Ashy dermatosis : A comprehensive review

Ashy dermatosis, first described by Ramirez in 1957 [1], is an idiopathic acquired macular hyperpigmentation disorder. The descriptive term “ashy or los cenicientos” was used because of the ashy blue-grey color of the lesions. The sites commonly affected include face, neck, trunk and upper limbs but any region of the body can be affected [2]. Convit, Kerdel-Vegas and Rodriguez in their case series reported the presence of raised erythematous borders in the early stages and proposed the term “erythema dyschromicum perstans (EDP)” [3]. Other authors however have noted that EDP can occur without marginal erythema [4,5]. Bhutani and his colleagues described similar hyperpigmented macules over the flexures and photoexposed areas in 40 Indian patients, about a third of whom had associated features of lichen planus on clinical evaluation and histopathological examination [6]. These entities were subsequently labeled as “lichen planus pigmentosus (LPP)”.


INTRODUCTION
Ashy dermatosis, first described by Ramirez in 1957 [1], is an idiopathic acquired macular hyperpigmentation disorder.The descriptive term "ashy or los cenicientos" was used because of the ashy blue-grey color of the lesions.The sites commonly affected include face, neck, trunk and upper limbs but any region of the body can be affected [2].Convit, Kerdel-Vegas and Rodriguez in their case series reported the presence of raised erythematous borders in the early stages and proposed the term "erythema dyschromicum perstans (EDP)" [3].Other authors however have noted that EDP can occur without marginal erythema [4,5].Bhutani and his colleagues described similar hyperpigmented macules over the flexures and photoexposed areas in 40 Indian patients, about a third of whom had associated features of lichen planus on clinical evaluation and histopathological examination [6].These entities were subsequently labeled as "lichen planus pigmentosus (LPP)".the keywords ashy dermatosis, erythema dyschromicum perstans, lichen planus pigmentosus, acquired hyperpigmentation and facial melanosis.All the articles published irrespective of the date of publication were accessed.The photographs displayed were taken by the author from the patients visiting the outpatient department of the Department of Dermatology at the Institute of Medicine, Tribhuvan University Teaching Hospital, Kathmandu, Nepal.

Ethics Statement
The photographs displayed in this review article were taken and illustrated after obtaining verbal consent from the patients.Attempts have been made to ensure that the photographs do not reveal the identity of the participants.

Epidemiology
The exact incidence and prevalence of these acquired macular hyperpigmentary disorders is unknown.Onset can occur at any age but the mean age of occurrence is usually in the 2 nd decade of life [7,8].The condition is most common in Asia and Central and South America, as the majority of the published cases have been from those regions [7][8][9].Silverberg and colleagues reported that most of the prepubertal patients suffering from Ashy dermatosis were Caucasians (52%) and Hispanics (36%) [10].There have been two case reports of Indian children with this condition [11,12].The condition affects both the sexes but is more common in women [7][8][9].

Aetiology and Associations
The exact cause of ashy dermatosis is unknown.However, it has been reported in association with the ingestion of ammonium nitrate and barium sulfate.The reported associated infections and infestations include hepatitis C virus infection, HIV infection and whipworm infestation [7][8][9].

Pathophysiology
The pathophysiology of ashy dermatosis or erythema dyschromicum perstans is currently unknown.An association with contrast agents, viral infections and worm infestations have been reported [7][8][9].It has been hypothesized that an immunological response to these agents may lead to the hyperpigmentation [13].Furthermore, Numata and his colleagues have hypothesized that a weaker immune response leads to ashy dermatosis while a stronger response can cause erythema dyschromicum perstans [13].

Genetics
Only one study has showed that the presence of HLA-DR4 *0407 is a risk factor in Mexican mestizos [14].

Pathology
There are no pathognomonic findings in the histology of the lesions [2].The most common finding in the epidermis is vacuolar degeneration of basal cells leading to pigmentary incontinence and accumulation of melanophages in the papillary dermis [9].The dermal changes include oedema of the papillary dermis and an infiltrate of lymphocytes and histiocytes [15].Vasquez-Ochoa et al. in their study, demonstrated predominance of CD8+ T lymphocytes and ICAM-1+ keratinocytes in the infiltrate [16].An interesting point to note is the absence of vacuolization of basal cells and decreased infiltrate in inactive lesions [17].
On direct immunofluorescence, there is colloid staining of IgM and C4 along with deposition of fibrinogen at the dermoepidermal junction [18].

Clinical Features
The condition usually starts in young adults between the first and second decades of life [12].The initial presentation is that of slowly increasing asymptomatic macules measuring 0.5 cm -2 cm with varying shades of gray [12].They typically start in the trunk (Fig. 1) and then spread to involve the face and extremities (Fig. 2a and b) [12].However, most of the cases seen in our hospital have predominant involvement of the face, neck (Fig. 3a) and upper trunk with absence of involvement of the extremities.The lesions also tend to follow a photodistribution with relative sparing of the neck creases (Fig. 3b and c).Some authors [7,12] have described presence of an elevated erythematous palpable border measuring 1-2 mm in width surrounding the lesions in the early phase.Most authors [12,19] agree that border eventually disappears with a few months.The initial erythematous border may not be present in all the cases and are especially difficult to appreciate in patients with Fitzpatrick skin types IV, V [12].There is sparing of palms, soles, scalp, nails, and mucous membranes.
The other differentials are the pigmented macules of the late pinta, post-inflammatory hyperpigmentation, multiple fixed drug eruption, haemochromatosis, Addison's disease, melasma, leprosy and confluent and reticulated papillomatosis of Gougerot and Carteaud [2].

Erythema dyschromicum perstans and ashy dermatosis
The only significant difference between erythema dyschromicum perstans and ashy dermatosis has been the presence of a palpable erythematous border measuring 1-2 mm in width in the early stages of the former [12,19].However, the border can be difficult to discern in darker skinned populations [12].A descriptive term such as macular pigmentation of uncertain aetiology should be used to describe the two conditions, which have similar clinical picture, histology and prognosis [20].

Lichen planus pigmentosus
The differential generating the most controversy is lichen planus pigmentosus.In this condition, there are hyperpigmented brown macules over the exposed areas [2], which can be associated with pruritus [21,22] and with frequent remissions and exacerbations.Both ashy dermatosis and lichen planus pigmentosus are characterized by presence of pigment laden macrophages in the papillary dermis and vacuolar degeneration of the basal cells in the epidermis.Max-Joseph spaces, resulting from liquefactive degeneration of the basal layer with separation from underlying lamina propria, can observed in cases of lichen planus pigmentosus but are absent in ashy dermatosis.A band-like infiltrate present in lichen planus is absent in erythema dyschromicum perstans.However, the subpopulations of lymphocytes and keratinocytes are similar in both the conditions [2].As a result, some authors still dispute whether the conditions are clinically and histopathologically distinct from one another [16,23].

Idiopathic eruptive macular pigmentation
Idiopathic eruptive macular pigmentation as the name suggests is a rare condition characterized by eruption of brownish, non-confluent, asymptomatic macules involving the trunk, neck and proximal extremities in children and adolescents [24].The two main differences between this condition and ashy dermatosis are frequent resolution and basal layer hyperpigmentation without degeneration in the latter.

Riehl's melanosis
Riehl's melanosis, a pigmented contact dermatitis to cosmetics or textiles [25,26] is characterized by  reticular pigmentation, often with satellite perifollicular pigmented macules.It occurs at the site of contact, can be preceded by erythema and pruritus and patients usually demonstrate positivity to allergic patch tests [27].

Approach to diagnosis
A n a l g o r i t h m d e v i s e d b y C h a n d r a n a n d Kumarasinghe [20] can be used to make an approach to diagnosis in these conditions.The salient features are: Lichen planus pigmentosus: Past or current evidence of lichen planus, with supportive histological features including band-like infiltrates, basal layer hyperpigmentation and presence or absence of vacuolar degeneration of basal cells [20].
Ashy dermatosis: Large macules (> 5 cm) or combination of small (< 5 cm) and large macules with grayish tinge and absence of erythematous border.
Riehl's melanosis: Persistent small brown macules (<5 cm) that may be accompanied by erythema and pruritus and are usually caused by cosmetics and clothing.

Prognosis
Although the initial erythematous phase in erythematous dyschromicum perstans tend to subside after several months, the residual hyperpigmentation persists and may gradually increase in size [3].

Treatment Options
Randomized controlled trials for the treatment of ashy dermatosis have not been performed till date [28].There are no consistently effective treatment options for these conditions.

Topical agents Cosmetics and camouflage creams
These creams while not bringing any change to the lesions appear to improve the appearance of the lesions by decreasing the contrast with the surrounding uninvolved skin.

Narrow band ultraviolet therapy
Tlougan and colleagues [28] advocate the use of narrow band ultraviolet therapy.However, the recommendation is based on a single case without any mention of the dose, duration of the treatment and degree of improvement using an outcome measure.

Tacrolimus ointment
Mahajan and colleagues [29] report that in two patients with erythema dyschromicum perstans, topical tacrolimus 0.1% ointment applied twice daily to the affected areas resulted in significant improvement after 3 weeks.Controlled trials are recommended to ascertain whether the benefit is statistically significant.

Fractionated laser
Non-ablative 1550 nm fractional laser therapy was not considered to be effective for the treatment of erythema dyschromicum perstans [30].Moreover, the therapy resulted in postinflammatory hyperpigmentation secondary to laser burns.

Systemic agents Clofazimine
Two studies were conducted in the last 20 years, assessing the efficacy of clofazimine for erythema dyschromicum perstans.The patients were given tablet clofazimine 100mg daily for 3 months [31,32].The response rates varied from 66% to 87%.The side effects noted were discolourations of the skin, cornea and body fluids along with gastrointestinal intolerance.One of the reasons for not using clofazimine more often could be the drug resulting in greater dyspigmentation compared to the original condition.

Dapsone
Dapsone, another antibiotic and anti-inflammatory agent, was used by Kontochristopoulos et al. in 1998 [33].They have reported that two patients with erythema dyschromicum perstans responded remarkably well to oral dapsone therapy at 100mg per day for three months.Subsequently, Bahadir et al. used oral dapsone therapy in one case of erythema dyschromicum perstans with excellent results [21].However, dapsone is associated with haemolysis and fatal dapsone hypersensitivity syndrome and should be used only with caution in controlled settings.

Vitamin A
Bhutani gave Vitamin A capsules to 140 patients with lichen planus pigmentosus at dosages of 100,000 units per day for 15 days followed by rest for 15 days.Due to the large number of patients lost to follow up, it is difficult to ascertain the exact benefit of this agent in the treatment of lichen planus pigmentosus.The authors do mention that nine out of 12 patients showed good to excellent response after 10 or more courses of the drug [34].

DISCUSSION
Acquired macular hyperpigmentary disorders have confused and confounded dermatologists for many years.The lack of a clear aetiology and pathophysiology has only added to the confusion.However, clinical and histopathological evaluation has provided a base from which the macular hyperpigmentary disorders can then be differentiated.Presence of bluish-gray macules with the presence of an erythematous border in the initial stages can be labeled as erythema dyschromicum perstans while its absence signifies ashy dermatosis.Similarly, the presence of lichen planus lesions in other body sites, past history of lichen planus, presence of basal cell layer pigmentation with or without vacuolization, leads to a diagnosis of lichen planus pigmentosus [35,36].
Riehl's melanosis is characterized by presence of persistent brown small macules less than 5 cm in size in the areas previously in contact with cosmetics or clothes.When there is presence of similar lesions that usually resolve on their own, the clinician can confidently albeit retrospectively, label the diagnosis as idiopathic eruptive macular pigmentation.
The treatment options for the conditions are rather limited and more often than not frustrating for the patients as well as dermatologists.While clofazimine and dapsone have been tried in the past, they are only useful in the initial inflammatory phase and carry a burden of unwanted side effects that can be more distressing than the original symptoms.
The three options showing promising results are narrow band ultraviolet therapy, topical tacrolimus ointment and oral vitamin A capsules.There is paucity of studies advocating the use of these agents but there is plenty of room for large scale studies to be conducted to determine the efficacy and safety of these agents in the treatment of ashy dermatosis and lichen planus pigmentosus.

CONCLUSION
An approach to diagnosis for the acquired macular pigmentary disorders of unknown significance can be made using the algorithm devised by Chandran and Kumarasinghe [20].This allows the clinician to make a confident diagnosis by excluding the other two simulatory conditions, idiopathic eruptive macular pigmentation and Riehl's melanosis.The promising therapeutic agents based on the isolated case reports include narrow band ultraviolet therapy and topical application of 0.1% tacrolimus ointment.The author recommends large blinded controlled trials to truly assess the efficacy and safety of these agents in the treatment of these conditions.

Figure 1 :
Figure 1: Multiple gray macules on the trunk.

Figure 2 :Figure 3 :
Figure 2: (a) Gray macules of ashy dermatosis on left axilla.(b) Similar lesions on the right axilla of same patient.ba