ARTICLE
Auteur(s) : Jaap de LEEUW, Nick van der BEEK, Gnther
MAIERHOFER, Wolfgang‐Dieter NEUGEBAUER
Multicare, Clinic for Dermatology and Laser treatment, Hoge
Naarderweg 7 H 1217 AB Hilversum, the Netherlands.
Reprints: J de Leeuw Fax: (+31) 35 624 67 07 E‐mail:
multicareplanet.nl
Article accepted on 10\07\2003
Vitiligo, an acquired depigmention disorder affecting about 1%
of the population [1, 2], may be a psychosocial disaster,
particular in people with pigmented skin, especially in those
countries where there is confusion of vitiligo with leprosy in the
public mind [3]. Vitiligo is histologically characterized by the
absence of melanocytes in the epidermis. Inactive melanocytes in
the outer root sheaths of the hair follicles are not affected.
During the process of repigmentation, these inactive melanocytes
proliferate and mature to an active condition as they migrate into
the epidermis [4]. Therapeutic approaches are aimed at reversing
the progressive loss of melanocytes and reconstituting normal skin
coloration, but none is uniformly effective and side effects may
occur. Most common treatments are topical corticosteroids, systemic
and topical PUVA, broad‐ and narrow‐band UVB, systemic and topical
L‐phenylalanine with UVA (PAUVA) [5‐9], systemic and topical
khellin with UVA (KUVA) [10‐14]. Surgical treatment is limited to
small and stable vitiligo maculae [1]. Khellin,
a furanochromone with a chemical structure closely resembling that
of the psoralen family, is activated by UVA (365 nm) [10].
Liposomes are small vesicles of membrane lipids. They can be used
as microscopic carrier capsules for selective delivery of drugs
into a specific disease site. Phosphatidylcholine‐based liposomes
have a high potential for selectively targeting molecules contained
in them into the hair follicles. [15, 16, 17]. Encapsulating
khellin in phosphatidylcholine liposomes may enhance the
penetration of khellin into the area of the inactive melanocytes in
the hair follicle in order to provide optimal availability of
khellin to stimulate the inactive melanocytes. L‐phenylalanine is
added to the formula in order to promote the stability of the
solution. L‐phenylalanine was also chosen because of its reputation
to be effective, both orally and topically, together with UVA
therapy in the treatment of vitiligo [8, 9]. Schallreuter has
suggested that oxidative stress plays a role in the pathomechanism
of vitiligo [18] and because L‐phenylalanine has anti‐oxidant
properties [19] this may be the way it works. The Arimed B light
source has a UV spectrum approximating that of sunlight
(approximately UVB 5% and UVA 95%). It can be argued that such a
simulated sunlight source represents a more cautious approach to
home therapy than conventional broad spectrum UVB therapy [20]. The
advantage of home therapy is that the high social and economic
costs of hospital visits are reduced. The disadvantage of home
therapy is that medical supervision is less frequent. In this open,
retrospective study the efficacy of topical treatment of vitiligo
with khellin encapsulated in L‐phenylalanine stabilized
phosphatidylcholine liposomes in combination with ultraviolet light
therapy (KPLUV) as home phototherapy is determined.
Subjects and methods
65 patients (50 females and 15 males) with
vitiligo vulgaris and 9 patients (5 females and
4 males) with vitiligo universalis were included in the study.
The average age was 43 years (range 12‐75 years). Mean
duration of vitiligo was 15 years (range 4‐60 years).
All patients had been treated before with topically applied
corticosteroids, 48 patients also with PUVA and
18 patients with broadband‐UVB, without notable
repigmentation.
Exclusion criteria were phenylketonuria, pregnancy and
breastfeeding, impaired hepatic and renal functions, malignant skin
diseases, history of exposure to arsenates or ionizing radiation
and photo‐induced diseases.
The patients were instructed to apply twice a day, in the morning
and half an hour prior to the UVA therapy, a spray containing
khellin in a concentration of 0.005% encapsulated in
phosphatidylcholine liposomes, stabilized with L‐phenylalanine
0.1%. The light source (Arimed B Cosmedico, Stuttgart, Germany) has
a spectrum from 295 to 400 nm and peak emissions at
317 and 356 nm. The photo treatment schedule started with
one minute daily 5 times a week raising the exposure time by
one minute every week until the erythematic dose was reached. The
treatment was continued with the suberythema dose. The exposure
time was never more than 15 minutes. The light source was
given to the patients for treatment at home as a panel and not as a
booth in order to save space, so that patients with vitiligo on the
frontal and dorsal parts of the body underwent two exposures. As
soon as a marked improvement was achieved, the treatment schedule
was reduced from 5 times a week to 3 times a week.
This study is a case‐study and not a placebo‐controlled,
randomized study.
The control group consisting of 30 patients used the same
UVA\B light source (Arimed B Cosmedico), with the same photo
treatment schedule, but not in combination with the application of
the khellin and phenylalanine containing liposomal solution.
The liposomal vehicle of the spray has an absorption spectrum from
190 to 210 nm. This is out of the range of the emission
spectrum of the used UVA\B light source, excluding the need to use
the vehicle in the control group.
Photographs (Fotofinder, TeachScreen Software GmbH, Germany) of
the subjects were taken at the beginning of the therapy and than
once every two months for one year. The extent of repigmentation
was recorded by visual comparison of the successive photographs,
making use of planimetry. The before‐and‐after evaluation was
performed by 2 experienced clinicians, who did not know
whether the patients were treated with UVA\B light therapy in
combination with topical liposomal solutions (study group) or with
UVA\B as monotherapy (control group).
Results
After a mean treatment period of 12 months (range
10‐14 months) 72% of treated locations had a repigmentation
response of 50% to 100%.
The repigmentation was not equal for different parts of the body.
Repigmentation of more than 50% was achieved on the face in 79%,
the back in 74%, the trunk in 73%, the arms in 76%, the legs in
70%, and on the hands in 65%.
Repigmentation of 75%‐100% was achieved in the face in 63%, on the
back in 59%, the arms in 58%, the trunk in 73%, the legs in 56% and
the hands in 4% (table I).
Table I. Table of 75‐100% repigmentation‘
Surprisingly eight out of the nine patients (88%) with vitiligo
universalis showed a repigmentation of more than 75%.
The patients in the control group treated with only UV‐light
(Arimed B), without the use of the khellin spray, hardly showed any
repigmentation (table II).
Table II. Percentage of patients in the control
group with localized repigmentation
| Repigmentation |
0‐10% |
10‐24% |
25‐74% |
75‐100% |
| Face |
100 |
0 |
0 |
0 |
| Arms |
90.9 |
0 |
9.1 |
0 |
| Legs |
100 |
0 |
0 |
0 |
| Trunk |
100 |
0 |
0 |
0 |
| Back |
100 |
0 |
0 |
0 |
| Hands |
100 |
0 |
0 |
0 |
| Overall |
100 |
0 |
0 |
0 |
.
.
.
Cumulative annual Joules doses of UVA and UVB:
|
UVA (J\cm2) |
UVB (J\cm2) |
| Mean |
679 |
25.9 |
| Maximum |
1680 |
61.7 |
| Minimum |
180 |
7.2 |
Side effects were not noticed.
Discussion
.
. The treatment of vitiligo can be frustrating to patients and
doctors. A standard modality that cures every patient does not yet
exist [1, 2]. Topical corticosteroids, topical‐ and systemic PUVA,
broad‐ and narrow‐band UVB light therapy are the most common
methods, although they are not always effective and side effects
may limit the therapeutic options [5‐9]. Narrow‐band UVB is
effective in the treatment of vitiligo. An overall repigmentation
of 75% in 53% of the patients and a stabilization of the disease in
80% has been seen [21]. But not all investigators came to the same
conclusion [22]. Surgical treatment is limited to small and stable vitiligo maculae [1].The results of systemic
khellin in combination with UVA [11‐14] are comparable to the rates
reported from psoralen phototherapy [1]. The major advantage of
khellin is that it does not induce phototoxic skin erythema and it
does not induce detectable DNA mutations in contrast to PUVA [11,
12]. Ortel et al. studied the effect of oral khellin in
combination with UVA light in 26 patients. A repigmentation of
more than 70% was achieved in 41% of the patients who had received
100 to 200 treatments. A mild elevation of liver
transaminases was observed in 28% of the patients on oral
treatment. Of three patients who were treated with topical khellin
and UVA, two patients had a repigmentation of only 30% [12]. In our
study with topically administered khellin in liposomes, a
repigmentation between 50% and 100% was seen in 72% of the
patients. Hofer et al. performed a study to assess the
effectiveness and short‐term and long‐term safety of oral khellin
plus UVA light therapy (KUVA) in patients with vitiligo. Of
17 patients, 41% had a response of more than 70%
repigmentation after a mean of 194 treatments. Short‐term side
effects were episodes of nausea in 29% of the patients, elevated
liver enzymes in 7% and gastritis in 7% of the patients. Long‐term
side effects have not been seen, no skin cancer or actinic damage
of vitiliginous skin was found in any patient. Their data indicate
that KUVA seems to be safe as well as effective for vitiligo,
provided treatment is administered long enough [13]. Orecchia et
al. concluded from their study that topically applied khellin
is effective in the treatment of vitiligo, but that the results are
vehicle dependant [14]. A potential concern is the hepatotoxic side
effect of khellin. The low active ingredient concentration of
0.005% khellin in the topically applied spray would tend to exclude
this risk. Vitiligo destroys only the active melanocytes in the
epidermis; inactive melanocytes in the outer root sheath of the
hair are not affected. During the process of repigmentation, these
inactive melanocytes proliferate and migrate from the outer root
sheath to the epidermis, meanwhile maturing from the inactive phase
to an active state [4].
The ideas behind the treatment of vitiligo with khellin in
L‐phenylalanine stabilized liposomes as described in this article
are based on:
Enhancing the penetration of khellin by carrier liposomes into the
hair follicles in order to provide optimal availability of khellin
in the area of the inactive, non‐affected melanocytes.
Stimulation of the melanogenesis by using topical khellin and UVA
light.
Avoidance of side effects by using only topical‐ and not systemic
khellin treatment.
L‐phenylalanine was added to the formula because of its
stabilizing effect on the solution, and its anti‐oxidant
properties.
The safe light source and the fact that topically applied khellin
has a very low phototoxic effect makes this approach suitable for
home therapy.
Home therapy is cost reducing and comfortable for the
patients.
This study demonstrates that KPLUV is effective and safe in the
treatment of vitiligo.
An open study has many shortcomings and further investigation is
needed to determine the optimal combination of the ingredients in
the spray and the optimal application frequencies
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