1.5% dosing of the 1.5% formulation. At 24 weeks, 3.1% of those receiving vehicle had 50% facial vitiligo resolution (P less than .0001, compared with vehicle for both doses).

Vitiligo affects about 3,000,000 people in the United States, and it is a plausible treatment target for the JAK inhibitor ruxolitinib, explained Dr. Rosmarin, a dermatologist at Tufts University, Boston. “Interferon-gamma, signaling through JAK1 and JAK2, is central to the pathogenesis of vitiligo,” he said. “Ruxolitinib is a potent inhibitor of JAK1 and JAK2, so it made sense to investigate it as a treatment for vitiligo.”

The 24-month randomized, double-blind, vehicle-controlled phase 2 study of ruxolitinib cream for vitiligo compared the vehicle to four different concentrations of ruxolitinib during the first phase of the study. For the first 24 weeks, patients were randomized to receive vehicle twice daily, or various doses of ruxolitinib ranging from 0.15% once daily to 1.5% twice daily.

At this point, the study’s primary endpoint was assessed, with investigators comparing the proportion of patients treated with ruxolitinib who had at least 50% improvement in facial repigmentation from baseline on the Facial Vitiligo Area Scoring Index (F-VASI50) compared with those who received vehicle. A secondary endpoint, also assessed at week 24, was the proportion of patients who were clear, or almost clear, of facial vitiligo; safety and tolerability were also assessed.

In addition to the F-VASI50 measure, Dr. Rosmarin and his coinvestigators also tracked 75% facial clearing (F-VASI75). Here, the 1.5% twice daily regimen topped the others, with 30% of those receiving that dose achieving F-VASI75, compared with almost 10%-17% of those on other doses.

Using another measure, More than one-third of patients using ruxolitinib (35.3%) had clear (no signs of vitiligo) or almost clear (only specks of depigmentation) facial skin at week 24, according to a clinician assessment tool. No patients on placebo had clear or almost clear facial skin at that point. “It is my hope that with continued use beyond week 24, more patients will meet this very stringent endpoint,” Dr. Rosmarin said.

The safety profile was good, with no serious treatment-related adverse events, and no application site reactions that reached clinical significance, although numerically more patients reported acne with ruxolitinib than with vehicle alone.


In the trial, patients aged 18-75 years with vitiligo were eligible if they had facial depigmentation that constituted at least half of their body surface area (BSA), as well as depigmentation of at least 3% of BSA on nonfacial areas. Patients were excluded if they had another dermatologic disease, infection, prior JAK inhibitor therapy, or recent use of biologic or experimental drugs, laser or light-based treatments, or immunomodulators. Of the 157 patients who were randomized, 18 patients (11.5%) had discontinued treatment by week 24, with 3 patients stopping for adverse events, 3 for protocol deviation or noncompliance, and 10 withdrawals. Two patients were lost to follow-up; all patients were included in analysis of the primary and secondary endpoints.

In the second year of the study, investigators rerandomized patients who had been receiving vehicle to an active arm of the study, and patients who had less than 25% improvement on a facial vitiligo scoring scale were rerandomized to one of the different doses. Twenty-eight weeks after rerandomization, all participants were given the opportunity to participate in a year-long open-label extension, receiving 1.5% ruxolitinib cream twice daily. Phototherapy was allowed in the extension arm, but not in the first year of the study.

Data beyond 24 weeks have not yet been reported, and the 2-year study plan acknowledged that “repigmentation takes a while,” Dr. Rosmarin said. He added that patients were allowed to use the study drug on body vitiligo as well, and many saw improvement there, although these results weren’t tracked in the study. “This isn’t a drug that’s meant just for the face,” he said.

Dr. Rosmarin and his coauthors reported financial arrangements with several pharmaceutical companies, including Incyte, which funded the study. An oral formulation of ruxolitinib (Jakafi), marketed by Incyte, was approved by the Food and Drug Administration in 2011, for myelofibrosis, and was recently approved for steroid-refractory acute graft-versus-host disease in adults and children aged 12 years and older.

[email protected]

MILAN – Targeting the Janus kinase (JAK) 1 and 2 pathways in vitiligo resulted in significant reduction of facial depigmentation after 24 weeks of treatment, in a phase 2b trial of topical ruxolitinib cream.

Kari Oakes/MDedge News

With all four doses of ruxolitinib in the cream formulation evaluated, significantly more patients with vitiligo had at least 50% facial repigmentation, compared with vehicle alone, said David Rosmarin, MD, speaking in a late-breaking abstracts session at the World Congress of Dermatology.

The highest response rate was seen with a higher dose: Among patients receiving ruxolitinib cream 1.5% once daily, 50% met the 50% clearing mark at 24 weeks, as did 45.5% of those with twice-daily 1.5% dosing of the 1.5% formulation. At 24 weeks, 3.1% of those receiving vehicle had 50% facial vitiligo resolution (P less than .0001, compared with vehicle for both doses).

Vitiligo affects about 3,000,000 people in the United States, and it is a plausible treatment target for the JAK inhibitor ruxolitinib, explained Dr. Rosmarin, a dermatologist at Tufts University, Boston. “Interferon-gamma, signaling through JAK1 and JAK2, is central to the pathogenesis of vitiligo,” he said. “Ruxolitinib is a potent inhibitor of JAK1 and JAK2, so it made sense to investigate it as a treatment for vitiligo.”

The 24-month randomized, double-blind, vehicle-controlled phase 2 study of ruxolitinib cream for vitiligo compared the vehicle to four different concentrations of ruxolitinib during the first phase of the study. For the first 24 weeks, patients were randomized to receive vehicle twice daily, or various doses of ruxolitinib ranging from 0.15% once daily to 1.5% twice daily.

At this point, the study’s primary endpoint was assessed, with investigators comparing the proportion of patients treated with ruxolitinib who had at least 50% improvement in facial repigmentation from baseline on the Facial Vitiligo Area Scoring Index (F-VASI50) compared with those who received vehicle. A secondary endpoint, also assessed at week 24, was the proportion of patients who were clear, or almost clear, of facial vitiligo; safety and tolerability were also assessed.

In addition to the F-VASI50 measure, Dr. Rosmarin and his coinvestigators also tracked 75% facial clearing (F-VASI75). Here, the 1.5% twice daily regimen topped the others, with 30% of those receiving that dose achieving F-VASI75, compared with almost 10%-17% of those on other doses.

Using another measure, More than one-third of patients using ruxolitinib (35.3%) had clear (no signs of vitiligo) or almost clear (only specks of depigmentation) facial skin at week 24, according to a clinician assessment tool. No patients on placebo had clear or almost clear facial skin at that point. “It is my hope that with continued use beyond week 24, more patients will meet this very stringent endpoint,” Dr. Rosmarin said.

The safety profile was good, with no serious treatment-related adverse events, and no application site reactions that reached clinical significance, although numerically more patients reported acne with ruxolitinib than with vehicle alone.


In the trial, patients aged 18-75 years with vitiligo were eligible if they had facial depigmentation that constituted at least half of their body surface area (BSA), as well as depigmentation of at least 3% of BSA on nonfacial areas. Patients were excluded if they had another dermatologic disease, infection, prior JAK inhibitor therapy, or recent use of biologic or experimental drugs, laser or light-based treatments, or immunomodulators. Of the 157 patients who were randomized, 18 patients (11.5%) had discontinued treatment by week 24, with 3 patients stopping for adverse events, 3 for protocol deviation or noncompliance, and 10 withdrawals. Two patients were lost to follow-up; all patients were included in analysis of the primary and secondary endpoints.

In the second year of the study, investigators rerandomized patients who had been receiving vehicle to an active arm of the study, and patients who had less than 25% improvement on a facial vitiligo scoring scale were rerandomized to one of the different doses. Twenty-eight weeks after rerandomization, all participants were given the opportunity to participate in a year-long open-label extension, receiving 1.5% ruxolitinib cream twice daily. Phototherapy was allowed in the extension arm, but not in the first year of the study.

Data beyond 24 weeks have not yet been reported, and the 2-year study plan acknowledged that “repigmentation takes a while,” Dr. Rosmarin said. He added that patients were allowed to use the study drug on body vitiligo as well, and many saw improvement there, although these results weren’t tracked in the study. “This isn’t a drug that’s meant just for the face,” he said.

Dr. Rosmarin and his coauthors reported financial arrangements with several pharmaceutical companies, including Incyte, which funded the study. An oral formulation of ruxolitinib (Jakafi), marketed by Incyte, was approved by the Food and Drug Administration in 2011, for myelofibrosis, and was recently approved for steroid-refractory acute graft-versus-host disease in adults and children aged 12 years and older.

[email protected]

MILAN – Targeting the Janus kinase (JAK) 1 and 2 pathways in vitiligo resulted in significant reduction of facial depigmentation after 24 weeks of treatment, in a phase 2b trial of topical ruxolitinib cream.

Kari Oakes/MDedge News

With all four doses of ruxolitinib in the cream formulation evaluated, significantly more patients with vitiligo had at least 50% facial repigmentation, compared with vehicle alone, said David Rosmarin, MD, speaking in a late-breaking abstracts session at the World Congress of Dermatology.

The highest response rate was seen with a higher dose: Among patients receiving ruxolitinib cream 1.5% once daily, 50% met the 50% clearing mark at 24 weeks, as did 45.5% of those with twice-daily 1.5% dosing of the 1.5% formulation. At 24 weeks, 3.1% of those receiving vehicle had 50% facial vitiligo resolution (P less than .0001, compared with vehicle for both doses).

Vitiligo affects about 3,000,000 people in the United States, and it is a plausible treatment target for the JAK inhibitor ruxolitinib, explained Dr. Rosmarin, a dermatologist at Tufts University, Boston. “Interferon-gamma, signaling through JAK1 and JAK2, is central to the pathogenesis of vitiligo,” he said. “Ruxolitinib is a potent inhibitor of JAK1 and JAK2, so it made sense to investigate it as a treatment for vitiligo.”

The 24-month randomized, double-blind, vehicle-controlled phase 2 study of ruxolitinib cream for vitiligo compared the vehicle to four different concentrations of ruxolitinib during the first phase of the study. For the first 24 weeks, patients were randomized to receive vehicle twice daily, or various doses of ruxolitinib ranging from 0.15% once daily to 1.5% twice daily.

At this point, the study’s primary endpoint was assessed, with investigators comparing the proportion of patients treated with ruxolitinib who had at least 50% improvement in facial repigmentation from baseline on the Facial Vitiligo Area Scoring Index (F-VASI50) compared with those who received vehicle. A secondary endpoint, also assessed at week 24, was the proportion of patients who were clear, or almost clear, of facial vitiligo; safety and tolerability were also assessed.

In addition to the F-VASI50 measure, Dr. Rosmarin and his coinvestigators also tracked 75% facial clearing (F-VASI75). Here, the 1.5% twice daily regimen topped the others, with 30% of those receiving that dose achieving F-VASI75, compared with almost 10%-17% of those on other doses.

Using another measure, More than one-third of patients using ruxolitinib (35.3%) had clear (no signs of vitiligo) or almost clear (only specks of depigmentation) facial skin at week 24, according to a clinician assessment tool. No patients on placebo had clear or almost clear facial skin at that point. “It is my hope that with continued use beyond week 24, more patients will meet this very stringent endpoint,” Dr. Rosmarin said.

The safety profile was good, with no serious treatment-related adverse events, and no application site reactions that reached clinical significance, although numerically more patients reported acne with ruxolitinib than with vehicle alone.


In the trial, patients aged 18-75 years with vitiligo were eligible if they had facial depigmentation that constituted at least half of their body surface area (BSA), as well as depigmentation of at least 3% of BSA on nonfacial areas. Patients were excluded if they had another dermatologic disease, infection, prior JAK inhibitor therapy, or recent use of biologic or experimental drugs, laser or light-based treatments, or immunomodulators. Of the 157 patients who were randomized, 18 patients (11.5%) had discontinued treatment by week 24, with 3 patients stopping for adverse events, 3 for protocol deviation or noncompliance, and 10 withdrawals. Two patients were lost to follow-up; all patients were included in analysis of the primary and secondary endpoints.

In the second year of the study, investigators rerandomized patients who had been receiving vehicle to an active arm of the study, and patients who had less than 25% improvement on a facial vitiligo scoring scale were rerandomized to one of the different doses. Twenty-eight weeks after rerandomization, all participants were given the opportunity to participate in a year-long open-label extension, receiving 1.5% ruxolitinib cream twice daily. Phototherapy was allowed in the extension arm, but not in the first year of the study.

Data beyond 24 weeks have not yet been reported, and the 2-year study plan acknowledged that “repigmentation takes a while,” Dr. Rosmarin said. He added that patients were allowed to use the study drug on body vitiligo as well, and many saw improvement there, although these results weren’t tracked in the study. “This isn’t a drug that’s meant just for the face,” he said.

Dr. Rosmarin and his coauthors reported financial arrangements with several pharmaceutical companies, including Incyte, which funded the study. An oral formulation of ruxolitinib (Jakafi), marketed by Incyte, was approved by the Food and Drug Administration in 2011, for myelofibrosis, and was recently approved for steroid-refractory acute graft-versus-host disease in adults and children aged 12 years and older.

[email protected]

MILAN – Subtle signs beyond depigmentation alone can guide management of vitiligo, Michelle Rodrigues, MBBS, said at the World Congress of Dermatology.

Kari Oakes/MDedge News

Signs of high disease activity can be visually observed and, when found, can compel urgent treatment, Dr. Rodrigues said. “If we identify and understand these [signs, they] can change our management plan, and the patient’s outcomes ... picking these up quickly, getting the best response you can, can help our patients tremendously.”

To assess clinical signs of severity in vitiligo, “use the tools that you have in your practice – your dermatoscope, your Wood’s lamp.”

Showing an image of the leg of a patient with vitiligo, Dr. Rodrigues said, “I know this patient’s vitiligo is very, very active. Why?” Clues come when there are areas of hypopigmentation at the rim of lesions, with depigmentation at the center. The presence of pigmentation, hypopigmentation, and depigmentation within the same lesion indicates high disease activity. This finding is the trichrome sign, also called the “blurry borders” sign in some regions, said Dr. Rodrigues, a dermatologist in Melbourne and the founder of Chroma Dermatology, which specializes in treating pigment problems and diagnosing and managing skin conditions in patients with skin of color.

Next, Dr. Rodrigues said, look at hair growth within the vitiliginous area. “If you’re unable to see that clinically, it’s really important to get that dermatoscope onto the patient, and look within a patch, to see whether or not you can actually see white hairs or normal colored hairs,” she said. This finding will help to determine both treatment plan and prognosis, since leukotrichia is a marker of disease severity in vitiligo.

Be alert to Koebnerization, said Dr. Rodrigues; the presentation may be subtle. As an example, she shared an image of a patient with depigmented patches on the dorsum of each foot. It wasn’t until the patient removed her foot gear – rubber slide-type sandals with a single broad strap over the dorsum – that Dr. Rodrigues recognized that “there was clear Koebnerization from the constant friction as a result of the wearing of the shoes.

“This can also be seen when patients scratch themselves, as can be seen with the itch that vitiligo can sometimes cause,” she said.

She noted that about 10% of patients with vitiligo have pruritus as a prominent symptom. Here, she said, is where a Wood’s lamp can be helpful as well. “Sometimes we can’t appreciate the very, very subtle Koebnerization, especially in patients with lighter skin. Getting out that Wood’s lamp and looking at other areas of involvement is really important,” she said. Areas of high disease activity and signs of progression that might otherwise be missed will be more obvious under the ultraviolet light.

It’s important to look beyond the obvious patches of vitiligo to examine the surrounding skin. Searching for “confetti depigmentation” – tiny white dots of depigmentation scattered over the otherwise normally pigmented skin – also marks high disease activity. An area with these dots – each often only a few millimeters in diameter – is likely destined for rapid depigmentation unless aggressive treatment is started. “We know that without treating these areas there will be very, very rapid and aggressive depigmentation. And remember that in areas that have a paucity of hair follicles, it might be irreversible ... so recognizing these signs is absolutely critical.”

The final clue to highly active disease that’s likely to move quickly without intervention can be found at the border of a vitiligo lesion. Look for a fine rim of erythema and some scale, Dr. Rodrigues said. This sign is common, and often seen early in the disease course. When this erythematous region is biopsied, ”You’ll see an intense inflammatory response, with an interface dermatitis. Again, this tells us that the patient may have a poorer prognosis if we don’t commence treatment early on.”

As a final clinical tip, Dr. Rodrigues reminded attendees that when one sign of disease activity is seen, others are often present. A thorough clinical examination is needed to document aggressive disease. “Please make sure that if you find one, you’re looking for other signs of disease severity as well.”

Dr. Rodrigues reported that she had no disclosures relevant to her presentation.

[email protected]

MILAN – Subtle signs beyond depigmentation alone can guide management of vitiligo, Michelle Rodrigues, MBBS, said at the World Congress of Dermatology.

Kari Oakes/MDedge News

Signs of high disease activity can be visually observed and, when found, can compel urgent treatment, Dr. Rodrigues said. “If we identify and understand these [signs, they] can change our management plan, and the patient’s outcomes ... picking these up quickly, getting the best response you can, can help our patients tremendously.”

To assess clinical signs of severity in vitiligo, “use the tools that you have in your practice – your dermatoscope, your Wood’s lamp.”

Showing an image of the leg of a patient with vitiligo, Dr. Rodrigues said, “I know this patient’s vitiligo is very, very active. Why?” Clues come when there are areas of hypopigmentation at the rim of lesions, with depigmentation at the center. The presence of pigmentation, hypopigmentation, and depigmentation within the same lesion indicates high disease activity. This finding is the trichrome sign, also called the “blurry borders” sign in some regions, said Dr. Rodrigues, a dermatologist in Melbourne and the founder of Chroma Dermatology, which specializes in treating pigment problems and diagnosing and managing skin conditions in patients with skin of color.

Next, Dr. Rodrigues said, look at hair growth within the vitiliginous area. “If you’re unable to see that clinically, it’s really important to get that dermatoscope onto the patient, and look within a patch, to see whether or not you can actually see white hairs or normal colored hairs,” she said. This finding will help to determine both treatment plan and prognosis, since leukotrichia is a marker of disease severity in vitiligo.

Be alert to Koebnerization, said Dr. Rodrigues; the presentation may be subtle. As an example, she shared an image of a patient with depigmented patches on the dorsum of each foot. It wasn’t until the patient removed her foot gear – rubber slide-type sandals with a single broad strap over the dorsum – that Dr. Rodrigues recognized that “there was clear Koebnerization from the constant friction as a result of the wearing of the shoes.

“This can also be seen when patients scratch themselves, as can be seen with the itch that vitiligo can sometimes cause,” she said.

She noted that about 10% of patients with vitiligo have pruritus as a prominent symptom. Here, she said, is where a Wood’s lamp can be helpful as well. “Sometimes we can’t appreciate the very, very subtle Koebnerization, especially in patients with lighter skin. Getting out that Wood’s lamp and looking at other areas of involvement is really important,” she said. Areas of high disease activity and signs of progression that might otherwise be missed will be more obvious under the ultraviolet light.

It’s important to look beyond the obvious patches of vitiligo to examine the surrounding skin. Searching for “confetti depigmentation” – tiny white dots of depigmentation scattered over the otherwise normally pigmented skin – also marks high disease activity. An area with these dots – each often only a few millimeters in diameter – is likely destined for rapid depigmentation unless aggressive treatment is started. “We know that without treating these areas there will be very, very rapid and aggressive depigmentation. And remember that in areas that have a paucity of hair follicles, it might be irreversible ... so recognizing these signs is absolutely critical.”

The final clue to highly active disease that’s likely to move quickly without intervention can be found at the border of a vitiligo lesion. Look for a fine rim of erythema and some scale, Dr. Rodrigues said. This sign is common, and often seen early in the disease course. When this erythematous region is biopsied, ”You’ll see an intense inflammatory response, with an interface dermatitis. Again, this tells us that the patient may have a poorer prognosis if we don’t commence treatment early on.”

As a final clinical tip, Dr. Rodrigues reminded attendees that when one sign of disease activity is seen, others are often present. A thorough clinical examination is needed to document aggressive disease. “Please make sure that if you find one, you’re looking for other signs of disease severity as well.”

Dr. Rodrigues reported that she had no disclosures relevant to her presentation.

[email protected]

MILAN – Subtle signs beyond depigmentation alone can guide management of vitiligo, Michelle Rodrigues, MBBS, said at the World Congress of Dermatology.

Kari Oakes/MDedge News

Signs of high disease activity can be visually observed and, when found, can compel urgent treatment, Dr. Rodrigues said. “If we identify and understand these [signs, they] can change our management plan, and the patient’s outcomes ... picking these up quickly, getting the best response you can, can help our patients tremendously.”

To assess clinical signs of severity in vitiligo, “use the tools that you have in your practice – your dermatoscope, your Wood’s lamp.”

Showing an image of the leg of a patient with vitiligo, Dr. Rodrigues said, “I know this patient’s vitiligo is very, very active. Why?” Clues come when there are areas of hypopigmentation at the rim of lesions, with depigmentation at the center. The presence of pigmentation, hypopigmentation, and depigmentation within the same lesion indicates high disease activity. This finding is the trichrome sign, also called the “blurry borders” sign in some regions, said Dr. Rodrigues, a dermatologist in Melbourne and the founder of Chroma Dermatology, which specializes in treating pigment problems and diagnosing and managing skin conditions in patients with skin of color.

Next, Dr. Rodrigues said, look at hair growth within the vitiliginous area. “If you’re unable to see that clinically, it’s really important to get that dermatoscope onto the patient, and look within a patch, to see whether or not you can actually see white hairs or normal colored hairs,” she said. This finding will help to determine both treatment plan and prognosis, since leukotrichia is a marker of disease severity in vitiligo.

Be alert to Koebnerization, said Dr. Rodrigues; the presentation may be subtle. As an example, she shared an image of a patient with depigmented patches on the dorsum of each foot. It wasn’t until the patient removed her foot gear – rubber slide-type sandals with a single broad strap over the dorsum – that Dr. Rodrigues recognized that “there was clear Koebnerization from the constant friction as a result of the wearing of the shoes.

“This can also be seen when patients scratch themselves, as can be seen with the itch that vitiligo can sometimes cause,” she said.

She noted that about 10% of patients with vitiligo have pruritus as a prominent symptom. Here, she said, is where a Wood’s lamp can be helpful as well. “Sometimes we can’t appreciate the very, very subtle Koebnerization, especially in patients with lighter skin. Getting out that Wood’s lamp and looking at other areas of involvement is really important,” she said. Areas of high disease activity and signs of progression that might otherwise be missed will be more obvious under the ultraviolet light.

It’s important to look beyond the obvious patches of vitiligo to examine the surrounding skin. Searching for “confetti depigmentation” – tiny white dots of depigmentation scattered over the otherwise normally pigmented skin – also marks high disease activity. An area with these dots – each often only a few millimeters in diameter – is likely destined for rapid depigmentation unless aggressive treatment is started. “We know that without treating these areas there will be very, very rapid and aggressive depigmentation. And remember that in areas that have a paucity of hair follicles, it might be irreversible ... so recognizing these signs is absolutely critical.”

The final clue to highly active disease that’s likely to move quickly without intervention can be found at the border of a vitiligo lesion. Look for a fine rim of erythema and some scale, Dr. Rodrigues said. This sign is common, and often seen early in the disease course. When this erythematous region is biopsied, ”You’ll see an intense inflammatory response, with an interface dermatitis. Again, this tells us that the patient may have a poorer prognosis if we don’t commence treatment early on.”

As a final clinical tip, Dr. Rodrigues reminded attendees that when one sign of disease activity is seen, others are often present. A thorough clinical examination is needed to document aggressive disease. “Please make sure that if you find one, you’re looking for other signs of disease severity as well.”

Dr. Rodrigues reported that she had no disclosures relevant to her presentation.

[email protected]

Sequential therapy of oral propranolol then topical timolol for infantile hemangioma helped shorten duration of propranolol and maintain treatment success, according to a study published in Pediatric Dermatology.

hypotekyfidler/Getty Images

Diana B. Mannschreck, BSN, of Johns Hopkins University, Baltimore, and colleagues performed a retrospective chart review of 559 patients with infantile hemangioma seen in the dermatology clinic at Johns Hopkins between December 2008 and January 2018. Patients received any of five courses of treatment, including oral propranolol followed by topical timolol, propranolol only, and timolol only. Of the courses evaluated, propranolol followed by timolol had the shortest duration of propranolol therapy – a median of 2.2 months shorter than propranolol-only therapy (P = .0006). This sequential regimen also was associated with no reinitiations of propranolol therapy following tapering, whereas 13% of those receiving propranolol alone had to reinitiate it after tapering.

This is of interest because oral beta-blockers, including propranolol, have been associated with rare but serious adverse events, such as bronchospasm, hypotension, and hypoglycemia.

Limitations of the study include its retrospective and single-center nature. There was no funding or disclosure information given.

[email protected]

SOURCE: Mannschreck DB et al. Pediatr Dermatol. 2019 Apr 9. doi: 10.1111/pde.13816.

Sequential therapy of oral propranolol then topical timolol for infantile hemangioma helped shorten duration of propranolol and maintain treatment success, according to a study published in Pediatric Dermatology.

hypotekyfidler/Getty Images

Diana B. Mannschreck, BSN, of Johns Hopkins University, Baltimore, and colleagues performed a retrospective chart review of 559 patients with infantile hemangioma seen in the dermatology clinic at Johns Hopkins between December 2008 and January 2018. Patients received any of five courses of treatment, including oral propranolol followed by topical timolol, propranolol only, and timolol only. Of the courses evaluated, propranolol followed by timolol had the shortest duration of propranolol therapy – a median of 2.2 months shorter than propranolol-only therapy (P = .0006). This sequential regimen also was associated with no reinitiations of propranolol therapy following tapering, whereas 13% of those receiving propranolol alone had to reinitiate it after tapering.

This is of interest because oral beta-blockers, including propranolol, have been associated with rare but serious adverse events, such as bronchospasm, hypotension, and hypoglycemia.

Limitations of the study include its retrospective and single-center nature. There was no funding or disclosure information given.

[email protected]

SOURCE: Mannschreck DB et al. Pediatr Dermatol. 2019 Apr 9. doi: 10.1111/pde.13816.

Sequential therapy of oral propranolol then topical timolol for infantile hemangioma helped shorten duration of propranolol and maintain treatment success, according to a study published in Pediatric Dermatology.

hypotekyfidler/Getty Images

Diana B. Mannschreck, BSN, of Johns Hopkins University, Baltimore, and colleagues performed a retrospective chart review of 559 patients with infantile hemangioma seen in the dermatology clinic at Johns Hopkins between December 2008 and January 2018. Patients received any of five courses of treatment, including oral propranolol followed by topical timolol, propranolol only, and timolol only. Of the courses evaluated, propranolol followed by timolol had the shortest duration of propranolol therapy – a median of 2.2 months shorter than propranolol-only therapy (P = .0006). This sequential regimen also was associated with no reinitiations of propranolol therapy following tapering, whereas 13% of those receiving propranolol alone had to reinitiate it after tapering.

This is of interest because oral beta-blockers, including propranolol, have been associated with rare but serious adverse events, such as bronchospasm, hypotension, and hypoglycemia.

Limitations of the study include its retrospective and single-center nature. There was no funding or disclosure information given.

[email protected]

SOURCE: Mannschreck DB et al. Pediatr Dermatol. 2019 Apr 9. doi: 10.1111/pde.13816.