Serum concentrations of interleukin-2 and tumour necrosis factor-α under cyclosporine versus acitretin treatment in plaque-type psoriasis

Abstract

Objective

A prospective, randomized clinical study to compare the short-term effects of cyclosporin and acitretin on psoriasis severity, and serum interleukin (IL)-2 and tumour necrosis factor (TNF)-α concentrations.

Methods

Patients with moderate-to-severe plaque-type psoriasis were randomly assigned to receive either 3 mg/kg per day cyclosporine or 0.3–0.5 mg/kg per day acitretin for 8 weeks. Disease severity (psoriasis area severity index [PASI] score) and serum IL-2 and TNF-α concentrations were determined before and after treatment.

Results

PASI scores and serum IL-2 and TNF-α concentrations were significantly decreased after treatment with either cyclosporine (n = 21) or acitretin (n = 25). There were no statistically significant between-group differences in any parameter.

Conclusions

Acitretin and cyclosporine are equally effective in the treatment of moderate-to-severe plaque-type psoriasis.

Introduction

The prevalance of psoriasis is approximately 1–5%.^1,2 Although the aetiology of psoriasis is not completely understood, it is thought to be an autoimmune, inflammatory disease characterized by the activation of keratinosites secondary to lymphocyte activation in the dermis and epidermis. Although the sequence of events between keratinocyte and immune-cell activation in psoriasis remains unclear, it has been shown that T cells are important in immunopathogenesis. ¹ Activated T lymphocytes secrete cytokines including interleukin (IL)-1, IL-2, IL-6, IL-8, tumour necrosis factor (TNF)-α, interferon γ, epidermal growth factor, fibroblast growth factor and platelet-mediated growth factor.^2,3

Biopharmaceuticals are increasingly used in psoriasis treatment, but are expensive compared with conventional drugs such as cyclosporine and acitretin. The beneficial effects of cyclosporine and acitretin in psoriasis are well known, ⁴ but their relative efficacy is unclear. The aim of the present study was to compare the short-term effects of cyclosporine and acitretin on psoriasis severity, and serum IL-2 and TNF-α concentrations.

Patients and methods

Study population

This single-centre, randomized, prospective study recruited patients with clinically and pathologically diagnosed moderate-to-severe plaque-type psoriasis (psoriasis area severity index [PASI] ⁵ score ≥10), who attended the Department of Dermatology, University of Gaziantep, Gaziantep, Turkey, between January 2008 and January 2009. Data regarding age, sex, disease duration and family history were recorded for each patient. Patients were required to have not received any systemic treatment (including acitretin, cyclosporine, methotrexate, phototherapy or biological agents) within the previous 3 months.

Patients provided written informed consent prior to enrolment. The study was approved by the Clinical and Drug Investment Ethics Committee of University of Gaziantep Faculty of Medicine, Gaziantep, Turkey.

Treatment

Patients were stratified into one of two groups via a computer-generated randomization schedule to receive either 3 mg/kg per day cyclosporine or 0.3–0.5 mg/kg per day acitretin for 8 weeks. Disease activity (PASI score) was recorded before and after treatment.

IL-2 and TNF-α assays

Peripheral venous blood (10 ml) was taken from each patient before and after treatment; serum was stored at −70℃ until analysis. IL-2 levels were quantified using an immunoenzimometric assay kit (Immunotech International, Marseille, France); TNF-α levels were quantified using an enzyme-linked immunosorbent assay kit (Immuno-Biological Laboratories, Minneapolis, MN, USA). Kits were used according to the manufacturer’s instructions.

Statistical analyses

Data were presented as mean ± SD or n. Between-group comparisons were made using variance analysis in repetitive measurements for parametric data and Mann–Whitney U-test for nonparametric data. Correlations between PASI scores and IL-2 or TNF-α concentrations were evaluated using Spearman’s rank correlation coefficient. Statistical analyses were performed using SPSS® version 15.0 (SPSS Inc., Chicago, IL, USA) for Windows®. P-values < 0.05 were considered statistically significant.

Results

The study recruited 55 patients, of whom nine were excluded (due to side-effects [n = 4] or missed appointments [n = 5]). The final analysis therefore included 46 patients (33 male/13 female; mean age 37.8 ± 10.1 years; age range 20–63 years). The mean duration of illness was 14.9 ± 10.4 years (range 2–40 years). The cyclosporine group included 21 patients and the acitretin group included 25 patients. There were no statistically significant between-group differences in age, sex, duration of disease or before-treatment PASI score (Table 1).

Table 1.

Demographic and clinical characteristics of patients with moderate-to-severe plaque psoriasis included in a study to compare the effect of short-term (8-week) treatment with cyclosporine or acitretin.

Parameter	Cyclosporine group n = 21	Acitretin group n = 25
Male/female	14/7	19/6
Age, years	37.8 ± 10.1	36.9 ± 14.7
Disease duration, years	14.9 ± 10.4	10.4 ± 6.1
PASI score
Before treatment	22.08 ± 6.58	19.96 ± 7.97
After treatment	6.43 ± 6.39***	7.23 ± 3.96***
Tumour necrosis factor-α level
Before treatment	35.46 ± 7.94	33.67 ± 6.99
After treatment	9.60 ± 0.67***	9.10 ± 0.65***
Interleukin-2 level
Before treatment	23.25 ± 9.20	22.93 ± 5.75
After treatment	5.67 ± 2.85***	5.35 ± 1.71***

Data presented as n or mean ± SD.

***

P < 0.001 vs before-treatment value; variance analysis in repetitive measurements for parametric data and Mann–Whitney U-test for nonparametric data.

PASI, psoriasis area severity index. ⁵

In both treatment groups, PASI scores and serum IL-2 and TNF-α concentrations were significantly lower after treatment than before treatment (P < 0.001 for each comparison, Table 1). There were no significant between-group differences in change in PASI score, or in serum IL-2 and TNF-α concentrations.

There was a significant positive correlation between PASI score and change in TNF-α concentration in the cyclosporine group (r = 0.672*, P = 0.002) but not in the acitretin group. There were no significant correlations between PASI score and change in IL-2 concentration in either treatment group.

Discussion

The present study found that cyclosporine and acitretin have similar effects on the severity of psoriasis, and on serum concentrations of IL-2 and TNF-α. Cyclosporine is known to inhibit the production of IL-2, helper T cells, regulatory T cells and natural killer cells, and to block the activation of monocytes.^6–9 Short-term maintenance treatment with cyclosporine has resulted in 86–95% improvement in psoriasis disease scores,^6–10 although side-effects associated with this drug limit the treatment duration to 2 years.^11,12 Cyclosporine can be combined with methotrexate or biopharmaceuticals, however.^4,13 Cyclosporine treatment has been shown to result in significantly lower soluble IL-2 receptor and IL-12 concentrations in patients with psoriasis compared with untreated healthy controls. ¹⁴ In addition, PASI scores were strongly correlated with soluble IL-2 receptor concentrations in patients undergoing cyclosporine treatment. ¹⁵

Despite the clinical success of acitretin therapy in psoriasis, its mechanism is not completely understood although its effect on epidermal cell growth and differentiation is well known. The efficacy of acitretin monotherapy in chronic plaque psoriasis is below that of both methotrexate and cyclosporine.^16–21 In terms of PASI scores, there was no significant difference between cyclosporine and acitretin short-term therapy in the present study, however. In addition, both treatments significantly decreased TNF-α and IL-2 concentrations compared with pretreatment values.

Data comparing the efficacy of cyclosporine and acitretin are limited, but there are several studies comparing cyclosporine and etretinate (another aromatic retinoid). Cyclosporine has been shown to be more easily tolerated, ²⁰ and to offer more rapid ²² and more effective treatment,^23,24 than etretinate.

The treatment-related decline in IL-2 and TNF-α concentrations was expected in the cyclosporine group in the present study, due to the immunosuppressive effects of this agent. IL-2 plays a key role in the mechanism of action of cyclosporine. ²⁵ Psoriatic skin is characterized by activated T lymphocyte infiltration and abnormal keratinocyte differentiation. The use of biopharmaceuticals in the treatment of psoriasis has revealed a correlation between clinical improvement and TNF-α concentrations, emphasizing the importance of TNF-α in psoriasis. ²⁶ The similar decrease in IL-2 and TNF-α concentrations observed in both treatment groups in the present study may be related to the antikeratinizing, anti-inflamatory and antiproliferative effects of acitretin.^17–19

In conclusion, the present study found that acitretin and cyclosporine are equally effective in the treatment of moderate-to-severe plaque psoriasis.