Rapid initiation of repigmentation in vitiligo with Dead Sea

Transcription

IJD_1463.fm Page 482 Wednesday, August 14, 2002 8:37 AM
Report
Oxford, UK
International
IJD
Blackwell
0011-9059
41
Science,
Journal
Ltdof Dermatology
2002
Rapid initiation of repigmentation in vitiligo with Dead Sea
climatotherapy in combination with pseudocatalase (PC-KUS)
Repigmentation
Schallreuter
et al.in vitiligo and hydrogen peroxide removal
Karen U. Schallreuter, MD, Jeremy Moore, PhD, Stephanie Behrens-Williams, MD,
Angela Panske, BSc, and Marco Harari, MD
From the Department of Biomedical
Sciences, Clinical and Experimental
Dermatology, University of Bradford, West
Yorkshire, BD7 1DP, UK, the Institute for
Pigmentary Disorders in association with the
Ernst Moritz Arndt University of Greifswald,
Greifswald, Germany, and DMZ-Mor Clinic,
Ein Bokek, Israel
Correspondence
K U Schallreuter, MD
Clinical and Experimental Dermatology
Department of Biomedical Sciences
University of Bradford
West Yorkshire
BD7 1DP
UK
E-mail: [email protected]
Abstract
Background Low catalase levels and cellular vacuolation in the epidermis of patients with
vitiligo support major oxidative stress in this compartment. There is now in vivo evidence for
increased epidermal hydrogen peroxide (H2O2) accumulation in this patient group by utilizing
noninvasive Fourier Transform Raman spectroscopy (FT Raman). Epidermal H2O2 can be
removed with a topical application of narrow band UVB activated pseudocatalase cream
(PC-KUS). (Mn / EDTA-bicarbonate complex, patent No. EPO 58471 1 A), yielding initiation of
repigmentation. Dead Sea climatotherapy is another successful treatment modality for vitiligo,
but the mode of action has escaped definition so far.
Methods Epidermal hydrogen peroxide (H2O2) was assessed in vivo before and after 21 days
treatment at the Dead Sea using noninvasive Fourier-Transform Raman spectroscopy. The
effectiveness of repigmentation was followed in 59 patients with vitiligo by comparing Dead Sea
climatotherapy alone with the combination of Dead Sea climatotherapy/pseudocatalase cream
(PC-KUS) as well as Dead Sea climatotherapy/placebo cream. Clinical repigmentation was
documented by standardized black /white photography using non-UV coated bulbs as flashlight
and by color photography.
Results This study on 59 patients who had vitiligo for an average time of 17 years (range
3 – 53 years) confirmed in vivo H2O2 accumulation in mM concentrations in the epidermis of
untreated patients. Furthermore, we demonstrated a pseudocatalase activity after 15 min of
Dead Sea bathing, but the decrease of epidermal H2O2 levels was significantly less compared
to narrowband UVB activated pseudocatalase cream (PC-KUS). Initiation of repigmentation
was already observed between day 10 and day 16 after a combination of Dead Sea
climatotherapy/pseudocatalase cream compared to conventional pseudocatalase
monotherapy (8 –14 weeks) and Dead Sea climatotherapy alone (5 – 6 weeks).
Conclusion The results of this study show a significantly faster initiation of repigmentation in
vitiligo after a combination of short-term climatotherapy (21 days) at the Dead Sea in
combination with a pseudocatalase cream (PC-KUS) compared to either conventional
climatotherapy at the Dead Sea alone or with placebo cream in combination with climatotherapy.
This combined therapy is significantly faster in repigmentation than narrowband UVB activated
pseudocatalase cream (PC-KUS) treatment alone.
The results of this study support the necessity of epidermal H2O2 removal as well as the
influence of solar UV-light in the successful treatment of vitiligo.
Introduction
482
Vitiligo is an acquired depigmentation disorder affecting
0.5–4% of the world population.1 Despite its early recognition,
the etiology is still unclear. There are several hypotheses but
none of them can satisfy the entire spectrum of this disfiguring
disorder.1,2 Almost all the publications describe decreased
International Journal of Dermatology 2002, 41, 482 –487
numbers of functioning melanocytes or the complete absence
of these cells in the involved skin.3 A recent paper by Tobin
et al. showed that melanocytes are still present even in long
standing disease.4 In addition, altered functionality of Langerhans cells has been stressed.5 Nowadays there is convincing
evidence for the presence of oxidative stress in the skin of
affected individuals.6–11 Extremely high concentrations of
© 2002 The International Society of Dermatology
Schallreuter et al.
Repigmentation in vitiligo and hydrogen peroxide removal Report
Figure 1 Clinical result of
narrowband UVB activated
pseudocatalase cream (PC-KUS)
therapy. Extensive repigmentation
of facial vitiligo in a female black
patient (photo skin type VI) before
(a) and after (b) 14 months
treatment with narrowband UVB
activated pseudocatalase (PC-KUS)
monotherapy twice daily.12–14 N.B.
This result can be achieved even
after the duration of vitiligo for
47 years
epidermal H2O2 together with low catalase levels have been
identified in vivo and in vitro using Fourier Transform Raman
spectroscopy (FT Raman).12,13 It has been shown that the
missing catalase activities can be substituted with a narrowband activated pseudocatalase cream (PC-KUS) which is
based on a bis manganese EDTA bicarbonate complex
(Patent No. EPO 58417 A). This complex successfully removes
the high H2O2 levels from these patients leading to initiation
of repigmentation and to recovery from vacuolation in the
epidermal cells.4,12–15 The time course for repigmentation can
vary considerably in the patients, but repigmentation can be
achieved in long-term vitiligo even after 47 years12 (Fig. 1).
Since the combination of solar radiation and sea water
bathing at the Dead Sea is a successful treatment modality in
various skin diseases, such as psoriasis and atopic eczema, as
well as vitiligo, we wanted to investigate whether we could
enhance the effect of the conventional pseudocatalase cream
(PC-KUS) monotherapy in combination with the Balneoclimatotherapy at the Dead Sea.16
Until now it is generally believed that the high salt concentration (346 g/L) contributes to the efficacy of the therapy
by several mechanisms. A release of pro-inflammatory and
chemotactic mediators has been proposed.16,17 Only recently
the effect of the high magnesium chloride (MgCl2) concentration of this water has been further elucidated by Schempps
et al. who were able to show that MgCl2 dramatically influences the antigen presenting capacity of Langerhans cells.18
Furthermore, it is generally believed that the unique solar UV
spectrum in the Dead Sea basin contributes to the sea water
bathing. In this context an increased photosensitivity after the
salt bathing has been implicated.19,20 Solar radiation at the
Dead Sea is filtered by an additional 400 m below sea level
atmosphere and it has been shown that the shortest part of
UVB does not arrive at the Dead Sea.21–23 These conditions
International Journal of Dermatology 2002, 41, 482– 487
483
484
Report Repigmentation in vitiligo and hydrogen peroxide removal
could foster activation of the inactive manganese-EDTA
bicarbonate complex of the conventional pseudocatalase
cream (PC-KUS) therapy.12,13
Patients and methods
Patient selection and study design
The clinical observation was based on a randomised three-arm
study, in order to compare the effect of climatotherapy alone
(group 1/control arm) vs. placebo cream in combination with
climatotherapy (group 2) and pseudocatalase cream (PC-KUS) in
combination with climatotherapy (group 3) at the Dead Sea basin
over 21 days.
The patients were eligible for the study when they had vitiligo
according to a full body clinical examination in association with
Wood’s light.
Fifty-nine English and German patients with vitiligo (14 men and
45 women) with a mean age of 38.6 years (range 18 – 62 years)
from the Institute for Pigmentary Disorders in Greifswald,
Germany were included in the study. The majority of the group
(86%) had the most common clinical subtype vulgaris and 14%
presented with acrofacial vitiligo. Only patients with photo skin type
III (Fitzpatrick classification) were included in order to exclude any
possible effect of other skin types.24
The duration of the disease process varied from 3 to 53 years
with a mean age of 16.7 years. Family history was positive in
28/59 patients (47.5%). The patients were otherwise healthy.
Written consent was obtained from the local ethics committee from
each patient prior to this clinical study.
The study took place at the DMZ-Mor Clinic in Ein Bokek, Israel
during the months of June and July
FT-Raman protocol to follow epidermal H2O2 removal in vivo
in the skin
All patients (n = 59) were tested in vivo before treatment and at
the end of the 21-day stay at the Dead Sea basin for epidermal
H2O2 concentrations using in vivo FT-Raman spectroscopy. The
results were compared to 15 healthy photo skin-type matched
controls.12 FT-Raman spectra were obtained with a Bruker RFS 100/S
spectrometer equipped with a liquid nitrogen cooled germanium
detector. Sample excitation was accomplished using a Nd3+/ YAG
laser operating at 1064 nm with a laser power of 400 mW. Each
spectrum was accumulated over 5 min with 300 scans and a
resolution of 4 cm−1. Total H2O2 was visualized as a well defined
peak at 875 cm−1 based on the oxygen-oxygen (O-O) stretch
vibration.12
The study design was approved by the local Ethics
Committees.
Atomic Absorption Spectroscopy
In order to elucidate the content of transition metals in the Dead
Sea water we utilized Atomic Absorption Spectroscopy. Total
transition metal analyzes were carried out using a Perkin-Elmer
Schallreuter et al.
model 1100 Atomic Absorption spectrometer. Samples of Dead
Sea water were diluted 1 : 20 with de-ionized distilled water and
made up to 1 L.
Treatment protocol
All patients had to bathe for 15 min in the Dead Sea twice daily.
The bath was followed by a shower to wash off the salt. Group 1
(n = 10) then underwent directly total body sun exposure, whereas
group 2 (n = 10) and group 3 (n = 39) applied their creams to the
entire body surface prior to sun exposure.
The exposure times were slowly increased to a maximum of 1 h.
The treatment took place in the morning between 7.30 am and
10.30 am and in the afternoon between 2.30 pm and 5.30 pm. The
patients had to record the exposure times.
Clinical assessment by standardized photography
For a valid clinical assessment of the repigmentation of the face
and hands we utilized black and white photographs using a fixed
frame assembly holding the camera (Pentax MZ-M with a 90-mm
lens and an Ilford 828 glass filter) and a Kodak T-MAX 400 film. The
flashlight with non-UV coated bulbs was also fixed (Bowens Esprit
500). This technique assures a good quality comparison of
subsequent photographs and allows, even in very fair skin, the
objective evaluation of affected areas. In addition, we used
whole body color photographs with a standard camera and
flash light (Minolta) to follow disease stability during this
treatment period.
Patients were photographed before treatment and at the end of
the therapy at the Dead Sea after 21 days.
Assessment of efficacy
The efficacy of each treatment modality was assessed after
21 days based on the special photographic documentation of the
face and hands. The grading was based on the repigmentation of
affected areas by comparison of the photos before and after
21 days.
Statistical analysis
For statistical analysis we used the Wilcoxon signed rank test for
paired samples. Values P < 0.05 were significant.
Results
The Dead Sea water has pseudocatalase activity
The Dead Sea water analysis showed the presence of
transition metals such as manganese (7140 p.p.m.), copper
(582 p.p.m.), and iron (1398 p.p.m.), as well as high concentrations of sodium bicarbonate and calcium chloride. These
results were obtained from analysis of the Dead Sea water
using Atomic Absorption Spectroscopy. Since these transition
metals can form the chemical base for pseudocatalases, we
expected that the Dead Sea water bathing would act as a
“pseudocatalase”.25–27 In order to test this assumption, we
Schallreuter et al.
Table 1 Photographic assessment of repigmentation in the face
after 21 days
Figure 2 Efficacy of a 15-min Dead Sea water bath on the
removal of epidermal H2O2, in patients (n = 16) with vitiligo
using in vivo FT-Raman spectroscopy. Measurements were
taken before and after the bath, showing a significant reduction
of H2O2 (p = 0.001)
Repigmentation*
3+
2+
1+
0
Group 1 (n = 10)
Group 2 (n = 10)
Group 3 (n = 39)
0
0
30
6
7
9
4
3
0
0
0
0
*Grading was based on a scale ranging from 0, 1 +, 2 + and
3 + 0. (0 = no signs of repigmentation; 1 + = minimal follicular
repigmentation; 2 + = follicular repigmentation < 50% of the
involved areas; 3 + > 50% follicular/confluent repigmentation
of involved areas).
10 patients with this placebo cream plus Dead Sea bathing for
21 days (group 2). There was no significant difference
between the H2O2 reduction after Dead Sea bathing alone
(group 1) and the combination of placebo cream/ Dead Sea
bathing (group 2) (P > 0.05) (Fig. 3).
Evaluation of repigmentation after 21 days
Figure 3 A comparison of the in vivo efficacy of Dead Sea water
and combination of Dead Sea water and pseudocatalase cream
(PC-KUS) on epidermal H2O2 removal in vitiligo using FTRaman spectroscopy. The results are presented in percentage of
H2O2 levels standardized to 100% before treatment. A
significantly stronger effect of pseudocatalase cream (PC-KUS)/
Dead Sea bath is shown. The pseudocatalase activity of the Dead
Sea water alone is much weaker. The placebo cream has no effect
on H2O2 removal. Healthy controls have no detectable H2O2
level in their skin (the data are presented ± SEM)
followed in vivo the reduction of H2O2 levels in 16 of 59
patients using FT Raman spectroscopy. The results showed a
significant decrease of epidermal H2O2 after a 15-min
bathing session (p = 0.001). The data of this analysis are presented in Fig. 2. This in vivo observation identified the Dead
Sea water as a pseudocatalase. A comparison of the efficacy of
the Dead Sea bathing alone (group 1), and pseudocatalase
cream (PC-KUS) plus Dead Sea bathing (group 3) showed a
significantly more potent catalase activity for pseudocatalase cream (PC-KUS)/ Dead Sea bathing after 21 days
(p = 0.0001). The results are presented in Fig. 3. In order to
rule out a possible contribution of the cream base, we treated
The clinical result was assessed after 21 days by Wood’s light
and by photodocumentation.
None of the patients was fully repigmented at day 21 nor
did any patient develop new white patches during this time.
The examination with Wood’s light identified more repigmentation which could not be appreciated by eye alone. Since
the hands and face were photodocumented under the special
UV-conditions as outlined in the methods section, we therefore only evaluated the face and the hands. The results on
facial regimentation are presented in Table 1. The repigmentation of the hands was not further evaluated because the
changes were too small after 21 days treatment.
The outcome showed that patients treated with placebo
cream /Dead Sea climatotherapy (n = 10) (group 2) and
patients treated with climatotherapy only (n = 10) (group 1)
had significantly less follicular repigmentation in the face
compared to the patient group treated with pseudocatalase
cream (PC-KUS) in combination with climatotherapy (group 3).
One example of extensive follicular repigmentation in the
face is shown in Fig. 4.
There was no significant difference between Dead Sea
climatotherapy (group 1) and placebo cream in combination
with climatotherapy (group 2).
Discussion
The positive healing effect of climatotherapy at the Dead Sea
basin has been well established in the treatment of psoriasis
and atopic eczema.28 The treatment protocol for these
diseases usually lasts for 28–42 consecutive days and the
response rates are described as high as 80%.29 Studies on
UV-intensities at the Dead Sea area showed that 9.4% of UVB
485
486
Report Repigmentation in vitiligo and hydrogen peroxide removal
Schallreuter et al.
Figure 4 Follicular repigmentation after
21 days. Initiation of extensive follicular
repigmentation in the face of a female
patient (photo skin type III) after only
21 days combination therapy
(climatotherapy/pseudocatalase cream
(PC-KUS)) twice per day following the
protocol as described in methods.
(a) before treatment, (b) after 21 days.
(For details of photographic
documentation see methods)
and 3.5% of UVA are filtered out yielding a unique environment in this region.29 The safety aspects of the solar phototherapy have been investigated and discussed extensively.30
It has been suggested that the UVB range at the Dead Sea
could be a natural narrow-band therapy.29 In addition, the
high mineral content of the Dead Sea has been considered a
major factor in this successful treatment modality. The study
presented here identified the Dead Sea water as a “pseudocatalase”. We were able to follow in vivo the reduction of
epidermal H2O2 directly in the skin of patients with vitiligo.
This reducing effect was much weaker than a narrowband
UVB activated pseudocatalase cream (PC-KUS) in combination with Dead Sea water bathing. However, whether this
H2O2 reduction was indeed beyond the mM range cannot yet
be concluded due to the limitation in sensitivity of in vivo
FT Raman spectroscopy.12
A significantly faster initiation of repigmentation compared to conventional pseudocatalase cream (PC-KUS)
monotherapy or climatotherapy alone was observed using
the combined protocol Dead Sea/pseudocatalase cream (PCKUS)/solar phototherapy twice daily in the early morning and
late afternoon.12–14 It should be noted that the treatment protocol in the study presented here used much less sun exposure
than the conventional treatment recommendation at the
Dead Sea for vitiligo. (2 h compared to 7–8 h per day). In conclusion, from the results of this placebo controlled study, it
appears that the combination of climatotherapy and conventional pseudocatalase cream (PC-KUS) initiates a faster repigmentation in all patients studied. A comparison of our own
results using narrow-band UVB activated pseudocatalase
cream (PC-KUS) and the combination therapy revealed that
the combination therapy is much more effective in the onset
of repigmentation.12–14 This fast repigmentation continues for
at least up to 3 months (unpublished results).
This study did not investigate the contribution of the
unique solar spectrum to the initiation of repigmentation in
vitiligo. Since all patients (groups 1, 2, and 3) underwent their
treatment at the same time of the year and during the same
sun hours of the day, we believe that the data of this clinical
observation are valid and support once more the importance
of epidermal H2O2 removal and also underline the significant
contribution of UV-light to initiating a successful repigmentation in this disease.12–14
Acknowledgments
We are grateful for the dedication of all patients. This work
was supported by Deutscher Vitiligo Verein e.V. Hamburg,
Germany, Bruker Karlsruhe, Germany and Stiefel International. Susan Shergill typed the manuscript.
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Rapid initiation of repigmentation in vitiligo with Dead Sea

Transcription

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