Accepted: 28 August 2017

DOI: 10.1111/jocd.12440

ORIGINAL CONTRIBUTION

Comparison between the efficacy of microneedling combined

with 5-fluorouracil vs microneedling with tacrolimus in the
treatment of vitiligo

Mary Mina MS1 | Lamia Elgarhy MD1 | Hanan Al-saeid MD2 | Zeinab Ibrahim MD1

1
Faculty of Medicine, Department of
Dermatology & Venereology, Tanta
University, Tanta, Egypt
2
Faculty of Medicine, Department of
pathology, Tanta University, Tanta, Egypt
Correspondence
Mary Mina, Department of Dermatology &
Venereology, Faculty of medicine, Tanta
University, Tanta, El-Gharbia, Egypt.
Email: mary-dermadr@hotmail.com
Summary
Background: Several treatment modalities had been used for the treatment of
vitiligo, but the optimal treatment has not yet been identified.
Objectives: To study the efficacy of microneedling with 5-flurouracil vs its efficacy
with tacrolimus in the treatment of vitiligo.
Patients and methods: Twenty-five patients with vitiligo were subjected to micro-
needling of 2 patches of vitiligo with dermapen, then application of 5-fluorouracil to
1 patch and tacrolimus on the other patch. This procedure was repeated every
2 weeks for every patient for maximum 6 months (12 sessions). The patients were
followed up for 3 months after the last session.
Results: The overall repigmentation was significantly higher in 5-fluorouracil-treated
patches compared with tacrolimus. Excellent improvement occurred in 48% of 5-
flurouracil-treated patches while only in 16% of tacrolimus-treated patches. In the
acral parts, 40% of the patches treated with 5-fluorouracil achieved excellent
improvement (repigmentation >75%), while no patch in the acral parts achieved
excellent improvement with tacrolimus. However, there was significant difference
between the 2 drugs,regarding inflammation, ulceration, and hyperpigmentation
which occurred with 5-fluorouracil.
Conclusion: Microneedling combined with 5-fluorouracil or tacrolimus is safe and
effective treatment of vitiligo. However, 5-fluorouracil achieved a greater percent-
age of repigmentation than tacrolimus particularly in the acral parts.

KEYWORDS
5-fluorouracil, tacrolimus, vitiligo

1 | INTRODUCTION the patients. The response to therapy is highly variable, but it

Vitiligo continues to be a major dermatologic challenge, in spite
of availability of large therapeutic modalities. Therapeutic strate-
gies for vitiligo include nonsurgical and surgical methods. Nonsur-
gical options like psoralen and ultraviolet A (PUVA), narrow-band
ultraviolet B (NB-UVB), corticosteroids, topical calcipotriol, and
tacrolimus.1 Surgical methods such as skin grafting, autologous
cultured melanocyte, or epidermal suspension transplantations.2
No single therapy for vitiligo produces satisfactory results in all
was found that the combination of surgical modalities and medi-
cal management might lead to faster improvement and better
pigmentation.3
Microneedling is used as a method of transdermal drug delivery
to increase the absorption of topical immunomodulator drugs. As,
application of microneedling device to the skin can create transport
pathways or micropores through the stratum corneum. This tech-
nique is used to augment the absorption of drugs, enhance the effi-
cacy, and decrease the period of therapy.4 In addition,microneedling

J Cosmet Dermatol. 2018;1–8. wileyonlinelibrary.com/journal/jocd © 2018 Wiley Periodicals, Inc. | 1

2 | IBRAHIM ET AL.

keeps the epidermis partially intact, hastens recovery, and limits the
risks of infection and scarring.4
Topical 5-fluorouracil was tried in treatment of vitiligo in combi-
nation with NB-UVB, but was preceded by either dermabrasion5 or
Er:YAG laser ablation6 of the vitiligo area to ensure more penetration
into the skin. Until now, it was difficult to understand why a topical
drug, such as 5-fluorouracil, well known for its antimitotic activity,
could improve the proliferation and migration of melanocytes. Suc-
cessively, it was postulated that a direct overstimulation of melano-
cyte proliferation, an inhibition of agents or cells able to destroy
pigment cells, and finally an immunomodulation stabilizing the vitiligo
may stimulate the reservoir of the follicular melanocytes or the per-
sistent Dopa-negative melanocytes in the depigmented epidermis.7
As there are numerous clues to the autoimmune nature of the
disease, the role of topical immunomodulatory drugs, calcineurine
inhibitors, such as tacrolimus has been investigated in vitiligo.8 It FIGURE 1 Pinpoint bleeding after microneedling of vitiliginous
patch
inhibits calcineurin action, thus preventing T-cell activation and the
production of various inflammatory cytokines.9 The efficacy and
safety of tacrolimus ointment were reported in the treatment of
childhood vitiligo with mild side effects.10

2 | PATIENTS AND METHODS

After approval of the research ethics committee (approval code

30288/05/15), this study was conducted as treatment trial study on
25 cases of stable vitiligo patients with no history of previous treat-
ment in the last 3 months, recruited from the Out-Patient Clinic of
Dermatology and Venereology Department, Tanta University Hospi-
tals during the period from June 2015 to March 2016. After sign-
ing informed consents, all patients were subjected to full history
taking, general and dermatological examination. Microneedling of 2
patches of vitiligo with dermapen was performed, then application of
5-fluorouracil on 1 patch and tacrolimus on the other patch.

2.1 | Steps of the procedure

After local anesthesia, the vitiliginous lesions were cleaned and ster-
ilized with 70% of alcohol. Microneedling was performed at the
F I G U R E 2 Topical application of 5-fluorouracil on right side and
depigmented patches with dermapen (My M Micro Needle Therapy, tacrolimus on the left side under occlusive dressing
Guangzhou, China) at the lowest speed and the needle penetration
depth at 0.25-0.5 mm according to the thickness of the skin. The
strokes were performed on vitiliginous area in uniform horizontal
2.2 | Evaluation of the treatment
and vertical directions until pinpoint bleeding was observed (Fig-
ure 1). After microneedling, 5-fluorouracil solution (50 mg/mL) was It was performed by photographs which were taken at baseline and
applied topically (with insulin syringe) on 1 patch and topical tacroli- before each session using Canon camera with 14.1 mega pixels. The
mus (0.03%) ointment on the other patch under occlusive dressing repigmentation responses were expressed qualitatively as the
(Figure 2). Patients were then advised to apply topical 5-fluorouracil following11:-
formula (5-fluorouracil ampule 250 mg/5 mL on 15 g liposomal base)
over 1 patch and topical tacrolimus ointment over the other patch • no change.
once daily for 2 weeks. This procedure was repeated every 2 weeks • (0%-25%) = mild improvement.
for every patient for maximum 6 months (12 sessions). The patients • (26%-50%) = moderate improvement.
were followed up for 3 months after the last session. • (51%-75%) = good improvement.
IBRAHIM ET AL. | 3

• (76%-100%) = excellent improvement. 3.1 | Repigmentation response

The repigmentation started faster in the patches treated with 5-
The color match and textural changes of skin were examined
fluorouracil than with tacrolimus. There was statistically significant
every session.
difference between both drugs regarding the start of response
Histological evaluation was performed by routine hematoxylin
(P = .001*; Table 2).
and eosin (H&E) stain and then stained with HMB45 to detect any
The overall qualitative response was better in the patches trea-
pathological or immunohistochemical changes.12
ted with 5-fluorouracil than the patches treated with tacrolimus.
Regarding the percentage of repigmentation, color match and textu-
2.3 | Statistical analysis ral changes of skin, the excellent result was 48% with 5-fluorouracil
and 16% with tacrolimus. The percentage of improvement ranged
The collected data were organized, tabulated, and statistically ana-
from 0%-100% with median 70% with 5-fluorouracil and 40% with
lyzed using SPSS software version 20 (IBM, Armonk, NY, USA). For
tacrolimus. There was statistically significant difference between the
quantitative data, the mean and standard deviation were calculated.
2 drugs (P = .023*; Table 2; Figures 3 and 4).
The difference between 2 means was statistically analyzed. P-Value
With 5-fluorouracil, the pattern of repigmentation was follicular in
≤.05 was considered statistically significant.
(16%), diffuse in (76%), and (8%) of the patches showed no repigmen-
tation. While with tacrolimus, repigmentation was follicular in (44%),
3 | RESULTS diffuse in (44%), and no repigmentation in (12%). There was no statisti-
cally significant difference between the 2 groups (P = .062; Table 2).
This study comprised 25 patients with localized stable nonsegmental
vitiligo, 10 males and 15 females. The patient’s demographics were
3.2 | Relation between the degree of improvement
shown in (Table 1).
and the site of lesion:
T A B L E 1 Clinical data of the studied cases (n = 25)
5-fluorouracil could show excellent to good improvement in lesions
No. % in different body parts. Interestingly, 40% of acral patches (4 from
Sex 10 patches in the hands and feet) achieved excellent improvement
Male 10 40.0 (repigmentation >75%) with 5-fluorouracil. While with tacrolimus,
Female 15 60.0 there was statistically significant relation as vitiligo of legs showed
Age (years) the best results; however, the acral parts (hands and feet) and over
≤20 13 52.0 bony prominence (elbows and knees) showed moderate response
>20 12 48.0 and hardly repigmented (P = .050*; Table 3; Figure 5).

Min-Max 10.0-64.0
Mean  SD 26.44  15.26 3.3 | Side effects
Median 20.0
Complications was detected in only 8 (32%) patches treated with 5-
Family history
fluorouracil in the form of hyperpigmentation in 4 patients (16%),
Negative 21 84.0
inflammation in 3 patients (12%), and ulceration in 1 patient (4%).
Positive 4 16.0
While in the patches treated with tacrolimus, there were no compli-
Type of skin
cations in all the patches (25 patches) (100%). There was statistically
III 12 48.0 significant difference between both drugs regarding the complica-
IV 13 52.0 tions (P = .004*).
Type of vitiligo
Nonsegmental(Generalized) 15 60.0
3.4 | Histopathological evaluation
Nonsegmental (Acral) 10 40.0
Duration of disease (years) The expression of HMB45 was marked in the basal keratinocytes
<5 y 13 52.0 with appearance of positivity in the dermal melanoblasts in case of 5-

>5 y 12 48.0 fluorouracil. While it was moderate in case of tacrolimus (Figure 6).

Site of lesion
Knees 3 12.0
4 | DISCUSSION
Legs 8 32.0
Elbow 4 16.0
Treating vitiligo still remains challenging. As a causative treatment is
Acral parts (hands and feets) 10 40.0
not available, current treatment modalities are directed toward
4 | IBRAHIM ET AL.

T A B L E 2 Comparison between 5-fluorouracil and tacrolimus according to the start of response, degree of improvement, percentage of
improvement,and pattern of repigmentation
5-fluorouracil (n = 25) Tacrolimus (n = 25)
Test of sig. P
No. % No. %
Start of response
No response 2 8.0 3 12.0 v2 = 10.840 MC
P = .018
After 2 sessions 5 20.0 1 4.0
After 3 sessions 11 44.0 4 16.0
After 4 sessions 7 28.0 14 56.0
After 5 sessions 0 0.0 3 12.0
Start of response
Min-Max 2.0-4.0 2.0-5.0 Z = 3.186 .001*
Mean  SD 3.09  0.73 3.86  0.71
Median 3.0 4.0
Degree of improvement
No 2 8.0 3 12.0 v2 = 9.236 MC
P = .051
Mild 5 20.0 3 12.3
Moderate 5 20.0 9 36.0
Good 1 4.0 6 24.0
Excellent 12 48.0 4 16.0
Percentage of improvement
Min-Max 0.0-100.0 0.00-100.0 Z = 2.281* .023*
Mean  SD 56.40  33.43 43.60  30.57
Median 70.0 40.0
Pattern of repigmentation
No repigmentation 2 8.0 3 12.0 v2 = 5.556 .062
Diffuse 19 76.0 11 44.0
Follicular 4 16.0 11 44.0

v , Chi-squared test; MC, Monte Carlo for Chi-squared test; Z, Z for Mann-Whitney test.
2

*Statistically significant at P ≤ .05.

F I G U R E 3 Female patient with

nonsegmental generalized vitiligo. A,
Before treatment in both knees (B) after
treatment (12 sessions), on the right side
with 5-fluorouracil (5FU) with excellent
(A) (B) improvement and with tacrolimus on the
left side with good improvement
IBRAHIM ET AL. | 5

F I G U R E 4 Male patient with

nonsegmental generalized vitiligo. A,
Before treatment in both legs (B) after
treatment (12 sessions), on the right side
with 5-fluorouracil (5FU) with excellent
improvement and with tacrolimus on the (A) (B)
left side with good improvement

T A B L E 3 Relation between the degree of improvement and the site of lesion

Degree of improvement

No Mild Moderate Good Excellent

Site of lesion No. % No. % No. % No. % No. % v2 MC

P
5-fluorouracil Knees 0 0.0 1 20.0 0 0.0 0 0.0 2 16.7 16.577 .311
Legs 0 0.0 0 0.0 3 60.0 1 100.0 4 33.3
Elbow joints 0 0.0 2 40.0 0 0.0 0 0.0 2 16.7
Hands 1 50.0 0 0.0 0 0.0 0 0.0 3 25.0
Feet 1 50.0 2 40.0 2 40.0 0 0.0 1 8.3
Tacrolimus Knees 0 0.0 0 0.0 0 0.0 3 50.0 0 0.0 19.525* .050*
Legs 0 0.0 0 0.0 4 44.4 1 16.7 3 75.0
Elbow joints 1 33.3 1 33.3 0 0.0 1 16.7 1 25.0
Hands 1 33.3 1 33.3 1 11.1 1 16.7 0 0.0
Feet 1 33.3 1 33.3 4 44.4 0 0.0 0 0.0

v , Chi-squared test; MC, Monte Carlo for Chi-squared test.

2

*Statistically significant at P ≤ .05.

stopping the progression of vitiligo and achieving repigmentation to
repair the morphology and functional deficiencies of the depig-
mented skin areas. However, no single treatment method has yet
been found that is consistently effective with relatively few side
effects.13
Several trials have demonstrated that combined treatments
improve the overall effectiveness and the time needed to achieve
repigmentation reducing the potential side effects.6,14,15 This strat-
egy has been proposed in subjects with lesions refractory or resis-
16
tant to monotherapies.
Although the idea of combination therapy is not a new approach
for treatment of vitiligo, to our knowledge, this is the first study to
date that use microneedling with dermapen combined by topical
immunomodulators as a method of improving response rate and has-
ten the duration of therapy in vitiligo.
This work was a comparative study between the efficacy of
microneedling with 5-fluorouracil and its efficacy with tarcolimus in
treatment of vitiligo. The start of response was faster in the patches
treated with 5-fluorouracil than with tacrolimus. The repigmentation
started after 3 sessions (within 6 weeks) in 44% of the patches trea-
ted by 5-fluorouracil combined with microneedling. This was faster
than using it combined with microdermabrasion as studied by Garg
et al,3 who found that half of the patches showed start of repigmen-
tation after 4 sessions within 2 months.3
On the other hand, the repigmentation started in 56% of the
patches treated by tacrolimus combined with microneedling after 4
6 |
(A) (B)
(A) (B)
sessions (within 6 weeks). However, this was faster than using pime-
crolimus 1% cream combined with microdermabrasion as studied by
Farajzadeh et al16 who found that 25.7% of the patches showed
start of repigmentation after 1 month from the end of the course of
treatment (10 sessions). This could be explained by the fact that the
microneedling device produced thin vertical skin pores reaching up
to 0.5 mm into the middermis created small epidermal defects which
allow delivery of topical drug to the melanocytes at the basal cell
layer.17 While microdermabrasion removed only the stratum cor-
neum barrier and this leads to increase the number of sessions to
deliver the topical drug to the melanocytes.18
In this study, 52% of patients showed good to excellent response
(repigmentation >50%) with 5-fluorouracil combined with microneed-
ling. These results were close to the results of combination of 5-
fluorouracil with dermabrasions which had been studied by Sethi
et al5, who found marked repigmentation (repigmentation >50%) in
56.7% of patients at 4 months.5. Delayed healing and hypertrophic
scarring were observed in the previous study using dermabrasions as
methods to increase skin penetration5and this could not be detected
in this study with microneedling. Microneedling device had nontrau-
matic tip radius of not more than 2-3 mm which could penetrate the
skin but without surrounding tissue necrosis. So, it leads to rapid
healing without scarring.17
Also, the response to 5-fluorouracil in this study (52% repigmen-
tation >50%) was better than its combination with Er:YAG laser and
IBRAHIM ET AL.
F I G U R E 5 Female patient with
nonsegmental acral vitiligo. A, before
treatment on the dorsum of the left hand
(B) after treatment (12 sessions), with 5-
fluorouracil (5FU) on the medial patch with
excellent improvement and with tacrolimus
on the lateral patch with good
improvement
F I G U R E 6 Comparison between 5-
fluorouracil and tacrolimus in a case of
vitiligo (A) with 5-fluorouracil showing
marked expression of HMB45 (B) with
tacrolimus showing moderate expression of
HMB45
NB-UVB which has been studied by Anbar et al6, who reported
43.8% marked response with 5-fluorouracil. However, they used an
expensive laser technique that was applied on relatively smaller
areas of vitiligo.
Although 5-fluorouracil was applied topically after microneedling
in this study, its efficacy was close to the results of its intradermal
injection combined with NBUVB which had been studied by Abd El
samad et al19, who reported that 48.3% of the treated patches
showed marked response (repigmentation >50%), while in this study,
52% showed marked response with 5-fluorouracil and microneedling.
This means that microneedling can be used as alternative procedure
to introduce the drug into the dermis instead of direct intradermal
injection. In addition, the cosmetic outcome of microneedling com-
bined with 5-fluorouracil was better than intradermal injection which
showed hyperpigmentation at the periphery of the treated lesions
and pigment incontinence in 25% of the patients.19
On the other hand, 40% of the patches treated with tacrolimus
achieved marked response (repigmentation >50%) in this study. While
50% of patches treated with the tacrolimus combined with the 308-
nm excimer laser (3 times per week for 10 weeks) showed response
15
(>75% repigmentation) as studied by Kawalek et al , who found
that the combination treatment was faster and more effective than
excimer laser as monotherapy. In another study, Park et al20, found
that the combination of tacrolimus plus excimer laser was signifi-
cantly more effective than either tacrolimus or excimer laser alone
IBRAHIM ET AL.
(P < .001 and P < .01, respectively) for the first 6 months. However,
this superiority was not observed after the initial 6 months of treat-
ment. Although this therapy is time-consuming and expensive,its
therapeutic effect on the extremities and genitals was poor.
Regarding the side effects of 5-fluorouracil in patients with viti-
ligo in this study; the reported side effects were few and minor and
all patients well tolerated the procedure. Hyperpigmentation
occurred in 16% of patients which improved within 2 months.
Inflammation occurred in 12% and ulceration in 4% of patients
which healed completely after treatment by topical antibiotic (2%
fusidic acid). The final outcome of the ulcer was transient hyperpig-
mentation which resolved within 2 months. There were no systemic
side effects in any patient. This may indicate that the combination of
5-fluorouracil with microneedling could be considered as safe and
tolerable techniques for treatment of vitiligo.
5
This agreed wih Sethi et al , who reported that hyperpigmenta-
tion is a known side effect of 5-fluorouracil. It could be considered
as postinflammatory hyperpigmentations on sites submitted to
repeated friction. Marked hyperpigmentation was seen in patches
treated with dermabrasion combined with 5-fluorouracil, which per-
sisted up to 6 months of follow-up. Moreover, delayed re-epitheliza-
tion and occurrence of keloids were observed when topical 5-
fluorouracil combined with dermabrasion. These side effects were
not noticed in our study.
On the other hand, no complications were reported in all the
patches treated by tacrolimus in this study. Farajzadeh et al,16 also
noted no adverse effects of the combination of pimecrolimus and
microdermabrasion. It was found that this combination was safe and
effective in the treatment of childhood vitiligo.
With regard to different body sites, 5-fluorouracil could show
excellent to good improvement in lesions in different body parts
(legs, knees, elbows,feet, and hands). While with tacrolimus, there
was statistically significant relation as vitiligo of legs showed the best
results; however, the acral parts (hands and feet) and over bony
prominence (elbows and knees) showed moderate response and
hardly repigmented.
21
In 2015, Mohamed et al , used CO2 laser skin ablation followed
by 5-fluorouracil application for acral vitiligo for a maximum period
of 5 months. Almost half (49.8%) of the lesions achieved marked
repigmentation. However, this was not achieved in periungual areas
in the hands and feet. While in this study, 40% of the patches in the
acral parts (4 from 10 patches in the hands and feet) achieved excel-
lent improvement (repigmentation >75%) with 5-fluorouracil com-
bined with microneedling. Moreover, the repigmentation was
achieved in periungual areas. In contrast to the above method, which
is time-consuming and expensive, this study showed more cost-
effective results and less painful than CO2 laser ablation technique.
5-fluorouracil has antimitotic activity, so it is surprising that it
would be implicated in the vitiligo repigmentation process which
obviously needs melanocyte proliferation. However, it was postu-
lated that 5-fluorouracil could exert repigmentation in vitiligo by
direct stimulation of melanocytes and increase number of melano-
somes in the keratinocytes.7
| 7
In this study,unlike the previous studies using tacrolimus com-
bined with 308-nm excimer laser15 or with NB-UVB14, the acral
parts did not show poor response with tacrolimus combined with
microneedling. As, 50% of the acral patches (5 from 10 patches in
the hands and feet) achieved moderate improvement (repigmenta-
tion 25%-50%), and 1 patch achieved good improvement (repigmen-
tation >50%). So, this combined therapy seems to be superior to
NB-UVB and excimer laser in terms of efficacy, costs, session
duration, response time, and safety.
Needling was used as an adjunct to NBUVB therapy in localized
vitiligo and concluded that patients showed marked response. Need-
ling and phototherapy were repeated 3 times every week for
6 months.22 The study reported that repigmentation of white
patches with needling occurs mainly from melanocytes which are
physically dragged or pushed by tip of the needle from colored mar-
gins of the patch or from islands of pigment present within the
patch.22 This coincides with this study, as melanocytes could be
pushed physically from colored margins to the depigmented center
of the patch but with microneedling device.
5 | CONCLUSION
The combination of microneedling with either 5-fluorouracil or tacro-
limus is safe and effective in the treatment of vitiligo, although 5-
fluorouracil was more effective in the acral vitiligo. However, much
more studies are still needed to find the exact mechanism of action
and the possible side effect of 5-fluorouracil by longer follow-up of
the patients.
ORCID
Mary Mina http://orcid.org/0000-0002-4673-2843
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