ARTICLE
Psoriasis vulgaris is a chronic inflammatory skin disease of
unknown etiology characterized by infiltration of neutrophils and lymphocytes,
and abnormal epidermal proliferation. Many investigators have focused
on defects in T cells as the primary cause of the disease [1-4]. These
defects include impaired T cell function and imbalanced T cell subsets.
Sauder et al. [1] postulated a faulty T cell regulation of the
immune system, demonstrating that concanavalin A-stimulated lymphocytes
of patients with psoriasis vulgaris showed an impaired ability to suppress
a mixed lymphocyte reaction as compared with lymphocytes from normal subjects.
Rubins et al. [2] studied the composition of helper and suppressor
T cells in peripheral blood of patients with psoriasis vulgaris. They
reported a significant decrease in the ratio of helper T cells/suppressor
T cells in patients at the onset of the disease. Although the mechanism
of T cell activation is unknown, Badsgard et al. [3] suggested
that the lymphocytes at the dermal epidermal junction in psoriasis represented
activated cells capable of producing several cytokines such as interleukin-2.
Interleukin-2 produced by activated T cells can modulate a number of immunologically
mediated responses. Nickolff et al. [4] suggested that in psoriasis
the cytokine-network generated autoreactive T cells around the psoriatic
lesions and, in turn, these autoreactive T cells returned to the blood
circulation. In addition, several humoral factors have been implicated
in the pathogenesis of psoriasis [2-4], such as IL-1, IL-2, IL-6 and IL-8,
TNF-alpha, IFN-gamma, and TGF-alpha. The true pathogenesis of the disease,
however, remains to be elucidated.
Thiamazole [8] is a thioureylene derivative that is often used as an
alternative to propylthiouracil and the first line treatment for patients
with hyperthyroidism in Japan. To date, only Elias et al. [9, 10]
have reported that the antithyroid thiourethylenes, propylthiouracil and
methimazole could be used as systemic treatment for psoriasis vulgaris.
Thiamazole and methimazole are similar compounds available for the treatment
of hyperthyroidism. We have previously reported the clinical usefulness
of thiamazole for Japanese patients with psoriasis vulgaris [11]. Although
the mechanism for the beneficial effects of thioureylenes on psoriasis
is unknown, its efficacy has been assumed to be mediated by immune mechanisms
[9, 10, 12-14].
In the present study, we asked if the peripheral blood lymphocyte subsets
and serum levels of some cytokines are affected by systemic administration
of thiamazole in patients with psoriasis vulgaris or not.
Materials and methods
Patients
Thirteen patients (10 men and 3 women) with psoriasis vulgaris were
enrolled in this study after informed consent was given. Their thyroid
function was evaluated by one of us (M. M.) and none of the patients had
any abnormalities on thyroid function tests. All patients suffered from
long-standing or active psoriasis vulgaris with the disease duration ranging
from 3 to 27 years and a mean age of 43.5 years. Severity of psoriasis
assessed by the Psoriasis Area and Severity Index score (PASI score) ranged
from 8.5 to 38.8 before thiamazole treatment. Each patient basically administered
thiamazole, 30 mg/day orally for 12 weeks. When the PASI score showed
85% reduction of the initial score, the dosage of thiamazole was tapered
to 20 mg/day. Only two patients received any systemic medications, and
they were treated with homochlorcyclizine hydrochlride for pruritus. During
the treatment, the patients were allowed to continue topical treatment
with tacalcitol or steroid ointment which had been used before thiamazole
treatment. The evaluation of PASI score, analysis of lymphocytic subsets,
measurement of serum cytokine concentrations and blood tests, including
free-T3, free-T4 and thyroid stimulating hormone (TSH) were performed
before and at 2nd, 4th, 6th, 8th and 12th week after administration. When
the PASI score showed an increase or remained unchanged as compared with
the initial one, or adverse effects due to thiamazole developed, we ceased
the treatment even before 12 weeks. Finally, five patients could not complete
a 12-week treatment.
Analysis of lymphocytic subsets
Peripheral blood mononuclear cells (PBMC) isolated by Ficol-Hypaque
density gradient method were stained with monoclonal antibodies. The monoclonal
antibodies used in this study were a panel of fluorescein isothiocyanate
(FITC)-labeled monoclonal antibodies against CD3 (Leu4), CD4 (Leu3a),
CD8 (Leu2a) and a panel of phycoerythrin (PE)-labeled monoclonal antibodies
against CD20 (Leu16), CD62L (Leu8), CD11B(Leu15) and HLA-DR (Becton Dickinson
Inc., Paramus, NJ, USA). After the correction for CD45/CD14 (Becton Dickinson
Inc., Paramus, NJ, USA) in the gate, the cells were analyzed by a fluorescent-activated
cell sorter (Becton Dickinson Inc., Paramus, NJ, USA). We carried out
two-color staining with the combination of CD3/CD20, CD4/HLA-DR, CD8/HLA-DR,
CD4/CD62L or CD8/CD11b. As a control, we established the normal range
of each subset in 40 healthy individuals.
Measurement of serum TNF-alpha and IL-1alpha
concentrations
The concentrations of serum TNF-alpha and IL-1beta were measured by
enzyme-linked immunosorbent assay (ELISA) (Biosource International Inc.,
California, USA). In brief, serum samples collected from the patients
before and at 2nd, 4th, 6th, 8th and 12th week after administration were
stored at - 80° C until use. The measurement was performed under
the manufacturer's instructions. The detection ranges of TNF-alpha and
IL-1beta ELISA kit were 0.5 to 32.0 pg/ml and 0.31 to 20.0 pg/ml, respectively.
The mean concentrations of serum TNF-alpha and IL-1beta of normal subjects
were within 12.0 pg/ml and 0.57 pg/ml, respectively.
Statistical analysis
The data were expressed as mean ± SD, and statistical difference
was examined by analysis of variance (ANOVA). The significance was defined
as P < 0.05.
Results
Clinical outcome of the patients
Table I summarizes the
clinical outcome of 13 patients. One patient achieved complete clearance
of psoriatic lesions (PASI score 0). Four patients showed a significant
improvement (PASI score reduction over 70%) and one patient had a fair
improvement (PASI score reduction over 50%). The lesions of most patients
showing a more than 50% clinical response tended to improve after 4 to
6 weeks thiamazole administration. We reduced thiamazole dosage to 20
mg/day in 3 patients whose PASI score showed over 85% reduction of the
initial score. Among the six patients whose PASI score had improved over
50%, four (No. 2-5) wanted to continue the treatment with thiamazole after
this trial period, and all of them maintained the improved states. We
ceased the treatment in five patients; two patients showed increased serum
transaminase levels, two had unsatisfactory improvements and another one
had a drug eruption. Although the serum TSH level fell below the normal
range in eight patients, clinically none of the patients developed hypothyroidism.
Likewise, one patient whose serum TSH level elevated above the normal
range did not develop hyperthyroidism. In all patients, serum free T3
and free T4 levels remained within normal range during thiamazole administration.
Analysis of lymphocyte subsets
The results are summarized in Table
II. There were no significant changes in the mean percentage of CD3+
(pan T cell) and CD20+ (pan B cell) cells during the treatment.
In addition, the mean percentage of CD3+ or CD20+
cells of the patients was same as those of 40 healthy individuals (CD3:
67.2 ± 7.1%, CD20: 19.0 ± 6.8%). The percentages of CD8+
HLA-DR+ (activated suppressor/cytotoxic T cell) cells and CD4+
HLA-DR+ (activated helper/inducer T cell) cells were also unchanged.
The mean percentage of CD8+ HLA-DR+ cells of the
patients (13.4 ± 3.4%) before treatment was higher than that of normal
subjects (7.6 ± 3.2%), though statistically not significant. The
mean percentage of CD4+ HLA-DR+ cells before and
during treatment was constantly higher than mean + SD of normal subjects
(7.9 ± 2.6%) (Fig. 1a).
The ratio of CD4+/CD8+ cells significantly increased
at the 4th week as compared with the initial valve (P < 0.05), and
then returned to the initial ratio at 8th week (Fig.
1b). The ratio of CD4+/CD8+, however, was within
the normal range (1.87 ± 0.68). The mean percentages of CD4+
CD62L- (helper T cell) and CD8+ CD11b+
(natural killer cell) cells were within normal range and showed no significant
change. The percentage of CD4+ CD62L- cells
and CD8+ CD11b+ cells remained within the normal
range.
Analysis of serum TNF-alpha and IL-1alpha
concentrations
The concentration of serum TNF-alpha in the patients was within normal
range (< 12 pg/ml) and showed no significant change during thiamazole
administration (Fig. 2).
Serum concentration of IL-1beta was under the detection level in all samples.
Discussion
In the present study, 9 patients obtained marked to moderate improvement
of PASI score by thiamazole administration, among whom 3 patients showed
nearly complete resolution. Two patients, however, showed aggravation.
Although serum TSH level fell below the normal range in 8 patients, clinically
none of the patients developed hypothyroidism or any adverse effects.
In Japan, three oral drugs such as cyclosporin, etretinate and methotrexate
are widely used for psoriasis vulgaris [11]. Despite the significant effects
for psoriasis vulgaris, they have adverse effects intolerable to some
patients. In addition, the expensive price is a matter of concern for
the patients treated with cyclosporin or etretinate [11]. Therefore, thiamazole
can be a promising choice as systemic treatment for psoriasis vulgaris
because of its low toxicity and safety as well as low cost [8, 15].
The pharmacological effects of thiamazole in patients with psoriasis
vulgaris is still unknown. It has been considered that the effect of thiamazole
on psoriasis was related to immune-mediated events [9, 10, 12-14]. In
Graves' disease, thioureylenes have been shown to decrease the number
of activated intrathyroidal T cells, enhance the number of suppressor
T cells and influence the production of interleukins, paticulary IL-2
[16-18]. However, Elias et al. [5, 6] reported that there was no
significant change in serum concentration of intercellular adhesion molecule-I
(ICAM-I) or IL-2 receptor during antithyroid thiourethylenes administration.
In the present study, the serum concentrations of TNF-alpha, known as
a proinflammatory cytokine, remained within normal range and showed no
significant change during thiamazole administration, suggesting that the
clinical effects were not reflected by TNF-alpha production.
Nakayama et al. [19] reported a significantly increased percentage
of CD4 lymphocytes in the peripheral blood of psoriatic patients without
any medications as compared with normal subjects. Ligresti et al.
[20] also reported a significant decrease in the percentage of suppressor
T cells and a significant increase in the percentage of helper T cells
as well as a highly significant increase in the helper/suppressor T cell
ratio in psoriatic patients without any medications. In the present study,
we reconfirmed that the mean percentage of CD4+ HLA-DR+
lymphocyte was elevated during the treatment as compared with normal subjects.
However, we could find no correlation between the PASI score and the percentage
of CD4+ HLA-DR+ lymphocyte before and during the
treatment in each patient. The percentage of suppressor T cells in the
patients was not different from normal subjects in accordance with the
previous observation [19].
The ratio of CD4+/CD8+ significantly increased
at the 4th week (P < 0.05) and subsequently returned to the initial
ratio. This change seems to be of note because CD4+ HLA-DR+
and CD8+ HLA-DR+ lymphocytes showed no significant
change during treatment. It is difficult to answer the question whether
the change observed was due to thiamazole administration or simply reflects
the improvement of the lesion. We have already reported the similar tendency
during cyclosporin administration [21]. Furthermore, Nakayama et al.
[19] reported that the ratio of CD4/CD8 increased during the first 6 weeks
and went back to the initial level after etretinate administration. They
postulated that etretinate reduced some cytokines capable of affecting
T cell subsets and T cells in psoriatic lesions would return to blood
circulation after the etretinate administration. Thus, it is possible
that the change in CD4/CD8 may not be associated with the direct pharmacological
effect of thiamazole on immune competent cells, but with the disease activity.
CONCLUSION
In conclusion, thiamazole may exert its pharmacological effects preferably
through other immune mechanisms or the effects can not be reflected by
the peripheral lymphocyte subsets which we examined and TNF-alpha. In
addition, the direct effect of thiourethylenes or TSH on keratinocytes
as well as immune mechanisms is of great interest.
Article accepted on 15/4/02
REFERENCES
1. Sauder DN, Bailin PL, Sundeen J. Suppressor cell function in
psoriasis. Arch Dermatol 1980; 116: 51-5.
2. Rubins AY, Merson AG. Subpopulation of T lymphocytes in psoriasis
patients and their changes during immunotherapy. J Am Acad Dermatol
1987; 17: 972-7.
3. Baadsgaad O, Fisher G, Voorhees JJ, Cooper KD. The role of
the immune system in the pathogenesis of psoriasis. J Invest Dermatol
1990; 95: S32-4.
4. Nickoloff BJ. The cytokine network in psoriasis. Arch Dermatol
1991; 127: 871-84.
5. Raychaudhuri SP, Farber EM, Raychaudhuri SK. Immunomodulatory
effects of peptide T on Th1/Th2 cytokines. Int J Immunopharmacol
1999; 21: 609-15.
6. Hong K, Chu A, Ludviksson BR, Berg EL, Ehrhardt RO. IL-12,
independently of IFN-gamma, plays a crucial role in the pathogenesis of
a murine psoriasis-like skin disorder. J Immunol 1999; 15: 7480-91.
7. Aragane Y, Yamada H, Schwarz A, Poppelmann B, Luger TA, Tezuka
T, Schwarz T. Transforming growth factor-alpha induces interleukin-6 in
the human keratinocyte cell line HaCaT mainly by transcriptional activation.
J Invest Dermatol 1996; 106: 1192-7.
8. Bartalena L, Bogazzi F, Martino E. Adverse effects of thyroid
hormone preparations and antithyroid drugs. Drug-Saf 1996; 15:
53-63.
9. Elias AN, Goodman MM, Rohan MK, Alpern K, Barr RJ. Methimazole
(2-mercapto 1-methyl imidazole) in psoriasis: results of an open trial.
Dermatology 1993; 187: 26-9.
10. Elias AN, Goodman MM, Liem WH, Barr RJ. Propylthiouracil
in psoriasis: results of an open trial. J Am Acad Dermatol 1993;
29: 78-81.
11. Abe M, Ohnishi K, Aoyama K, Tamura A, Ishikawa O, Murakami
M. The clinical usefulness of psoriasis vulgaris treatment with an antithyroid
drug by the Gunma university method. Jap J Dermatol 2000; 110:
1549-56 (in Japanese).
12. Elias AN, Barr RJ, Rohan MK, Dangaran K. Effect of orally
administered antithyroid thioureylenes on PCNA and P53 expression in psoriatic
lesions. Int J Dermatol 1995; 34: 280-3.
13. Elias AN, Goodman MM, Rohan MK. Effect of propylthiouracil
and methimazole on serum levels of interleukin-2 receptors in patients
with psoriasis. Int J Dermatol 1993; 32: 537-40.
14. Elias AN, Goodman MM, Rohan MK. Serum ICAM-1 concentrations
in patients with psoriasis treated with antithyroid thioureylenes. Clin
Exp Dermatol 1993; 18: 526-9.
15. Elias AN, Barr RJ. Low-dose oral propylthiouracil in the
treatment of plaque psoriasis. Int J Dermatol 1995; 34: 519-20.
16. Weetman AP. Effect of antithyroid drug methimazole on interleukin-1
and interleukin-2 levels in vitro. Clin Endocrinol 1986; 25: 133-42.
17. Tötterman TH, Karlsson FA, Bengtsson M, Mendel-Hartvig
I. Induction of circulating activated suppressor-like T cells by methimazole
therapy for Graves' disease. N Eng J Med 1987; 316: 15-22.
18. Ohashi H, Okugawa T, Itoh M. Circulating activated T cell
subsets in autoimmune thyroid disease; differences between untreated and
treated patients. Acta Endocrinol 1991; 125: 502-9.
19. Nakayama J, Hori Y. Changes of T lymphocyte subset in the
peripheral blood of patients with psoriasis with aromatic retinoid administration.
Nishinihon J Dermatol 1992; 54: 500-6 (in Japanese).
20. Ligresti DJ, Neff JC, Lowney ED. Increased helper-suppressor
T cell ratio in psoriasis. Arch Dermatol 1982; 118: 966-70.
21. Abe M, Ishikawa O, Miyachi Y. Changes in peripheral blood
lymphocyte subsets during cyclosporin administration in patients with
psoriasis vulgaris. Eur J Dermatol 1997; 7: 417-20.
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