Comparison of the Efficacy of Intralesional TriamcinoloneAcetonide and 5-Fluorouracil Tattooing for the Treatmentof Keloids

ALI SADEGHINIA, MD AND SAEED SADEGHINIA

BACKGROUND Hypertrophic scars and keloids may complicate wound healing secondary to trauma orsurgery. A variety of treatment regimens have been used for treatment of keloids.

OBJECTIVE To compare 5-fluorouracil (5-FU) tattooing and intralesional steroid for treatment of keloids.

METHODS In this 44-week, double-blind, clinical trial, 40 patients were randomized into two study groups.Patients in group 1 were given intralesional triamcinolone acetonide (TAC), and patients in group 2 weretreated with 5-FU tattooing; both groups received treatment every 4 weeks for 12 weeks. Lesions wereassessed for erythema, pruritus, height, surface, and induration at baseline (initiation of treatment) and atweeks 4, 8, 12, 20, 28, 36, and 44. All patients had complete blood count, liver function tests, and renalfunction tests before treatment and at week 20.

RESULTS All the patients completed the study. At the 44-week follow-up visits, both groups showedimprovement in all parameters, but improvement was more significant in the 5-FU group (p < .05). No sideeffect was detected in either of the groups.

CONCLUSION 5-FU tattooing was more effective than intralesional TAC for the treatment of keloids.

The authors have indicated no significant interest with commercial supporters.

Keloids result from abnormal wound

responses. They are more common in darker

skin types and in specific anatomic sites such as the

chest, upper back, and shoulders. Several types of

injury, including surgery, piercings, burns, lacera-

tions, abrasions, tattooing, vaccinations, insect

bites, and inflammatory processes, such as acne,

varicella, and folliculitis, can produce keloids.1,2

External factors such as increased wound tension

and wound infection increase the risk of keloid for-

mation.3,4 Patients with keloids often experience

marked physical deformity, restricted range of

motion, pain, pruritus and psychological prob-

lems.5 Different treatment modalities such as radia-

tion,6 pressure therapy,7 cryotherapy,8 intralesional

injections of steroids,9 interferon10 5-fluorouracil

(5-FU),11 topical silicone,12 PDL,13 excision fol-

lowed by primary suture,14 healing by secondary

intention,15and skin flap and graft16,17 have been

used for treatment of keloids. It has been suggested

that fibroblasts derived from keloid and hypertro-

phic scar tissue produce increased amounts of col-

lagen compared with normal fibroblasts,18 Thus,

suppression of the overwhelming and uncontrolled

fibroblast activity in keloids and hypertrophic scars

may be essential in therapeutic approaches to these

abnormal wound responses.19

5-FU, a pyrimidine analogue with antimetabolite

activity, has been shown to inhibit fibroblast prolif-

eration in tissue culture.20 Different studies show

the efficacy of 5-FU for treatment of keloids.19–23

Department of Dermatology, Tehran University of Medical Sciences, Tehran, Iran

© 2011 by the American Society for Dermatologic Surgery, Inc. � Published by Wiley Periodicals, Inc. �ISSN: 1076-0512 � Dermatol Surg 2012;38:104–109 � DOI: 10.1111/j.1524-4725.2011.02137.x

104

The efficacy of corticosteroid injections has been

proved in the treatment of keloids.19,24–27

The most commonly used corticosteroid is triamci-

nolone acetonide (TAC). Although intralesional

TAC administration has shown clinical efficacy,

the outcome has been uncertain and associated

with multiple adverse effects, including atrophy,

telangiectasia, and pigmentary changes.28

Although different studies have compared the

efficacy of intralesional steroids and intralesional

5-FU, but in our knowledge, there is no study

demonstrating the efficacy of 5-FU tattooing in

treatment of keloids, so we decided to compare the

efficacy of Intralesional triamcinolone and 5-FU

tattooing for the treatment of keloids.

Patients and Methods

This was a 12-week, double-blind, randomized

clinical trial. The study was approved by Derma-

tology Department, and Research Administration

of Lorestan University of Medical Sciences, Lore-

stan, Iran. Informed consent was obtained from all

participants. The study was approved by the Insti-

tutional Ethics Committee. We checked CBC, renal

and liver function tests for all of the patients

before and at week 20.

Exclusion criteria:

(1) Treatment within the past 6 months.

(2) Chronic renal failure.

(3) Patients with any abnormalities in their liver

function tests or CBC.

(4) Pregnancy or planning pregnancy in the near

future.

(5) Lactation.

(6) Patients without similar keloids.

In this 44-week, double-blind, clinical trial, 40

patients were randomized into two study groups.

A computer-generated table of random numbers was

used for allocation. Patients in group 1 were given

intralesional TAC, and patients in group 2 were trea-

ted with 5-FU; both groups received treatment every

4 weeks for 12 weeks. Lesions were assessed for ery-

thema, pruritus, pliability, height, length and width.

In TAC group, the lesions were anesthetized with

intralesional 2% lidocain injection, then intrale-

sional TAC (40 mg/mL) was administered using a

27G needle until infiltration of lesions. All lesions

were treated every 4 weeks with intralesional TAC

40 mg/mL for a total of 3 sessions. Twenty milli-

grams (0.5 mL) of TAC (40 mg/mL) was injected

per 1 cm2 of the lesions. In 5-FU group, the lesions

were anesthetized with intralesional 2% lidocain

injection. 1 mL of 5-FU solution (50 mg/mL) was

dripped onto each 1 cm2 of the lesions and then

40 punctures per 5 mm2 were made on the lesions

using a 27-G needle. 5-FU penetrated into the

lesion, then again 1 mL of 5-FU solution (50 mg/

mL) was dripped onto the surface of lesion, and

the lesions were covered subsequently. Patients

were treated with 5-FU tattooing every 4 weeks for

a total of 3 treatments. Assessments of the lesions

were performed at baseline and weeks 4, 8, 12, 20,

28, 36, and 44 by another dermatologist. The sec-

ond dermatologist who evaluated the lesions was

blinded to the lesions. All the lesions were anesthe-

tized before intralesional injection of TAC or 5-FU

tattooing. Patient’s visions were blocked by special

goggles, so all of them were blinded to treatment.

For groups 1 and 2, respectively, mean ± SD age

was 45 ± 8.2 and 43.36 years, and duration of the

lesions was 13.5 ± 5.2 and 14.3 ± 4.5 months. The

site distribution of lesions was: 40% on the face

and neck, 60% on the trunk, 30% on upper limbs

and 10% on the lower limbs.

Evaluation Procedures

Surface and Height

A dial caliper was used to determine greatest

length, width and height of the lesion (millimeter).

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38 :1 : JANUARY 2012 105

Percentage of height reduction was measured after

treatment compared with baseline, Also percentage

of surface reduction was monitored at weeks 4, 8,

12, 20, 28, 36, 44.

Erythema, Induration, and Pruritus

Erythema and induration were graded by the

observer and pruritus by the patients on a 5-point

scale (0 = no erythema, induration, or pruritus;

1 = mild; 2 = moderate; 3 = severe; 4 = very

severe erythema, induration, or pruritus). Percent-

ages of erythema, induration and pruritus reduc-

tion were measured at weeks 4, 8, 12, 20, 28, 36,

44 compared with baseline.

Patient Self-Assessment and Observer

Assessment

At weeks 4, 8, 12, 20, 28, 36, 44 of the study,

overall improvement was graded by patients and a

blinded observer on a 5-point scale (no/poor: up to

25%; fair: 26–50%; good: 51–75%; excellent:

76–100% improvement).

Improvement was assessed with respect to pruritus,

surface, height, induration and erythema.

Statistical Analysis

Statistical analysis was carried out using SPSS 17

software for Windows (SPSS Inc., Chicago, IL).

Data were analyzed using repeated measure test

and the paired t-test. All statistical tests were two-

tailed with significance set at p < .05.

Results

All the patients completed the study. At baseline,

there were no significant differences in, duration,

surface, height, induration, erythema, and pruritus

between two study groups (p > .05 for all).

Height

There was a significant decrease in height of lesions

in both study groups at weeks 4, 8, 12, compared

with baseline (p < .05 for all). After week 12, the

mean height of the lesions did not change signifi-

cantly in two groups.

At the follow-up visits at weeks 4, 8, 12, 20, 28,

36, 44, the height reduction, were greater in the

5-FU than in the TAC group compared with base-

line (p < .05 for all) (Figure 1).

Surface

There was a significant decrease in surface of the

lesions in both study groups at weeks 4, 8, 12, 20,

compared with baseline (p < .05 for all). There

was no decrease in surface of the lesions in both

study groups after week 20 (p > .005). The surface

reduction were greater in the 5-FU than in the

TAC group at weeks 4, 8, 12, 20, 28, 36, 44

compared with baseline (p < .05 for all) (Figure 2).

Figure 1. Mean lesion height reduction during 44-weekfollow-up.

Figure 2. Mean lesion surface reduction during 44-weekfollow-up.

TATTOOING FOR THE TREATMENT OF KELOIDS

DERMATOLOGIC SURGERY106

Erythema

Decrease in erythema score was significant in study

groups during weeks 4, 8, 12, 20 and 28 (p < .05

for all). After week 28, erythema increased in 5FU

group. The erythema reduction were greater in the

5-FU than in the TAC group at weeks 4, 8, 12,

20, 28, compared with baseline (p < .05 for all)

(Figure 3).

Induration

A significant decrease in induration score of lesions

versus baseline was observed in both groups at the

follow-up visits in weeks 4, 8, 12 (p < .05). After

week 12, induration decreased in 5-FU group but

not in TAC group (p < .05 for all). In comparison

between groups, decrease in induration were signif-

icantly higher in the 5-FU than TAC group

(p < .05) (Figure 4).

Pruritus

A significant decrease in pruritus score of lesions

versus baseline was observed in both groups at

the follow-up visits in weeks 4, 8, 12. After week

12, pruritus score decreased in 5-FU group

(p < .05), but in TAC group, pruritus score

increased (p > .05). In comparison between

groups, decrease in pruritus was significantly

higher in the 5-FU than TAC group (p < .05)

(Figure 5).

Patient Self-Assessment

At the end of the study (week 44), patient self-assess-

ment was significantly better (p <.05) in the 5-FU

group. Good to excellent response was reported by

85% of the patients, and poor to fair response by

15% of the patients. In TAC group, good to excel-

lent response was reported in 40%, and poor to fair

response in 60% of the patients (Figure 6).

Observer Assessment

At weeks 44, significantly better results were found

for the 5-FU group (p <.05). In the 5-FU group,

good to excellent response was reported in 95%,

and poor to fair response in 5% of the patients. In

TAC group, good to excellent response was

reported in 50%, and poor to fair response in 50%

of the patients (Figure 7).

Figure 3. Decrease in erythema score during 44-weekfollow-up.

Figure 4. Decrease in induration score during 44-weekfollow-up.

Figure 5. Decrease in pruritus score during 44-weekfollow-up.

SADEGHINIA AND SADEGHINIA

38 :1 : JANUARY 2012 107

Side Effects

During the study, no abnormalities were detected

in laboratory data and no side effect was detected

in any of the two groups.

Discussion

5-FU, a pyrimidine analogue with antimetabolite

activity, suppresses cell division and produces

growth arrest at any stage of the cell cycle. It is

known to affect cell membrane proteins mandatory

for cell-to-cell communication and autoregula-

tion.29 5-FU has been shown in tissue culture to

inhibit fibroblast proliferation.30 Also, it is likely

that the combination of raised levels of TGF-b and

the abnormal response of proliferative scar fibro-

blasts to this cytokine are important for keloid for-

mation.22 For this particular property, 5-FU has

been used as an adjuvant to glaucoma operation.27

Fibroblast regression is dependent on the duration

of exposure to the drug and the dose.11 It has been

found that 5-FU delivered intralesionally once

weekly or once every 2 weeks in keloids and

hypertrophic scars is effective.19,21,22,27 Nanda and

Reddy reported that almost 80% of their patients

showed >50% improvement.23 Gupta demon-

strated that intralesional administration of 5FU

can cause more than 50% flattening of the treated

keloids.21 Kontochristopoulos and colleagues

showed that of 20 patients, 17 (85%) showed

more than 50% improvement. Only one did not

respond favorably.22 Davidson and colleagues

demonstrated that patients who received 5-FU/

steroid without excision had an average lesion size

reduction of 81%.31 Clinical improvement of

keloids after Intralesional 5-FU alone was compa-

rable to treatment with intralesional corticosteroid

alone or combined with 5-FU, 5-FU alone, and

PDL, with the exceptions of the incidence of

adverse reactions, which were most common with

intralesional corticosteroid.19 In all above men-

tioned studies 5-FU was administered every 1 to

2 weeks intralesionally, but in our study we did

5-FU tattooing every 4 weeks.The results of our

study are comparable to these studies. We did not

see any side effects in our patients in this study,

and we relate this to longer intervals (every

4 weeks) and tattooing method of administration.

We think that double dripping of 5-FU after tat-

tooing and subsequent occlusion of keloids may

increase the efficacy of tattoing. To our knowl-

edge, this is the first randomized clinical trial to

compare 5-FU tattooing and intralesional steroid

for treatment of keloids. Although both treatment

groups in this study showed improvement in all

parameters, but treatment with 5-FU was more

effective.

Acknowledgments I am grateful to Dr. Behnam

Hashemi, Dr. Sharhani, M.J. Tarrahi, and

Z. Shahabi for their cooperation in this study.

Figure 6. Patient self-assessment.

Figure 7. Observer assessment at the end of the study.

TATTOOING FOR THE TREATMENT OF KELOIDS

DERMATOLOGIC SURGERY108

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Address correspondence and reprint requests to: AliSadeghinia, MD, Shariati Hospital, Kargare ShomaliAve., Tehran, Iran, or e-mail: asadeghinia@tums.ac.ir

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38 :1 : JANUARY 2012 109

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