Occlusion for Psoriasis

Pharmacology and therapeutics
Basis of occlusive therapy in psoriasis: correcting defects in
permeability barrier and calcium gradient
Sang Min Hwang, MD, Sung Ku Ahn, MD, Gopinathan K. Menon, PhD,
Eung Ho Choi, MD, and Seung Hun Lee, MD
From the Department of Dermatology,
Abstract
Yonsei University Wonju College of
Background Although occlusive dressings have great potential in the management of
Medicine, Wonju, South Korea, Avon
psoriasis vulgaris, the therapeutic mechanism is not completely understood. Occlusion
Products, Inc., Suffern, New York,
arti(R)cially restores and corrects the defective barrier in psoriasis plaques. Additionally,
and Department of Dermatology and
Brain Korea 21 Project for Medical
occlusion is know to normalize the epidermal calcium gradients in hyperproliferative murine
Sciences, Yonsei University College
skin models.
of Medicine, Seoul, South Korea
Methods To investigate the basis of the therapeutic effect of occlusion on psoriatic plaques,
we investigated the ultrastructural morphology of intercorneocyte lipid layers, lamellar bodies,
Correspondence
and calcium gradient in chronic plaque-type psoriasis after occlusion with a water vapor-
Seung Hun Lee, MD
Department of Dermatology
impermeable membrane. The specimens were processed for electron microscopy using: (i)
Young Dong Severance Hospital
ruthenium tetroxide post(R)xation; and (ii) ion-capture cytochemistry for calcium localization.
Yonsei University College of Medicine
Results Occlusion for 7 days resulted in a nearly mature pattern of intercellular multilamellar
146-92, Dogok-dong Kangnam-ku
structures, re-establishment of the near-normal epidermal calcium gradient, and disappear-
Seoul, 135-270
ance of calcium precipitates from the stratum corneum interstices.
South Korea
E-mail: ydshderm@yumc.yonsei.ac.kr
Conclusions The normalization of the permeability barrier and epidermal calcium gradient
may play important roles in the therapeutic effects of occlusive dressings in chronic plaque-
type psoriasis.
Introduction
the calcium gradient, and permeability barrier recovery
Psoriasis, a common inammatory cutaneous disorder with
parallels its reappearance.46 Furthermore, barrier recov-
a prevalence of 23% in the general population, is
ery appears to be regulated by changes in calcium ions
characterized both by an approximately eight-fold short-
of the upper epidermis. Exogenous replenishment of
ening of the normal cell cycle and by a signi(R)cant increase
calcium, suf(R)cient to maintain the high extracellular
in the pool of proliferative cells.1 The main pathophysio-
calcium concentration in the upper SG, signi(R)cantly
logic event in psoriasis is an abnormality in keratinocyte
retards permeability barrier repair due to both inhibition
proliferation, leading to incomplete differentiation and
of the lamellar body secretion and lipid synthesis.7,8
parakeratotic plaques.
Extracellular lipid layers form as a result of enzymatic
The normal differentiation of keratinocytes is depen-
processing of the secreted disks of lamellar body origin
dent on the existence of an epidermal calcium gradient,
which compose the pro-barrier lipids.
from a low level of calcium ions in the basal and
The permeability barrier resides in the stratum corneum
spinous layers, to a progressive increase with the level
(SC). In psoriasis, as in several other scaling dermatoses,
of calcium ions reaching its maximal density within the
the lipid layers have an abnormal morphologic pattern.
outer stratum granulosum (SG).24 This pattern of
The permeability barrier is impaired and skin susceptibility
calcium gradient is lost in psoriatic plaques, but not
to irritants is increased.911
in uninvolved epidermis. It has also been shown that the
It is known that arti(R)cial restoration of the perme-
integrity of the permeability barrier maintains the
ability barrier by occlusion results in regression of
epidermal calcium gradient.4 Acute perturbation of
lesions in psoriasis.1219 The precise mechanisms for the
the permeability barrier induces an immediate loss of
therapeutic effects of occlusion on psoriasis are not
223
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224
Pharmacology and therapeutics Occlusive therapy in psoriasis
Hwang et al.
known with certainty. A reduction in mitotic rate and a
Electron microscopic examination
reappearance of the granular layer in psoriatic lesions
RuO
after plastic occlusive dressing have been reported.12
4 post(R)xation
Samples were immediately cut into 1-mm pieces and immersed
Inhibition of enzyme activity,13 a reduction in the
in modi(R)ed Karnovsky's (R)xative, left at room temperature for 1 h,
mitotic index,14 and local temperature elevation of the
and then stored in the refrigerator at 4 C for 1824 h (overnight).
occluded psoriatic lesion15 have all been postulated as
Specimens were then rinsed with 0.1 M cacodylate buffer, three
potential mechanisms. Fisher and Maibach16 suggested
times at 40-min intervals, and post(R)xed in 0.25% RuO4
that occlusion might be important by establishing an
(Polysciences, Inc., Warrington, PA, USA), 0.1 M cacodylate
arti(R)cial water barrier and/or by reducing traumatic loss
buffer for 45 min at room temperature in the dark.20
of the abnormal SC. Although occlusive dressings have
potential in the management of psoriasis vulgaris, the
Ion-capture cytochemistry for calcium localization
therapeutic mechanism is not completely understood.
Specimens were cut into small pieces (0.5 mm3) in a drop of ice-
Furthermore, no study has been performed to clarify the
cold (R)xative containing 2% glutaraldehyde, 2% formaldehyde,
90 mM potassium oxalate, and 1.4% sucrose, and (R)xed overnight
role of the permeability barrier and epidermal calcium
on ice. Following this, samples were post(R)xed in osmium/
gradient in the therapeutic effects of occlusive dressings.
pyroantimonate for 2 h on ice, washed for 10 min in ice-cold
The aim of this study was to investigate the effects of
distilled water at pH 10.0,2 and rinsed in 0.1 M cacodylate buffer
occlusion on the lipid structures that form the perme-
for 10 min. All samples for electron microscopy were dehydrated
ability barrier and on the calcium gradients in chronic
in a graded series of ethanol and embedded in an epoxy resin.
plaque-type psoriasis.
Ultrathin sections were cut, stained, and examined in a Jeol
electron microscope (Jeol, Tokyo, Japan). For calcium
cytochemistry, control sections were incubated in an
Patients and methods
ethylenediaminetetraacetic acid (EDTA) solution for 1 h.
Experimental protocol
In (R)ve volunteers with chronic plaque-type psoriasis, untreated
Results
for at least 4 weeks and stationary for over 6 months, the lesions
Light microscopy
(n = 10) were occluded with water vapor-impermeable Latexq
Light microscopic observations after occlusion showed
membrane for 7 days, after informed consent had been obtained.
decreased hyperkeratosis, parakeratosis, and neutrophilic
Latexq membranes were designed to be larger than the
in(R)ltration following 7 days of occlusion, as opposed to the
con(R)guration of the lesions and tightly occluded with Tegadermq
well-de(R)ned hyperkeratosis, parakeratosis, and neutrophi-
(3M, Ontario, Canada) and MicroporeTM surgical tape (3M,
lic microabscess in the SC of unoccluded (control) chronic
Ontario, Canada). The lesions selected were on the back. The
plaque-type psoriasis. Occlusion resulted in reduced
uninvolved skin from two patients was also occluded and served
inammation, but the histology of a hyperplastic epider-
as a control. During the test period, the patients were allowed to
mis, with regular elongation of the rete ridges, remained
proceed with normal daily activities, except bathing. Patients
unchanged.
were cautioned about potential complications, such as infection,
and advised to keep the patch adherent and not to allow water to
seep under the patch edges. The study was approved by the
Change in intercorneocyte lipid layers
local ethics committee. After 7 days of occlusion, the Latexq
The ultrastructural features in chronic plaque-type psor-
membrane was removed from the occluded site, which was dried
iasis have been well characterized.21 The abnormal
for 10 min in order to minimize the moisturizing effect of
morphologic pattern includes a few retained lamellar
occlusion. Skin biopsies were taken for electron microscopic
bodies (RLBs) and multivesicular bodies (MVBs) within
study. The specimens were divided into three parts, and (R)xed for
the corneocyte cytosol, as well as an unfurled, incompletely
light microscopy, for ruthenium tetroxide (RuO4) post(R)xation
processed, extracellular lamellar structure in the SC
(Polysciences, Inc., Warrington, PA, USA), and for ion-capture
interstices. Following occlusion, a decrease in the thickness
cytochemistry for calcium localization.
of SC, decreased lipid droplets, and fewer transitional cells
were noted (Fig. 1). Seven days of occlusion produced a
52 T 3.5% (mean T SD) decrease in the thickness of SC,
Light microscopic examination
compared with preocclusion. Lipid droplets and transi-
For light microscopy, the specimens were (R)xed in 10% neutral
tional cells were less frequent. As shown in Fig. 2, there
buffered formalin, routinely processed for paraf(R)n sections, and
were abnormalities of the intercorneocyte lipid layers and
stained with hematoxylin and eosin.
lamellar body secretory system in chronic plaque-type
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Hwang et al.
Occlusive therapy in psoriasis Pharmacology and therapeutics
225
Figure 1 Thickness of SC and lipid
droplets after occlusion. Following
occlusion, a decrease in the thickness of
SC, decreased lipid droplets, and fewer
transitional cells were noted. Seven days
of occlusion (B) produced a decrease in
the thickness of SC of 52 T 3.5%
(mean T SD) compared with
preocclusion (A). Lipid droplets were
less frequent than before occlusion
(RuO4, Q 50,000)
psoriasis. The intercellular spaces contained a paucity of
Change in the pattern of calcium distribution
lipid layers (Fig. 2A) and intercorneocyte lipid layers
In uninvolved epidermis, the distribution pattern of
showed unfurled lamellae (Fig. 2B), as opposed to the
calcium ions was similar to that in normal epidermis.
mature pattern of lipid layers in the uninvolved epidermis
Briey, within the basal and spinous layers, the extra-
of psoriasis. Numerous lipid droplets, MVBs and RLBs
cellular domains contained very few calcium deposits, but
(Fig. 2C,D), and extracellular whorls (Fig. 2E) were pre-
both the number and size of such precipitates progressively
sent.
increased towards the outer epidermis, reaching the highest
After occlusion with a water vapor-impermeable
density within the extracellular spaces of the upper SG. The
membrane for 7 days, intercorneocyte lipid layers in
intercellular domains of the lower SC contained small
chronic plaque-type psoriasis showed dilatation of
quantities of precipitates, but they disappeared in the upper
lacunar spaces and revealed a nearly mature pattern of
levels of the SC. In psoriatic epidermis, the distribution of
intercorneocyte lipid layers (Fig. 3); in contrast, unin-
calcium, both in extracellular and intracellular loci, was
volved epidermis of psoriasis showed distorted lamellar
disturbed in the nucleated cell layers. Additionally, calcium
lipid layers and expanded lacunae in the SC interstices
precipitates in the SC increased and appeared character-
(data not shown). The MVBs, however, remained (data
istically as large clusters within extracellular as well as
not shown). Increased secretion of lamellar bodies was
intracellular domains. Thus, the epidermal calcium gradi-
also noted. The results of the electron microscopy
ents in psoriatic epidermis were signi(R)cantly altered
(R)ndings are summarized in Table 1. These results show
(Fig. 4A).
that occlusion with water vapor-impermeable membrane
In uninvolved skin, occlusion with a water vapor-
tended to normalize intercorneocyte lipid layers in
impermeable membrane for 7 days did not obliterate the
chronic plaque-type psoriasis, although MVBs were
normal epidermal calcium gradient (data not shown). The
retained and some features of intercorneocyte lipid
calcium contents were, however, slightly increased within
layers were not fully normalized.
the whole epidermal layers, intracellularly and extracellu-
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Pharmacology and therapeutics Occlusive therapy in psoriasis
Hwang et al.
Figure 2 Abnormalities of the
intercorneocyte lipid layers and lamellar
body secretory system in chronic plaque-
type psoriasis. The intercellular spaces
contain a paucity of lipid layers (A). The
intercorneocyte lipid layers show an
unfurled pattern (B), as opposed to the
mature pattern of lipid layers in the
uninvolved epidermis of psoriasis.
Numerous lipid droplets (asterisks),
retained lamellar bodies (RLBs) (open
arrows), and multivesicular bodies
(MVBs) (white arrows) are present.
MVBs (C), RLBs (D), and extracellular
whorls (E) are present (RuO4, Q 50,000
(A, B, D, E); Q 40,000 (C))
larly. Increased calcium precipitates were present within
Discussion
the extracellular spaces of the SGSC interface and lower
SC. In contrast, in psoriatic epidermis, occlusion produced
An abundance of information supports a defective barrier
a reversal of the epidermal calcium precipitate pattern
function and disruption of the calcium gradient in
towards normal, including: (i) re-establishment of the
psoriasis.911 Involved psoriatic skin displays defective
normal epidermal calcium gradient; and (ii) disappearance
permeability barrier function with transepidermal water
of calcium precipitates from SC intercellular domains
loss (TEWL) levels up to 20 times normal.21 With ion-
(Fig. 4B). The results of calcium distribution are summar-
capture cytochemistry, the distribution of calcium, both in
ized in Table 2. These results show that occlusion with a
extracellular and intracellular loci, is disturbed in all layers
water vapor-impermeable membrane tended to re-establish
of the epidermis.10 The psoriatic lesions display a loss of
the normal epidermal calcium gradient in chronic plaque-
the normal calcium gradient and retained calcium ions in
type psoriasis.
intercellular domains of the upper SC which may underlie
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Hwang et al.
Occlusive therapy in psoriasis Pharmacology and therapeutics
227
Figure 3 Intercorneocyte lipid layers and lamellar body secretory system in chronic plaque-type psoriasis, occluded with water
vapor-impermeable membrane for 7 days. Occlusion induced the dilatation of lacunae spaces (asterisks) and revealed a nearly
mature pattern of intercorneocyte lipid layers (A, B) (RuO4, Q 50,000)
Table 1 Summary of the change in intercorneocyte lipid layers and lamellar bodies after occlusion in chronic plaque-type psoriasis
Preocclusion
After occlusion
Intercorneocyte, lipid layers
Devoid of lipid layers
More layers than preocclusion,
unfurled and
nearly mature pattern
whorled pattern
Lamellar body (LB) structure
Normal
Normal and nascent LB
Retained lamellar bodies
Occasional
Occasional and decreased
Multivesicular bodies
Occasional
Occasional and decreased
the abnormal desquamation and permeability barrier.
calcium-mediated cell signaling, rather than a localized
Moreover, the phenotype of psoriasis correlates with the
defect in response to altered extracellular calcium gradi-
permeability barrier, both functionally and structurally.21
ents.22 The present results show that the normalization of
A recent study has demonstrated that ceramide I, an
the epidermal calcium gradient is one of the therapeutic
epidermal sphingolipid, inhibits cell proliferation and
effects of occlusive dressings in chronic plaque-type
induces epidermal differentiation in vitro; ceramide is
psoriasis. Normalization of the epidermal calcium gradient
altered in psoriatic plaques.11
may be responsible for correction of the proliferation- and
A key question is: what induces the restoration of the
differentiation-related defects in psoriatic plaques. Calcium
proliferation- and differentiation-related defects of psor-
plays an important part in regulating proliferation and
iasis? A recent study has shown that psoriatic keratinocytes
differentiation in the epidermis.10,23 Extracellular changes
have an inborn error in calcium metabolism, involving
in the calcium content in the epidermis may induce changes
downregulated capacitative calcium inux and defective
in epidermal proliferation in vitro.24 Increased extracellu-
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lar calcium ions coordinate the expression of differentia-
mal calcium distribution pattern towards normal, normal-
tion-speci(R)c keratins.25,26 Furthermore, low calcium con-
ization of the SGSC junction, and a compact arrangement
centrations stimulate proliferation, whereas high calcium
of secreted lamellar body contents.4 The extracellular
concentrations inhibit proliferation and enhance differen-
calcium reservoir was only partially re-established in EFAD
tiation.24,27 In psoriasis, it has been shown that arti(R)cial
epidermis. In our study, the calcium gradient was re-
restoration of the skin barrier will reduce epidermal
established. Recently, we have shown that the epidermal
proliferation directly and indirectly.28,29 A recent study
calcium gradient in the hairless mouse is normalized by
has revealed that expression of differentiation markers,
60 h of occlusion.5
such as (R)laggrin and involucrin, was normalized in
Although the change in calcium ions has been the focus
psoriatic epidermis after 3 weeks of occlusion therapy with
of most studies as a regulator of the permeability barrier
hydrocolloid dressings.30 Thus the restoration of the
and keratinocyte differentiation, a role for other ions has
proliferation- and differentiation-related defects of psor-
also been implicated. High extracellular potassium ions are
iasis may be attributed to normalization of epidermal
synergistic with high extracellular calcium ions in inhibit-
calcium gradients.
ing barrier recovery after acute barrier perturbation,
The increase in (R)laggrin expression in psoriatic epider-
suggesting that potassium channels mediate calcium
mis with occlusion therapy has a major function in
inux.7,8 Recent studies have shown that the epidermal
maintaining a normal hydration state of the SC.30 After
concentration of potassium also decreases after barrier
having ful(R)lled its role in aggregating keratin (R)bers and
abrogation, although to a lesser extent than calcium ions,
catalyzing the formation of disul(R)de bonds between
and potassium channels mediate calcium inux in differ-
keratin, (R)laggrin becomes enzymatically degraded to free
entiated keratinocytes.31,32 The changes in these ionic
amino acids, termed natural moisturizing factors (NMFs),
channels after barrier perturbation and following occlusion
which are retained within the corneocytes. Their role is in
remain to be determined.
maintaining a normal hydration state of the SC despite
The effects of occlusion on the permeability barrier are
increasing dryness of the environment. The increase in
complex and quite different for a chronic permeability
(R)laggrin expression after occlusion results in a normal-
barrier abnormality, as in psoriasis, compared with acute
ization of the hydration of the SC.
barrier perturbation following tape stripping. Whereas
Previous studies have shown that arti(R)cial restoration of
occlusion with a water vapor-impermeable membrane,
barrier function with prolonged occlusion (48 h) of
immediately after tape stripping, blocks not only the
essential fatty acid-de(R)cient (EFAD) mice, which display
restoration of the permeability barrier but also the recovery
a chronic barrier abnormality, with a water vapor-
of the epidermal calcium gradient,46 in psoriasis, it
impermeable membrane, produces reversion of the epider-
enhances the recovery of the calcium gradient and the
Table 2 Summary of the change in intracellular calcium ions after occlusion in chronic plaque-type psoriasis
Preocclusion
After occlusion
Uninvolved
Psoriatic
Uninvolved
Psoriatic
SC upper

+


SC lower

+++
T

SG upper
++++
+++
+++
++++
SG lower
+++
++
+++
+++
SS
++
++
++
++
SB
++
+
++
++
SC, stratum corneum; SG, stratum granulosum; SS, stratum spinosum; SB, stratum basale. Density of calcium precipitates is
from to ++++, with indicating absence of precipitates and ++++ indicating highest observed density of precipitates.
Figure 4 Cytochemical localization of calcium. Preocclusion (A). Note the disruption of the epidermal calcium gradients and
the presence of signi(R)cant extracellular and intracellular calcium precipitates at all levels. Calcium precipitates at the SC
increased and appeared as characteristically large clusters within extracellular domains (inset, top) and intracellular domains
(inset, bottom). Seven days of occlusion (B). Occlusion produced re-establishment of the calcium gradient and disappearance of
calcium precipitates from the SC. SC, stratum corneum; SG, stratum granulosum; SS, stratum spinosum; SB, stratum basale.
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Pharmacology and therapeutics Occlusive therapy in psoriasis
Hwang et al.
SCSG junction towards normal. How occlusion enhances
9 Serup J, Blichmann C. Epidermal hydration of psoriasis
the restoration of the calcium gradient of chronic plaque-
plaques and the relation to scaling. Acta Derm Venereol
type psoriasis is not clear at present. It may occur via
1987; 67: 357366.
shutting down the synthesis of speci(R)c cytokines, by
10 Menon GK, Elias PM. Ultrastructural localization of
altering membrane-associated calcium ATPase (calcium
calcium in psoriatic and normal human epidermis. Arch
pump), by decreasing DNA synthesis, or a combination of
Dermatol 1991; 127: 5763.
all these.
11 Motta S, Monti M, Sesana S, et al. Abnormality of water
In summary, our results demonstrate that the normal-
barrier function in psoriasis. Role of ceramide fractions.
ization of the permeability barrier and of the epidermal
Arch Dermatol 1994; 13: 452456.
12 Fry L, Almeyda J, McMinn RMH. Effects of plastic
calcium gradient plays an important role in the therapeutic
occlusive dressings on psoriatic epidermis. Br J Dermatol
effect of occlusive dressings in chronic plaque-type
1970; 82: 458462.
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13 Halprin KM, Fukui K, Ohkawara A. Flurandrenolon
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duces the full normalization of the epidermis, the nature of
Arch Dermatol 1969; 100: 336341.
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14 Baxter DL, Stoughton RB. Mitotic index of psoriatic
epidermal calcium gradient, and psoriasis is complex and
lesions treated with anthralin, glucocorticosteroid and
remains to be determined.
occlusion only. J Invest Dermatol 1970; 54: 410412.
15 Urabe H, Nishitani K, Kohda H. Hyperthermia in the
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Acknowledgment
770774.
Supported in part by Brain Korea 21 Project for Medical
16 Fisher LB, Maibach HI. Physical occlusion controlling
Sciences, Yonsei University.
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17 Friedman SJ. Management of psoriasis vulgaris with a
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