Introduction

Glial cell derived neurotrophic factor (GDNF) has an important role in the regulation of neuroinflammatory processes and pain syndrome of many diseases. Neuroinflammation causes GDNF expression in activated astrocytes and microglia, infiltrating macrophages, nestin-positive reactive astrocytes and neuroglial cells. Disease-related overexpression of GDNF can be compensatory and have a tissue-protective effect, as well as being harmful with negative consequences, depending on the location in the brain and the level and duration of glial cell activation [1]. Studies of GDNF have demonstrated its neuroprotective properties [2] and its ability to regulate dopamine metabolism and improve brain biodistribution [3]. The available data indicate an important role of GDNF in the regulation of the psycho-emotional sphere; the disturbance of the psycho-emotional sphere is quite often associated with chronic pain syndrome [4].

Alexithymia – difficulties with describing and verbalizing one’s own emotions and sensations – belongs to disorders of the psycho-emotional sphere. Modern studies have shown the association of alexithymia with chronic pain [5], systemic autoimmune diseases [6] and pathological conditions with somatic symptoms of uncertain origin [7]. Rheumatoid arthritis (RA) patients are characterized by significantly higher scores of alexithymic scales [6]; alexithymia in these patients is closely related to the deterioration of the psycho-emotional state and the severity of chronic pain [8].

The relationship between alexithymia and GDNF level in the blood plasma of RA patients needs more detailed research. The results of the study may provide valuable information regarding the biological role of GDNF in RA and the details of the relationship between alexithymia and GDNF in the pathogenetic mechanisms of RA.

The aim of the study was to determine the level of GDNF in the blood plasma of RA patients according to the presence of alexithymia and evaluate the relationship of GDNF level with clinical manifestations and quality of life.

Material and methods

We examined 88 patients (15 men and 73 women) who were hospitalized at the Center of Rheumatology, Osteoporosis and Biological Therapy of the communal non-profit enterprise Vinnytsya Regional Clinical Hospital named after M.I. Pirogov. Diagnosis of RA was established according to the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria. For the measurement of plasma GDNF level, a total of 10 ml of blood was drawn from each participant. All blood samples were centrifuged and stored at –70^oC immediately after collection. The GDNF in the blood plasma was determined by the ELISA method using the Human GDNF (Glial Cell Line Derived Neurotrophic Factor) ELISA Kit (Elabscience, USA, Lot CV09HB482125) according to the manufacturer’s instructions. Rheumatoid arthritis activity was assessed by the DAS28 (ESR) index [9], the Simple Disease Activity Index (SDAI) [10] and the Rheumatoid Arthritis Clinical Disease Activity Index (CDAI) [11]. Pain intensity was assessed by the Visual Analogue Scale (according to the assessment of the patient – VAS-P and the assessment of the doctor – VAS-D) [12]. General state of health and functions was assessed according to the Health Assessment Questionnaire (HAQ) [13]. Alexithymia was revealed by the Ukrainian version of the Toronto Alexithymia Scale (TAS-20) [14]; if the value of the TAS-20 was above 60 points, alexithymia was established in patients. The disability was determined by the validated and cross-cultural adapted Ukrainian version of the Disability Rating Index (DRI) questionnaire [15]. Quality of life was assessed by the SF-36 Health Survey [16].

Results

Discussion

Comparing the results of our study with previous studies, which found in patients with RA an increase in the level of brain-derived neurotrophic factor (BDNF) and a decrease in the level of GDNF compared to the control group [17], there can be noted some consistency of the data we obtained with the results of previous studies. Experimental models of GDNF influence proved the dependence of GDNF effects on the duration of its action: in an acute process GDNF showed neuroregenerative properties [18–20], while long-term expression and high concentration of GDNF caused a negative effect on the homeostasis of neurotransmitters [21–24]. The patients in our study represented persons with a chronic disease (average duration more than 8 years); the association of GDNF level with disease activity and worse quality of life could be due to this factor. Interpreting the data of our study, one should take into account the report of Lundborg et al. that the level of GDNF in chronic pain increased intrathecally but decreased in blood plasma [25], as well as the data of Hulander et al., indicating that a reduced serum level of GDNF may lead to reduced activation of inflammatory pathways and that GDNF expression is significantly modulated by external influences [26].

Higher levels of RA activity, pain intensity and worse functional capacity and health status of patients were associated with a higher level of GDNF – generally in line with data from research by Elfving et al.; the authors found that the level of GDNF in the plasma of RA patients was higher than in the control group and correlated with the severity of the pain syndrome [27]. At the same time the available studies testify to the complex and ambiguous nature of the physiological function of GDNF [28], and in evaluating the regularities, one should take into account as many relevant factors as possible that can influence the effects of GDNF.

In our opinion, alexithymia can be one of these factors. The data of our study proved that the RA patients had a higher level of alexithymia. This data are consistent with the results of Vadacca et al. [6] and Chimenti et al. [29]; they found a significant prevalence of alexithymia in RA patients, as well as the relationship of alexithymia in RA with the psychoemotional state of patients [8] and pain perception [30].

As the relationship between alexithymia and the level of GDNF in RA patients has not been studied yet, based on the data of our study we can assume that the presence of alexithymia not only modifies the clinical manifestation of RA, but also significantly changes the physiological effect of GDNF.

In the group of patients with alexithymia the level of GDNF was directly correlated with disease activity and pain intensity, while in the group of patients without alexithymia, significant correlations were not found. At the same time, in the group of patients with alexithymia, significant differences in disease activity, severity of pain, functional activity and health status of patients were found between patients with different levels of GDNF, while in the group of patients without alexithymia, such differences were not found.

In our opinion the features of the quality of life are a natural reflection of the trends revealed regarding disease activity, pain intensity, functional activity, general state of health and the state of the psycho-emotional sphere. As patients with a higher level of GDNF were characterized by a worse state of these functions, it seems logical that the quality of life in the related areas would decrease.

Conclusions

Alexithymia was found in 40% of RA patients.

Rheumatoid arthritis patients with alexithymia had a nonsignificantly higher GDNF level compared to patients without alexithymia.

In RA patients with alexithymia, an association of GDNF level with rheumatoid arthritis activity, loss of functional capacity and reduced quality of life was established.

Alexithymia in RA patients is an important factor in the clinical manifestation of RA and modification of the pathophysiological role of GDNF.