ARTICLE
Auteur(s) : Rosanne G van Lingen, Elke
MGJ de Jong, Piet EJ van Erp, Wilmy SEC van Meeteren, Peter CM van
De Kerkhof, Marieke MB Seyger
Department of Dermatology, Radboud University Medical Centre,
P.O. Box 9101, NL- 6500 HB Nijmegen, The Netherlands
accepté le 28 Mai 2008
Often, some chronic and localized plaque psoriasis appears to be
therapy resistant and no adequate solution, in terms of effective
treatment modalities, seems available for these patients to clear
these remaining recalcitrant plaques. In general, these plaques are
restricted to a small body surface area, which makes the choice for
a systemic therapy unattractive. Therefore, an unmet need exists
for an effective treatment of such chronic, therapy resistant
psoriatic lesions.
Psoriasis is a chronic inflammatory skin disease in which
epidermal proliferation, angioneogenesis and T-cell expansion
within the papillary dermis are the most impressive features [1,
2]. Traditional therapies for psoriasis target the inhibition of
epidermal proliferation, or inflammation, or both. The earliest
changes noted in an early psoriatic lesion, however, are elongated,
widened and tortuous microvessels [3-5]. The use of lasers in
dermatology has increased during the past two decades. As new laser
devices continue to emerge, an expanding range of versatile laser
systems has developed but also an extremely broad spectrum of
potential candidate disorders has developed, which presently
includes the psoriatic lesion. As compared to other treatment
options for psoriasis, the use of lasers aims at a selective
removal of the diseased endothelial target structures whilst the
epidermis is particularly protected from heat injury, rendering it
an excellent potential treatment option for localized plaque
psoriasis. Studies have led to the idea that the selective
destruction of the dilated papillary vessels by the principle of
selective photothermolysis eliminates the extravasation of
inflammatory mediators into the interstitium inducing an
improvement of the psoriatic plaques [6-10]. This selectivity can
be achieved by choosing the appropriate laser light wavelength and
pulse duration responsible for the amount of heat diffusion.
Psoriasis has previously been shown to respond to several types of
lasers [7, 11-14]. In particular, with respect to vascular lasers,
psoriatic lesions have been shown to improve with pulsed dye laser
treatment (PDL, 595 nm) although some debate between different
groups exists with respect to the efficacy and tolerability
[15-19]. However, the remission is usually transient, as studies
have shown that the persistent secretion of cytokines in treated
psoriatic lesions was responsible for a relapse of endothelial
proliferation, causing a rebound in vasculature and a return of the
psoriatic plaque [1].
Infrared light with a wavelength of 1,064 nm, like that of the
neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, can
penetrate the skin up to a depth of 7 mm [20]. So far, no
study has been carried out asses the place of the Nd:YAG laser in
the array of treatment modalities for localized psoriasis. The deep
penetration could well represent a great advantage for the Nd:YAG
laser over the PDL, since the target endothelial structures in
psoriasis are located up to a few millimeters deep in the psoriatic
skin. As the psoriatic blood vessels play an important role in
immunocyte trafficking in psoriasis, it is credible that selective
removal of the deeper abnormal psoriatic vasculature in the dermis
by means of the Nd:YAG 1,064 nm laser may be of benefit for
treatment. In the long run, this could possibly result in a more
long-lasting therapeutic effect.
The current pilot study evaluates the clinical efficacy and
tolerability of a Nd:YAG 1,064 nm against an active
well-established comparator: calcipotriol/betamethasone
dipropionate ointment (CBD). An intra-patient, left-right
comparative study was conducted, wherein patients with localized
psoriasis were treated with both the Nd:YAG laser (1,064 nm) and
topical therapy with CBD for a period of three months.
CBD-treatment was given once daily whereas the number of Nd:YAG
treatments was three, with a 4-week interval between treatments. In
addition, in order to elucidate the mode of action,
immunohistochemical assessments were performed on lesional skin
biopsies. Our goal herein was to provide insight on the effects of
the 1,064-nm wavelength and CBD ointment on key phenomena in the
psoriatic dermis and epidermis, e.g. keratinocyte differentiation
(K10), T-lymphocytes (CD3+ cells) and capillary expansion (Von
Willebrand factor and CD31).
Patients and methods
Patients
Six patients aged at least 18 years with stable, localized plaque
psoriasis were included in the study after giving written informed
consent. All patients had a washout of systemic treatments or
phototherapy for at least four weeks and had not used topical
treatment for the last two weeks prior to participation. Other
exclusion criteria were pregnancy, lactation and a history of
photosensitivity. The study was approved by the local medical
ethics committee.
Study design
Two weeks before the start of treatment, 10% salicylic acid in
petrolatum album was prescribed in order to reduce desquamation of
the plaque and enhance light penetration and penetration of the
CBD-ointment through the stratum corneum, ultimately standardizing
and optimizing the pretreatment situation for both topical and
laser treatment. Since treatment with the Nd:YAG 1,064 nm (“Gentle
YAG VR”, wavelength 1,064 nm, with a dynamic cryogen cooling device
for minimizing patient discomfort, Candela Corporation) has not
been described before, questions remain as to the 1,064 nm
laser’s optimal operating parameters for positively affecting
dermal endothelial structures. Therefore, we first tested for
optimal settings in three patients with psoriasis, for final use in
the main pilot study. At the initial visit, two similar plaques of
at least 10 cm2 were selected. These plaques were
similar in terms of body localization and clinical severity score
(SUM-score). Consequently, one psoriatic plaque was treated,
varying in spot sizes and fluences, all within the spectrum of
optimal depth for effective endothelial destruction (table 1). Primary outcome measures, which were
used after 4 weeks and further throughout the study, comprised the
SUM-score (for evaluating the clinical effect) and the occurrence
of adverse events (for evaluating safety). No major significant
differences in clinical effect between the settings could be
observed, nor did any interfering adverse events occur. All
fluences were tolerated equally. As no specific preferable setting
in terms of clinical efficacy or safety was deducible from the
testing, the maximal applied fluence per spot size (1.5 mm
spot, 375 J cm–2; 3 mm spot,
310 J cm–2) from the testing was chosen for
application in the main pilot study. Comparing PDL-studies with
different time intervals, the intervals vary from weekly to once
every 2 to 3 weeks. Even then, sometimes residual crusting resulted
in postponement of the laser treatment. Therefore, we opted for a
time interval of four weeks between Nd:YAG treatments.
In the main study, at random, one of the two selected
SUM-comparable plaques was treated with calcipotriol
50 μg g-1 and betamethasone dipropionate
0.5 mg g-1 ointment (CBD) (Daivobet/Dovobet; Leo Pharma,
Ballerup, Denmark) once daily for the duration of three months. The
other plaque was symmetrically divided in half, to treat one half
with the 1.5 mm spot (fluence 375 J cm–2)
and the other with the 3 mm spot (fluence
310 J cm–2) each by a single pass, once every
4 weeks. In total, the plaque was treated three times. Prior to
Nd:YAG treatment, watery oil was applied on the designated
psoriatic plaque in order to further reduce the amount of
scattering and enhance light penetration through the stratum
corneum. After three months of treatment, patients entered a
follow-up period of eight weeks, in which they neither applied the
CBD ointment nor received Nd:YAG laser treatment.
Table 1 Nd:YAG 1,064 nm test settings varying in spot
sizes and fluence
|
Nd:YAG 1,064 nm settings
|
Spot size 1.5 mm – Pulse duration 10 ms
|
Spot size 3 mm – Pulse duration 20 ms
|
|
Fluence J cm–2
|
300
|
250
|
|
325
|
270
|
|
350
|
290
|
|
375
|
310
|
Clinical assessments
Clinical severity of the designated plaques was assessed using the
SUM-score at baseline and after 4 and 8 weeks and during the
follow-up period. The SUM score is a cumulative measure which
includes scores for eythema, induration (plaque thickness) and
scaling on the following scale: 0, absent; 1, minimal (very light
pink, hardly any elevation, rare scale); 2, mild (light red/pink,
slight elevation, poorly defined scale); 3, moderate (red, moderate
elevation, defined scales); 4, severe (very red, marked ridge,
heavy scaling). Ultimately, a global SUM score (range 0-12) was
determined as the sum of all three scores together, reflecting the
overall plaque severity. Furthermore, the Visual Analogue Scale
(VAS) for pain (range 0-10) was used for patients to report the
level of experienced pain during Nd:YAG treatment with the two spot
sizes. A score of 0 represented a total absence of pain and 10
represented maximum pain.
Biopsies
Biopsies (4 mm) were taken at a central representative site in
the target lesions after 3 months of treatment (week 12): one from
the Nd:YAG treated, one from the CBD treated lesion and one from an
untreated psoriatic plaque which served as a control. Before the
biopsy procedure, local anesthesia was given (xylocaine/adrenaline
1:100,000). Skin defects were optionally closed using one suture.
Immunohistochemical staining
Immunohistochemical staining on paraffin and cryostat sections was
performed as previously described [21, 22]. The following primary
antibodies (mouse anti-human) were used: anti-CD3 (1:100)
(cryostat, clone UCTH1), anti-K10 (paraffin, 1:100, clone RKSE60)
(Monosan Laboratories Uden Netherlands), anti-von Willebrand Factor
(paraffin, vWF, 1:200, clone F8/86) and anti-CD31 (paraffin, 1:200,
clone JC70A) both from DAKO (Copenhagen, Denmark). Furthermore,
from each patient we performed an H&E staining to verify that
the biopsies under study fulfilled the psoriasis-specific
histological criteria.
Blinded quantification of markers
Quantification of K10 and CD3 and determination of the thickness of
the epidermis was enforced as previously reported [23], using the
image processing programs, ImageJ 1.37 (National Institutes of
Health, USA) and IP-lab (Scanalytics, USA). Quantitative cell
counts of the T lymphocytes (CD3) were expressed as ‘Positive cells
per mm skin length’. K10 was quantified using the percentage of a
representative region of interest (ROI) in the epidermal surface,
as a unit. As the stainings of both CD31 and vWF showed a similar
pattern, CD31 was chosen as the endothelial marker used for
quantification. Quantification of CD31 was enabled, creating a
division in several distinct ROIs, as depicted in figure 1, ultimately
expressing CD31 as a positive area in a percentage of the ROI. In
order to observe and evaluate the potential depth of penetration of
the Nd:YAG laser in the dermis, two separate parts of the dermis
were selected; on the one hand comprising the inter rete ridges
dermis and on the other hand, the lower papillary dermis. The
choice for this separation was based on the background information
that the PDL was shown to target primarily the more superficial
capillaries in the rete ridges and the Nd:YAG was theorized to
penetrate deeper, down to the lower papillary dermis. All sections
were analyzed in a blinded manner as the sections were coded by an
independent co-worker before assessment.
Statistical analyses
To compare SUM-scores between different moments in time during
treatments, we performed the Kruskal-Wallis test. In addition, we
performed matched pair analysis using the Wilcoxon signed Ranks
test to compare the SUM-scores over time with the non-treated
plaques.
To compare the epidermal thickness and immunohistochemical
expression of K10, CD3 and CD31 between the two treatments (Nd:YAG
3 mm spot and CBD) and the untreated psoriatic biopsy, the
Student’s t-test was used. A statistically significant difference
was set at p < 0.05. All analyses were carried out using SPSS
software version 14.0.
Results
In total, 6 patients participated in this study (4 males, 2
females) with a mean age of 47.7 ± 5.2 years. Two patients had to
be excluded, one because of refusal of the biopsy procedure, the
other because the applied fluences had to be reduced since the
patient reported intolerable pain at the initial fluences.
Clinical efficacy
The results for the mean SUM-scores per treatment modality during
the study are shown in figure 2A. A quick glance
at the figure shows that at baseline all plaques had a comparable
SUM-score, that the treatment with CBD caused the largest reduction
of SUM-score, and thus clinical effect, and that the two spot sizes
used for the Nd:YAG laser did not differ greatly in clinical
effect. The mean reductions in SUM-score between baseline and week
12 for Nd:YAG 1,5 mm, Nd:YAG 3 mm and the CBD-ointment
were 17%, 27%, 62% respectively. With respect to the control
plaque, there was a 9% increase in SUM-score after 12 weeks. The
reduction in SUM-score induced by the CBD-ointment reached
statistical significance at week 4, week 8 and week 12 (all p <
0.05) as compared to baseline. There was a significant reduction in
SUM-score caused by treatment with the Nd:YAG (both 1.5 and
3 mm spot size) at week 4, 29% and 24% respectively, compared
to baseline. However, this effect was not maintained further
throughout the study. Between weeks 12 and 16 (follow-up period),
only the mean SUM-score for the CBD treated plaques augmented
significantly to a moderate extent (+33%, p < 0.05).
Visual Analogue Scale (VAS)
With respect to the level of experienced pain during Nd:YAG
treatment, the mean VAS-score per spot size at the different
time-points is depicted in figure 2B. It can be seen
that all patients reported a higher VAS-score when treated with the
3mm spot and corresponding fluence than with the 1.5 mm spot.
In addition, the VAS-score was comparable in range during the
first, second and third treatment and did not differ greatly,
except for one patient who experienced intolerable pain at the
initial fluences. Therefore, the fluences for this particular
patient were reduced by ± 40% and this patient was excluded from
further clinical and immunohistochemical analyses.
Morphological and immunohistochemical analyses
Figure 3
illustrates the results of the quantities of the epidermal
thickness, the endothelial marker (CD31), keratinocyte
differentiation (K10) and CD3-counts after treatment with CBD and
the Nd:YAG laser compared to the non-treated control biopsies
(No Tx). The number of CD3+ lymphocytes decreased
significantly (p < 0.05) in the epidermis of the CBD treated
group and only a tendency to decrease after therapy (p < 0.1)
was observed in the epidermis of the Nd:YAG treated group, compared
to the amount of CD3+ T cells in the control biopsies of
non-treated psoriatic plaques. With respect to the dermis, in the
Nd:YAG treated group, the CD3+ T cells were significantly decreased
after therapy (p < 0.05) as compared to the control group of
biopsies, whereas the CBD group showed no significant reduction in
CD3+ T cells. The epidermal thickness decreased significantly in
the CBD group of biopsies (–43.2%, p < 0.05), whilst for the
Nd:YAG group no significant decrease could be observed (–24.9%, p
> 0.05) compared to the untreated biopsies. The area positive
for CD31 in the ROI in both the inter-rete ridge dermis and the low
papillary dermis, was not significantly different between either of
the two treatment groups versus the control group. As for the K10
positive epidermal area, no significantly increased amount of
normal differentiating keratinocytes after treatment with CBD or
the Nd:YAG laser could be observed.
Side-effects: Nd:YAG laser
Two patients experienced a burning sensation on the Nd:YAG treated
lesions 2-6 hrs after therapy. Two patients reported transient
purpuric discoloration of small areas of the laser lesions. One
patient had several white spots on the Nd:YAG treated psoriatic
lesion directly after laser treatment. Four patients reported the
development of mild crusts in the week after receiving laser
treatment. One patient reported slight fluid leakage from the
Nd:YAG treated lesion. Another patient experienced increased itch
on the Nd:YAG treated lesion compared to the CBD-treated plaque.
Scarring was not seen in any of the patients. With respect to the
treatment with the CBD-ointment, no side-effects were observed, in
particular, no atrophy of the skin.
Discussion
As psoriasis persists to become a chronic skin disease of which the
pathogenesis is not completely understood, the search for new
treatments and insights continues. Psoriasis is probably not one
single disease entity, as multiple expression patterns are
observed, ranging in severity, extent, aspect of lesions.
Furthermore, individual needs vary among patients. The need and
search for adequate and effective specialized therapies for
recalcitrant localized psoriatic lesions persists, as no optimal
treatment solution is yet available. In the field of lasers, many
have investigated the effects of (laser) light for targeting
diseased psoriatic skin structures. The PDL was shown by some
groups to be a good therapy for recalcitrant localized psoriasis,
although the effect was momentary and results can be at variance
[6, 19]. The present pilot study is the first to evaluate whether
the Nd:YAG laser is a potential treatment modality for this kind of
psoriatic lesion. It is plausible that, when targeting the deeper
vasculature more effectively, damage can be caused, possibly
resulting in a longer lasting effect of the clearance of psoriatic
plaques. Subsequently, when focusing on the histological changes
that ensue after irradiation with the 1,064 nm-wavelength,
clarification of the relevant microscopic events can be obtained.
However, in contrast to the hypothesis outlined, in this study
clinical and well-defined histological evidence supporting this
Nd:YAG theory was not obtained. In order to explain this
discrepancy, several interpretations can be envisaged, bearing in
mind that the present pilot study comprised a minimal sample size.
It is necessary for pulse duration to be matched to vessel size;
the larger the vessel diameter, the longer the pulse duration
required to effectively damage the vessel thermally. Absorption by
hemoglobin in the long visible to near infrared range appears to
become more important for vessels over 0.5 mm and at least
0.5 mm below the skin surface. However, high energies must be
used for adequate penetration. The key is eventually to find the
optimal parameters for this laser to positively affect the dermal
endothelial structures without the excess heat that may cause
collateral damage. It can be theorized that if the energy level was
below the chromophore threshold and the pulse width was extended
beyond the thermal relaxation time, the heat could be absorbed by
the chromophore but then dissipated to surrounding tissues before
reaching a destructive threshold level [24] and an ensued clinical
effect. Alternatively, it could well be, based on the results of
this study, that the overlying diseased psoriatic skin is
irresponsive in terms of clearance when a deeper lying vasculature
is being targeted by a 1,064 nm Nd:YAG laser. In addition, as the
inflammation in psoriatic plaques is highly visible, it could well
be reasonable to treat these plaques more frequently than once a
month in order to achieve a clinical effect from the Nd:YAG
laser.
Although lacking clinical efficacy, Nd:YAG treatment instigated
a substantially reduced number of CD3+ T cells in the dermis in the
present pilot study. The present study is at variance with the
findings of Bovenschen et al. [6], however, who showed a reduction
in CD3+ T cells in psoriatic skin after PDL therapy but also a
marked clinical effect of PDL in psoriasis. One could question
therefore whether changes in the numbers of CD3+ T lymphocytes
after laser therapy can alone lead to clinically improved psoriatic
lesions. Some have found that the peak epidermal temperature can
have an important influence on the histological changes after
non-ablative laser therapy [25]. Therefore, a possible diffuse
thermal effect on the T cell after Nd:YAG therapy could lie at the
basis of changes in amount of CD3+ T cells, as previously touched
upon by Ruiz-Esparza et al. [12]. Three anecdotal reports on
psoriatic plaques responding to low-energy Nd:YAG (1320 nm)
irradiance have been described, corresponding to a diffuse thermal
effect, even though the exact mechanism of this therapy remains
unknown.
In order to minimize patient discomfort and epidermal sparing,
cooling through direct contact was used throughout the present
study, optimally practising minimal pressure against the skin not
to compress the target vessel with excessive hand pressure. Trained
staff is a pre-requisite to guarantee proper and consistent use of
the laser. It is important to notice that scatter and reflection
are two key aspects influencing the penetration of the laser light
to the targeted depth. Although patients were pretreated with 10%
salicylic acid in petrolatum album, and watery oil was applied in
order to enhance an optimal penetration, in the end psoriatic
plaques have a different texture compared to non-psoriatic skin,
presumably influencing the ultimate depth of penetration.
With respect to the active comparator (CBD-ointment), and
consistent with earlier findings [6], the clinical severity of the
treated plaques reduced significantly, as did the epidermal
thickness. Although effectively reducing the thickness of the
epidermis and a corresponding reduction in the SUM-score, the
CBD-ointment does not tend to have an effect on the number of
abnormal differentiating keratinocytes and on the excessive
microvascular expansion in psoriasis.
To summarize, in the present pilot investigation, the Nd:YAG
1,064 nm laser was found not to be of additional value in the array
of treatment modalities for chronic localized plaque psoriasis,
since no clinical and histological evidence came across to support
this. It is evident that the superficial dermal vasculature remains
a major contributor to the pathogenesis of this disease and
targeting this vascular expansion is a good way to try to tackle
the influx of immunocytes to the site of inflammation. However,
this study brings to light that the amount of CD31 positive
endothelium in the papillary dermis of psoriatic plaques was not
significantly altered by the effect of the Nd:YAG 1,064 nm laser.
Dermatologists in the field of lasers should take the present
findings to heart and be vigilant when considering the Nd:YAG laser
as a potential treatment option for chronic therapy-resistant
psoriatic lesions. Targeting more superficially located vascular
expansion in psoriasis is likely to be of more importance in
achieving clinical effect than targeting the deeper vasculature.
However, further studies incorporating changes in methodology, in
particular shortened time-intervals between treatments, are needed
in order to refute or confirm this position.
Acknowledgements
We would like to acknowledge Mr Niels Tanja of Dalton Medical BV
for providing us the laser equipment to carry out this study. No
funding financial sources to declare. Prof. Dr. PCM van de Kerkhof
has consultancy services for Schering-Plough, Centocor, Allmirall,
UCB,Wyeth, Pfizer, Abbott, Actelion, Galderma, Novartis,
Janssen-Cilag and Leo Pharma.
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