PILOT STUDY TO EVALUATE THE EFFICACY OF MINOCYCLINE IN THE TREATMENT OF PROGRESSIVE MACULAR HYPOMELANOSIS (PMH)

Received on 16/02/2009
Approved on 25/02/2009
We declare no conflict of interest.

Abstract

Introduction: Progressive macular hypomelanosis (PMH) is characterized by hypopigmented maculae on the thorax, abdomen, and lumbar region. It is often misdiagnosed, and its etiology is unknown. Recently, suggestive lesions of porphyria, produced by Propionibacterium acnes, were discovered by red fluorescence of the lesions.
Objective: Evaluating the efficacy of Minocycline, 100 mg/day, in the treatment of progressive macular hypomelanosis.
Material and methods: Patients older than 16 with at least a 3-month history, without allergies to tetracycline derivatives, and without a history of treatment with antibiotics for 90 days before the study, were included. Pictures were taken before beginning treatment and after 30, 60, 90, and 120 days and after this whenever possible.
Results: Out of 19 patients, 11 completed the study. All of them showed recovery of the color in the affected areas. Treatment success could be demonstrated for a minimum of 7 months and a maximum of 11 months after treatment.
Conclusion: The isolated use of minocycline, 100 mg/day for 3 months, was effective in the treatment of PMH, confirming the probable role of P. acnes as the etiological agent.

INTRODUCTION

Progressive macular hypomelanosis (PMH) is a common skin disorder, frequently misdiagnosed. It is characterized by well-defined, non-scaly, nummular, hypopigmented maculae. Lesions are symmetrically distributed in areas of greater density of sebaceous glands, sparing sun-exposed areas. They affect especially the trunk, thorax, abdomen, and lumbar region. Lesions are confluent in the midline and rarely extend to proximal extremities and neck. Usually, they are not associated with pain or any systemic changes, and they are not preceded by inflammation, infection, or injury.^1,2 They represent an important aesthetic problem, stigmatizing carriers and influencing their daily activities, since their exposure calls attention to them and lead to unwarranted questioning.

Its etiology is still unknown. According to Borelli,³ the disease is a genodermatosis, while for Guillet et al.⁴ it represents an acquired inactivation of the melanin production in the affected areas. For Fitzpatrick,⁵ this is a long-lasting inactivation, secondary to a fungal infection, persisting even after the disappearance of the causative agent. The presence of fungi has been investigated by several authors^1,2 through direct mycological exams with KOH but it has never been confirmed. In 2004, Westerhof6 observed that the lesions were more visible with the Wood’s lamp, presenting a reddish color only in the hypopigmented areas. The same fluorescence could not be observed in individuals with pityriasis versicolor or pityriasis alba, which also present with hypopigmented maculae on the trunk. Some authors postulate that the red fluorescence would be caused by the presence of porphyrin produced by the bacteria Propionibacterium acnes. The bacteria would produce a factor that interferes with melanogenesis, causing the hypopigmented maculae (“skin-lightening” factor).

The hypothesis that P. acnes could be the etiological factor of PMH motivated us to try a medication that, by reducing the population of this bacterium, could be therapeutically effective. In our study, Minocycline was chosen because it is the most effective tetracycline derivative, used for more than 18 years in dermatology⁷, and safe for prolonged use, besides being easy to administer, since it has a once a day dosage. At the moment, we are not aware of any publications reporting the use of minocycline in the treatment of PMH.

OBJECTIVE

The objective of this study was to evaluate the clinical efficacy of 100 mg/day of minocycline, used isolatedly, in the treatment of Progressive Macular Hypomelanosis (PMH).

MATERIAL AND METHODS

This is a non-controlled, open, prospective study undertaken at the Hospital do Servidor Público Municipal de São Paulo.

Patients from the Dermatology outpatient clinic, at least 16 years old, and with a presentation consistent with PMH for at least 3 months were included in this study. The first subject was included in November 2007 and the last two in April 2008. Patients who had used tetracycline derivatives in the 6 months prior to the study, had a history of allergy to tetracycline derivatives, and pregnant women or recently post-partum were excluded.

The following evaluation was undertaken: physical exam with Wood’s lamp; biopsy and anatomo-pathological exam to exclude other pathologies; direct mycologic exam; and standardized pictures (0, 60, and 90 days and after 4 months). Gram staining and electron microscopy were not performed.

Treatment consisted of Minocycline, 100 mg/day for 3 months, and return appointments were scheduled for 60 and 90 days. All patients were reevaluated 4 months after the end of the treatment and afterwards, whenever possible, until October 2008.

RESULTS

Nineteen individuals with the diagnosis of PMH were included in the study. Of those, 11, nine females and two males, completed the study. According to the Fitzpatrick classification, patients presented the following phototypes: III (3 cases), IV (6 cases), and V (2 cases). Patients had an average age of 24 years old (varying from 16 to 34 ), and the average time of disease was 44 months (from 4 months to 15 years). All patients presented lesions on the dorsum. Six patients also presented lesions on the abdomen; two, on the legs; and four had associated involvement of one of the following areas: neck, anterior aspect of the thorax, arms, and groin, confirming its predilection for covered areas. Of the 11 patients, only four presented a family history for the same disorder. Table I presents the data of all patients.

The results of the evaluations were as follows: all patients presented negative direct mycologic exams; positive fluorescence to Wood’s lamp (red color of affected areas) on the five individuals who underwent this exam (Figure 1). Anatomo-pathological exam was performed in 18 patients to exclude other pathologies, which showed chronic superficial perivascular dermatitis with discrete lymphomononuclear inflammatory infiltrate.

Patients were evaluated by two dermatologists, with a physical exam on every visit and comparison of pictures. On the 60-day follow-up, a reduction in the contrast between the normal skin color and the affected area could be seen, and the improvement was even more visible after three months of treatment. At the end of 90 days of treatment, the affected area had recovered the normal skin color in all patients (Figures 2A and 2B and 3A and 3B). Since recruiting was done in variable periods, of the 11 patients who completed the study, therapeutic success persisted after seven months in 4 patients; after 8 months in one; after 9 months in 2; after 10 months in one; and after 11 months in 3 cases. The last patients included in the study had shorter follow-up.

DISCUSSION

The expression progressive macular hypomelanosis was introduced in 1980 by Guilet et al.⁴ to describe a pigment disorder in Caribbean French. At that same year, Menke1 described Dutch people with an identical disorder, calling it nummular hypomelanosis confluent of the trunk. A similar entity was described, with different nomenclature, by authors from different parts of the world:1 Berelli (Venezuela), “cutis trunci variata”; Leuser et al. (Martinique), “creole dyschromia”; Fitzpatrick (USA), “idiopathic multiple large hypomelanosis maculae”; and Zaynount et al, “extensive pityriasis alba (EPA)”.

Its prevalence is unknown, although it is believed to be very common. It is universally distributed; however, the diagnosis is more frequent in countries whose population has pigmented skin (phototypes II to VI). Some authors have suggested that it is more common in individuals with racial miscegenation^3-5; nevertheless, Relyveld et al.^1,2 did not observe this type of association, also diagnosing it in non-miscigenated individuals.

Progressive macular hypomelanosis affects especially teenagers and young adults. It is not seen in the elderly and, according to data in the literature, it is more common in women, at a proportion of 7:1. Only one author3 believes it is equally distributed in both genders. As for its evolution, although its natural history is unknown, it seems to be persistent for more than 10 years in several reports.^2,8

Our population, which showed a predominance of women, teenagers, and young adults, with elevated phototypes, and greater incidence of lesions in the dorsum, was similar to that described in the literature. The average time of the disease in our population was 44 months (3.6 years), which also agrees with the data in the references encountered.

The differential diagnosis should include other disorders that present hypopigmented maculae, such as: pityriasis versicolor, pityriasis alba, tuberculous or dimorphous leprosy, mycosis fungoides, and post-inflammatory hypopigmentation.¹

The histopathological aspects described by most authors^1,2,9 included: reduction in melanin content, and absence of spongiosis in the epidermis, as well as absence of dermal changes in the affected skin. According to Relyveld1,² and Westerhof,⁶ a high density of Gram-positive bacteria, consistent with P. acnes, by Gram staining, has been found.

In electron microscopy studies, some authors^2,3,9,11 found deficiency in melanosome melanization. Changes in size and number, maturation, and distribution of melanosomes in damaged skin of patients with phototypes V and VI are seen. In lower phototypes, the differences between healthy and damaged skin are less obvious because their melanosomes are smaller, have less melanin, and are aggregated.

In our study, histological analysis was performed only to exclude possible differential diagnosis; however, a discrete dermal inflammatory infiltrate was identified in all samples. This finding differs from that found by most authors,^1,2,9 but it is similar to that described by Vi Di Lernia.

An effective treatment for this disorder does not exist. Systemic and topic antifungal agents, as well as topical corticosteroids, have been proposed, but without response.1 Phototherapy with ultraviolet light associated with psoralen has obtained satisfactory but transitory results, with relapse shortly after discontinuation of the treatment.8 A comparative study² between the association of benzoyl peroxide and clindamycin, on one side of the body, and fluticasone, on the other, both associated with the exposure to ultraviolet light (UVA 20 minutes, 3 times a week, for 14 weeks), was more effective on the side treated with the antimicrobial medication.

None of the therapeutic successes reported in the literature used a single medication; it was always associated with exposure to ultraviolet light. In the report of the case treated with doxycycline plus ultraviolet light,¹² improvement could be confirmed six months after the end of the treatment. In the comparative study by Relyveld,2 the response was better and persisted for up to 12 weeks on the side treated with antimicrobial therapy associated with UVA. The fluticasone-UVA side showed only partial recovery of the skin, but recurrence was seen after 12 weeks.

Since the lesions of PMH affect, predominantly, covered areas, if Westerhof et al. are right regarding the role of P. acnes as the etiological agent,6 isolated antimicrobial therapy, specific for the agent, would be effective, even without sun exposure.

Tetracyclines have bacteriostatic action against a wide range of Gram-positive and Gram-negative organisms. They are considered the first choice in the treatment of acne and rosacea, and act by reducing the number of P. acnes.^7,13 A recent publication of the American Academy of Dermatology with guidelines on the treatment of acne, considers that “Doxycycline and minocycline are more effective than tetracycline, and there is evidence that minocycline is superior to doxycycline in reducing P. acnes”. Only one report using Doxycycline for 6 weeks in the treatment of PMH was found in the literature.¹² The treatment was successful but, in this case, it was associated with solar exposure.

In our study, minocycline, knowingly effective against P. acnes, was the only agent used, without exposure to ultraviolet radiation, obtaining satisfactory and lasting results. Clinical improvement has persisted even 11 months after the end of the treatment in patients with at least a 24-month history of the disease.

CONCLUSION

The use of 100 mg a day of minocycline for 3 months was effective in the treatment of progressive macular hypomelanosis, even without sun exposure, therefore confirming the probable role of P. acnes as the etiological agent of this disorder.

References

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2 . Relyveld GN, Kingswijk MM, Reitsma JB, Menke HE, Bos JD, Westerhof W.Benzoyl peroxide/clindamycin/UVA is more effective than fluticasone/UVA in progressive macular hypomelanosis: a randomized study. J Am Acad Dermatol. 2006;55:836-43

3 . Borelli D. Cutis trunci variata: nueva genodermatosis. Med Cutanea Ibero Lat Am. 1987;15:317-9

4 . Guillet G, Helenon R, GauthierY et al. Progressive macular hypomelanosis of the trunk: primary acquired hypopigmentation. J Cutan Pathol. 1988;15:286-9

5 . Ortonne J, Bahadoran P, Fitzpatrick T, Mosher D, Hori Y. Hypomelanoses and hypermeloses. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, editors. Fitzpatrick’s dermatology in general medicine. 6th ed. New York: McGraw-Hill. 2003;90:861-2

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8 . Lesuer A, Garcia-Granel V, Helenon R et al. Hypomélanose maculeuse confluente et progressive du métis mélanoderme: etude epidemiologique sur 511 subjets. Ann Dermatol Venereol. 1994;121:880-3

9 . Kumarasinghe SPW, Tan SH, Med M, Thng S, Thamboo P, Liang S, Lee YS. Progressive macular hypomelanosis in Singapore: a clinico-pathological study. International J Dermatol. 2006;45:737-42

10 . Di Lernia V, Ricci C. Progressive and extensive hypomelanosis and extensive pityriasis alba: same disease, different names? JEADV. 2005;19:370-2.

11 . Relyveld GN, Dingemans KP, Menke HE, JD Bos JD, Westerhof W. Ultrastructural findings in progressive macular hypomelanosis indicate decreased melanin production. JEADV. 2008;22:568-74

12 . Perman M, Sheth P, Lucky A. Progressive macular hypomelanosis in a 16 year old. Pediatric Dermatology. 2008;25:63-5

13 . Sampaio SAP, Rivitti EA. Dermatologia. 3ª edição. São Paulo: Artes médicas; 2007. Terapêutica sistêmica, p. 1417-69