Pigmentation Disorders

To the Editor:

A 40-year-old white woman presented with a waxing and waning erythematous pruritic rash on the chest, back, and axillae of 3 years’ duration. The appearance of the rash coincided with an intentional weight loss of more than 100 lb, achieved through various diets, most recently a Paleolithic (paleo) diet that was high in protein; low in carbohydrates; and specifically restricted dairy, cereal grains, refined sugars, processed foods, white potatoes, salt, refined oils, and legumes.¹ The patient had been monitoring blood glucose and ketone levels. Prior to presentation, she received various treatments including clotrimazole cream and topical steroids with no improvement. 

On physical examination, there were scaly, pink-red, reticulated papules and plaques coexisting with tan reticulated patches that were symmetrically distributed on the central back, lateral and central chest (Figure 1A), breasts, and inframammary areas. During the most severe flare-up, the blood ketones measured 1 mmol/L. There was no relevant medical history. She was of Spanish and Italian descent.

Prurigo pigmentosa is a rare inflammatory dermatosis that was initially described in 1971 as “a peculiar pruriginous dermatosis with gross reticular pigmentation” by Nagashima et al.² Prurigo pigmentosa is most frequently diagnosed in Japan, and since its discovery, it has been reported in more than 300 cases worldwide.^2-4

Fewer than 50 non-Japanese cases have been reported, with the possibility of an additional ethnic predisposition among the Turkish and Sicilian populations, though only 6 cases have been reported in the United States.^3-6 Prurigo pigmentosa tends to occur in the spring and summer months and is most common among young females, with a mean age of 24 years. The typical lesions of PP are symmetrically distributed on the trunk with a tendency to localize on the upper back, nape of the neck, and intermammary and inframammary regions. Eruptions have been reported to occur on additional areas; however, mucus membranes are always spared.⁶

Individual lesions differ in appearance depending on the stage of presentation and are categorized as early, fully developed, resolving, and late lesions.⁶ Pruritic macules and papules are present early in the disease state and resolve into crusted and/or scaly papules followed by pigmented macules. Early lesions tend to be intensely pruritic with signs of excoriation, while resolving lesions lack symptoms. Lesions last approximately 1 week but tend to reappear at the site where they were previously present, which allows for lesions of different ages to coexist, appearing in a reticular arrangement with hyperpigmented mottling lasting from a few weeks to months.⁶

Just as the clinical picture transpires rapidly within 1 week, so do the histopathologic findings.⁶ Early lesions are categorized by a superficial perivascular and interstitial infiltrate of neutrophils, spongiosis, ballooning, and necrotic keratinocytes. These early lesions are present for less than 48 hours, and these histopathologic findings are diagnostic of PP. Within 2 days, lymphocytes predominate in the dermal infiltrate, and a patchy lichenoid aspect is established in the fully developed lesion along with reticular and vacuolar alterations. Late lesions show a parakeratotic and hyperpigmented epidermis with melanophages present in the papillary and reticular dermis. At this last stage, the histopathologic features of PP are indistinguishable from any other disease that results in postinflammatory hyperpigmentation, making diagnosis difficult.⁶

A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.^6-10

Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.^2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.^3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.^3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.^3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.^6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.

Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.¹¹ The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.¹¹ In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.¹¹

Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.^10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.^12,13 Teraki et al¹³ observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.^12,13

Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.¹⁴ Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.¹⁴ This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.

Middleton and Norris¹⁵ observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.

We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.

To the Editor:

A 40-year-old white woman presented with a waxing and waning erythematous pruritic rash on the chest, back, and axillae of 3 years’ duration. The appearance of the rash coincided with an intentional weight loss of more than 100 lb, achieved through various diets, most recently a Paleolithic (paleo) diet that was high in protein; low in carbohydrates; and specifically restricted dairy, cereal grains, refined sugars, processed foods, white potatoes, salt, refined oils, and legumes.¹ The patient had been monitoring blood glucose and ketone levels. Prior to presentation, she received various treatments including clotrimazole cream and topical steroids with no improvement. 

On physical examination, there were scaly, pink-red, reticulated papules and plaques coexisting with tan reticulated patches that were symmetrically distributed on the central back, lateral and central chest (Figure 1A), breasts, and inframammary areas. During the most severe flare-up, the blood ketones measured 1 mmol/L. There was no relevant medical history. She was of Spanish and Italian descent.

Prurigo pigmentosa is a rare inflammatory dermatosis that was initially described in 1971 as “a peculiar pruriginous dermatosis with gross reticular pigmentation” by Nagashima et al.² Prurigo pigmentosa is most frequently diagnosed in Japan, and since its discovery, it has been reported in more than 300 cases worldwide.^2-4

Fewer than 50 non-Japanese cases have been reported, with the possibility of an additional ethnic predisposition among the Turkish and Sicilian populations, though only 6 cases have been reported in the United States.^3-6 Prurigo pigmentosa tends to occur in the spring and summer months and is most common among young females, with a mean age of 24 years. The typical lesions of PP are symmetrically distributed on the trunk with a tendency to localize on the upper back, nape of the neck, and intermammary and inframammary regions. Eruptions have been reported to occur on additional areas; however, mucus membranes are always spared.⁶

Individual lesions differ in appearance depending on the stage of presentation and are categorized as early, fully developed, resolving, and late lesions.⁶ Pruritic macules and papules are present early in the disease state and resolve into crusted and/or scaly papules followed by pigmented macules. Early lesions tend to be intensely pruritic with signs of excoriation, while resolving lesions lack symptoms. Lesions last approximately 1 week but tend to reappear at the site where they were previously present, which allows for lesions of different ages to coexist, appearing in a reticular arrangement with hyperpigmented mottling lasting from a few weeks to months.⁶

Just as the clinical picture transpires rapidly within 1 week, so do the histopathologic findings.⁶ Early lesions are categorized by a superficial perivascular and interstitial infiltrate of neutrophils, spongiosis, ballooning, and necrotic keratinocytes. These early lesions are present for less than 48 hours, and these histopathologic findings are diagnostic of PP. Within 2 days, lymphocytes predominate in the dermal infiltrate, and a patchy lichenoid aspect is established in the fully developed lesion along with reticular and vacuolar alterations. Late lesions show a parakeratotic and hyperpigmented epidermis with melanophages present in the papillary and reticular dermis. At this last stage, the histopathologic features of PP are indistinguishable from any other disease that results in postinflammatory hyperpigmentation, making diagnosis difficult.⁶

A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.^6-10

Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.^2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.^3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.^3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.^3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.^6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.

Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.¹¹ The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.¹¹ In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.¹¹

Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.^10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.^12,13 Teraki et al¹³ observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.^12,13

Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.¹⁴ Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.¹⁴ This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.

Middleton and Norris¹⁵ observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.

We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.

To the Editor:

A 40-year-old white woman presented with a waxing and waning erythematous pruritic rash on the chest, back, and axillae of 3 years’ duration. The appearance of the rash coincided with an intentional weight loss of more than 100 lb, achieved through various diets, most recently a Paleolithic (paleo) diet that was high in protein; low in carbohydrates; and specifically restricted dairy, cereal grains, refined sugars, processed foods, white potatoes, salt, refined oils, and legumes.¹ The patient had been monitoring blood glucose and ketone levels. Prior to presentation, she received various treatments including clotrimazole cream and topical steroids with no improvement. 

On physical examination, there were scaly, pink-red, reticulated papules and plaques coexisting with tan reticulated patches that were symmetrically distributed on the central back, lateral and central chest (Figure 1A), breasts, and inframammary areas. During the most severe flare-up, the blood ketones measured 1 mmol/L. There was no relevant medical history. She was of Spanish and Italian descent.

Prurigo pigmentosa is a rare inflammatory dermatosis that was initially described in 1971 as “a peculiar pruriginous dermatosis with gross reticular pigmentation” by Nagashima et al.² Prurigo pigmentosa is most frequently diagnosed in Japan, and since its discovery, it has been reported in more than 300 cases worldwide.^2-4

Fewer than 50 non-Japanese cases have been reported, with the possibility of an additional ethnic predisposition among the Turkish and Sicilian populations, though only 6 cases have been reported in the United States.^3-6 Prurigo pigmentosa tends to occur in the spring and summer months and is most common among young females, with a mean age of 24 years. The typical lesions of PP are symmetrically distributed on the trunk with a tendency to localize on the upper back, nape of the neck, and intermammary and inframammary regions. Eruptions have been reported to occur on additional areas; however, mucus membranes are always spared.⁶

Individual lesions differ in appearance depending on the stage of presentation and are categorized as early, fully developed, resolving, and late lesions.⁶ Pruritic macules and papules are present early in the disease state and resolve into crusted and/or scaly papules followed by pigmented macules. Early lesions tend to be intensely pruritic with signs of excoriation, while resolving lesions lack symptoms. Lesions last approximately 1 week but tend to reappear at the site where they were previously present, which allows for lesions of different ages to coexist, appearing in a reticular arrangement with hyperpigmented mottling lasting from a few weeks to months.⁶

Just as the clinical picture transpires rapidly within 1 week, so do the histopathologic findings.⁶ Early lesions are categorized by a superficial perivascular and interstitial infiltrate of neutrophils, spongiosis, ballooning, and necrotic keratinocytes. These early lesions are present for less than 48 hours, and these histopathologic findings are diagnostic of PP. Within 2 days, lymphocytes predominate in the dermal infiltrate, and a patchy lichenoid aspect is established in the fully developed lesion along with reticular and vacuolar alterations. Late lesions show a parakeratotic and hyperpigmented epidermis with melanophages present in the papillary and reticular dermis. At this last stage, the histopathologic features of PP are indistinguishable from any other disease that results in postinflammatory hyperpigmentation, making diagnosis difficult.⁶

A variety of therapeutic options are used in the treatment of PP, with the most effective agents being oral antibiotics including dapsone, minocycline, and doxycycline, all of which limit the local tissue inflammatory response and cytotoxic effects. Topical and systemic antihistamines as well as corticosteroids are ineffective and have not been shown to prevent the postinflammatory reticular pigmentation.^6-10

Various underlying factors have been associated with PP, including friction, heat, sunlight, sweating, allergic contact sensitization, and ketosis due to nutritional deficiency or diabetes mellitus; however; the exact etiology remains ambiguous.^2-7 The association with ketosis and nutrition is of particular interest in this case. Onset of PP has been reported to coincide with dieting, fasting, weight loss, anorexia nervosa, and diabetes mellitus.^3,6-9 Roughly 50 patients with PP had ketosis subsequent to these metabolic disturbances.^3,6-10 As of now, the only reported correlation between ketosis and PP is that upon diet modification, lesions resolved following ketone normalization, as was observed in our patient.^3,6-8 Reports of PP in diabetic patients while in ketoacidosis describe resolution of lesions with insulin administration.^6-9 The pathophysiology of ketosis and its association with PP is unclear; however, the similarities seen in the immune response of PP and that stimulated by ketosis may expose an associated mechanism.

Ketosis is a temporary condition characterized by elevated serum ketones that are used as an alternative energy source when blood glucose is low or insulin is deficient.¹¹ The most common causes of ketosis are the physiologic responses to fasting, prolonged exercise, or a high-protein/low-carbohydrate diet, though pathologic causes include insulin-dependent diabetes mellitus, alcoholism, and salicylate overdose.¹¹ In healthy individuals, blood ketone levels rarely approach 0.5 mmol/L. Prolonged fasting or restricting intake of carbohydrates to less than 40 g daily can induce mild ketosis that resolves with re-introduction of carbohydrates.¹¹

Ketone bodies pass from the circulating blood into tissues or remain near the blood vessels, inducing cytotoxic effects and perivascular inflammation.^10,11 Increased ketone bodies have been shown to upregulate intercellular adhesion molecule 1 (ICAM-1) and leukocyte function-associated antigen 1 (LFA-1), a phenomenon also seen in lesional keratinocytes of PP.^12,13 Teraki et al¹³ observed that epidermal keratinocytes exhibited increased expression of ICAM-1 as well as intense expression of LFA-1 on dermal and epidermotropic leukocytes, which was thought to be due to cell-mediated cytotoxicity. Not only do increased ketone bodies upregulate ICAM-1 and LFA-1, but they also are involved in increasing many proinflammatory mediators that may be capable of inducing the response seen in PP keratinocytes.^12,13

Intercellular adhesion molecule 1 is important in initiating cellular interactions in the immune response and is the ligand for LFA-1 found on most leukocytes.¹⁴ Increased ICAM-1/LFA-1 interaction is thought to be the major pathway by which leukocytes are able to attach to keratinocytes and endothelial cells, allowing for leukocyte tissue migration and specific immunologic reactions, including leukocyte-mediated cytotoxicity. Interestingly, glucocorticoids are ineffective in reducing the expression of ICAM-1 in cultured keratinocytes.¹⁴ This connection between ketosis and inflammation that results in leukocyte migration and ultimately keratinocyte cytotoxicity may well be fundamental to the pathophysiology of PP and may provide a possible explanation for the ineffectiveness of corticosteroid treatment.

Middleton and Norris¹⁵ observed that individual keratinocyte strains show considerable variability in ICAM-1 expression that was found to be attributable to genetic polymorphisms. The presence of a particular polymorphism affecting ICAM-1 expression on human keratinocytes may explain the apparent ethnogeographic predisposition of PP as well as the ease at which ICAM-1 is expressed in the presence of ketones.

We describe a case of a 40-year-old white woman who was diagnosed with PP that was prompted by a 100-lb weight loss and self-induced ketosis while following a paleo diet with carbohydrate restriction. Successful treatment was attained through diet modification alone. This interesting case was another instance in which the pathophysiology of PP was attributed to ketosis. Because not all patients that are in ketosis have PP, larger prospective cohort studies are needed to further elucidate the association of PP and ketosis.

WASHINGTON – Many patients with vitiligo are interested in treating their condition with vitamins, supplements, or a modified diet, but research on whether these measures have an impact remains limited, Nada Elbuluk, MD, said at the annual meeting of the American Academy of Dermatology.

While the literature suggests that supplements with antioxidant properties benefit patients who are receiving phototherapy for vitiligo, “we need more well designed, controlled studies in the future to know where this belongs in our treatment armamentarium,” said Dr. Elbuluk of the department of dermatology at the University of Southern California, Los Angeles.

During a session at the AAD meeting, Dr. Elbuluk, who is also director of the pigmentary disorders clinic at USC, reviewed the evidence for the use of these adjunctive therapies in patients with vitiligo.
 

Vitamins

The pathogenesis of vitiligo includes the overproduction of reactive oxygen species and oxidative stress, factors that contribute to melanocyte damage and death. In addition, many patients with vitiligo are deficient in certain vitamins and minerals, the basis of the hypothesis that supplementation could be beneficial, according to Dr. Elbuluk.

Vitamin B₁₂ and folic acid contribute to DNA repair, synthesis, and methylation, and researchers have hypothesized that these vitamins also play a role in melanin synthesis. In a review of the literature, Dr. Elbuluk and her colleagues found four studies that evaluated vitamin B₁₂ and folic acid in vitiligo. In one study, a controlled trial in which patients took B₁₂ and folic acid with and without phototherapy, the investigators observed no significant difference in repigmentation between groups. The other three studies were uncontrolled and thus provide an insufficient understanding of the effect of B₁₂ and folic acid, said Dr. Elbuluk.

Vitamin D is involved in melanocyte and keratinocyte growth and differentiation, and inhibits T cell activation. Data indicate that low vitamin D levels are common in patients with vitiligo and comorbid autoimmune diseases. In one study, patients who received narrow-band UVB had an increase in vitamin D levels that could contribute to photo-induced melanogenesis, and an open-label study indicated that patients who took vitamin D daily (without phototherapy) for 6 months had an increase of repigmentation over time. “Topical vitamin D analogs have also been used in vitiligo treatment with varying success,” Dr. Elbuluk noted.

“I check vitamin D levels on my patients and make sure that they are within normal range. But I think the degree of supplementation and its role in vitiligo needs to be further elucidated,” she said. And because vitamin D is fat soluble, there is a risk of toxicity if a patient takes too much.

Vitamin C, vitamin E, and alpha-lipoic acid have antioxidant properties. In a double-blind, randomized, controlled trial, one group of patients took vitamins C and E and alpha-lipoic acid for 2 months before and during treatment with narrow-band UVB twice per week (Clin Exp Dermatol. 2007 Nov;32[6]:631-6). Another group underwent phototherapy without supplementation. A significantly greater proportion of patients who received the antioxidants obtained more than 75% repigmentation compared with those who did not. In another study, 73% of patients who received oral vitamin E and narrow band UVB phototherapy had marked to excellent repigmentation, compared with 55.6% of those who had phototherapy only (J Clin Pharmacol. 2009 Jul;49[7]:852-5).

The results of these studies support the idea that antioxidants can stabilize disease, reduce oxidative stress, and improve the effect of phototherapy, Dr. Elbuluk said.
 

Herbal supplements

Several research teams have examined Ginkgo biloba as a possible treatment for vitiligo. This plant is native to China and has antioxidant and anti-inflammatory properties; its most common side effect is gastrointestinal distress. Because it entails a risk of coagulopathy, it may not be appropriate for patients receiving anticoagulant treatment, Dr. Elbuluk pointed out. In a double-blinded, randomized, controlled trial comparing ginkgo biloba alone with placebo in patients with vitiligo, treatment was associated with cessation of active disease in most patients, and more than 40% of patients receiving ginkgo biloba had 75% repigmentation or more.

Polypodium leucotomos, a fern native to Central and South America, protects against UV radiation damage, modulates the immune system, and has anti-inflammatory and antioxidant effects. It has a good safety profile and is well tolerated at a dose of 240 mg/day, she said. It sometimes causes gastrointestinal discomfort or pruritus. Several randomized, controlled trials in patients with vitiligo showed that supplementation with polypodium leucotomos improves repigmentation, particularly in photo-exposed areas, she noted.

Khellin is an extract from the Mediterranean khella plant that is thought to stimulate melanocyte proliferation and melanogenesis. Several studies have examined khellin supplementation in combination with phototherapy. Khellin can be administered orally or topically and appears to be more beneficial than sunlight or phototherapy alone in stabilizing disease or inducing repigmentation. Oral khellin can cause many side effects, including nausea, transaminitis, and hypotension, so researchers have been more interested in using topical khellin as a liposomal vehicle to improve drug delivery, Dr. Elbuluk said.
 

Minerals

Some patients with vitiligo have deficiencies in zinc and copper. Zinc is an antioxidant that aids wound healing, protects against free radicals, supports melanogenesis, and possibly prevents melanocyte death, but can cause gastrointestinal irritation. Copper, too, is an antioxidant and coenzyme involved in melanogenesis. One study compared topical steroid treatment with and without oral zinc supplementation. Dual treatment was associated with greater repigmentation, but the difference was not statistically significant. No studies have examined copper supplementation, she said.

L-phenylalanine, diet, and green tea

Investigators have proposed that the amino acid L-phenylalanine, a precursor to tyrosine in the pathway of melanin synthesis, might interfere with antibody production against melanocytes. This supplement is administered orally by weight, typically in conjunction with phototherapy or sunlight. Various studies have observed positive outcomes of L-phenylalanine combined with phototherapy or sunlight. L-phenylalanine tends to be safe and has been administered to children with vitiligo.

Many patients with vitiligo “have already tried diets by the time they come to me,” said Dr. Elbuluk. No controlled studies have analyzed the role of diet in the prevention or treatment of vitiligo, but case reports describe gluten-free diets in this population, including one report of a patient with celiac disease whose vitiligo improved after adoption of such a diet. Another case report described a patient without celiac disease who had refractory acrofacial vitiligo, which improved after the adoption of a gluten-free diet. Evidence supports a gluten-free diet for patients with celiac disease, but does not support this challenging diet for people without celiac disease, she pointed out.

Green tea includes catechins, which have antioxidant and anti-inflammatory properties. Its main component is epigallocatechin gallate (EGCG), which is thought to modulate T cell mediated responses. In one animal study, administration of EGCG delayed the onset of vitiligo and decreased the area of depigmentation in a mouse model. Although these findings are promising, clinical trials are needed to determine whether EGCG is beneficial in humans with vitiligo, said Dr. Elbuluk.

The literature on diets and supplementation as treatments for vitiligo has several shortcomings, with studies that used heterogeneous methodologies, and many that used nonstandard outcome measures that have not been validated. Sample sizes often are small, and many trials are uncontrolled. “These limitations make it harder to make sense of the data and have take-home conclusions,” Dr. Elbuluk said.

She had no disclosures.

egreb@mdedge.com

SOURCE: Elbuluk N. AAD 19, Session S002.

WASHINGTON – Many patients with vitiligo are interested in treating their condition with vitamins, supplements, or a modified diet, but research on whether these measures have an impact remains limited, Nada Elbuluk, MD, said at the annual meeting of the American Academy of Dermatology.

While the literature suggests that supplements with antioxidant properties benefit patients who are receiving phototherapy for vitiligo, “we need more well designed, controlled studies in the future to know where this belongs in our treatment armamentarium,” said Dr. Elbuluk of the department of dermatology at the University of Southern California, Los Angeles.

During a session at the AAD meeting, Dr. Elbuluk, who is also director of the pigmentary disorders clinic at USC, reviewed the evidence for the use of these adjunctive therapies in patients with vitiligo.
 

Vitamins

The pathogenesis of vitiligo includes the overproduction of reactive oxygen species and oxidative stress, factors that contribute to melanocyte damage and death. In addition, many patients with vitiligo are deficient in certain vitamins and minerals, the basis of the hypothesis that supplementation could be beneficial, according to Dr. Elbuluk.

Vitamin B₁₂ and folic acid contribute to DNA repair, synthesis, and methylation, and researchers have hypothesized that these vitamins also play a role in melanin synthesis. In a review of the literature, Dr. Elbuluk and her colleagues found four studies that evaluated vitamin B₁₂ and folic acid in vitiligo. In one study, a controlled trial in which patients took B₁₂ and folic acid with and without phototherapy, the investigators observed no significant difference in repigmentation between groups. The other three studies were uncontrolled and thus provide an insufficient understanding of the effect of B₁₂ and folic acid, said Dr. Elbuluk.

Vitamin D is involved in melanocyte and keratinocyte growth and differentiation, and inhibits T cell activation. Data indicate that low vitamin D levels are common in patients with vitiligo and comorbid autoimmune diseases. In one study, patients who received narrow-band UVB had an increase in vitamin D levels that could contribute to photo-induced melanogenesis, and an open-label study indicated that patients who took vitamin D daily (without phototherapy) for 6 months had an increase of repigmentation over time. “Topical vitamin D analogs have also been used in vitiligo treatment with varying success,” Dr. Elbuluk noted.

“I check vitamin D levels on my patients and make sure that they are within normal range. But I think the degree of supplementation and its role in vitiligo needs to be further elucidated,” she said. And because vitamin D is fat soluble, there is a risk of toxicity if a patient takes too much.

Vitamin C, vitamin E, and alpha-lipoic acid have antioxidant properties. In a double-blind, randomized, controlled trial, one group of patients took vitamins C and E and alpha-lipoic acid for 2 months before and during treatment with narrow-band UVB twice per week (Clin Exp Dermatol. 2007 Nov;32[6]:631-6). Another group underwent phototherapy without supplementation. A significantly greater proportion of patients who received the antioxidants obtained more than 75% repigmentation compared with those who did not. In another study, 73% of patients who received oral vitamin E and narrow band UVB phototherapy had marked to excellent repigmentation, compared with 55.6% of those who had phototherapy only (J Clin Pharmacol. 2009 Jul;49[7]:852-5).

The results of these studies support the idea that antioxidants can stabilize disease, reduce oxidative stress, and improve the effect of phototherapy, Dr. Elbuluk said.
 

Herbal supplements

Several research teams have examined Ginkgo biloba as a possible treatment for vitiligo. This plant is native to China and has antioxidant and anti-inflammatory properties; its most common side effect is gastrointestinal distress. Because it entails a risk of coagulopathy, it may not be appropriate for patients receiving anticoagulant treatment, Dr. Elbuluk pointed out. In a double-blinded, randomized, controlled trial comparing ginkgo biloba alone with placebo in patients with vitiligo, treatment was associated with cessation of active disease in most patients, and more than 40% of patients receiving ginkgo biloba had 75% repigmentation or more.

Polypodium leucotomos, a fern native to Central and South America, protects against UV radiation damage, modulates the immune system, and has anti-inflammatory and antioxidant effects. It has a good safety profile and is well tolerated at a dose of 240 mg/day, she said. It sometimes causes gastrointestinal discomfort or pruritus. Several randomized, controlled trials in patients with vitiligo showed that supplementation with polypodium leucotomos improves repigmentation, particularly in photo-exposed areas, she noted.

Khellin is an extract from the Mediterranean khella plant that is thought to stimulate melanocyte proliferation and melanogenesis. Several studies have examined khellin supplementation in combination with phototherapy. Khellin can be administered orally or topically and appears to be more beneficial than sunlight or phototherapy alone in stabilizing disease or inducing repigmentation. Oral khellin can cause many side effects, including nausea, transaminitis, and hypotension, so researchers have been more interested in using topical khellin as a liposomal vehicle to improve drug delivery, Dr. Elbuluk said.
 

Minerals

Some patients with vitiligo have deficiencies in zinc and copper. Zinc is an antioxidant that aids wound healing, protects against free radicals, supports melanogenesis, and possibly prevents melanocyte death, but can cause gastrointestinal irritation. Copper, too, is an antioxidant and coenzyme involved in melanogenesis. One study compared topical steroid treatment with and without oral zinc supplementation. Dual treatment was associated with greater repigmentation, but the difference was not statistically significant. No studies have examined copper supplementation, she said.

L-phenylalanine, diet, and green tea

Investigators have proposed that the amino acid L-phenylalanine, a precursor to tyrosine in the pathway of melanin synthesis, might interfere with antibody production against melanocytes. This supplement is administered orally by weight, typically in conjunction with phototherapy or sunlight. Various studies have observed positive outcomes of L-phenylalanine combined with phototherapy or sunlight. L-phenylalanine tends to be safe and has been administered to children with vitiligo.

Many patients with vitiligo “have already tried diets by the time they come to me,” said Dr. Elbuluk. No controlled studies have analyzed the role of diet in the prevention or treatment of vitiligo, but case reports describe gluten-free diets in this population, including one report of a patient with celiac disease whose vitiligo improved after adoption of such a diet. Another case report described a patient without celiac disease who had refractory acrofacial vitiligo, which improved after the adoption of a gluten-free diet. Evidence supports a gluten-free diet for patients with celiac disease, but does not support this challenging diet for people without celiac disease, she pointed out.

Green tea includes catechins, which have antioxidant and anti-inflammatory properties. Its main component is epigallocatechin gallate (EGCG), which is thought to modulate T cell mediated responses. In one animal study, administration of EGCG delayed the onset of vitiligo and decreased the area of depigmentation in a mouse model. Although these findings are promising, clinical trials are needed to determine whether EGCG is beneficial in humans with vitiligo, said Dr. Elbuluk.

The literature on diets and supplementation as treatments for vitiligo has several shortcomings, with studies that used heterogeneous methodologies, and many that used nonstandard outcome measures that have not been validated. Sample sizes often are small, and many trials are uncontrolled. “These limitations make it harder to make sense of the data and have take-home conclusions,” Dr. Elbuluk said.

She had no disclosures.

egreb@mdedge.com

SOURCE: Elbuluk N. AAD 19, Session S002.

WASHINGTON – Many patients with vitiligo are interested in treating their condition with vitamins, supplements, or a modified diet, but research on whether these measures have an impact remains limited, Nada Elbuluk, MD, said at the annual meeting of the American Academy of Dermatology.

While the literature suggests that supplements with antioxidant properties benefit patients who are receiving phototherapy for vitiligo, “we need more well designed, controlled studies in the future to know where this belongs in our treatment armamentarium,” said Dr. Elbuluk of the department of dermatology at the University of Southern California, Los Angeles.

During a session at the AAD meeting, Dr. Elbuluk, who is also director of the pigmentary disorders clinic at USC, reviewed the evidence for the use of these adjunctive therapies in patients with vitiligo.
 

Vitamins

The pathogenesis of vitiligo includes the overproduction of reactive oxygen species and oxidative stress, factors that contribute to melanocyte damage and death. In addition, many patients with vitiligo are deficient in certain vitamins and minerals, the basis of the hypothesis that supplementation could be beneficial, according to Dr. Elbuluk.

Vitamin B₁₂ and folic acid contribute to DNA repair, synthesis, and methylation, and researchers have hypothesized that these vitamins also play a role in melanin synthesis. In a review of the literature, Dr. Elbuluk and her colleagues found four studies that evaluated vitamin B₁₂ and folic acid in vitiligo. In one study, a controlled trial in which patients took B₁₂ and folic acid with and without phototherapy, the investigators observed no significant difference in repigmentation between groups. The other three studies were uncontrolled and thus provide an insufficient understanding of the effect of B₁₂ and folic acid, said Dr. Elbuluk.

Vitamin D is involved in melanocyte and keratinocyte growth and differentiation, and inhibits T cell activation. Data indicate that low vitamin D levels are common in patients with vitiligo and comorbid autoimmune diseases. In one study, patients who received narrow-band UVB had an increase in vitamin D levels that could contribute to photo-induced melanogenesis, and an open-label study indicated that patients who took vitamin D daily (without phototherapy) for 6 months had an increase of repigmentation over time. “Topical vitamin D analogs have also been used in vitiligo treatment with varying success,” Dr. Elbuluk noted.

“I check vitamin D levels on my patients and make sure that they are within normal range. But I think the degree of supplementation and its role in vitiligo needs to be further elucidated,” she said. And because vitamin D is fat soluble, there is a risk of toxicity if a patient takes too much.

Vitamin C, vitamin E, and alpha-lipoic acid have antioxidant properties. In a double-blind, randomized, controlled trial, one group of patients took vitamins C and E and alpha-lipoic acid for 2 months before and during treatment with narrow-band UVB twice per week (Clin Exp Dermatol. 2007 Nov;32[6]:631-6). Another group underwent phototherapy without supplementation. A significantly greater proportion of patients who received the antioxidants obtained more than 75% repigmentation compared with those who did not. In another study, 73% of patients who received oral vitamin E and narrow band UVB phototherapy had marked to excellent repigmentation, compared with 55.6% of those who had phototherapy only (J Clin Pharmacol. 2009 Jul;49[7]:852-5).

The results of these studies support the idea that antioxidants can stabilize disease, reduce oxidative stress, and improve the effect of phototherapy, Dr. Elbuluk said.
 

Herbal supplements

Several research teams have examined Ginkgo biloba as a possible treatment for vitiligo. This plant is native to China and has antioxidant and anti-inflammatory properties; its most common side effect is gastrointestinal distress. Because it entails a risk of coagulopathy, it may not be appropriate for patients receiving anticoagulant treatment, Dr. Elbuluk pointed out. In a double-blinded, randomized, controlled trial comparing ginkgo biloba alone with placebo in patients with vitiligo, treatment was associated with cessation of active disease in most patients, and more than 40% of patients receiving ginkgo biloba had 75% repigmentation or more.

Polypodium leucotomos, a fern native to Central and South America, protects against UV radiation damage, modulates the immune system, and has anti-inflammatory and antioxidant effects. It has a good safety profile and is well tolerated at a dose of 240 mg/day, she said. It sometimes causes gastrointestinal discomfort or pruritus. Several randomized, controlled trials in patients with vitiligo showed that supplementation with polypodium leucotomos improves repigmentation, particularly in photo-exposed areas, she noted.

Khellin is an extract from the Mediterranean khella plant that is thought to stimulate melanocyte proliferation and melanogenesis. Several studies have examined khellin supplementation in combination with phototherapy. Khellin can be administered orally or topically and appears to be more beneficial than sunlight or phototherapy alone in stabilizing disease or inducing repigmentation. Oral khellin can cause many side effects, including nausea, transaminitis, and hypotension, so researchers have been more interested in using topical khellin as a liposomal vehicle to improve drug delivery, Dr. Elbuluk said.
 

Minerals

Some patients with vitiligo have deficiencies in zinc and copper. Zinc is an antioxidant that aids wound healing, protects against free radicals, supports melanogenesis, and possibly prevents melanocyte death, but can cause gastrointestinal irritation. Copper, too, is an antioxidant and coenzyme involved in melanogenesis. One study compared topical steroid treatment with and without oral zinc supplementation. Dual treatment was associated with greater repigmentation, but the difference was not statistically significant. No studies have examined copper supplementation, she said.

L-phenylalanine, diet, and green tea

Investigators have proposed that the amino acid L-phenylalanine, a precursor to tyrosine in the pathway of melanin synthesis, might interfere with antibody production against melanocytes. This supplement is administered orally by weight, typically in conjunction with phototherapy or sunlight. Various studies have observed positive outcomes of L-phenylalanine combined with phototherapy or sunlight. L-phenylalanine tends to be safe and has been administered to children with vitiligo.

Many patients with vitiligo “have already tried diets by the time they come to me,” said Dr. Elbuluk. No controlled studies have analyzed the role of diet in the prevention or treatment of vitiligo, but case reports describe gluten-free diets in this population, including one report of a patient with celiac disease whose vitiligo improved after adoption of such a diet. Another case report described a patient without celiac disease who had refractory acrofacial vitiligo, which improved after the adoption of a gluten-free diet. Evidence supports a gluten-free diet for patients with celiac disease, but does not support this challenging diet for people without celiac disease, she pointed out.

Green tea includes catechins, which have antioxidant and anti-inflammatory properties. Its main component is epigallocatechin gallate (EGCG), which is thought to modulate T cell mediated responses. In one animal study, administration of EGCG delayed the onset of vitiligo and decreased the area of depigmentation in a mouse model. Although these findings are promising, clinical trials are needed to determine whether EGCG is beneficial in humans with vitiligo, said Dr. Elbuluk.

The literature on diets and supplementation as treatments for vitiligo has several shortcomings, with studies that used heterogeneous methodologies, and many that used nonstandard outcome measures that have not been validated. Sample sizes often are small, and many trials are uncontrolled. “These limitations make it harder to make sense of the data and have take-home conclusions,” Dr. Elbuluk said.

She had no disclosures.

egreb@mdedge.com

SOURCE: Elbuluk N. AAD 19, Session S002.

After last month’s column about the difficulty of firing employees, several readers raised the equally dicey issue of dismissing patients from your practice.

One might assume that, just as patients are free to choose or reject their doctors, physicians have an equal right to reject their patients; and to a certain extent, that’s true. There are no specific laws prohibiting a provider from terminating a patient relationship for any reason, other than a discriminatory one – race, nationality, religion, age, sex, sexual orientation, and so on. However, our ethical obligations to “do no harm” and to place our patients’ welfare above our own self-interests dictate that dismissing a patient should be the absolute last resort, after all other options have been exhausted.

First, to avoid charges of arbitrary termination, you should draw up a specific list of situations that could merit a dismissal from your office, and add it to your office manual. Every list will probably differ in some respects, but for the sake of example, here is mine:

• Threats or violence toward physicians or staff.
• Inappropriate sexual advances toward physicians or staff.
• Providing false or misleading medical history.
• Repeated rude or disruptive behavior.
• Demands for unapproved, unindicated, or inappropriate treatments or medications (particularly controlled substances).
• Refusal to adhere to agreed-upon treatment plans.
• Repeated failure to keep scheduled appointments.
• Repeated failure to pay medical bills.

As with pretty much everything in a private practice, accurate and written documentation of dismissible behavior is essential. Record all incidents and assemble as much material evidence as possible from all available sources.

In most cases (except the first two infractions on our list, for which we have zero tolerance), we make every effort to resolve the problem amicably. We communicate with the patients in question, explain our concerns, and discuss options for resolution. I also may send a letter, repeating my concerns and proposed solutions, as further documentation of our efforts to achieve an amicable resolution. All verbal and written warnings are, of course, documented as well. If the patient has a managed care policy, we review the managed care contract, which sometimes includes specific requirements for dismissal of its patients.

When such efforts fail, we send the patient two letters – one certified with return receipt, the other by conventional first class, in case the patient refuses the certified copy – explaining the reason for dismissal, and that care will be discontinued in 30 days from the letter’s date. (Most attorneys and medical associations agree that 30 days is sufficient reasonable notice.) We offer to provide care during the interim period, include a list of names and contact information for potential alternate providers, and offer to transfer records after receiving written permission.

Following these precautions will usually protect you from charges of “patient abandonment,” which is generally defined as the unilateral severance by the physician of the physician-patient relationship without giving the patient sufficient advance notice to obtain the services of another practitioner, and at a time when the patient still requires medical attention.

Some states have their own unique definitions of patient abandonment. You should check with your state’s health department, and your attorney, for any unusual requirements in your state, because violating these could lead to intervention by your state licensing board. There also is the risk of civil litigation, which typically is not covered by malpractice policies and may not be covered by your general liability policy either.

Patients who feel that termination was unjustified also may respond with negative reviews on social media, which I’ve discussed in recent columns, and will again, soon.

If something untrue is posted about you on a doctor-rating site, take action. Reputable sites have their own reputations to protect and can usually be persuaded to remove anything that is demonstrably false, although you may need a lawyer’s letter to get their attention. Try to get the error removed entirely or corrected within the original posting. An erratum on some distant page of the website is likely to be ignored, and will leave the false information online, intact.

Unfair comments are unlikely to be removed unless they are blatantly libelous; but many sites allow you to post a response, giving your side of the story. (More on that in the near future.) Also, there is nothing wrong with encouraging happy patients to write favorable reviews on those same sites. Sauce for the goose, and all that.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

After last month’s column about the difficulty of firing employees, several readers raised the equally dicey issue of dismissing patients from your practice.

One might assume that, just as patients are free to choose or reject their doctors, physicians have an equal right to reject their patients; and to a certain extent, that’s true. There are no specific laws prohibiting a provider from terminating a patient relationship for any reason, other than a discriminatory one – race, nationality, religion, age, sex, sexual orientation, and so on. However, our ethical obligations to “do no harm” and to place our patients’ welfare above our own self-interests dictate that dismissing a patient should be the absolute last resort, after all other options have been exhausted.

First, to avoid charges of arbitrary termination, you should draw up a specific list of situations that could merit a dismissal from your office, and add it to your office manual. Every list will probably differ in some respects, but for the sake of example, here is mine:

• Threats or violence toward physicians or staff.
• Inappropriate sexual advances toward physicians or staff.
• Providing false or misleading medical history.
• Repeated rude or disruptive behavior.
• Demands for unapproved, unindicated, or inappropriate treatments or medications (particularly controlled substances).
• Refusal to adhere to agreed-upon treatment plans.
• Repeated failure to keep scheduled appointments.
• Repeated failure to pay medical bills.

As with pretty much everything in a private practice, accurate and written documentation of dismissible behavior is essential. Record all incidents and assemble as much material evidence as possible from all available sources.

In most cases (except the first two infractions on our list, for which we have zero tolerance), we make every effort to resolve the problem amicably. We communicate with the patients in question, explain our concerns, and discuss options for resolution. I also may send a letter, repeating my concerns and proposed solutions, as further documentation of our efforts to achieve an amicable resolution. All verbal and written warnings are, of course, documented as well. If the patient has a managed care policy, we review the managed care contract, which sometimes includes specific requirements for dismissal of its patients.

When such efforts fail, we send the patient two letters – one certified with return receipt, the other by conventional first class, in case the patient refuses the certified copy – explaining the reason for dismissal, and that care will be discontinued in 30 days from the letter’s date. (Most attorneys and medical associations agree that 30 days is sufficient reasonable notice.) We offer to provide care during the interim period, include a list of names and contact information for potential alternate providers, and offer to transfer records after receiving written permission.

Following these precautions will usually protect you from charges of “patient abandonment,” which is generally defined as the unilateral severance by the physician of the physician-patient relationship without giving the patient sufficient advance notice to obtain the services of another practitioner, and at a time when the patient still requires medical attention.

Some states have their own unique definitions of patient abandonment. You should check with your state’s health department, and your attorney, for any unusual requirements in your state, because violating these could lead to intervention by your state licensing board. There also is the risk of civil litigation, which typically is not covered by malpractice policies and may not be covered by your general liability policy either.

Patients who feel that termination was unjustified also may respond with negative reviews on social media, which I’ve discussed in recent columns, and will again, soon.

If something untrue is posted about you on a doctor-rating site, take action. Reputable sites have their own reputations to protect and can usually be persuaded to remove anything that is demonstrably false, although you may need a lawyer’s letter to get their attention. Try to get the error removed entirely or corrected within the original posting. An erratum on some distant page of the website is likely to be ignored, and will leave the false information online, intact.

Unfair comments are unlikely to be removed unless they are blatantly libelous; but many sites allow you to post a response, giving your side of the story. (More on that in the near future.) Also, there is nothing wrong with encouraging happy patients to write favorable reviews on those same sites. Sauce for the goose, and all that.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

After last month’s column about the difficulty of firing employees, several readers raised the equally dicey issue of dismissing patients from your practice.

One might assume that, just as patients are free to choose or reject their doctors, physicians have an equal right to reject their patients; and to a certain extent, that’s true. There are no specific laws prohibiting a provider from terminating a patient relationship for any reason, other than a discriminatory one – race, nationality, religion, age, sex, sexual orientation, and so on. However, our ethical obligations to “do no harm” and to place our patients’ welfare above our own self-interests dictate that dismissing a patient should be the absolute last resort, after all other options have been exhausted.

First, to avoid charges of arbitrary termination, you should draw up a specific list of situations that could merit a dismissal from your office, and add it to your office manual. Every list will probably differ in some respects, but for the sake of example, here is mine:

• Threats or violence toward physicians or staff.
• Inappropriate sexual advances toward physicians or staff.
• Providing false or misleading medical history.
• Repeated rude or disruptive behavior.
• Demands for unapproved, unindicated, or inappropriate treatments or medications (particularly controlled substances).
• Refusal to adhere to agreed-upon treatment plans.
• Repeated failure to keep scheduled appointments.
• Repeated failure to pay medical bills.

As with pretty much everything in a private practice, accurate and written documentation of dismissible behavior is essential. Record all incidents and assemble as much material evidence as possible from all available sources.

In most cases (except the first two infractions on our list, for which we have zero tolerance), we make every effort to resolve the problem amicably. We communicate with the patients in question, explain our concerns, and discuss options for resolution. I also may send a letter, repeating my concerns and proposed solutions, as further documentation of our efforts to achieve an amicable resolution. All verbal and written warnings are, of course, documented as well. If the patient has a managed care policy, we review the managed care contract, which sometimes includes specific requirements for dismissal of its patients.

When such efforts fail, we send the patient two letters – one certified with return receipt, the other by conventional first class, in case the patient refuses the certified copy – explaining the reason for dismissal, and that care will be discontinued in 30 days from the letter’s date. (Most attorneys and medical associations agree that 30 days is sufficient reasonable notice.) We offer to provide care during the interim period, include a list of names and contact information for potential alternate providers, and offer to transfer records after receiving written permission.

Following these precautions will usually protect you from charges of “patient abandonment,” which is generally defined as the unilateral severance by the physician of the physician-patient relationship without giving the patient sufficient advance notice to obtain the services of another practitioner, and at a time when the patient still requires medical attention.

Some states have their own unique definitions of patient abandonment. You should check with your state’s health department, and your attorney, for any unusual requirements in your state, because violating these could lead to intervention by your state licensing board. There also is the risk of civil litigation, which typically is not covered by malpractice policies and may not be covered by your general liability policy either.

Patients who feel that termination was unjustified also may respond with negative reviews on social media, which I’ve discussed in recent columns, and will again, soon.

If something untrue is posted about you on a doctor-rating site, take action. Reputable sites have their own reputations to protect and can usually be persuaded to remove anything that is demonstrably false, although you may need a lawyer’s letter to get their attention. Try to get the error removed entirely or corrected within the original posting. An erratum on some distant page of the website is likely to be ignored, and will leave the false information online, intact.

Unfair comments are unlikely to be removed unless they are blatantly libelous; but many sites allow you to post a response, giving your side of the story. (More on that in the near future.) Also, there is nothing wrong with encouraging happy patients to write favorable reviews on those same sites. Sauce for the goose, and all that.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at dermnews@mdedge.com.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

WASHINGTON – When repigmentation therapy fails, dermatologists may offer depigmentation therapy to patients with vitiligo, Seemal Desai, MD, said at the annual meeting of the American Academy of Dermatology.

Depigmentation therapy is “an underutilized resource for those patients who have recalcitrant disease or whose disease is so bad that you have not been able to improve their clinical, visible outcome,” said Dr. Desai, clinical assistant professor of dermatology at the University of Texas, Dallas. “Some of these patients simply desire to be one uniform color.”

Therapy is administered through medications that destroy residual melanocytes with the goal of achieving a uniform appearance of the skin. Monobenzyl ether of hydroquinone (MBEH) is the most common drug used in depigmentation therapy, according to Dr. Desai. It is available in concentrations of 20% and 40% and can be compounded in other concentrations. At first, patients should apply MBEH to a nickel-sized area of the skin (such as the forearm, the back of the hand, or the thigh) for 3 or 4 days. Treatment is administered in the morning and evening, but not at bedtime. A common side effect is irritant contact dermatitis.

When the patient is able to tolerate the medication in the first area, he or she can apply it to larger areas of the skin. Parts of the body are treated one at a time, and successful treatment takes time, he noted. Hair may become depigmented, but patients can be assured that the eyes will not.

Repigmentation has been reported after sun exposure. For all patients undergoing depigmentation therapy, dermatologists should provide extensive counseling about the need for lifelong photoprotection, said Dr. Desai. Protective measures can include wide-brimmed hats and broad-spectrum sunscreen. Paradoxical repigmentation can be treated with a stronger concentration of MBEH, liquid nitrogen therapy, microdermabrasion, and peels.

For patients with vitiligo, which results from the immune-mediated destruction of melanocytes, dermatologists should assess the patient’s psychological status and discuss “the impact that the disease has on not only the patient, but also the family,” Dr. Desai said. “The psychological trauma from this disease, especially for our patients who have rapidly progressing vitiligo or who have failed multiple therapies, is something that we cannot discount.”

Patients with vitiligo often have comorbid depression, and evening of the skin tone that depigmentation provides can benefit the patient’s mental state, he observed. Patients with severe depression related to vitiligo should be referred to a psychologist or psychiatrist. Finally, counseling and appropriate patient selection for depigmentation is of paramount importance.

During the presentation, he noted that hair dyes, resin products and adhesives, detergents, and leather preservatives have been associated with vitiligo. Dermatologic drugs such as imiquimod, chemotherapeutic agents, and interferon also may cause the condition.

He referred to the thousands of reported cases of vitiligo related to rhododenol, a phenolic compound that has been used in cosmetics and topical products. Most cases resolved when those affected stopped using the product, but some developed vitiligo vulgaris. Cosmetics containing rhododenol have been recalled in Japan since 2013, but over-the-counter products in Asia and Africa have been found to contain similar compounds, so dermatologists should ask patients about their travel history and about what products they are using for their skin, Dr. Desai advised.

He reported receiving grants and research funding from AbbVie, Dermira, Dr. Reddy’s Laboratories, and Menlo Therapeutics and serving as a consultant for several pharmaceutical companies.

egreb@mdedge.com

WASHINGTON – When repigmentation therapy fails, dermatologists may offer depigmentation therapy to patients with vitiligo, Seemal Desai, MD, said at the annual meeting of the American Academy of Dermatology.

Depigmentation therapy is “an underutilized resource for those patients who have recalcitrant disease or whose disease is so bad that you have not been able to improve their clinical, visible outcome,” said Dr. Desai, clinical assistant professor of dermatology at the University of Texas, Dallas. “Some of these patients simply desire to be one uniform color.”

Therapy is administered through medications that destroy residual melanocytes with the goal of achieving a uniform appearance of the skin. Monobenzyl ether of hydroquinone (MBEH) is the most common drug used in depigmentation therapy, according to Dr. Desai. It is available in concentrations of 20% and 40% and can be compounded in other concentrations. At first, patients should apply MBEH to a nickel-sized area of the skin (such as the forearm, the back of the hand, or the thigh) for 3 or 4 days. Treatment is administered in the morning and evening, but not at bedtime. A common side effect is irritant contact dermatitis.

When the patient is able to tolerate the medication in the first area, he or she can apply it to larger areas of the skin. Parts of the body are treated one at a time, and successful treatment takes time, he noted. Hair may become depigmented, but patients can be assured that the eyes will not.

Repigmentation has been reported after sun exposure. For all patients undergoing depigmentation therapy, dermatologists should provide extensive counseling about the need for lifelong photoprotection, said Dr. Desai. Protective measures can include wide-brimmed hats and broad-spectrum sunscreen. Paradoxical repigmentation can be treated with a stronger concentration of MBEH, liquid nitrogen therapy, microdermabrasion, and peels.

For patients with vitiligo, which results from the immune-mediated destruction of melanocytes, dermatologists should assess the patient’s psychological status and discuss “the impact that the disease has on not only the patient, but also the family,” Dr. Desai said. “The psychological trauma from this disease, especially for our patients who have rapidly progressing vitiligo or who have failed multiple therapies, is something that we cannot discount.”

Patients with vitiligo often have comorbid depression, and evening of the skin tone that depigmentation provides can benefit the patient’s mental state, he observed. Patients with severe depression related to vitiligo should be referred to a psychologist or psychiatrist. Finally, counseling and appropriate patient selection for depigmentation is of paramount importance.

During the presentation, he noted that hair dyes, resin products and adhesives, detergents, and leather preservatives have been associated with vitiligo. Dermatologic drugs such as imiquimod, chemotherapeutic agents, and interferon also may cause the condition.

He referred to the thousands of reported cases of vitiligo related to rhododenol, a phenolic compound that has been used in cosmetics and topical products. Most cases resolved when those affected stopped using the product, but some developed vitiligo vulgaris. Cosmetics containing rhododenol have been recalled in Japan since 2013, but over-the-counter products in Asia and Africa have been found to contain similar compounds, so dermatologists should ask patients about their travel history and about what products they are using for their skin, Dr. Desai advised.

He reported receiving grants and research funding from AbbVie, Dermira, Dr. Reddy’s Laboratories, and Menlo Therapeutics and serving as a consultant for several pharmaceutical companies.

egreb@mdedge.com

WASHINGTON – When repigmentation therapy fails, dermatologists may offer depigmentation therapy to patients with vitiligo, Seemal Desai, MD, said at the annual meeting of the American Academy of Dermatology.

Depigmentation therapy is “an underutilized resource for those patients who have recalcitrant disease or whose disease is so bad that you have not been able to improve their clinical, visible outcome,” said Dr. Desai, clinical assistant professor of dermatology at the University of Texas, Dallas. “Some of these patients simply desire to be one uniform color.”

Therapy is administered through medications that destroy residual melanocytes with the goal of achieving a uniform appearance of the skin. Monobenzyl ether of hydroquinone (MBEH) is the most common drug used in depigmentation therapy, according to Dr. Desai. It is available in concentrations of 20% and 40% and can be compounded in other concentrations. At first, patients should apply MBEH to a nickel-sized area of the skin (such as the forearm, the back of the hand, or the thigh) for 3 or 4 days. Treatment is administered in the morning and evening, but not at bedtime. A common side effect is irritant contact dermatitis.

When the patient is able to tolerate the medication in the first area, he or she can apply it to larger areas of the skin. Parts of the body are treated one at a time, and successful treatment takes time, he noted. Hair may become depigmented, but patients can be assured that the eyes will not.

Repigmentation has been reported after sun exposure. For all patients undergoing depigmentation therapy, dermatologists should provide extensive counseling about the need for lifelong photoprotection, said Dr. Desai. Protective measures can include wide-brimmed hats and broad-spectrum sunscreen. Paradoxical repigmentation can be treated with a stronger concentration of MBEH, liquid nitrogen therapy, microdermabrasion, and peels.

For patients with vitiligo, which results from the immune-mediated destruction of melanocytes, dermatologists should assess the patient’s psychological status and discuss “the impact that the disease has on not only the patient, but also the family,” Dr. Desai said. “The psychological trauma from this disease, especially for our patients who have rapidly progressing vitiligo or who have failed multiple therapies, is something that we cannot discount.”

Patients with vitiligo often have comorbid depression, and evening of the skin tone that depigmentation provides can benefit the patient’s mental state, he observed. Patients with severe depression related to vitiligo should be referred to a psychologist or psychiatrist. Finally, counseling and appropriate patient selection for depigmentation is of paramount importance.

During the presentation, he noted that hair dyes, resin products and adhesives, detergents, and leather preservatives have been associated with vitiligo. Dermatologic drugs such as imiquimod, chemotherapeutic agents, and interferon also may cause the condition.

He referred to the thousands of reported cases of vitiligo related to rhododenol, a phenolic compound that has been used in cosmetics and topical products. Most cases resolved when those affected stopped using the product, but some developed vitiligo vulgaris. Cosmetics containing rhododenol have been recalled in Japan since 2013, but over-the-counter products in Asia and Africa have been found to contain similar compounds, so dermatologists should ask patients about their travel history and about what products they are using for their skin, Dr. Desai advised.

He reported receiving grants and research funding from AbbVie, Dermira, Dr. Reddy’s Laboratories, and Menlo Therapeutics and serving as a consultant for several pharmaceutical companies.

egreb@mdedge.com

A 7-year-old girl’s giant congenital melanocytic nevus (GCMN) was effectively treated with the MEK inhibitor trametinib, according to a case report presented in Pediatrics.

Her nevus covered most of her back and much of her torso and had thickened significantly over the years since initial presentation to the point of disfigurement, even invading the fascia and musculature of the trunk and pelvis, reported Adnan Mir, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas, and his coauthors. Furthermore, she presented with intractable pruritus and pain that interfered with sleep and responded minimally to treatments. Although initial immunohistochemical staining and gene sequencing did not reveal any mutations, such as BRAF V600E, further testing uncovered an AKAP9-BRAF fusion.

There are few if any effective ways of treating GCMNs. With that knowledge, as well as general theories of the mechanism GCMNs in mind, the patient’s health care team decided to try a 0.5-mg daily dose of trametinib when she was 7 years old. Her pruritus and pain resolved completely, and after 6 months of treatment with trametinib, repeat MRI “revealed decreased thickening of the dermis and near resolutions of muscular invasion.” According to the patient’s family, her quality of life improved dramatically.

cpalmer@mdedge.com

SOURCE: Mir A et al. Pediatrics. 2019;143(3):e20182469.

A 7-year-old girl’s giant congenital melanocytic nevus (GCMN) was effectively treated with the MEK inhibitor trametinib, according to a case report presented in Pediatrics.

Her nevus covered most of her back and much of her torso and had thickened significantly over the years since initial presentation to the point of disfigurement, even invading the fascia and musculature of the trunk and pelvis, reported Adnan Mir, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas, and his coauthors. Furthermore, she presented with intractable pruritus and pain that interfered with sleep and responded minimally to treatments. Although initial immunohistochemical staining and gene sequencing did not reveal any mutations, such as BRAF V600E, further testing uncovered an AKAP9-BRAF fusion.

There are few if any effective ways of treating GCMNs. With that knowledge, as well as general theories of the mechanism GCMNs in mind, the patient’s health care team decided to try a 0.5-mg daily dose of trametinib when she was 7 years old. Her pruritus and pain resolved completely, and after 6 months of treatment with trametinib, repeat MRI “revealed decreased thickening of the dermis and near resolutions of muscular invasion.” According to the patient’s family, her quality of life improved dramatically.

cpalmer@mdedge.com

SOURCE: Mir A et al. Pediatrics. 2019;143(3):e20182469.

A 7-year-old girl’s giant congenital melanocytic nevus (GCMN) was effectively treated with the MEK inhibitor trametinib, according to a case report presented in Pediatrics.

Her nevus covered most of her back and much of her torso and had thickened significantly over the years since initial presentation to the point of disfigurement, even invading the fascia and musculature of the trunk and pelvis, reported Adnan Mir, MD, PhD, of the University of Texas Southwestern Medical Center, Dallas, and his coauthors. Furthermore, she presented with intractable pruritus and pain that interfered with sleep and responded minimally to treatments. Although initial immunohistochemical staining and gene sequencing did not reveal any mutations, such as BRAF V600E, further testing uncovered an AKAP9-BRAF fusion.

There are few if any effective ways of treating GCMNs. With that knowledge, as well as general theories of the mechanism GCMNs in mind, the patient’s health care team decided to try a 0.5-mg daily dose of trametinib when she was 7 years old. Her pruritus and pain resolved completely, and after 6 months of treatment with trametinib, repeat MRI “revealed decreased thickening of the dermis and near resolutions of muscular invasion.” According to the patient’s family, her quality of life improved dramatically.

cpalmer@mdedge.com

SOURCE: Mir A et al. Pediatrics. 2019;143(3):e20182469.

The Diagnosis: Pigmented Bowen Disease

A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).

Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.^1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.³ Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.^2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.⁵ In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.

Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.^3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.⁷ Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.⁸

The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.⁶ Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).

In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.

The Diagnosis: Pigmented Bowen Disease

A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).

Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.^1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.³ Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.^2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.⁵ In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.

Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.^3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.⁷ Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.⁸

The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.⁶ Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).

In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.

The Diagnosis: Pigmented Bowen Disease

A biopsy of the lesion was performed for suspected acral malignant melanoma. Hematoxylin and eosin staining revealed acanthosis, elongation of rete ridges, and keratinocytes in complete disorder with atypical mitoses and pleomorphism affecting the full layer of the epidermis (Figure 1). The basement membrane was intact. Melanin pigmentation was increased in the lower epidermis and the upper dermis, and a lymphohistiocytic inflammatory infiltrate was present in the dermis. Staining for carcinoembryonic antigen (Figure 2) and melanoma
antigen (Figure 3) recognized by T cells (melan-A) both revealed negative results. Histopathologic findings led to the diagnosis of pigmented Bowen disease (BD).

Pigmented BD is a rare variant that accounts for 1.7% (N=420) to 5.5% (N=951) of all cases of BD.^1,2 It is reported to affect men more than women and to be more prevalent in individuals with higher Fitzpatrick skin types.³ Furthermore, exposure to UV radiation, chemicals (eg, arsenic), or human papillomavirus, as well as immunosuppression, are known to be related to pigmented BD.^2,4 Clinically, pigmented BD commonly involves nonexposed areas such as the anogenital area, trunk, and extremities, unlike typical BD that involves sun-exposed areas.⁵ In addition, it most frequently presents as a well-delineated, irregularly pigmented, asymptomatic
plaque and not as a scaly erythematous plaque. Therefore, the clinical diagnosis may be challenging. The differential diagnosis includes malignant melanoma, pigmented extramammary Paget disease, pigmented basal cell carcinoma, seborrheic keratosis, pigmented actinic keratosis, solar lentigo, and melanocytic nevi.

Histopathologically, a varying amount of melanin deposit is noted on hematoxylin and eosin staining, along with features of BD, including disarrayed atypical keratinocytes involving the full epidermis but not the basement membrane, with atypical individual cell keratinization.^3,5,6 Pigmented extramammary Paget disease can mimic pigmented BD clinically and pathologically, but Paget cells stain positive for anticytokeratin (CAM 5.2), carcinoembryonic antigen, and mucicarmine, whereas cells in pigmented BD stain negative.⁷ Moreover, negative staining for human melanoma black, melan-A, and S-100 helps differentiate malignant melanoma from pigmented BD.⁸

The prognosis of pigmented BD is similar to classic BD and is independent of the presence of melanin pigment.⁶ Therefore, the treatment options do not differ from those for typical BD and include surgical excision, cryotherapy, laser ablation, topical imiquimod or 5-fluorouracil, curettage, electrosurgery, and photodynamic therapy (PDT).

In our case, the patient and her family did not want surgical removal; therefore, 1 course of fractional laser-assisted PDT and 2 courses of ablative laser-assisted PDT were performed. Unfortunately, the lesion persisted, possibly because it was too large and pigmented. Two months later, ingenol mebutate gel 0.05% was applied (4 courses) after using an ablative laser over 3 consecutive days with a 1-month interval between courses. The lesion resolved without any adverse events.

To the Editor:

Patients with concurrent neurofibromatosis type 1 (NF-1) and systemic lupus erythematosus (SLE) rarely have been reported in the literature. Neurofibromatosis type 1 is one of the most common genetic disorders, with a worldwide birth incidence of 1 in 2500 individuals and prevalence of 1 in 4000 individuals.¹ The incidence and prevalence of SLE varies widely depending on race and geographic location. Estimated incidence rates for SLE range from 1 to 25 per 100,000 individuals annually in North America, South America, Europe, and Asia.^2,3 The reported worldwide prevalence is 20 to 150 cases per 100,000 individuals annually.^2,4,5

Given the high prevalence of both conditions, the association between SLE and NF-1 likely is underrecognized; therefore, identifying more patients with concurrent SLE and NF-1 and describing the interplay between the 2 conditions may have important therapeutic implications. We present the case of a middle-aged woman with a history of SLE who had cutaneous lesions characteristic of NF-1 to further the understanding of these concurrent conditions.

A middle-aged woman presented to our academic dermatology clinic for evaluation and removal of dark spots that had been present diffusely on the trunk and extremities since birth. She reported a history of SLE with lupus nephritis, hypertension, and a nodular goiter following a partial thyroidectomy. She noted that she did not seek treatment for the skin findings sooner because she was more concerned about her other medical conditions; however, because she felt these conditions were now stable, she decided to seek treatment for the “rash.” Physical examination revealed hundreds of café au lait macules and numerous neurofibromas diffusely distributed on the trunk and extremities (Figure 1) as well as bilateral axillary freckling. A clinical diagnosis of NF-1 was made.

The interplay between an autoimmune condition such as SLE and NF-1, a condition traditionally thought to be due to a genetic mutation, may have greater clinical and therapeutic implications beyond just these two disorders. Although it is well established that RAS pathway disruption causes NF-1, it has been uncovered that dysfunction in the RAS pathway also can contribute to melanoma oncogenesis.^13,14 These insights have led to the development of and approval of targeted drugs designed to inhibit the RAS pathway (eg, vemurafenib, dabrafenib, trametinib).^14-17 Melanoma also is considered a “model” tumor for studying the relationship between the immune system and cancer.¹⁸AKT is a signal transduction pathway that promotes cell survival and growth in various cancers.¹⁵ In addition, deactivation of MEK (part of the RAS pathway) can cause activation of AKT (protein kinase B) signaling and lupus like autoimmune conditions¹⁹ (Figure 2). Likewise, an understanding of the RAS pathway and T-cell function in patients with both SLE and NF-1 may give us more information about melanoma and other cancers.

To make a clinical diagnosis of NF-1, a patient must have 2 of 7 cardinal clinical features as defined by the National Institutes of Health (Table).²⁴ In our patient with hundreds of café au lait macules and dozens of neurofibromas, the diagnosis was clear; however, in other patients, the skin findings of NF-1 may not be as prominent. A patient could meet criteria for NF-1 diagnosis with the inconspicuous presentation of 6 café au lait macules and either 1 plexiform neurofibroma or 2 neurofibromas (of any type) on the entire body.

To the Editor:

Patients with concurrent neurofibromatosis type 1 (NF-1) and systemic lupus erythematosus (SLE) rarely have been reported in the literature. Neurofibromatosis type 1 is one of the most common genetic disorders, with a worldwide birth incidence of 1 in 2500 individuals and prevalence of 1 in 4000 individuals.¹ The incidence and prevalence of SLE varies widely depending on race and geographic location. Estimated incidence rates for SLE range from 1 to 25 per 100,000 individuals annually in North America, South America, Europe, and Asia.^2,3 The reported worldwide prevalence is 20 to 150 cases per 100,000 individuals annually.^2,4,5

Given the high prevalence of both conditions, the association between SLE and NF-1 likely is underrecognized; therefore, identifying more patients with concurrent SLE and NF-1 and describing the interplay between the 2 conditions may have important therapeutic implications. We present the case of a middle-aged woman with a history of SLE who had cutaneous lesions characteristic of NF-1 to further the understanding of these concurrent conditions.

A middle-aged woman presented to our academic dermatology clinic for evaluation and removal of dark spots that had been present diffusely on the trunk and extremities since birth. She reported a history of SLE with lupus nephritis, hypertension, and a nodular goiter following a partial thyroidectomy. She noted that she did not seek treatment for the skin findings sooner because she was more concerned about her other medical conditions; however, because she felt these conditions were now stable, she decided to seek treatment for the “rash.” Physical examination revealed hundreds of café au lait macules and numerous neurofibromas diffusely distributed on the trunk and extremities (Figure 1) as well as bilateral axillary freckling. A clinical diagnosis of NF-1 was made.

The interplay between an autoimmune condition such as SLE and NF-1, a condition traditionally thought to be due to a genetic mutation, may have greater clinical and therapeutic implications beyond just these two disorders. Although it is well established that RAS pathway disruption causes NF-1, it has been uncovered that dysfunction in the RAS pathway also can contribute to melanoma oncogenesis.^13,14 These insights have led to the development of and approval of targeted drugs designed to inhibit the RAS pathway (eg, vemurafenib, dabrafenib, trametinib).^14-17 Melanoma also is considered a “model” tumor for studying the relationship between the immune system and cancer.¹⁸AKT is a signal transduction pathway that promotes cell survival and growth in various cancers.¹⁵ In addition, deactivation of MEK (part of the RAS pathway) can cause activation of AKT (protein kinase B) signaling and lupus like autoimmune conditions¹⁹ (Figure 2). Likewise, an understanding of the RAS pathway and T-cell function in patients with both SLE and NF-1 may give us more information about melanoma and other cancers.

To make a clinical diagnosis of NF-1, a patient must have 2 of 7 cardinal clinical features as defined by the National Institutes of Health (Table).²⁴ In our patient with hundreds of café au lait macules and dozens of neurofibromas, the diagnosis was clear; however, in other patients, the skin findings of NF-1 may not be as prominent. A patient could meet criteria for NF-1 diagnosis with the inconspicuous presentation of 6 café au lait macules and either 1 plexiform neurofibroma or 2 neurofibromas (of any type) on the entire body.

To the Editor:

Patients with concurrent neurofibromatosis type 1 (NF-1) and systemic lupus erythematosus (SLE) rarely have been reported in the literature. Neurofibromatosis type 1 is one of the most common genetic disorders, with a worldwide birth incidence of 1 in 2500 individuals and prevalence of 1 in 4000 individuals.¹ The incidence and prevalence of SLE varies widely depending on race and geographic location. Estimated incidence rates for SLE range from 1 to 25 per 100,000 individuals annually in North America, South America, Europe, and Asia.^2,3 The reported worldwide prevalence is 20 to 150 cases per 100,000 individuals annually.^2,4,5

Given the high prevalence of both conditions, the association between SLE and NF-1 likely is underrecognized; therefore, identifying more patients with concurrent SLE and NF-1 and describing the interplay between the 2 conditions may have important therapeutic implications. We present the case of a middle-aged woman with a history of SLE who had cutaneous lesions characteristic of NF-1 to further the understanding of these concurrent conditions.

A middle-aged woman presented to our academic dermatology clinic for evaluation and removal of dark spots that had been present diffusely on the trunk and extremities since birth. She reported a history of SLE with lupus nephritis, hypertension, and a nodular goiter following a partial thyroidectomy. She noted that she did not seek treatment for the skin findings sooner because she was more concerned about her other medical conditions; however, because she felt these conditions were now stable, she decided to seek treatment for the “rash.” Physical examination revealed hundreds of café au lait macules and numerous neurofibromas diffusely distributed on the trunk and extremities (Figure 1) as well as bilateral axillary freckling. A clinical diagnosis of NF-1 was made.

The interplay between an autoimmune condition such as SLE and NF-1, a condition traditionally thought to be due to a genetic mutation, may have greater clinical and therapeutic implications beyond just these two disorders. Although it is well established that RAS pathway disruption causes NF-1, it has been uncovered that dysfunction in the RAS pathway also can contribute to melanoma oncogenesis.^13,14 These insights have led to the development of and approval of targeted drugs designed to inhibit the RAS pathway (eg, vemurafenib, dabrafenib, trametinib).^14-17 Melanoma also is considered a “model” tumor for studying the relationship between the immune system and cancer.¹⁸AKT is a signal transduction pathway that promotes cell survival and growth in various cancers.¹⁵ In addition, deactivation of MEK (part of the RAS pathway) can cause activation of AKT (protein kinase B) signaling and lupus like autoimmune conditions¹⁹ (Figure 2). Likewise, an understanding of the RAS pathway and T-cell function in patients with both SLE and NF-1 may give us more information about melanoma and other cancers.

To make a clinical diagnosis of NF-1, a patient must have 2 of 7 cardinal clinical features as defined by the National Institutes of Health (Table).²⁴ In our patient with hundreds of café au lait macules and dozens of neurofibromas, the diagnosis was clear; however, in other patients, the skin findings of NF-1 may not be as prominent. A patient could meet criteria for NF-1 diagnosis with the inconspicuous presentation of 6 café au lait macules and either 1 plexiform neurofibroma or 2 neurofibromas (of any type) on the entire body.

Postnflammatory hyperpigmentation (PIH) is an acquired hypermelanosis that can occur in children and adults following an inflammatory cutaneous disease or trauma. Postinflammatory hyperpigmentation may last for months to even years. Although PIH may occur in all skin types, it is more common and presents with greater severity and intensity in individuals with skin of color. By the year 2050, 1 in 3 US residents is projected to be Hispanic.¹ It is projected that by 2044, non-Hispanic white individuals (all ages) will make up less than 50% of the US population.² Currently, the majority of the US residents younger than 18 years are minorities. The majority minority population in the United States already exists in those younger than 18 years and is predicted to occur in the adult population by 2044.²

Effective treatment options and management strategies for PIH in adults with skin of color have been described in the literature.³ Due to a paucity of research, the approach to management of PIH in children with skin of color has been based on clinical experience and lessons learned from adult patients. This article focuses on management of PIH in pediatric patients with skin of color, which includes black/African American, African-Caribbean, Hispanic, Asian, Pacific Islander, and American Indian individuals.

Underlying Inflammatory Dermatoses Resulting in PIH

There are numerous conditions that may result in PIH, including but not limited to atopic dermatitis (AD), acne, arthropod bites, and injuries to the skin. Postinflammatory hyperpigmentation may have more of a psychological impact than the inciting disease or injury itself. The most important step in the approach to managing PIH is treating the underlying inflammatory condition that caused the pigmentation.

Parents/guardians may report a chief concern of dark spots, manchas (stains), blemishes, or stains on the skin, often with no mention of a coexisting inflammatory dermatosis. Parents/guardians of children with skin of color often have personally experienced PIH and may be determined to shield their children from similar angst associated with the condition. Although physicians may see just another pediatric patient with PIH, the child’s parents/guardians may see a condition that will be readily perceptible during major life events, such as the child’s prom or even his/her wedding day. Promptly diagnosing and instituting early treatment of inflammatory conditions associated with PIH may accelerate resolution and prevent worsening of the pigmentation.³

Select inflammatory dermatoses that are common in children with skin of color and may lead to PIH are highlighted below. Although this list is not comprehensive, the approach and management strategies should prompt creation of plans that keep PIH in mind when treating primary inflammatory skin diseases.

Atopic Dermatitis
Atopic dermatitis may induce PIH or hypopigmentation of the skin in children with skin of color. Developing a plan for AD flare prevention, as well as management of mild, moderate, and severe AD flares, is imperative in pediatric patients. Prevention plans should include gentle skin care, twice-daily application of emollients to the full body, and reduction of Staphylococcus aureus loads on the skin. The treatment action plan for mild to moderate flares may include topical corticosteroids, immunomodulators, and nonsteroidal agents. Treatment options for severe AD or patients who were unsuccessfully treated with other therapies may include phototherapy, biologics, and methotrexate, among others.⁴ Creating action plans for AD flares is a vital step in the prevention of PIH in patients with skin of color. Additionally, PIH should not be considered a sign of AD treatment failure.

Acne
Acne is a common skin disorder seen in patients with skin of color.⁵ A prospective observational study found that 34.3% of 683 children aged 9 to 14 years in a pediatric ambulatory clinic had acne.⁶ The number of preadolescents with acne is growing. Most cases are not associated with underlying endocrinopathy.⁷ With the growing population of children with skin of color in the United States along with the increasing childhood acne rate and subsequent inherent risk for hyperpigmentation, early acne interventions should be considered in pediatric acne patients with skin of color to reduce the impact of PIH in those at risk.

In a survey study of 313 adult acne patients with skin of color, 37.2% reported the presence of dark marks lasting 4 months or longer.⁵ Regardless of the severity of the acne, treatment should be initiated as tolerated in those with PIH. Adolescent acne patients with skin of color may develop PIH that is more severe and longer lasting than the acne itself.

The foundation for treatment of acne in adolescent skin of color patients is the same as those without skin of color, including topical retinoids, topical antibiotics, oral antibiotics, and isotretinoin when needed. Topical tretinoin, adapalene, azelaic acid, and tazarotene not only treat acne but also are a valuable part of the treatment armamentarium for PIH. Several studies in adults with skin of color have demonstrated improvement of PIH from the use of topical retinoids alone.^8-10 Despite wanting to treat the acne aggressively, special guidance should be given to prevent retinoid dermatitis, which may lead to PIH.¹⁰ Demonstrating the application of the topical acne medications, discussing how to avoid potential side effects, and giving permission to skip applications, if needed, may empower families to make adjustments between visits to limit irritation that might prompt further PIH. Incorporating α-hydroxy acid–based cleansers, α-hydroxy acid–based chemical peels, or salicylic acid chemical peels may be warranted in the setting of intense PIH. Selecting treatments that not only help the inflammatory disease leading to the PIH but also can help improve the pigmentation are preferred; however, the risks and benefits have to be weighed because many treatments that work well for PIH also may cause irritation, leading to new or worsening PIH.

Arthropod Bites
Arthropod bites cause inflamed pruritic papules and nodules, and the resulting PIH in those with darker skin types may be quite dramatic. Parents/guardians should be instructed to have a low-potency topical corticosteroid on hand to use on bites for a few days when they appear, which will not only help with the inflammation associated with the bite but also will help decrease pruritus and subsequently skin injury from scratching. In homes with pets, checking animals routinely for fleas and other infestations is helpful. In the setting of repeated arthropod bites in the spring and summer, applying bug repellant with 10% to 30% DEET (N,N-diethyl-meta-toluamide) on the child’s clothing and exposed body areas before playing outside or in the morning before school or camp may prevent some bites. There are DEET alternatives, such as picaridin, that may be used. Product instructions should be followed when using insect repellants in the pediatric population.¹¹

PIH Management Strategies

Gentle Skin Care Routine
There are misconceptions that areas of hyperpigmentation on the skin are caused by dirt and that scrubbing the skin harder may help to lighten the affected areas. Parents/guardians may report that the child’s skin looks dirty or, in the setting of acne, view dirt as the cause of the skin condition, which may prompt the patient to scrub the skin and the friction further worsens the PIH. Use of daily gentle cleansers and moisturizers is advised to keep the skin moisturized and free of further potential irritation and dryness that may prompt scratching or flares of the underlying condition.

Photoprotection
During the treatment course for PIH, using sun protection is helpful to prevent further darkening of the PIH areas. Sun protection may be in the form of broad-spectrum sunscreen, hats, or sun-protective clothing. Patients should be encouraged to apply sunscreen daily and to reapply every 2 hours and after water-based activities.¹² For pediatric and adolescent populations, practicing sun-protective behaviors before school or outdoor activities also should be advised, as many families only think about sun protection in the setting of sunny vacation activities. Research has demonstrated that individuals with skin of color may not realize that they can be affected by skin cancer,¹³ thus they may not have any experience selecting, applying, or regularly using sunscreens. Products that do not leave a white hue on the skin are suggested for adolescents who may be sensitive about their appearance following sunscreen application.

Skin Lightening Treatments

Although the most important therapy for PIH is to treat the underlying inflammatory conditions, some parents/guardians may desire additional options due to the extent of involvement of the PIH, its psychological impact on the child, or adverse effect on the child’s quality of life.¹⁴ In adolescents, incorporating an α-hydroxy acid–based cleanser, glycolic acid chemical peels, salicylic acid chemical peels, and topical cosmeceuticals may be warranted in the setting of intense PIH and acne. However, irritation may lead to further dyspigmentation.

Topical ammonium lactate 12% is lactic acid neutralized with ammonium hydroxide that is formulated as a lotion or a cream. It is used to hydrate dry skin and may decrease corneocyte cohesion.¹⁵ Topical ammonium lactate also has been used anecdotally for PIH on the body during periods of watchful waiting.

Topical hydroquinone, the gold standard for treating hyperpigmentation,^3,16 is not approved in children, but some parents/guardians elect to utilize hydroquinone off label to accelerate the clearing of distressing PIH in adolescents. Careful consideration including a discussion of potential risks and alternatives (eg, watchful waiting) should be highlighted.

In the setting of chronic inflammatory conditions that recur and remit, potentially irritating topical treatments should be used only during periods when symptoms of inflammation such as itching or erythema are absent.

Conclusion

Despite the best management efforts, PIH in some patients with skin of color may be present for months to years. In the pediatric skin of color population, treatment of the underlying inflammatory condition, gentle skin care, use of photoprotection, and time may be all that is needed for PIH resolution. With their parent/guardians’ consent, adolescents distressed by PIH may decide to pursue more aggressive, potentially irritating treatments. Above all, the most important management in the setting of PIH is to treat the underlying inflammatory condition causing the PIH and set reasonable expectations. For challenging cases, pediatric dermatologists with special expertise in treating pediatric and adolescent patients with skin of color may be consulted.

Postnflammatory hyperpigmentation (PIH) is an acquired hypermelanosis that can occur in children and adults following an inflammatory cutaneous disease or trauma. Postinflammatory hyperpigmentation may last for months to even years. Although PIH may occur in all skin types, it is more common and presents with greater severity and intensity in individuals with skin of color. By the year 2050, 1 in 3 US residents is projected to be Hispanic.¹ It is projected that by 2044, non-Hispanic white individuals (all ages) will make up less than 50% of the US population.² Currently, the majority of the US residents younger than 18 years are minorities. The majority minority population in the United States already exists in those younger than 18 years and is predicted to occur in the adult population by 2044.²

Effective treatment options and management strategies for PIH in adults with skin of color have been described in the literature.³ Due to a paucity of research, the approach to management of PIH in children with skin of color has been based on clinical experience and lessons learned from adult patients. This article focuses on management of PIH in pediatric patients with skin of color, which includes black/African American, African-Caribbean, Hispanic, Asian, Pacific Islander, and American Indian individuals.

Underlying Inflammatory Dermatoses Resulting in PIH

There are numerous conditions that may result in PIH, including but not limited to atopic dermatitis (AD), acne, arthropod bites, and injuries to the skin. Postinflammatory hyperpigmentation may have more of a psychological impact than the inciting disease or injury itself. The most important step in the approach to managing PIH is treating the underlying inflammatory condition that caused the pigmentation.

Parents/guardians may report a chief concern of dark spots, manchas (stains), blemishes, or stains on the skin, often with no mention of a coexisting inflammatory dermatosis. Parents/guardians of children with skin of color often have personally experienced PIH and may be determined to shield their children from similar angst associated with the condition. Although physicians may see just another pediatric patient with PIH, the child’s parents/guardians may see a condition that will be readily perceptible during major life events, such as the child’s prom or even his/her wedding day. Promptly diagnosing and instituting early treatment of inflammatory conditions associated with PIH may accelerate resolution and prevent worsening of the pigmentation.³

Select inflammatory dermatoses that are common in children with skin of color and may lead to PIH are highlighted below. Although this list is not comprehensive, the approach and management strategies should prompt creation of plans that keep PIH in mind when treating primary inflammatory skin diseases.

Atopic Dermatitis
Atopic dermatitis may induce PIH or hypopigmentation of the skin in children with skin of color. Developing a plan for AD flare prevention, as well as management of mild, moderate, and severe AD flares, is imperative in pediatric patients. Prevention plans should include gentle skin care, twice-daily application of emollients to the full body, and reduction of Staphylococcus aureus loads on the skin. The treatment action plan for mild to moderate flares may include topical corticosteroids, immunomodulators, and nonsteroidal agents. Treatment options for severe AD or patients who were unsuccessfully treated with other therapies may include phototherapy, biologics, and methotrexate, among others.⁴ Creating action plans for AD flares is a vital step in the prevention of PIH in patients with skin of color. Additionally, PIH should not be considered a sign of AD treatment failure.

Acne
Acne is a common skin disorder seen in patients with skin of color.⁵ A prospective observational study found that 34.3% of 683 children aged 9 to 14 years in a pediatric ambulatory clinic had acne.⁶ The number of preadolescents with acne is growing. Most cases are not associated with underlying endocrinopathy.⁷ With the growing population of children with skin of color in the United States along with the increasing childhood acne rate and subsequent inherent risk for hyperpigmentation, early acne interventions should be considered in pediatric acne patients with skin of color to reduce the impact of PIH in those at risk.

In a survey study of 313 adult acne patients with skin of color, 37.2% reported the presence of dark marks lasting 4 months or longer.⁵ Regardless of the severity of the acne, treatment should be initiated as tolerated in those with PIH. Adolescent acne patients with skin of color may develop PIH that is more severe and longer lasting than the acne itself.

The foundation for treatment of acne in adolescent skin of color patients is the same as those without skin of color, including topical retinoids, topical antibiotics, oral antibiotics, and isotretinoin when needed. Topical tretinoin, adapalene, azelaic acid, and tazarotene not only treat acne but also are a valuable part of the treatment armamentarium for PIH. Several studies in adults with skin of color have demonstrated improvement of PIH from the use of topical retinoids alone.^8-10 Despite wanting to treat the acne aggressively, special guidance should be given to prevent retinoid dermatitis, which may lead to PIH.¹⁰ Demonstrating the application of the topical acne medications, discussing how to avoid potential side effects, and giving permission to skip applications, if needed, may empower families to make adjustments between visits to limit irritation that might prompt further PIH. Incorporating α-hydroxy acid–based cleansers, α-hydroxy acid–based chemical peels, or salicylic acid chemical peels may be warranted in the setting of intense PIH. Selecting treatments that not only help the inflammatory disease leading to the PIH but also can help improve the pigmentation are preferred; however, the risks and benefits have to be weighed because many treatments that work well for PIH also may cause irritation, leading to new or worsening PIH.

Arthropod Bites
Arthropod bites cause inflamed pruritic papules and nodules, and the resulting PIH in those with darker skin types may be quite dramatic. Parents/guardians should be instructed to have a low-potency topical corticosteroid on hand to use on bites for a few days when they appear, which will not only help with the inflammation associated with the bite but also will help decrease pruritus and subsequently skin injury from scratching. In homes with pets, checking animals routinely for fleas and other infestations is helpful. In the setting of repeated arthropod bites in the spring and summer, applying bug repellant with 10% to 30% DEET (N,N-diethyl-meta-toluamide) on the child’s clothing and exposed body areas before playing outside or in the morning before school or camp may prevent some bites. There are DEET alternatives, such as picaridin, that may be used. Product instructions should be followed when using insect repellants in the pediatric population.¹¹

PIH Management Strategies

Gentle Skin Care Routine
There are misconceptions that areas of hyperpigmentation on the skin are caused by dirt and that scrubbing the skin harder may help to lighten the affected areas. Parents/guardians may report that the child’s skin looks dirty or, in the setting of acne, view dirt as the cause of the skin condition, which may prompt the patient to scrub the skin and the friction further worsens the PIH. Use of daily gentle cleansers and moisturizers is advised to keep the skin moisturized and free of further potential irritation and dryness that may prompt scratching or flares of the underlying condition.

Photoprotection
During the treatment course for PIH, using sun protection is helpful to prevent further darkening of the PIH areas. Sun protection may be in the form of broad-spectrum sunscreen, hats, or sun-protective clothing. Patients should be encouraged to apply sunscreen daily and to reapply every 2 hours and after water-based activities.¹² For pediatric and adolescent populations, practicing sun-protective behaviors before school or outdoor activities also should be advised, as many families only think about sun protection in the setting of sunny vacation activities. Research has demonstrated that individuals with skin of color may not realize that they can be affected by skin cancer,¹³ thus they may not have any experience selecting, applying, or regularly using sunscreens. Products that do not leave a white hue on the skin are suggested for adolescents who may be sensitive about their appearance following sunscreen application.

Skin Lightening Treatments

Although the most important therapy for PIH is to treat the underlying inflammatory conditions, some parents/guardians may desire additional options due to the extent of involvement of the PIH, its psychological impact on the child, or adverse effect on the child’s quality of life.¹⁴ In adolescents, incorporating an α-hydroxy acid–based cleanser, glycolic acid chemical peels, salicylic acid chemical peels, and topical cosmeceuticals may be warranted in the setting of intense PIH and acne. However, irritation may lead to further dyspigmentation.

Topical ammonium lactate 12% is lactic acid neutralized with ammonium hydroxide that is formulated as a lotion or a cream. It is used to hydrate dry skin and may decrease corneocyte cohesion.¹⁵ Topical ammonium lactate also has been used anecdotally for PIH on the body during periods of watchful waiting.

Topical hydroquinone, the gold standard for treating hyperpigmentation,^3,16 is not approved in children, but some parents/guardians elect to utilize hydroquinone off label to accelerate the clearing of distressing PIH in adolescents. Careful consideration including a discussion of potential risks and alternatives (eg, watchful waiting) should be highlighted.

In the setting of chronic inflammatory conditions that recur and remit, potentially irritating topical treatments should be used only during periods when symptoms of inflammation such as itching or erythema are absent.

Conclusion

Despite the best management efforts, PIH in some patients with skin of color may be present for months to years. In the pediatric skin of color population, treatment of the underlying inflammatory condition, gentle skin care, use of photoprotection, and time may be all that is needed for PIH resolution. With their parent/guardians’ consent, adolescents distressed by PIH may decide to pursue more aggressive, potentially irritating treatments. Above all, the most important management in the setting of PIH is to treat the underlying inflammatory condition causing the PIH and set reasonable expectations. For challenging cases, pediatric dermatologists with special expertise in treating pediatric and adolescent patients with skin of color may be consulted.

Postnflammatory hyperpigmentation (PIH) is an acquired hypermelanosis that can occur in children and adults following an inflammatory cutaneous disease or trauma. Postinflammatory hyperpigmentation may last for months to even years. Although PIH may occur in all skin types, it is more common and presents with greater severity and intensity in individuals with skin of color. By the year 2050, 1 in 3 US residents is projected to be Hispanic.¹ It is projected that by 2044, non-Hispanic white individuals (all ages) will make up less than 50% of the US population.² Currently, the majority of the US residents younger than 18 years are minorities. The majority minority population in the United States already exists in those younger than 18 years and is predicted to occur in the adult population by 2044.²

Effective treatment options and management strategies for PIH in adults with skin of color have been described in the literature.³ Due to a paucity of research, the approach to management of PIH in children with skin of color has been based on clinical experience and lessons learned from adult patients. This article focuses on management of PIH in pediatric patients with skin of color, which includes black/African American, African-Caribbean, Hispanic, Asian, Pacific Islander, and American Indian individuals.

Underlying Inflammatory Dermatoses Resulting in PIH

There are numerous conditions that may result in PIH, including but not limited to atopic dermatitis (AD), acne, arthropod bites, and injuries to the skin. Postinflammatory hyperpigmentation may have more of a psychological impact than the inciting disease or injury itself. The most important step in the approach to managing PIH is treating the underlying inflammatory condition that caused the pigmentation.

Parents/guardians may report a chief concern of dark spots, manchas (stains), blemishes, or stains on the skin, often with no mention of a coexisting inflammatory dermatosis. Parents/guardians of children with skin of color often have personally experienced PIH and may be determined to shield their children from similar angst associated with the condition. Although physicians may see just another pediatric patient with PIH, the child’s parents/guardians may see a condition that will be readily perceptible during major life events, such as the child’s prom or even his/her wedding day. Promptly diagnosing and instituting early treatment of inflammatory conditions associated with PIH may accelerate resolution and prevent worsening of the pigmentation.³

Select inflammatory dermatoses that are common in children with skin of color and may lead to PIH are highlighted below. Although this list is not comprehensive, the approach and management strategies should prompt creation of plans that keep PIH in mind when treating primary inflammatory skin diseases.

Atopic Dermatitis
Atopic dermatitis may induce PIH or hypopigmentation of the skin in children with skin of color. Developing a plan for AD flare prevention, as well as management of mild, moderate, and severe AD flares, is imperative in pediatric patients. Prevention plans should include gentle skin care, twice-daily application of emollients to the full body, and reduction of Staphylococcus aureus loads on the skin. The treatment action plan for mild to moderate flares may include topical corticosteroids, immunomodulators, and nonsteroidal agents. Treatment options for severe AD or patients who were unsuccessfully treated with other therapies may include phototherapy, biologics, and methotrexate, among others.⁴ Creating action plans for AD flares is a vital step in the prevention of PIH in patients with skin of color. Additionally, PIH should not be considered a sign of AD treatment failure.

Acne
Acne is a common skin disorder seen in patients with skin of color.⁵ A prospective observational study found that 34.3% of 683 children aged 9 to 14 years in a pediatric ambulatory clinic had acne.⁶ The number of preadolescents with acne is growing. Most cases are not associated with underlying endocrinopathy.⁷ With the growing population of children with skin of color in the United States along with the increasing childhood acne rate and subsequent inherent risk for hyperpigmentation, early acne interventions should be considered in pediatric acne patients with skin of color to reduce the impact of PIH in those at risk.

In a survey study of 313 adult acne patients with skin of color, 37.2% reported the presence of dark marks lasting 4 months or longer.⁵ Regardless of the severity of the acne, treatment should be initiated as tolerated in those with PIH. Adolescent acne patients with skin of color may develop PIH that is more severe and longer lasting than the acne itself.

The foundation for treatment of acne in adolescent skin of color patients is the same as those without skin of color, including topical retinoids, topical antibiotics, oral antibiotics, and isotretinoin when needed. Topical tretinoin, adapalene, azelaic acid, and tazarotene not only treat acne but also are a valuable part of the treatment armamentarium for PIH. Several studies in adults with skin of color have demonstrated improvement of PIH from the use of topical retinoids alone.^8-10 Despite wanting to treat the acne aggressively, special guidance should be given to prevent retinoid dermatitis, which may lead to PIH.¹⁰ Demonstrating the application of the topical acne medications, discussing how to avoid potential side effects, and giving permission to skip applications, if needed, may empower families to make adjustments between visits to limit irritation that might prompt further PIH. Incorporating α-hydroxy acid–based cleansers, α-hydroxy acid–based chemical peels, or salicylic acid chemical peels may be warranted in the setting of intense PIH. Selecting treatments that not only help the inflammatory disease leading to the PIH but also can help improve the pigmentation are preferred; however, the risks and benefits have to be weighed because many treatments that work well for PIH also may cause irritation, leading to new or worsening PIH.

Arthropod Bites
Arthropod bites cause inflamed pruritic papules and nodules, and the resulting PIH in those with darker skin types may be quite dramatic. Parents/guardians should be instructed to have a low-potency topical corticosteroid on hand to use on bites for a few days when they appear, which will not only help with the inflammation associated with the bite but also will help decrease pruritus and subsequently skin injury from scratching. In homes with pets, checking animals routinely for fleas and other infestations is helpful. In the setting of repeated arthropod bites in the spring and summer, applying bug repellant with 10% to 30% DEET (N,N-diethyl-meta-toluamide) on the child’s clothing and exposed body areas before playing outside or in the morning before school or camp may prevent some bites. There are DEET alternatives, such as picaridin, that may be used. Product instructions should be followed when using insect repellants in the pediatric population.¹¹

PIH Management Strategies

Gentle Skin Care Routine
There are misconceptions that areas of hyperpigmentation on the skin are caused by dirt and that scrubbing the skin harder may help to lighten the affected areas. Parents/guardians may report that the child’s skin looks dirty or, in the setting of acne, view dirt as the cause of the skin condition, which may prompt the patient to scrub the skin and the friction further worsens the PIH. Use of daily gentle cleansers and moisturizers is advised to keep the skin moisturized and free of further potential irritation and dryness that may prompt scratching or flares of the underlying condition.

Photoprotection
During the treatment course for PIH, using sun protection is helpful to prevent further darkening of the PIH areas. Sun protection may be in the form of broad-spectrum sunscreen, hats, or sun-protective clothing. Patients should be encouraged to apply sunscreen daily and to reapply every 2 hours and after water-based activities.¹² For pediatric and adolescent populations, practicing sun-protective behaviors before school or outdoor activities also should be advised, as many families only think about sun protection in the setting of sunny vacation activities. Research has demonstrated that individuals with skin of color may not realize that they can be affected by skin cancer,¹³ thus they may not have any experience selecting, applying, or regularly using sunscreens. Products that do not leave a white hue on the skin are suggested for adolescents who may be sensitive about their appearance following sunscreen application.

Skin Lightening Treatments

Although the most important therapy for PIH is to treat the underlying inflammatory conditions, some parents/guardians may desire additional options due to the extent of involvement of the PIH, its psychological impact on the child, or adverse effect on the child’s quality of life.¹⁴ In adolescents, incorporating an α-hydroxy acid–based cleanser, glycolic acid chemical peels, salicylic acid chemical peels, and topical cosmeceuticals may be warranted in the setting of intense PIH and acne. However, irritation may lead to further dyspigmentation.

Topical ammonium lactate 12% is lactic acid neutralized with ammonium hydroxide that is formulated as a lotion or a cream. It is used to hydrate dry skin and may decrease corneocyte cohesion.¹⁵ Topical ammonium lactate also has been used anecdotally for PIH on the body during periods of watchful waiting.

Topical hydroquinone, the gold standard for treating hyperpigmentation,^3,16 is not approved in children, but some parents/guardians elect to utilize hydroquinone off label to accelerate the clearing of distressing PIH in adolescents. Careful consideration including a discussion of potential risks and alternatives (eg, watchful waiting) should be highlighted.

In the setting of chronic inflammatory conditions that recur and remit, potentially irritating topical treatments should be used only during periods when symptoms of inflammation such as itching or erythema are absent.

Conclusion

Despite the best management efforts, PIH in some patients with skin of color may be present for months to years. In the pediatric skin of color population, treatment of the underlying inflammatory condition, gentle skin care, use of photoprotection, and time may be all that is needed for PIH resolution. With their parent/guardians’ consent, adolescents distressed by PIH may decide to pursue more aggressive, potentially irritating treatments. Above all, the most important management in the setting of PIH is to treat the underlying inflammatory condition causing the PIH and set reasonable expectations. For challenging cases, pediatric dermatologists with special expertise in treating pediatric and adolescent patients with skin of color may be consulted.

Vitiligo and major depressive disorder have a bidirectional relationship, according to a new study that examined data from a cohort of more than 6 million people.

“Ultimately, this suggests that mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo, which in turn can increase the risk of MDD, especially in younger patients,” wrote Isabelle Vallerand, PhD, and her colleagues. The report is in the Journal of the American Academy of Dermatology.

Dr. Vallerand and her colleagues found that patients with major depressive disorder (MDD, n = 405,397) had a 64% increased risk of vitiligo, compared with a referent cohort (n = 5,739,048; 95% confidence interval, 1.43-1.87; P less than .0001). Conversely, patients who had vitiligo also were at an increased risk of MDD. Patients who were younger than 30 years old at diagnosis (n = 7,104) had a hazard ratio of 1.31 for MDD (P less than .0001), compared with 1.22 for patients aged 30 years and older (P = .001).

Individuals who took antidepressants, whether or not they also had an MDD diagnosis, had a decreased risk for vitiligo.

Though it’s known that vitiligo increases the risk of MDD, less clarity has been in the literature about whether the converse also might be true. “The question of whether vitiligo onset can be precipitated by MDD has received less attention, despite the notion that patients often ask their dermatologists if stress or depression may have contributed to their disease,” wrote Dr. Vallerand, an epidemiologist and medical student at the University of Calgary, Alberta, and her colleagues.

There is a biologic plausibility for a bidirectional relationship, said Dr. Vallerand and her colleagues, since depression can boost systemic inflammation, and the risk for autoimmune disease such as vitiligo can be increased by proinflammatory states.

Access to a large dataset gave Dr. Vallerand and her collaborators the numbers to look at the relationship between vitiligo and MDD in the context of potential confounders, and to correct for those in their statistical analysis. Using medical records from The Health Improvement Network (THIN) database in the United Kingdom, the investigators conducted two independent population-based cohort studies. Each looked at risk in one direction of the MDD-vitiligo association.

The first analysis looked at MDD as a risk factor for vitiligo, following all patients with an incident diagnostic code for MDD. Patients without the MDD diagnosis code were the referent cohort. Patients in each cohort were followed until they reached the outcome of interest – a diagnosis of vitiligo – or were censored. Patients who had a vitiligo diagnosis before receiving an MDD diagnosis were not included.

The second analysis examined whether vitiligo was a risk factor for MDD, with a similar design that used nonvitiligo patients as the referent cohort. This analysis followed all patients until a diagnosis of MDD was recorded, or patients were censored. Again, patients with MDD diagnoses that came before the vitiligo diagnosis were excluded.

For the analysis of risk of vitiligo, the investigators looked at the effects of multiple covariates, including age, sex, alcohol use and smoking status, socioeconomic status, medical comorbidities, and whether patients were taking antidepressants. The covariates included in the analysis of risk of MDD were age, sex, medical comorbidities, and type of vitiligo treatment.

After the researchers determined unadjusted hazard ratios, each covariate was removed one at a time to see where there were substantial changes to the HR. Two additional models, one unadjusted and one that fully adjusted for all covariates, also were built.

The sensitivity analyses showed “an overall protective effect of antidepressants among both cohorts,” wrote Dr. Vallerand and her colleagues. The incidence rate of vitiligo among patients with MDD using antidepressants was 19.7 per 100,000 person-years, compared with 27.5 among MDD patients not using antidepressants (P = .0053).

“Similarly, those in the referent cohort who used antidepressants had about half the risk of vitiligo,” compared with the nonusers in the referent group, the investigators said. Serotonin also is present in the skin, and neurons and melanocytes share embryonic ectodermal origins, Dr. Vallerand and her colleagues said. Though the exact mechanisms are not known, patients with vitiligo may have lower skin serotonin, so there’s a potential role for serotonergic medication in the incidence of vitiligo in the THIN cohorts, they noted.

Though younger patients with vitiligo were at higher risk for MDD than were those aged 30 years and older, the overall cohort of individuals with vitiligo still had an unadjusted elevated risk for MDD, compared with the referent cohort (HR 1.27; 95% confidence interval, 1.16-1.40; P less than .0001).

“Unexpectedly, the magnitude of the reciprocal association was highest with MDD being a risk factor for vitiligo,” wrote Dr. Vallerand and her colleagues. “This highlights the notion that mental health may have a greater impact on the body, specifically with dermatologic manifestations, than previously thought.”

Some misclassification of both conditions is likely in such a large dataset, the investigators acknowledged. Also, subclinical depression was not evaluated, and there was no way to track the severity of either depression or vitiligo, they noted. Still, the big data approach “renders this one of the largest studies on psychodermatology to date,” said Dr. Vallerand and her colleagues, and the independent bidirectional analyses support causality.

Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRX, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.

koakes@mdedge.com

SOURCE: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.

Vitiligo and major depressive disorder have a bidirectional relationship, according to a new study that examined data from a cohort of more than 6 million people.

“Ultimately, this suggests that mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo, which in turn can increase the risk of MDD, especially in younger patients,” wrote Isabelle Vallerand, PhD, and her colleagues. The report is in the Journal of the American Academy of Dermatology.

Dr. Vallerand and her colleagues found that patients with major depressive disorder (MDD, n = 405,397) had a 64% increased risk of vitiligo, compared with a referent cohort (n = 5,739,048; 95% confidence interval, 1.43-1.87; P less than .0001). Conversely, patients who had vitiligo also were at an increased risk of MDD. Patients who were younger than 30 years old at diagnosis (n = 7,104) had a hazard ratio of 1.31 for MDD (P less than .0001), compared with 1.22 for patients aged 30 years and older (P = .001).

Individuals who took antidepressants, whether or not they also had an MDD diagnosis, had a decreased risk for vitiligo.

Though it’s known that vitiligo increases the risk of MDD, less clarity has been in the literature about whether the converse also might be true. “The question of whether vitiligo onset can be precipitated by MDD has received less attention, despite the notion that patients often ask their dermatologists if stress or depression may have contributed to their disease,” wrote Dr. Vallerand, an epidemiologist and medical student at the University of Calgary, Alberta, and her colleagues.

There is a biologic plausibility for a bidirectional relationship, said Dr. Vallerand and her colleagues, since depression can boost systemic inflammation, and the risk for autoimmune disease such as vitiligo can be increased by proinflammatory states.

Access to a large dataset gave Dr. Vallerand and her collaborators the numbers to look at the relationship between vitiligo and MDD in the context of potential confounders, and to correct for those in their statistical analysis. Using medical records from The Health Improvement Network (THIN) database in the United Kingdom, the investigators conducted two independent population-based cohort studies. Each looked at risk in one direction of the MDD-vitiligo association.

The first analysis looked at MDD as a risk factor for vitiligo, following all patients with an incident diagnostic code for MDD. Patients without the MDD diagnosis code were the referent cohort. Patients in each cohort were followed until they reached the outcome of interest – a diagnosis of vitiligo – or were censored. Patients who had a vitiligo diagnosis before receiving an MDD diagnosis were not included.

The second analysis examined whether vitiligo was a risk factor for MDD, with a similar design that used nonvitiligo patients as the referent cohort. This analysis followed all patients until a diagnosis of MDD was recorded, or patients were censored. Again, patients with MDD diagnoses that came before the vitiligo diagnosis were excluded.

For the analysis of risk of vitiligo, the investigators looked at the effects of multiple covariates, including age, sex, alcohol use and smoking status, socioeconomic status, medical comorbidities, and whether patients were taking antidepressants. The covariates included in the analysis of risk of MDD were age, sex, medical comorbidities, and type of vitiligo treatment.

After the researchers determined unadjusted hazard ratios, each covariate was removed one at a time to see where there were substantial changes to the HR. Two additional models, one unadjusted and one that fully adjusted for all covariates, also were built.

The sensitivity analyses showed “an overall protective effect of antidepressants among both cohorts,” wrote Dr. Vallerand and her colleagues. The incidence rate of vitiligo among patients with MDD using antidepressants was 19.7 per 100,000 person-years, compared with 27.5 among MDD patients not using antidepressants (P = .0053).

“Similarly, those in the referent cohort who used antidepressants had about half the risk of vitiligo,” compared with the nonusers in the referent group, the investigators said. Serotonin also is present in the skin, and neurons and melanocytes share embryonic ectodermal origins, Dr. Vallerand and her colleagues said. Though the exact mechanisms are not known, patients with vitiligo may have lower skin serotonin, so there’s a potential role for serotonergic medication in the incidence of vitiligo in the THIN cohorts, they noted.

Though younger patients with vitiligo were at higher risk for MDD than were those aged 30 years and older, the overall cohort of individuals with vitiligo still had an unadjusted elevated risk for MDD, compared with the referent cohort (HR 1.27; 95% confidence interval, 1.16-1.40; P less than .0001).

“Unexpectedly, the magnitude of the reciprocal association was highest with MDD being a risk factor for vitiligo,” wrote Dr. Vallerand and her colleagues. “This highlights the notion that mental health may have a greater impact on the body, specifically with dermatologic manifestations, than previously thought.”

Some misclassification of both conditions is likely in such a large dataset, the investigators acknowledged. Also, subclinical depression was not evaluated, and there was no way to track the severity of either depression or vitiligo, they noted. Still, the big data approach “renders this one of the largest studies on psychodermatology to date,” said Dr. Vallerand and her colleagues, and the independent bidirectional analyses support causality.

Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRX, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.

koakes@mdedge.com

SOURCE: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.

Vitiligo and major depressive disorder have a bidirectional relationship, according to a new study that examined data from a cohort of more than 6 million people.

“Ultimately, this suggests that mental health appears to play a large role in the pathogenesis of autoimmune diseases like vitiligo, which in turn can increase the risk of MDD, especially in younger patients,” wrote Isabelle Vallerand, PhD, and her colleagues. The report is in the Journal of the American Academy of Dermatology.

Dr. Vallerand and her colleagues found that patients with major depressive disorder (MDD, n = 405,397) had a 64% increased risk of vitiligo, compared with a referent cohort (n = 5,739,048; 95% confidence interval, 1.43-1.87; P less than .0001). Conversely, patients who had vitiligo also were at an increased risk of MDD. Patients who were younger than 30 years old at diagnosis (n = 7,104) had a hazard ratio of 1.31 for MDD (P less than .0001), compared with 1.22 for patients aged 30 years and older (P = .001).

Individuals who took antidepressants, whether or not they also had an MDD diagnosis, had a decreased risk for vitiligo.

Though it’s known that vitiligo increases the risk of MDD, less clarity has been in the literature about whether the converse also might be true. “The question of whether vitiligo onset can be precipitated by MDD has received less attention, despite the notion that patients often ask their dermatologists if stress or depression may have contributed to their disease,” wrote Dr. Vallerand, an epidemiologist and medical student at the University of Calgary, Alberta, and her colleagues.

There is a biologic plausibility for a bidirectional relationship, said Dr. Vallerand and her colleagues, since depression can boost systemic inflammation, and the risk for autoimmune disease such as vitiligo can be increased by proinflammatory states.

Access to a large dataset gave Dr. Vallerand and her collaborators the numbers to look at the relationship between vitiligo and MDD in the context of potential confounders, and to correct for those in their statistical analysis. Using medical records from The Health Improvement Network (THIN) database in the United Kingdom, the investigators conducted two independent population-based cohort studies. Each looked at risk in one direction of the MDD-vitiligo association.

The first analysis looked at MDD as a risk factor for vitiligo, following all patients with an incident diagnostic code for MDD. Patients without the MDD diagnosis code were the referent cohort. Patients in each cohort were followed until they reached the outcome of interest – a diagnosis of vitiligo – or were censored. Patients who had a vitiligo diagnosis before receiving an MDD diagnosis were not included.

The second analysis examined whether vitiligo was a risk factor for MDD, with a similar design that used nonvitiligo patients as the referent cohort. This analysis followed all patients until a diagnosis of MDD was recorded, or patients were censored. Again, patients with MDD diagnoses that came before the vitiligo diagnosis were excluded.

For the analysis of risk of vitiligo, the investigators looked at the effects of multiple covariates, including age, sex, alcohol use and smoking status, socioeconomic status, medical comorbidities, and whether patients were taking antidepressants. The covariates included in the analysis of risk of MDD were age, sex, medical comorbidities, and type of vitiligo treatment.

After the researchers determined unadjusted hazard ratios, each covariate was removed one at a time to see where there were substantial changes to the HR. Two additional models, one unadjusted and one that fully adjusted for all covariates, also were built.

The sensitivity analyses showed “an overall protective effect of antidepressants among both cohorts,” wrote Dr. Vallerand and her colleagues. The incidence rate of vitiligo among patients with MDD using antidepressants was 19.7 per 100,000 person-years, compared with 27.5 among MDD patients not using antidepressants (P = .0053).

“Similarly, those in the referent cohort who used antidepressants had about half the risk of vitiligo,” compared with the nonusers in the referent group, the investigators said. Serotonin also is present in the skin, and neurons and melanocytes share embryonic ectodermal origins, Dr. Vallerand and her colleagues said. Though the exact mechanisms are not known, patients with vitiligo may have lower skin serotonin, so there’s a potential role for serotonergic medication in the incidence of vitiligo in the THIN cohorts, they noted.

Though younger patients with vitiligo were at higher risk for MDD than were those aged 30 years and older, the overall cohort of individuals with vitiligo still had an unadjusted elevated risk for MDD, compared with the referent cohort (HR 1.27; 95% confidence interval, 1.16-1.40; P less than .0001).

“Unexpectedly, the magnitude of the reciprocal association was highest with MDD being a risk factor for vitiligo,” wrote Dr. Vallerand and her colleagues. “This highlights the notion that mental health may have a greater impact on the body, specifically with dermatologic manifestations, than previously thought.”

Some misclassification of both conditions is likely in such a large dataset, the investigators acknowledged. Also, subclinical depression was not evaluated, and there was no way to track the severity of either depression or vitiligo, they noted. Still, the big data approach “renders this one of the largest studies on psychodermatology to date,” said Dr. Vallerand and her colleagues, and the independent bidirectional analyses support causality.

Dr. Vallerand is a partner in a pharmaceutical consulting firm, GlacierRX, and was funded by Alberta Innovates. The authors reported having no conflicts of interest.

koakes@mdedge.com

SOURCE: Vallerand IA et al. J Am Acad Dermatol. 2019. doi: 10.1016/j.jaad.2018.11.047.