Vitiligo is an acquired pigmentary disorder that presents with depigmented macules or patches that is due to absence of epidermal melanocytes.
Men and women are equally affected. At least 30% of patients have positive family history of vitiligo [
In most cases, the disorder begins between 10 and 30 years [
Generalized form (symmetric involvement of more than 20% of body surface area) is the most common type.
Antibodies to melanocytes are suggested as one possible cause of vitiligo [
In another hypothesis, expression of epidermal cytokines in lesions may be different when compared to normal skin. Keratinocyte-derived cytokines such as tumor necrosis factor-alpha (TNF-alpha) are thought to affect melanocyte survival and function [
There are increased levels of TNF-alpha and interleukin-1 (IL-1) in vitiligo lesions compared to normal skin. These cytokines seem to be able to destroy melanocytes [
Keratinocytes are involved in melanocyte homeostasis, so any change in keratinocytes may cause melanocyte dysfunction. High levels of TNF-alpha may play a role in keratinocyte apoptosis, which leads to less production of melanogenic cytokines and therefore melanocyte loss [
This polymorphism (TNF-alpha 308 GA genotype) has also been possible in Mexican population and is believed to increase plasma levels of TNF-alpha [
Some resistant generalized cases were associated with high skin levels of TNF-alpha, and improvement with TNF-alpha inhibitors like etanercept is reported [
Tetracyclines reduce production of TNF-alpha and IL-1 [
This study was done for the first time (to our knowledge).
Our study was double-blind, randomized, placebo-controlled clinical trial. The patients were randomly selected from the Outpatient Dermatology Clinic of Faghihi Hospital (we randomly selected patients via choosing some numbers among patient receipt numbers for phototherapy in phototherapy center each day). Patients with generalized, stable vitiligo (nonprogressive or no new lesions in the last 3 months) were included in our study.
Pregnant or lactating cases, children less than 8 years old, cases of photodermatoses or cutaneous malignancy, or those who had used other medications for vitiligo in the last 3 months were excluded.
Ethical committee of Shiraz University of Medical Sciences approved the study. Informed consent was signed by each patient.
A questionnaire about family history of vitiligo, associated diabetes or thyroid problems, demographic information, medications taken by patient, number of phototherapies prior to study, distribution of lesions, status of disease (stable or progressive), and side effects during trial was filled out.
Vitiligo cases were randomly told to apply tetracycline ointment twice daily on the right or left side assigned lesion and placebo (vaseline colored yellow by artificial dyes used in cooking) twice daily on the other side lesion (almost same size and position). All patients were told to apply ointments only at night if they receive phototherapy in the morning, since tetracycline ointment may induce photosensitivity in the patients if applied in the morning and then get phototherapy. Patients also were receiving narrow band ultraviolet B (NB-UVB) phototherapy twice or thrice weekly. Each case was evaluated and visited at the end of the 4th, 8th, and 12th week.
A third person assigned A and B to both ointments, so both patient and physician were blinded to treatment and placebo.
Pigmentation of selected lesions on both sides was determined based on vitiligo area severity index (VASI) prior to study and photos were taken of both sides (baseline, at the end of 4th, 8th, and 12th weeks).
Images were compared to baseline based on VASI.
Cases were told to report any side effect whether from phototherapy or ointments.
Paired
All results were significant if
There were 30 cases (17 (56.7%) females and 13 (43.3%) males), with generalized stable vitiligo, aged from 11 to 66 years, enrolled in our study. Cases were assigned randomly to apply treatment and placebo ointments to right or left side lesions (similar location and size). The patients also were receiving NB-UVB, 2-3 times weekly. All cases completed the 12-week study. The process of patient selection is shown Figure
Results showed that 23.3% of cases had positive family history of vitiligo, 16.6% were diabetic, and 13.3% had thyroid problem. Sites tested during this study and number of cases were as follows: elbow 12, knee 2, leg 5, wrist 2, neck 1, arm 2, forearm 3, abdomen 1, and chest 2. In Table
Pigmentation of lesions, based on VASI (baseline, end of trial).
Patient number | Pig. (VASI) before Med. | Pig. (VASI) before placebo | VASI 12th week Med. | VASI 12th week placebo | Phototherapy sessions before study | Site of lesion |
---|---|---|---|---|---|---|
1 | 100 | 100 | 100 | 90 | 1 | elbow |
2 | 100 | 100 | 100 | 100 | 8 | elbow |
3 | 75 | 75 | 75 | 50 | 170 | elbow |
4 | 100 | 100 | 90 | 100 | 150 | leg |
5 | 100 | 100 | 100 | 100 | 51 | elbow |
6 | 100 | 100 | 100 | 90 | 24 | leg |
7 | 100 | 100 | 100 | 100 | 17 | leg |
8 | 100 | 100 | 100 | 90 | 70 | neck |
9 | 75 | 100 | 75 | 100 | 34 | leg |
10 | 75 | 50 | 50 | 50 | 60 | knee |
11 | 50 | 50 | 50 | 50 | 45 | elbow |
12 | 90 | 90 | 75 | 90 | 48 | knee |
13 | 90 | 90 | 75 | 75 | 100 | leg |
14 | 100 | 100 | 100 | 100 | 22 | elbow |
15 | 100 | 100 | 100 | 100 | 15 | forearm |
16 | 100 | 100 | 100 | 100 | 150 | forearm |
17 | 90 | 90 | 90 | 90 | 20 | wrist |
18 | 90 | 100 | 75 | 100 | 32 | forearm |
19 | 100 | 100 | 100 | 100 | 1 | elbow |
20 | 75 | 75 | 75 | 75 | 3 | elbow |
21 | 90 | 100 | 90 | 100 | 7 | wrist |
22 | 90 | 90 | 90 | 90 | 115 | abdomen |
23 | 75 | 75 | 75 | 75 | 130 | elbow |
24 | 100 | 75 | 90 | 75 | 60 | elbow |
25 | 75 | 75 | 75 | 75 | 30 | elbow |
26 | 100 | 100 | 100 | 100 | 43 | elbow |
27 | 90 | 90 | 90 | 90 | 22 | chest |
28 | 100 | 100 | 100 | 100 | 42 | arm |
29 | 100 | 100 | 100 | 100 | 12 | arm |
30 | 75 | 50 | 75 | 50 | 36 | chest |
Mean scores of pigmentation based on VASI (medication and placebo sides).
Mean pigmentation |
|
Std. deviation | |
---|---|---|---|
Before med. | 90.1667 | 30 | 12.69560 |
After med. | 86.6667 | 30 | 14.87496 |
Before placebo | 89.6667 | 30 | 15.97052 |
After placebo | 86.8333 | 30 | 17.24486 |
Difference in mean pigmentation between medication and placebo sides.
Mean (depig.-repig.) |
|
Std. deviation | |
---|---|---|---|
Diff. med. side | 3.5000 | 30 | 6.65444 |
Diff. placebo side | 2.8334 | 30 | 5.21106 |
There was a significant change in medication side in terms of pigmentation compared to baseline (
Also similar change in the placebo side was observed (
There was no significant difference between medication and placebo sides in terms of pigmentation (
In summary in the five cases (16.6%), improvement in pigmentation was observed on medication side compared to placebo side. Similarly, 16.6% of cases showed better repigmentation on placebo side compared to medication side.
A few patients complained of stinging at the site of treatment, but in general, no adverse cutaneous effect reported.
This study evaluates the efficacy of topical tetracycline ointment in enhancing the effect of NB-UVB (narrow band ultraviolet B) phototherapy against generalized, stable vitiligo (nonprogressive or no new lesions in the last 3 months), after the end of the 4th, 8th, and 12th week.
Since we know systemic tetracyclines can reduce production of proinflammatory cytokines such as TNF-alpha and IL-1 [
Two cases of refractory generalized vitiligo were reported by Kim et al. [
Vitiliginous lesions of a patient (reported by Lv et al. [
In a study by Laddha et al. [
On the other hand, in a study by AlGhamdi et al. [
In a case report, the use of etanercept (TNF-alpha inhibitor) subcutaneously improved a patient affected by both psoriasis and vitiligo, although there was mild improvement of vitiligo. Thus in this case report, the role of TNF-alpha seems probable in vitiligo [
Infliximab (TNF-alpha inhibitor, IV) improves not only ankylosing spondylitis, but also the vitiligo, probably due to anti-TNF-alpha activity blockage. This was a case report [
So, based on the aforementioned studies, some are in favor, and some are against it. It is sensible to do larger studies on TNF-alpha inhibiting agents since there is no definite cure or safe therapy for vitiligo patients so far. It is suggested that topical agent that may reduce TNF-alpha in the epidermis (like tetracycline) is evaluated further in the treatment of vitiligo, since it is safe and not as expensive as TNF-alpha blocking agents.
Limitation in this study is the short duration of clinical trial and the limited number of patients, although based on a textbook [
Our study on 30 cases of generalized vitiligo showed no significant improvement in pigmentation in the lesions on topical tetracycline side, compared to placebo sides. Although theoretically the application of tetracycline ointment might be helpful, reducing of TNF-alpha in the epidermis, other pathogenic events like autoantibodies against melanocytes or oxidative stress may be stronger. Since this study on topical tetracycline was done for the first time (to our knowledge), we recommend further and larger studies be done on the agents that reduce expression of TNF-alpha in the epidermis of vitiliginous skin, preferably topical in order to lessen side effects.
The authors declare that there is no conflict of interests regarding the publication of this paper.