Randomized, double-blind study of minocycline vs. placebo in the treatment of progressive macular hypomelanosis

Received on: 08/08/2011
Approved on: 10/09/2011

This study was carried out in the
Dermatology Department of the Hospital do
Servidor Público Municipal de São Paulo –
São Paulo (SP), Brazil.

Conflicts of interests: none
Financial support: Medication and placebo
provided by Rambaxy laboratory

Abstract

Introduction: Progressive macular hypomelanosis is a common skin hypopigmentation found in all ethnicities, yet it is seldom diagnosed. It affects young adults, especially women, and is often mistaken with pityriasis alba and pityriasis versicolor. It is character- ized by symmetric, well-defined, non-desquamative nummular hypopigmented macules in body areas with a greater concentration of sebaceous glands (trunk, thorax, abdomen and lumbar regions). Its etiology is poorly understood, and there is no effective treatment. A red fluorescence has recently been discovered in the lesion, suggesting the presence of porphyrin, produced by Propionibacterium acnes.
Objective: To compare the efficacy of 100 mg/day minocycline vs. placebo in the treat- ment of progressive macular hypomelanosis.
Methods: Patients over 18 (n = 20), who had suffered from the condition for more than 3 months (without treatment in the previous 3 months), who did not have an allergy to tetracycline, were randomized to receive minocycline or placebo. Wood''''''''s Lamp examina- tions and clinical evaluations (with descriptions and classifications using a color scale), and standardized picture records were conducted at baseline and 30 and 90 days after treatment.
Results: Eighteen patients completed the study. The group treated with minocycline pre- sented a statistically significant improvement (p < 0.05) compared to the control group.,br> Conclusion: 100 mg/day minocycline for 30 days was effective in treating progressive macular hypomelanosis, meaning that Propionibacterium acnes probably has a role in the condition''''''''s pathogeny.

Keywords: MINOCYCLINE, HYPOPIGMENTATION, PLACEBO EFFECT, TREATMENT

INTRODUCTION

Progressive macular hypomelanosis is a common skin hypopigmentation that occurs in all ethnic groups and is found all over the world. It affects young adults, especially women, and is often mistaken with pityriasis alba and pityriasis versicolor. 1,2 Only one study has described an increase in incidence among men. 3

Progressive macular hypomelanosis is characterized by well-defined and symmetrical hypopigmented nummular mac- ules in body areas that have a greater concentration of sebaceous glands 2,4,5 (trunk, thorax, abdomen, lumbar region and proximal region of upper limbs); there is no systemic manifestation. Lesions are not preceded by inflammation, and get progressive- ly worse. It occurs most commonly on the back (90%), followed by the abdomen (85%), buttocks (35%), thorax (15%) and upper extremities (5%).

Progressive macular hypomelanosis is an important derma- tologic problem that stigmatizes the people that suffer from it, affects their daily activities, and elicits undesirable questions about the lesions.

Guilet and colleagues 6,7 found that the condition''''''''s progres- sion phase lasts approximately one year, while its regression phase is most likely to last between two and five years. However, other authors believe that spontaneous regression does not occur and that hypomelanosis can remain stable for many years or progress slowly and gradually. 1,3

Its etiology is still unknown. Dutch researchers 8 have observed follicular red fluorescence of the lesions under Wood''''''''s light, suggesting a possible correlation with the Propionibacterium acnes (P acnes) bacterium, which produces porphyrin. That type of fluorescence is not observed in patients with pityriasis alba or pityriasis versicolor. Westerhof and others 1 concluded that there must be a correlation between the presence of P acnes and the hypopigmented macules; they postulated that the bacterium produces the whitening factor that causes hypopigmentation.

Histopathologic findings are usually unspecific, however a common characteristic is a smaller amount of melanin in the lesion9 and an absence of spongiosis. Using biopsies and elec- tronic microscopy, Relyvelt and colleagues 4 compared the nor- mal and affected skin of eight patients with a clinical diagnosis of progressive macular hypomelanosis and concluded that there was a decrease in melanin production and in the distribution of melanosomes. In other studies, Relyveld 4,5 and Westerhof 1 have found a high density of gram-positive bacteria compatible with P acnes through Gram staining.

The proposed treatments described in the literature include phototherapy (Psoralen + ultraviolet A (PUVA), ultra- violet A (UVA) or narrowband ultraviolet B (NBUVB)), topical 5% benzoyl peroxide combined with 1% clindamycin, and oral minocycline. There is also a report of using oral doxycycline. One study compared benzoyl peroxide and clindamycin on one side of the body and fluticasone on the other, with UV expo- sure on both sides; the side treated with antimicrobials showed steady improvement. 5 In a case report, Perman and others 10 treated patients with doxycycline and UV radiation, and improvements lasted for six months. Duarte and colleagues 2 described improvement in both PUVA and NBUVB, however the lesions returned in 72% of their patients.

In a recent publication on approaches to acne treatment, the American Academy of Dermatology 11 asserted that "doxy- cycline and minocycline are more effective than tetracycline, with evidence that minocycline is superior to doxycycline in reducing the Propionibacterium acnes population."

A prospective, open, uncontrolled study demonstrated repigmentation in all patients after the use of 100 mg/day minocycline for three months, without the combined exposure to the sun. Eleven patients were followed up, and the clinical improvement was found to persist at least 11 months after the end of treatment. 12

In the literature describing therapeutic success, it was not possible to find controlled, randomized double-blind studies. Most studies combine this treatment with exposure to UV radi- ation.

OBJECTIVE

To compare the clinical efficacy of 100 mg/day minocy- cline vs. placebo, without sun exposure, in the treatment of pro- gressive macular hypomelanosis.

METHODS

This was a double-blind, randomized, placebo-controlled study of 20 progressive macular hypomelanosis patients of the Dermatology outpatient clinic of the Hospital Servidor Público Municipal de São Paulo, (SP) Brazil. Study participants were randomized to receive 100 mg/day minocycline or placebo for 30 days. All were instructed on the study''''''''s details and procedures and signed a term of informed consent and authorization for photographs to be taken. The study protocol was submitted to and approved by the Clinical Research Ethics Committee of the Hospital Servidor Público Municipal de São Paulo (n. 189/2010).

The diagnosis was based on the clinical appearance of the skin lesions, which were assessed by two dermatologist physi- cians who verified the presence of follicular red fluorescence under Wood''''''''s light and negative direct fungal examination.

The study included patients aged 18-60 years who had been inflicted with the disorder for more than three months and who had not taken topical, systemic, antibiotic or antifungal medication in the 3 months preceding the study. Pregnant or breastfeeding women, and patients with a hypersensitivity to tetracyclines, were excluded.

Twenty patients of both genders (17% men, 83% women) aged 18-60 (average 24 years), who had lesions for 8-240 months (average 54 months) on their back/abdomen (61%) or back (39%) were randomized.

The pre-treatment assessment involved a clinical examina- tion that included a description of the lesions and standardized photographs, a direct fungal examination and assessment under Wood''''''''s light (long-wave UVA light beamed through Wood''''''''s filter, which only allows 320-400 nm wavelength radiation to pass through). 13,14

In order to obtain a less subjective evaluation of clinical improvement, the hue of the normal and adjacent altered skin were compared using a numerical skin color scale (1 = lightest, 20 = darkest, see Figure 1). A decrease in the numerical differ- ence between the affected skin of the macule and the normal skin (i.e., a lower contrast between the skin colors) signified clinical improvement. The photographs, taken with a Sony DSC-W170 digital camera, each used the same focal distance and lighting.

The patients were followed up 30 and 90 days after treat- ment. The clinical and Wood''''''''s light examinations, the classifica- tion with the numerical skin color scale, and photographs were repeated in the follow-up consultations, and possible adverse effects and intercurrences were assessed. Clinical improvement was defined as a decrease in the lesion''''''''s red fluorescence under Wood''''''''s light and an increase in the color scale score, with an emphasis on a decrease in the difference between the hues of the lesion and the normal skin. A smaller difference between the scores of the normal and affected skin indicated less color dis- crepancy, with the macule''''''''s color more closely matching that of the normal skin.

Fisher''''''''s and Student''''''''s t-tests were used in the statistical analysis to calculate relative risk. Statistical significance was defined as p < 0.05.

RESULTS

Of the 20 volunteers selected, 18 completed the study (nine in each group). Two participants dropped out due to trav- el and relocation. Between-group comparisons of gender, age, duration and lesion site, evaluations with Wood''''''''s light and dif- ference in color between normal and affected skin before, 30 and 90 days after treatment is shown in table 1 . There were no statistically significant differences in gender, age, site or duration of lesions between the placebo and medicated groups (Table 2) .

Regarding clinical improvement, the statistical analysis indicated that there was a significant difference (p = 0.0285) and relative risk of 3.5. In the control group, 78% of patients did not improve, while 78% of patients in the medicated group present- ed clinical improvement, as shown in (Table 2) . Clinical improve- ment was quantified according to the numerical skin color scale''''''''s gradient (0: absence of improvement in the macule''''''''s color; 1: darkening of the macule''''''''s color by one hue; 2: darken- ing of the macule''''''''s color by two hues, and 3: darkening of the macule''''''''s color by three hues). As shown in Table 3 , 22% of patients in the medicated group did not demonstrate clinical improvement; 34% presented a one-point improvement in the color scale, 22% improved by two points, and 22% improved by three points, with a more significant and evident improvement in the last group (Figure 2). In the placebo group, only 22% of patients demonstrated a two-point improvement.

All nine patients (100%) of the placebo group continued to demonstrate red fluorescence under Wood light. Six patients (67%) in the medicated group stopped displaying red fluores- cence after treatment, and three (33%) remained unchanged.

None of the patients in the placebo group presented any side effects, while five medicated patients (56%) presented mild side effects (nausea, vomiting, improvement of acne), and four (44%) did not present any symptoms linked to the use of minocycline.

DISCUSSION

The term progressive macular hypomelanosis was used for the first time by Guillet and colleagues to describe lesions in young women in Southern India and in the population of Caribbean immigrants in France.6 Other descriptions of this condition are "Cutis trunci Variata,"15 "Creole dyschromia," 7 "Idiopathic multiple large-blemish hypomelanosis "16 and "Extensive pityriasis alba."17

While its prevalence is unknown, it is believed to be very common, but is seldom diagnosed because it is often confused with other pathologies that present a similar clinical picture. For that reason, direct fungal examination was carried out in the lesions, and a negative result was found in all study patients.

In this study, lesions were located on the abdomen and back, with an average duration of 54 months, and there was pre- dominance in women (83% of cases) and a higher incidence among young adults, all of which coincides with the data described in the literature. Although this pathology''''''''s predomi- nance in women has been described in many studies, this find- ing might be partly explained by the fact that women seek der- matological care more frequently. Although it has been described as rarely affecting patients older than 30,1 three study patients fell into that age group (36, 43 and 46 years old).

Progressive macular hypomelanosis'''''''' etiology is uncertain. Among the explanations of its origins are genodermatoses 1,8 and, more recently, a correlation with P acnes. The link with P acnes is based on the observation of follicular red fluorescence under Wood''''''''s light and a positive culture of P acnes in the lesions, as demonstrated by Westerhoff and others. 1 In a recent- ly published case report, Neynaber and colleagues found no evidence of P acnes using Wood''''''''s light or in the histopathologic analysis, which used a special stain for bacteria. 18

In the present study, all patients who were clinically diag- nosed before treatment presented positive red fluorescence under Wood''''''''s light, a result that was sustained after treatment in all patients in the placebo group (Table 4) .

There is no consensus on a widely recognized and effec- tive treatment option. Kwah and others 19 evaluated the effec- tiveness of NBUVB as a monotherapy, which demonstrated sat- isfactory yet short-lived results. Duarte and colleagues 2 found similar satisfactory results with PUVA and NBUVB; there was no statistically significant difference between the two methods. However, 72% of the patients experienced a recurrence of the lesions.

Based on Westerhoff and others'''''''' hypothesis 1 about the inhibitory role of P acnes in melanogenesis, some authors have used antibiotics to treat progressive macular hypomelanosis. One study obtained satisfactory results with the topical combination of 5% benzoyl peroxide gel and 1% clindamycin, 5 while anoth- er also obtained a satisfactory outcome in one case using topi- cal benzoyl peroxide and erythromycin 20 . A third case success- fully used a combination of doxycycline and sun exposure. 10 An earlier pilot study (prospective, open, non-controlled) conduct- ed by the authors found that 100 mg/day minocycline for three months stimulated repigmentation in all patients even without exposure to the sun. No recurrences were observed in the 11 months of post-treatment follow-up. 12

In therapeutic successes reported in the literature, no other randomized, placebo-controlled, double-blind studies that did not involve solar exposure were found. The present research yielded improvement in seven out of nine individuals who used the medication, which matches the satisfactory results of minocycline described by Almeida and colleagues 12 . Yet repig- mentation occurred in only two cases in the placebo group.

Despite descriptions of rare cases of hypersensitivity to minocycline, 21 induction of lupus-like, autoimmune hepatitis, hyperpigmentation and vasculitis, 22,23 the only effects reported in this study were nausea and vomiting in three patients and improvement of acne in two (56% of patients in the medicated group). Although the causes of these effects are not fully under- stood, hypotheses have been proposed that suggest a reduction in the production of free radicals, inhibition of phospholipase a2 , and changes in the expression of the tumorous necrosis factor and alpha interferon are involved. 24-26 The improvement in acne can be even considered as an advantage provided by the med- ication that increases patient satisfaction.

Of the nine participants in the minocycline group, two (22%) did not respond. This outcome might be explained by the duration of the treatment (30 days), which is considerably less than the three months described by Almeida and colleagues'''''''' study 12 that demonstrated 100% repigmentation in all treated cases.

The statistically significant difference between the cases treated with placebo and minocycline demonstrates that the latter – a recognizably effective agent against P acnes even when not combined with UV exposure – is an effective ther- apeutic option in treating progressive macular hypomelanosis. Studies with a larger sample and a longer follow-up period are necessary to confirm these results and assess their long-term permanence.

CONCLUSION

The use of 100 mg/day minocycline for 30 days was effec- tive in treating progressive macular hypomelanosis, even with- out solar exposure.

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