Serum adenosine deaminase levels in patients with psoriasis: a prospective case-control study

ARTICLE

Adenosine deaminase (ADA) catalyzes the conversion of adenosine to ammonia and inosine in purine metabolism or purine salvage pathway. ADA is found widely in human tissues with its highest activity in lymphoid tissues. Among lymphocytes, it is mainly associated with T-lymphocytes [1] and studies have shown increased serum ADA levels in diseases characterized by T cell proliferation or activation [2, 3].

Psoriasis is regarded as an immunologically mediated disease. Recent evidence suggests that T cell activation plays an important role in its pathogenesis and cytokines released by both T cells and keratinocytes mediate keratinocyte proliferation [4].

There is little data regarding ADA activity in patients with psoriasis. In psoriatic epidermis, ADA activity has been found to be elevated compared to normal or uninvolved epidermis [5]. Although it has been reported to be elevated in tissue, to our knowledge, there is only one study regarding serum ADA activity in psoriasis. However this study has failed to show any increase in serum ADA levels [6].

The purpose of this study was to clarify the significance of serum ADA levels in psoriasis and to investigate its association with disease activity.

Materials and methods

Twenty-five patients with moderate to severe chronic plaque type psoriasis were included as the study group for determination of serum ADA activity. The patients did not have any other systemic problems. None of the patients had received ultraviolet therapy or systemic drug therapy during the last 3 months. Among the study group, 10 patients were randomized to treatment with either PUVA (psoralen + ultraviolet A) three times a week (n = 5) or cyclosporin A with a dose of 5 mg/kg/day (n = 5). When clinical improvement had been achieved after at least 30 sessions of PUVA or one month of cyclosporin treatment, serum ADA measurements were repeated. Clinical improvement was assessed by pre- and post-treatment psoriasis area severity index (PASI) scores [7].

As the control group, 15 healthy volunteers provided serum samples for ADA measurements. Subjects were age-matched with the study group.

Serum ADA determinations

Sera obtained from patients and controls were kept at -20° C until assayed. Serum ADA activity was determined by a colorimetric method as described previously [8]. This method is based on the fact that ammonia, which is measurable colorimetrically, is produced when adenosine is metabolized to inosine and ammonia by the action of ADA. The normal range for serum ADA activity was 5-20 units/ml.

All statistical evaluations were done with the SPSS 7.01 (Statistical Packages for Social Sciences; SPSS Inc., Chicago, Illinois, USA). Mean and standard deviations were used for evaluation of ages, serum ADA and PASI measurements. Independent t-test was used for comparison of age and sex differences between groups. Mann-Whitney U test was used for comparison of both ADA levels of study and control groups. Serum ADA levels and PASI scores of patients before and after treatment were compared by Wilcoxon signed rank test. Spearman's correlation coefficient was calculated to study the relation between ADA activity and PASI scores.

Results

The study group of twenty-five patients with psoriasis was composed of 4 women and 21 males with a mean age of 34.2 ± 14.8 years. The control group consisted of 8 female and 7 male subjects with the mean age of 33.3 ± 11.2 years.

In the study group, ADA values before treatment or at least after three months of a systemic treatment (ADA 1, pretreatment) were between 5-15 units/ml and mean was 8.2 ± 2.1 units/ml (median = 8 units/ml). In the control group ADA activity was measured between 4-9 units/ml with a mean of 6.4 ± 1.2 units/ml (median = 6 units/ml). Serum ADA levels of psoriatic patients were significantly elevated compared to subjects in the control group (p = 0.003, < 0.05) (Fig. 1).

ADA levels were reevaluated (ADA 2, posttreatment) after treatment in 10 patients. In those patients, ADA 1 levels were between 5-10 units/ml with a mean of 7.4 ± 1.4 units/ml, whereas ADA 2 differed between 3-9 units/ml with a mean of 5.1 ± 2.0 units/ml. There was a significant decrease in the ADA activity following treatment in these patients (p = 0.015, < 0.05) (Fig. 2).

Clinical improvement was experienced by all patients who received systemic treatment in the study group. In 10 patients, pretreatment PASI (PASI1) scores were between 10.5-54.2 with a mean of 24.5 ± 12.2; after treatment, PASI scores (PASI 2) differed between 0-12.8 with a mean of 2.9 ± 4.8. There was a significant decrease in the PASI scores after treatment (p = 0.005, < 0.05). But there was no correlation between the pretreatment ADA (ADA1) and PASI (PASI 1) scores of all 25 patients, also no correlation could be found between the posttreatment ADA (ADA2) and PASI (PASI 2) scores of 10 patients (p > 0.05).

Discussion

We have demonstrated that serum ADA activity was elevated over mean of the control in psoriatic patients. There are many studies reporting increased ADA activity in diseases with T cell activation [9, 10]. Among dermatological diseases, in patients with progressive systemic sclerosis, serum ADA levels were found to be elevated compared to controls in 85% of the patients. The authors suggested that increased serum ADA activity reflects T cell activation in systemic sclerosis [11].

According to the studies by Koizumi et al. [5], and later by Tikhonovlu et al. [12], ADA activity was elevated in psoriatic epidermis compared to uninvolved skin, possibly due to an increase in nucleic acid metabolism of the hyperproliferating epidermis of psoriasis. But ADA levels could be elevated in lymphocyte cultures after exposure to a mitogen, before DNA synthesis starts [13]. Also during monocyte maturation, it was observed that ADA activity was elevated without any difference in other enzymes of purine metabolism [14]. So ADA activity cannot simply reflect increased metabolism.

Activity of adenosine deaminase and purine nucleoside phosphorylase in lymphocytes from patients with psoriasis vulgaris was studied and results yielded a statistically significant increase in the activities of adenosine deaminase and purine nucleoside phosphorylase in comparison to the control group of healthy subjects. Also methotrexate administration significantly decreased the activity of both enzymes in lymphocytes [15].

We could only find one study in the literature where serum ADA levels were examined. In this study, serum ADA levels were found to be high in patients with mycosis fungoides and T cell leukemia. ADA levels did not show any significant difference from the normal laboratory values in psoriatic patients. In addition, ADA levels did not correlate with severity of the disease [6]. But since this study did not have any control group, it was not possible to compare the values of psoriatic patients with normal subjects. In our study, all the pretreatment ADA values of psoriatic patients were also within the normal laboratory range, but they were found to be significantly elevated when they were compared with the control group.

In our study, serum ADA activity decreased significantly in patients after PUVA or cyclosporine treatment. These two treatment modalities are known to affect lymphocytes. PUVA therapy has been found to have suppressive effects on lymphocytes both in circulation and in psoriatic plaques [16-18]. It has been reported that long-term PUVA therapy alters lymphocyte function and cell-surface markers or their distribution [19]. Again, long-term PUVA therapy is associated with a reduction in circulating helper/inducer T cells that may be related to the altered immune functions reported in PUVA-treated patients [20]. Cyclosporine is also known to be a selective immunosuppressant in psoriasis because it blocks T-helper cells in psoriatic skin leading to diminished expression of cytokines and inhibition of keratinocyte activation [21]. In accordance with this evidence, our finding of a decrease in ADA activity after both PUVA and cyclosporin treatment shows that ADA activity is closely related to T cell activation.

Although serum ADA activity was elevated in psoriatic patients, we could not find any correlation between ADA levels and disease activity as assessed by PASI scores. This may result from a lack of objectivity of the PASI scoring system in estimating disease activity. PASI scoring system was first described in 1978 by Fredriksson and Pettersson [7]. Since then it has been used in many studies as a marker of clinical response to different treatment modalities. However, it has been criticized by several authors since it is a subjective method that is very examiner-dependent and because it does not reflect disease activity accurately [22, 23].

CONCLUSION

As a conclusion, finding high ADA activity in psoriatic patients' sera before treatment and its decrease after treatment shows that ADA activity is related to disease activity. Also since it is regarded as a nonspecific marker of T cell activation, our findings support the hypothesis of T cell activation in the pathogenesis of psoriasis. Further studies are needed to determine its sensitivity in disease follow-up and in predicting relapses before clinical findings.

Article accepted on 11/1/00

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