Evaluation of Therapeutic Effects of Aloe Vera: Coal Tar Mixture in Psoriasis: An Immunohistochemical Study
Maha A. El-Gayyar,
Amany A. El-Hawwary
Nagwa I. Bakre
Although the use of aloe vera and coal tar in psoriasis treatment is well established, their mechanism of action is poorly understood. The aim of this study was to evaluate the therapeutic effectiveness of topical mixture of aloe vera extract and 1% coal tar (AMIX) in psoriasis and evaluate its antiproliferative, apoptotic and antiangiogenic effects as possible therapeutic mechanisms. AMIX was used in 279 patients with mild to moderate plaque psoriasis and PASI scores were recorded monthly. Skin biopsies from 30 patients before and after 3 months of therapy and 10 biopsies of normal skin were immunohistochemically stained using Ki67, Bcl-2 and CD34 antibodies as markers of cell proliferation, apoptosis and neoangiosis, respectively. Results: PASI scores decreased from 8.2±1.6 to 1.3±1.1 after 12 weeks of treatment (p<0.001) with complete clearance in 145 patients (~52%) without relapse during follow up period. Psoriatic skin showed higher expression of Ki67 in epidermal keratinocytes, Bcl-2 in basal keratinocytes and dermal inflammatory cells and CD34 in the dermal blood vessels compared to normal skin (p<0.001, p<0.01 and p<0.001, respectively). After treatment, Ki67, epidermal and dermal Bcl-2 and CD34 showed decreased expression (p<0.001, p<0.01, p>0.05 and p<0.001, respectively). These changes were positively correlated with the decrease in PASI scores. In conclusion, aloe vera and coal tar (AMIX) is an effective topical treatment of psoriasis without noticeable side effects. It causes inhibition of epidermal cell proliferation, neoangiogenesis and induction of apoptosis together with its immune modulatory effects.
Received: February 02, 2012;
Accepted: April 16, 2012;
Published: July 10, 2012
Psoriasis is an immune T-cell mediated inflammatory skin disease characterized
by epidermal hyperplasia, dermal neoangiogenesis and greatly accelerated epidermal
turnover (Krueger, 2002; Kocak et
al., 2003). In normal human skin, keratinocytes (Kcs) in the superficial
layers of the epidermis undergo apoptosis and regulate proliferation of basal
cells. On the other hand, Kc hyperproliferation is a characteristic of psoriatic
lesions and could be marked by over expression of growth regulating proteins
as Ki67 (Wrone-Smith et al., 1995). Ki67 is expressed
in all cell cycle phases reflecting the dynamics of epidermal hyperplasia. Therefore,
it is considered as a marker of cell proliferation (Li
et al., 2007). Moreover, Kcs derived from psoriatic plaques were shown
to be resistant to apoptosis (Wrone-Smith et al.,
1997). Bcl-2 and its homologous proteins, are considered the most important
regulators of programmed cell death and play a crucial role in the balance between
cell survival and cell death (Haupt et al., 2003).
According to current concepts, blockage of normal apoptotic process in the epidermis
is one of the factors implicated in the pathogenesis of psoriasis (Kocak
et al., 2003). Neoangiogenesis, including the formation of new dermal
blood vessels, starts with early psoriatic changes. It increases intralesional
microcirculation so as to facilitate the passage of T-lymphocytes to the skin
and disappears with disease clearance. Therefore, neoangiogenesis is a key component
of the psoriatic process (Heidenreich et al., 2009).
The CD34 protein is a transmembrane protein expressed in the endothelial linning
of blood vessels. So, it can be used as a marker for neoangiogenesis (Nielsen
and McNagny, 2008).
The topical coal tar has been used for the treatment of psoriasis long time
ago (Slutsky et al., 2010). It was reported to
be an effective keratolytic agent especially when combined with other treatment
modalities (Thami and Sarkar, 2002) and even as effective
as calcipotriol in treatment of psoriasis (Tzaneva et
al., 2003) but so more cheaper.
Aloe vera plant secretes a mucilaginous gel possessing diverse putative pharmacological
activities including anti-inflammatory and anti-oxidative effects. It was reported
to be effective in various medicinal purposes (Shelton,
1991; Vazquez et al., 1996). Syed
et al. (1996) used aloe vera extract effectively in the treatment
of psoriasis and reported that it had no toxic or objective side effects. In
a previous work, we used a mixture of aloe vera extract and coal tar (AMIX)
efficiently in the treatment of psoriasis and found it to be effective in its
improvement. It has been found to significantly decrease CD3+, CD4+ cellular
infiltrate, a finding that documents its immune modulating properties (El-Gayyar
et al., 2006). Choonhakarn et al. (2010)
reported that aloe vera cream was more effective than 0.1% triamcinolone acetonide
cream in reducing the clinical symptoms and signs of psoriasis.
The aim of this study was to evaluate the effectiveness of aloe vera and coal
tar mixture in the treatment of psoriasis and to investigate its antiproliferative,
apoptotic and antiangiogenic effects as possible therapeutic mechanisms.
MATERIALS AND METHODS
This study was carried out on 279 patients with mild to moderate chronic plaque
psoriasis attending the outpatient clinics of Dermatology and Venereology Department,
Mansoura University Hospital and Mansoura University Student Hospital, Egypt.
All patients were subjected to thorough history taking and skin examination.
Complete blood picture, renal and hepatic function tests were done for each
patient and those with normal results were enrolled in the study. All patients
had to discontinue any systemic or topical antipsoriatic medication for at least
8 or 4 weeks prior to therapy, respectively. Therapy was administered as twice
daily application of the mixture of aloe vera extract plus 1% coal tar cream
for 12 weeks. The Psoriasis Area and Severity Index scoring method (PASI) as
described by Saleh et al. (2008) was performed
at the beginning and monthly during the treatment period. The patients were
followed up monthly for another 6 months. Each participant gave an informed
written consent to share in the study after the procedure was explained to him.
Full-thickness 6 mm elliptical skin biopsies were obtained from lesional skin
in 30 patients before treatment and from the same area after 12 weeks of treatment
and 10 control biopsy specimens of normal skin after surgical procedure were
used as control. Formalin fixed specimens were prepared, then 3-5 micron thick
sections were deparaffinized and used for immunohistochemical staining for detection
of Ki67, Bcl-2 and CD34 proteins. The standard immunoperoxidase avidin-biotin
method was used. The following primary antibodies were used: mouse monoclonal
antibodies for Ki67 (Dako, Glostrup, Denmark), for Bcl-2 (from Neomarkers, Labvision,
Fremont, CA, USA), for CD34 (from Dako, Glostrup, Denmark). Universal ultravision
anti-polyvalent, HRO DAB detection kit was used (from Labvision, Fremont, CA,
USA). Ki67 was used as a marker for proliferation. Bcl-2 was used as an antiapoptotic
marker and CD34 was used as a marker of neoangiogenesis.
Positive cells (showing nuclear staining for Ki67 and cytoplasmic staining for Bcl-2) were counted under light microscope and expressed as number of positive cells per 100 counted cells (%). Grading was done as follows: (-) for negative results, (+1) for less than 10% positivity, (+2): 10-20% positivity and (+3) for >20% positivity for Ki67 and Bcl-2 expression in dermal lymphocytes. For epidermal Bcl-2 expression, grading was: (+1) for less than 10% positivity, (+2): 10-30% positivity and (+3) for >30% positivity. The visualized blood vessels detected by CD34 immune reaction were counted under light microscope at power 400 and graded as follows: (+1) for less than 5 blood vessels, (+2): 5-10 vessels and (+3) for >10 vessels. Ten fields were counted for each biopsy and the median value was considered.
The data were expressed in the form of Mean±SD. Student t-test was used to compare variables between two groups. Pearson's correlation coefficient was used to correlate variables. The p≤0.05 is considered significant. The tests were run on an IBM compatible personal computer using the Statistical Package for Social Science (SPSS) program version 16 (SPSS Inc., Chicago, IL, USA).
Clinical results: This study included 279 psoriatic patients (160 females and 119 males), the mean age was 28.7±12.6 years (range: 8-50 years). The mean disease duration was 19.6±7.6 years (range: 1-30 years). In areas treated with the mixture, PASI score was significantly lowered from a mean of 8.2±1.6 at the start of treatment to 1.3±1.1 after 12 weeks (p<0.001) (Table 1). Nearly half of the patients (145 patients~52%) showed complete improvement without recurrence during the next 6 months of follow up. Apart from staining of clothes, no other side effects were reported during treatment with AMIX.
As for Ki67-immune staining, most cases of normal skin (90%) showed few (+1) positive basal cells in the epidermis. In psoriatic cases, there was higher expression of Ki67 in the basal and suprabasal cells in most cases compared to normal (p<0.001). After treatment, there was significant decrease of the number of Ki67 +ve cells compared to pretreatment cases (p<0.001) (Table 1, Fig. 1-4).
As for Bcl-2 immune staining, normal skin biopsies showed (+1) weakly positive
staining in basal cells in 70% of cases and in dermal inflammatory cells in
30% of cases. In psoriasis, Bcl-2 expression in epidermal cells and dermal inflammatory
cells was significantly higher compared to normal (p<0.01). After treatment,
a significant decrease of Bcl-2 expression occurred in epidermal cells where
<10% positive cells was found in 60% of cases (p<0.01) while the decrease
in dermal inflammatory cells was statistically insignificant (p>0.05) (Table
1, Fig. 5-8).
As for CD34-immune staining, most normal skin biopsies showed few (+1) positively
stained dermal vessels. In psoriatic cases, many elongated tortuous blood vessels
were found compared to normal (p<0.001) and were significantly decreased
after treatment (p<0.001) (Table 1, Fig.
||The effect of treatment on PASI and immunostaining results
for Ki67, Bcl-2 and CD34 among psoriatic cases compared to normal (control)
|r1a,b: Correlation between PASI and Ki67 expression
before and after treatment, r2a ,b and r3a ,b: Correlation
between PASI and epidermal and dermal Bcl-2 before and after treatment,
r4a,b: Correlation between PASI and CD34 before and after treatment
|| Few Ki67 +ve basal keratinocytes (+1) in normal (control)
||Many Ki67 +ve basal and suprabasal keratinocytes (+3) in a
psoriatic case before therapy (x100)
||Another pretreatment psoriatic case with many basal and suprabasal
Ki67 +ve cells (+3) (x400)
||Few Ki67 +ve basal cells (+1) in a psoriatic case after treatment
||Weak Bcl-2 cytoplasmic reaction (+1) in some basal cells of
normal (control) skin (x400)
||Bcl-2 + ve reaction (weak: arrow heads, strong: arrows) in
basal keratinocytes (+2) of a psoriatic case (x400)
||Another psoriatic case with Bcl-2 +ve reaction in dermal lymphocytes
|| Few Bcl-2 +ve basal keratinocytes (+1) in a psoriatic case
after treatment (x400)
|| Few weakly CD34 +ve dermal blood vessels (+1) in normal (control)
The changes in Ki67, Bcl-2 and CD34 were positively correlated with PASI scores
before and after treatment (p<0.05).
Figure 12 demonstrates the mean values ±SD of % of positive cells for Ki67, epidermal and dermal Bcl-2 with the maximum values seen in psoriasis before treatment (23.3±3.1, 22.8±4.9 and 29±9.5, respectively) and minimum values observed in the control (3±1.53±1.5, 12.8±1.92 and 7.3±2.5, respectively).
Figure 13 demonstrates the mean values ±SD of CD34 positive blood vessels with the maximum value seen in psoriasis before treatment (15.2±1.48) and minimum value detected in the control (3.4±1.14). Figure 13 also demonstrates the difference in PASI mean values before and after AMIX treatment (8.2±1.6 and 1.3±1.1, respectively).
||Many strongly CD34 +ve elongated tortuous blood vessels in
the dermal papillae (+2) of a psoriatic case before treatment (x400)
|| Few CD34 +ve dermal blood vessels (+1) in a post treatment
psoriatic case (x400)
||Comparison of immunostaining results for Ki67, epidermal and
dermal Bcl-2 in normal skin and psoriatic cases before and after treatment
||Comparison of immunostaining results for CD34 in normal and
psoriatic cases in addition to PASI before and after treatment
Aloe vera and coal tar, from the natural therapy field, have been tried successfully
as topical treatments for psoriasis. However, their mechanisms of action has
not yet been fully elucidated (El-Gayyar et al.,
2006). Kumar et al. (1997) reported improvement
of psoriasis in 76.5% of their study patients using coal tar without side effects.
El-Gayyar et al. (2006) reported good improvement
of 30 psoriatic patients where PASI decreased from 7.28±3.75 to 3.88±1.17
when treated with topical coal tar for 12 weeks. Moreover, an evidence-based
review of 25 studies on the efficacy of tar preparations in the treatment of
psoriasis was made by Slutsky et al. (2010) and
they concluded that the majority of these studies (21) supported the use of
coal tar preparations in the treatment of psoriasis. The mechanism of action
of coal tar is exactly unknown but the possibility of suppression of DNA synthesis
has been proposed producing the antiproliferative action in addition to the
anti-inflammatory and keratolytic effects. Many modifications have been made
to tar preparations to increase their acceptability as some dislike its odour,
messy application and staining of clothing (Thami and Sarkar,
2002; Paghdal and Schwartz, 2009).
Clinical improvement of psoriasis treated with aloe vera alone was reported
by some researches. Syed et al. (1996) and Vogler
and Ernst (1999) reported a cure rate of nearly 83.3% of psoriatic patients
treated with topical 0.5% hydrophilic aloe vera cream compared with placebo
(6.6%). Patients received the treatment over four weeks and were followed-up
for 12 months without relapse. Similarly, Choonhakarn et
al. (2010) reported marked improvement of 40 psoriatic patients treated
with topical aloe vera after 8 weeks where PASI decreased from 11.6 to 3.9 compared
with a decrease from 10.9 to 4.3 with 0.1% triamcinolone acetonide treatment.
El-Gayyar et al. (2006) reported good improvement
of 30 psoriatic patients treated with topical aloe vera cream alone after 12
weeks of therapy where PASI decreased from 6.65±3.09 to 3.64±1.51.
On the other hand, when we used the mixture of aloe vera extract and coal tar
(AMIX) in the treatment of 180 psoriatic patients, marked improvement was found
where PASI decreased from 7.31±5.13 to 1.29±1.46 with complete
cure in 42.5% of patients after 12 weeks of treatment (El-Gayyar
et al., 2006). Moreover, immunohistochemical staining of skin biopsies
of the responding cases revealed significant decrease of CD3+ and CD4+ positive
cells in the cellular infiltrate (p<0.05), a finding that documents its immune
modulating properties (El-Gayyar et al., 2006).
The clinical improvement of psoriasis after the treatment with (AMIX) was confirmed
by the results of the current study as shown by the decrease in the PASI from
8.2±1.6 to 1.3±1.1 (p<0.001) after 12 weeks of treatment in
addition to complete cure in about 52% of patients.
In the present study, we have investigated the antiproliferative, apoptotic
and antiangiogenic effects of AMIX in psoriasis. For this purpose, we assessed
the expression of Ki67, Bcl-2 and CD34 proteins using immunohistochemical techniques
in normal and psoriatic skin. Ki67, as a proliferative marker, was reported
to be highly expressed in psoriasis and is correlated with its clinical severity
(Chang et al., 2010). Bcl-2 plays a major role
in the balance between cell survival and cell death. Its expression is restricted
to cell populations with a long lifespan or proliferative activity, as it prevents
apoptosis (Ceovic et al., 2007). CD34 expression
was reported to facilitate the opening of vascular lumen and cell migration
(Blanchet et al., 2007; Strilic
et al., 2009).
Our results revealed significant increased expression of Ki67 in psoriatic
epidermis compared to normal (p<0.001). Similar results were reported by
Zhang et al. (2009) and Lin
et al. (2011) who concluded that the overexpression of Ki67 implies
an abnormality of cell cycle regulation in psoriatic keratinocytes. The abnormality
might be related to the hyperproliferation and abnormal differentiation of psoriatic
After treatment with AMIX, a significant decrease of Ki67 expression was detected
(p<0.001), a finding that confirms its expected antiproliferative effect
in psoriasis. These results coincide with that reported after treatment of psoriasis
with oral bexarotene, methotrexate, rambazole, an oral retinoic acid metabolism
blocking agent and narrow-band UVB therapy by Smit et
al. (2004), Yazici et al. (2005), Bergstrom
(2007) and Yu et al. (2009), respectively.
Smit et al. (2004) made a study including twenty-nine
psoriatic patients who were treated with oral bexarotene in doses up to 3.0
mg/kg/day and reported a significant reduction in Ki67 expression after 12 weeks
of treatment. Yazici et al. (2005) study included
ten patients using methotrexate. Bergstrom (2007) study
included six adult patients with moderate to severe plaque psoriasis used oral
rambazole 1 mg daily for 8 weeks. Clinical assessment was made by SUM score,
a modified PASI score of one target lesion and found it improved by 34% (p<0.05)
and the expression of Ki67 decreased by 63% (p<0.01). Similarly, a decrease
of Ki67 was reported after treatment of psoriasis with either topical calcipotriol
or methylprednisolone aceponate (Adisen et al., 2006).
Ceovic et al. (2007) reported similar reducing
effects on Ki67 expression in two groups of patients (each included 30 patients)
treated with either PUVA or topical corticosteroids. Saleh
et al. (2008) made a study including 30 psoriatic patients to compare
the effect of bath PUVA to the effect of salt water bath before UVB. Although
both lines produced clinically similar effect but salt water bath before UVB
sessions proved to decrease epidermal proliferation with decreased Ki67 expression
to a statistically significant difference (p<0.05).
Bcl-2 expression in normal skin was confined mainly to the basal cell layers
of the epidermis, a finding that was supported by Batinac
et al. (2007) who provided an explanation of this pattern of expression
in protecting the proliferative compartment from apoptotic stimuli. Our results
demonstrated positive Bcl-2 reaction in 86.67% of psoriatic patients. Statistically,
Bcl-2 showed a significant higher expression when compared to normal skin (p<0.01).
Then a significant decrease of Bcl-2 expression was detected after treatment
Adisen et al. (2006) made a study that included
thirty psoriatic patients and applied either calcipotriol or methylprednisolone
aceponate (MPA) ointment for 6 weeks. They reported higher Bcl-2 expression
in psoriatic than normal skin (p<0.05) supporting our results. However, they
found more increased expression of Bcl-2 following both treatments (p<0.05
each), a finding which is contradictory to our results after treatment with
AMIX. On the other hand, Batinac et al. (2007)
stated that Bcl-2 protein expression was significantly decreased in psoriatic
skin samples, as compared to normal (3.23 vs. 6.25; p<0.01). They suggested
that this finding could be a result of intense proliferation, probably secondary
to inflammatory stimuli in psoriasis. Kocak et al.
(2003) suggested that the psoriatic epidermal hyperplasia may result from
excessive mitogenic stimuli that might promote an increase in the proliferative
cell compartment, rather than being a consequence of the loss of antiproliferative
The current study revealed also Bcl-2 expression in the dermal lymphocytes
of 86.67% psoriatic patients. Coinciding with our results, Yildiz
et al. (2003) observed Bcl-2 expression in lymphocytes of 71% of
his study psoriatic patients, 20 out of 25 and related this to the prolonged
survival of lymphocytes resulting in the relapsing and chronic course of psoriasis
and suggested that Bcl-2-mediated inflammation plays a part in the pathogenesis
and recurrent character of psoriasis. Also, El-Hadidi et
al. (2008) detected Bcl-2 expression in dermal lymphocytic infiltrate
in 80% of the examined psoriatic patients, 15 patients. In the current study,
a decrease of Bcl-2 expression in dermal lymphocytes was detected after treatment
with AMIX, however, it was statistically insignificant (p>0.05). This finding
is supported by El-Domyati et al. (2007) who
studied ten cases with generalized plaque psoriasis and reported a significant
decrease of Bcl-2 in lymphocytes (p = 0.01) following topical calcipotriol therapy
suggesting it to promote apoptosis of dermal lymphocytes leading to healing
of psoriasis. and found that most of them showed evident decline of Bcl-2 level
after 24 sessions of PUVA phototherapy.
In the present study, there was a significant increase in the number of CD34
positive dermal blood vessels of psoriatic skin compared to normal control (p<0.001).
Similar results were detected by Li et al. (2006)
who detected a significant overexpression of CD34 in the papillary dermal microvessels
in psoriatic lesions and Simonetti et al. (2006)
who found a significantly higher CD34 expression in psoriasis compared to control
skin (19.15±12.61 vs. 3.0±0.23; p<0.05). After treatment, a
significant decrease in the number of blood vessels within the treated areas
was detected (p<0.001), a finding that reflects the antiangiogenic activity
of AMIX as one of the key mechanisms in the management of psoriasis.
Going with these results, other researchers as Ceovic et
al. (2007) studied neoangiogenesis in psoriasis before and after PUVA
and local steroid therapy for five weeks and reported that both treatments decreased
it markedly (p<0.001). They used anti-F-8 antibody as angiogenesis marker.
Avramidis et al. (2010) reported that etanercept
caused a statistically significant time-dependent reduction in the number of
dermal blood vessels using endothelial nuclear factor-κB (NF-κB),
angiogenic Vascular Endothelial Growth Factor (VEGF) and endothelial cell marker
The topical mixture of aloe vera extract and 1% coal tar is a safe, cheap and highly effective treatment in mild to moderate plaque psoriasis without any noticeable side effects apart from staining of clothes. It causes inhibition of epidermal cell proliferation, induction of apoptosis and amelioration of neovascularization that may be the possible mechanisms by which AMIX exerts its therapeutic effect beside its previously proved immune modulating effects. Studies of this old/new topical therapy on larger groups of patients are recommended.
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