A single blind, randomized clinical trial comparing MMP^®, MMP^® with 5-FU, and 5-FU intradermal injection for the treatment of idiopathic guttate hypomelanosis: a pilot study

Received on: 27/03/2020
Approved on: 29/05/2020

Financial support: None
Conflict of interest: None

Research performed at the Department of Dermatology, Hospitaldo ServidorMunicipaldeSãoPaulo,São Paulo (SP),Brazil

Abstract

INTRODUCTION: Idiopathic guttate hypomelanosis (IGH) is a common photoaging manifestation, with no standard treatment and presenting mixed results to interventions. In Brazil, the use of micro-needling associated with 5-fluorouracil (5-FU) has been proposed to treat IGH.
OBJECTIVE: To compare the use of MMP^® (micro-infusion of drugs on the skin) with 5-FU, with MMP^® only as micro-needling (with no drugs), and intralesional 5-FU injected with an insulin syringe in the treatment of IGH.
METHODS: In a single blind randomized clinical trial, we compared the three treatments: MMP^® versus MMP with 5-FU and intralesional 5-FU injection for 180 IGH lesions in the forearm of nine patients.
RESULTS: After two treatment sessions, 5-FU alone was the most effective treatment, with statistical significance, compared with micro-needling alone. MMP+5-FU efficacy was lower than intralesional 5-FU injection and higher than micro-needling alone, although without statistical significance.
CONCLUSIONS: The intralesional application of 5-FU was more effective in the treatment of solar leukoderma. The use of a smaller quantity of medication is the great advantage of the MMP + 5-FU technique. Further studies are needed to standardize these techniques.

Keywords: Drug delivery systems; Fluorouracil; Hypopigmentation; Skin aging

INTRODUCTION

Idiopathic guttatehypomelanosis (IGH) is a manifestation of photoaging that occurs mainly on the extensor surface of the forearms and pretibial areas, and which still has no standardized treatment and presents varied response to interventions.¹ The use of micro-needlingassociated with 5-fluorouracil(5-FU)has beenproposed for the treatmentofIGH.²

5-FUis a pyrimidineanalog used in the treatment of many skin diseases. Intralesional infiltration of this medication and its use in the micro-needled area have been used in the treatmentofvitiligo.^3,4

Arbacheetal.described repigmentation of IGHwith administration of 5-FU via a tattooing machine, using the technique called MMP^® (micro-infusion of medications in the skin), with exclusive use bydermatologists.²

In the search for an effective therapy forIGH, thecurrent study aims to assess the efficacy of MMP with 5-FU compared to MMP without medication and intralesional5-FU with a single puncture in the treatmentofleukodermas on the forearm.

MATERIALS AND METHODS

This single-blind randomized clinical trial compared MMP^® with 5-FU to micro-needling (MMP^® without drugs)and intralesional 5-FUvia single puncture with an insulin needle for treatmentof180IGHlesions on the forearmin ninepatients. Ten lesions were treated on each forearm, totaling 180 treated lesions (Figure 1). The treatment technique used on each forearmwas selected randomly, each one on six forearms,with a total of 60 lesions.The study was approved by the Institutional Review Board of Hospital do Servidor Público Municipal de São Paulo (CAAE:51923415.1.0000.5442).

Micro-needling 5 was performed with a tattooing machine(Cheyenne,Germany,TRADERM^®,SP, Brazil) approved by the Brazilian National Health Regulatory Agency (ANVISA). The cartridge needles used for thisprotocol, model 7-liner-mt, were immersed in 5-FU or used only for micro-needling (Figure 2). Micro-needlingwas performed from the periphery towards the center of the depigmented area(2mm or 20 clicks of the machine) until a mild blood dew appeared, a sign that the dermis had been reached. Maximum dose was 50mg/1ml/forearm per session.

Intradermal injection of 5% 5-FU was 0.1ml in each IGH lesion with BD^® syringes mounted with a 0.3ml needle, maximum of 50mg/1ml/forearm per session (Figure 3).

All treatments were performed in twosessions with a 30-day interval. Final evaluation was performed at 120 days.

Improvement was evaluated with images of each lesion (standardized clinical photos), classified by a blinded observer using the repigmentation scale (Figure 4). The results were compared using chi-square test (k proportions) or ANOVA, followed by LSD multiple comparison. Statistical significance was set at 5%.

RESULTS

Mean age was 61years (range: 49 to 70 years), eight patientswere females(89%),two were photo type II, four were photo typeIII, and three were photo type IV.

Of the 180 lesions, sixpresented hyperpigmentationas an adverseeffect and were excluded from the analysis.Of the174 lesions, all presented repigmentation,162(93.1%) with total repigmentation with normochromia, 12 (6.9%) with partial repigmentation. The great majority of the lesions showed total repigmentationwith normochromiafor all the treatments, with 57/57=100%for5-FU, 50/58=86,2% for MMP, and 55/59=93,2% for MMP+ 5-FU (Figure 5).

Eight forearms were not submitted to a second session, for different reasons, namely: four reached the treatment target(total repigmentationand normochromia), two of whom usingMMP and two MMP+5-FU;three due to erythemain the lesion sites(one used MMPand two MMP+5-FU);and one due to hyperpigmentation of all the lesionsafter the first session with 5-FUalone.

Significant differences were found in the proportions of lesionswith total repigmentationwith normochromiabetween the groups treated with 5-FU andwith MMP (k proportions test;p=0.014).The proportion was lower in lesionstreated with MMP, compared to lesions treated with 5-FU, suggesting greater efficacy with 5-FU injection.

Of the repigmented lesions, 162 (93.1%) presented total repigmentationwith normochromiafor all the treatments, which was the best result of the five possible results in the repigmentationscale (Figure4).

Treatmentwith MMP + 5-FU was the second most effective treatment, although without statistical significance. The lowest efficacy was with micro-needling, which may due to the lack of use of 5-FU;thetreatmentswith MMP+5-FUand5-FU alone showed better clinical and statistical response.

Pain was assessed subjectively by patients, and no statistically significant differences were found between the three treatments. However, pain in the treatmentwith MMP + 5-FU was considered more intense than in the othertreatments.

As for adverse effects such as burning sensation, pruritis, and pain, there were no statistically significant differences between the treatments.

On day 30, one patient presented hyperpigmentation in 10 lesionswith the use of intralesional 5-FU. However, on day 120 all the lesions were normochromic.

At the end of the study, six lesions presentedhyperpigmentation, one of which had been treated with MMP+- 5-FU, two with MMP, and three with 5-FU

DISCUSSION

Abd El-Samad andShaamad, in 2012, were the first to useintralesional 5-FU to treat vitiligo. In60patients, there was greater overall repigmentationin the group in which 5-FUwas injected, compared to controls(p<0.001).3Attwa, Khashaba, and Ezzat, in 2019, compared to needling and needling followed by topical 5-FU to treat stable localized vitiligo in 27 patients. Micro-needling followed by topical 5-FU showed a better response than micro-needlingalone, with minimal adverse effects.⁴

Arbache S. et al.² treated eight patients with IGH lesions, with MMP + 5-FU versus MMP with placebo. Repigmentation of the lesionwith MMP + 5-FU was statistically superior to MMP with placebo (repigmentationwith 5-FU=75.3% versus repigmentationwith placebo 33.8%, p<0.001).

In our protocol,all 174 lesions(96.7%)presented repigmentation, and none remained achromic after the procedures, which indicates clinical improvement with all three treatments used. No statistically significant differences were observed between the three techniques.However, in the head-to-head comparison, the proportion was statistically lower (k proportions test; p=0.014) for lesions treated with MMP for micro-needling (50/58 = 86.2%) compared to lesions treated with 5-FU(57/57=100%), suggesting better efficacy of treatment with 5-FU.

After two treatment sessions, intralesional 5-FUwas the most effective treatment, with statistical significance, when compared to the use of micro-needling. The efficacy of MMP + 5-FU was inferior to intralesional 5-FUand superior to micro-needling alone, although without statistical significance. The use of a smaller amount of 5-FU (1.175µg/cm2 orabout 0.00116ml for each 10 lesions), followed by the technique described by Arbache 2 and the speed and ease of the techniques are the main advantages of MMP + 5-FU compared to injectionwith insulin needle, which used about 50mg (1ml) of medication persession. The adverse effects of 5-FU include pain, pruritis, hyperpigmentation, and burning sensation atthe application site^3,4Other less frequent reactions include allergic contact dermatitis, pain, tenderness, suppuration, desquamation, and edema.

In our protocol, there were no statistically significant differences between the treatments in relation to pain.

CONCLUSIONS

Intralesional infiltration of 5-FU was the most effective treatmentof localleukoderma.The use of lower amounts of medications and the technique’s speed and ease are the main advantages of the MMP + 5-FU technique. More studies are needed on the maintenance of the level of improvement in thelesionswith these three techniques.

AUTHOR’S CONTRIBUTION:

Gilmayara Alves Abreu Maciel Pereira | 0000-0002-0850-0427
Statistical analysis;approval of the finalversion of themanuscript;conception and planning of the study;elaboration and writing of the manuscript;data collection, analysis, and interpretation;effective participation in orientation of the research; intellectual participation in the propaedeutic and/ortherapeutic conduct of the cases;critical review of the literature;critical revision of the manuscript.

Diego Leonardo Bet | 0000-0002-7548-4797
Conception and planning of the study; data collection, analysis, and interpretation; effective participation in orientation of the research; intellectual participation in the propaedeutic and/ortherapeutic conduct of the cases; critical revision of the manuscript.

Maria Victoria Suarez Restrepo | 0000-0002-2614-6011
Statistical analysis;conception and planning of the study;elaboration and writing of the manuscript; data collection, analysis, and interpretation;effective participation in orientation of the research; intellectual participation in the propaedeutic and/ortherapeutic conduct of the cases; critical revision of the manuscript.

Vanessa Barreto Rocha | 0000-0001-6795-398X
Approval of the finalversion of themanuscript; elaboration and writing of the manuscript; critical review of the literature; critical revision of the manuscript.

Leticia Arsie Contin | 0000-0002-4783-9909
Approval of the finalversion of themanuscript; conception and planning of the study;elaboration and writing of the manuscript; data collection, analysis, and interpretation;effective participation in orientation of the research;intellectual participation in the propaedeutic and/ortherapeutic conduct of the cases; critical review of the literature; critical revision of the manuscript.

REFERENCES

1. Juntongjin P, Laosakul K. Idiopathic guttate hypomelanosis: a review of its etiology, pathogenesis, findings, and treatments. Am J Clin Dermatol. 2016;17(4):403-11.

2. Arbache S, Roth D, Steiner D, Breunig J, Michalany NS, Arbache ST, et al. Activation of melanocytes in idiopathic guttate hypomelanosis after 5-fluorouracil infusion using a tattoo machine: Preliminary analysis of a randomized, split-body, single blinded, placebo controlled clinical trial. J Am Acad Dermatol. 2017;78(1):212-5.

3. Abd El-Samad Z, Shaaban D. Treatment of localized non-segmental vitiligo with intradermal 5-flurouracil injection combined with narrow-band ultraviolet B: a preliminary study. J Dermatolog Treat. 2012;23(6):443-8.

4. Attwa EM, Khashaba SA, Ezzat NA. Evaluation of the additional effect of topical 5-fluorouracil to needling in the treatment of localized vitiligo. J Cosmet Dermatol. 2020;19(6):1473-8.

5. Arbache S, Mattos EC, Diniz MF, Paiva PYA, Roth D, Arbache ST, et al. How much medication is delivered in a novel drug delivery technique that uses a tattoo machine? Int J Dermatol. 2019;58(6):750-5.