To study the features of vegetative homeostasis in patients with ankylosing spondylitis with anxiety-depressive spectrum disorders

Introduction

Today, it is known that the autonomic nervous system (ANS) not only provides for the needs of homeostasis by regulating the state of internal organs but also implements a response to external stimuli, such as stress, in individuals at risk of high stress vulnerability. During a stress reaction, the ANS triggers a cascade of endocrine mechanisms that release hormones of the hypothalamus-pituitary-adrenal axis. An imbalance in the work of the ANS departments, as well as other functional and morphological changes that contribute to the deterioration of the patients’ well-being, a decrease in their quality of life (QOL), and the development of psycho-emotional disorders, are observed in various diseases, including autoimmune processes [1–3].

Chronic stress, leading to hyperactivation of the sympathetic nervous system (SNS), is associated with a wide range of immunological effects, and psycho-traumatic events are often predictors of autoimmune inflammation [4][5].

According to various studies, in patients with ankylosing spondylitis (AS), the incidence of anxiety-depressive spectrum disorders (ADSDs) ranges from 25% to 60%, and the ANS imbalance observed in this category of patients is aggravated by increased anxiety and depressive disorders [6][7].

Depressive disorders are often combined with increased anxiety, which changes the ANS tone towards the predominance of sympathetic effects, increases pressor reactions, and the release of catecholamines. A number of studies reveal that depression is accompanied by an ANS imbalance with suppression of parasympathetic tone and low heart rate variability (HRV) [8][9].

Assessing the ANS balance using the HRV method is widely used in practical medicine, since this method, which is an indicator of functional flexibility in the autonomic regulation system, allows assessing and predicting psycho-emotional reactions based on the state of the autonomic background [10–12].

Systemic inflammation that develops in individuals with autoimmune pathology, in particular with AS, negatively affects the autonomic regulation of cardiac activity and reduces the ANS ability to adaptively restructure in response to various external stimuli, which is manifested in a decrease in HRV. Low HRV, which is a marker of autonomic imbalance, in turn, is independently associated with an increased risk of death from cardiovascular diseases and their complications, even in the absence of cardiovascular pathology in patients [13–15].

A number of studies thoroughly regard the influence of autonomic imbalance on cardiac activity in patients with rheumatoid arthritis and systemic scleroderma, which is reflected in increased SNS tone, and prove a link between decreased HRV and immune inflammation activity in this category of patients [11][16–18].

However, only a few studies are devoted to autonomic regulation features in patients with AS [19][20]. At the same time, the problem of assessing the features of autonomic regulation in patients with AS with psycho-emotional disorders remains unaddressed. This is of interest due to the high frequency of ADSDs in this category of patients and therefore requires active study.

The study aims to analyze the indicators of autonomic homeostasis and psychosocial functioning in patients with AS with ADSDs.

Materials and methods

The study included 112 patients with AS, aged 25–58 (43.7±7.9 years; 71 males and 41 females), observed in the rheumatology department of Lugansk Regional Clinical Hospital in 2016–2019. The diagnosis was established in accordance with the modified New York criteria (ACR, 1984); the degree of activity of the pathological process was assessed taking into account the Bath AS disease activity index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) in accordance with the EULAR criteria. The study was conducted after obtaining permission from the local ethics committee.

The inclusion criteria for the study were: informed consent, verified diagnosis, AS duration of more than three years, and the absence of diagnosed CNS disorders in patients that could lead to the development of ADSDs. The exclusion criteria were AS duration of less than 3 years, age over 60 years, organic brain damage, manifestations of anxious depression detected before the diagnosis, and regular intake of additional drug therapy due to concomitant diseases (hypotensive, lipid-lowering, antiarrhythmic drugs).

A questionnaire was conducted in order to identify ADSDs in patients. The Taylor Manifest Anxiety Scale (TMAS) with the Russian-language adaptation by Nemchinov was used to assess the level of anxiety. The questionnaire includes 50 questions to which the patients were to answer “yes” or “no”; the results are assessed in points and interpreted according to the following principle: 0–5 points indicate a low level of anxiety; 5–15 points – average to low; 15–25 points – average to high; 20–40 points – high; 40–50 points – very high. The Spielberger State-Trait Anxiety Inventory (STAI) was also used, according to which an anxiety level of less than 30 points was assessed as low, 30–45 as moderate, and more than 45 as high. To identify symptoms of depression, the Hamilton Depression Scale (HDS) was used, according to which, when summing up the points obtained, 16–18 points in young people and 18–20 points in older people indicate a non-psychotic depressive state.

The presence and severity of autonomic dysfunction were studied by testing using the Wayne-Patient (WP) and Wayne-Doctor (WD) methods, where possible autonomic dysfunction is more than 15 points according to the WP, and confirmed autonomic dysfunction is more than 25 points according to the WD.

The patients' QOL was assessed using the Medical Outcomes Study Short Form (SF-36) questionnaire, which allows assessing two components of health – total physical (PSH) and psychological (MSH). The results are expressed in points from 0 to 100, where the higher the value of the indicator, the better the condition according to the selected scale [21].

The HRV indices were recorded using a 03260D cardiac recorder (Ukraine, 2012) with a 5-minute ECG recording in cases where the HR differed from the average (60–80 per minute); the recording duration ranged from 300 to 500 recorded cardiac cycles. The DiaCard program was used to study the HRV; it allows calculating the statistical characteristics and spectral analysis results: Mode (Mo) is the most frequently occurring value of the R-R interval duration; Mode amplitude (AMo) is the percentage of the most frequently occurring cardiac intervals or their number (in % of their total number) corresponding to the mode range; the Standard Deviation of Normal-Normal (SDNN) interbeat interval is the total effect of autonomic regulation of blood circulation. pNN50 (number of pairs of intervals with a difference of more than 50 ms in % of the total number of intervals) indicates the degree of predominance of the parasympathetic link of regulation over the sympathetic (relative value); variation range (VR), ΔХ is the difference between the maximum and minimum values ​​of intervals; the tension index (TI) is the ratio TI=AMo/Mo*2ΔХ; the Cardiac Autonomic Balance (CAB) – CAB=AMo/ΔХ indicates the ratio between the activity of parasympathetic control (HF) and sympathetic control (PEP) of the ANS; total spectrum power (TP, ms²) (0.003–0.40 Hz) is the total level of activity of regulatory systems, that is, the total influence of the HF and PEP of the ANS on the heart rhythm. The power of individual spectral components was also determined: high-frequency (HF, ms²) in the range of 0.15–0.4 Hz, low-frequency (LF, ms²) in the range of 0.04–0.15 Hz, very low-frequency (VLF, ms²) in the range ≤ 0.04 Hz and the vagosympathetic interaction index LF/HF.

Pain syndrome and the duration of morning stiffness in the spine and joints were assessed by the patients themselves using a visual analogue scale (VAS). Laboratory parameters were also examined: CRP, ESR, calcium, uric acid (UA), fibrinogen and ceruloplasmin (CP) levels in the blood serum.

Statistical analysis of the obtained results was performed using the Statistica 10.0 statistical software package (Statsoft, USA). For normal distribution, the data were presented as the mean ± standard deviation (m±σ), in other cases as Me (LQ-UQ), where Me is the median, LQ is the lower quartile, and UQ is the upper quartile. To compare quantitative characteristics between the groups, the nonparametric Mann-Whitney U test was used. Correlation analysis was performed using the nonparametric Spearman rank correlation method. Differences were considered statistically significant at p<0.05.

Results

Signs of ADSDs corresponding to clinical manifestations of anxious depression (F41.2) were detected in 67 patients (42 males, 25 females), which amounted to 59.8% of the total number of those examined; the average age was 44.1±8.3 years, the average duration of the disease was 10.2±4.5 years. A moderate inflammatory process was established in 33 (49.2%) patients, and high in 17 (25.4%) patients. All these patients were included in observation Group I, and the remaining 45 patients (without signs of ADSDs) in Group II. In Group II, the average age was 44.1±8.2 years, and the average duration of the disease was 8.4±4.2 years. A moderate inflammatory process was observed in 20 (44.4%) cases, and high in 11 (24.4%) patients.

When comparing the indices in the groups, no reliable differences were found in BASDAI, BASFI, CRP, and ESR (all p>0.05). In Group I, significantly higher indices of pain and severity of stiffness in the spine (according to VAS), increased UA, and a reliable decrease in CP were established, compared with patients in Group II (all p<0.05). The data are presented in Table 1.

In patients of Group I, according to the indices of ADSD severity – HDS, TMAS, RA, and PA, the results, taking into account the age of the subjects, generally corresponded to non-psychotic depressive state; the revealed increased anxiety, according to the Spielberger and Taylor scales, generally corresponded to a moderately high level of anxiety in the group of examined AS with ADSDs. In Group II, according to the anxiety and depression scales, the results indicated a low level of anxiety. However, in 18 cases (40% of observations) in Group II, complaints of chronic fatigue were recorded, and sleep disorders and depressed mood in 16 cases (35.6%). In patients with ADSDs, these complaints were observed more often: chronic fatigue and sleep disorders in 38 cases (56.7%), and depressed mood in 37 cases (55.2%). All the patients of Group I showed signs of autonomic dysfunction (AD) according to the WP scale, and confirmed AD according to the WD was established in 59 cases (88%). Signs of AD were observed in Group II significantly less often (p<0.001) than in patients of Group I, which confirms a higher frequency of autonomic disorders in patients with AS with ADSDa. The QOL indicators recorded in the examined Group I can be assessed as low in the total physical component of health (PSH) and in the general psychological component of health (MSH). In patients without ADSDa, significantly higher QOL indicators were recorded (both p<0.001) than in Group I. The results are presented in Table 2.

The assessment of autonomic reactivity conducted in patients of both groups (Table 3) revealed significant differences (all p<0.05) in all statistical and spectral characteristics of HRV with lower indicators of Mo, AMo, pNN50, VR (ΔX), TP, HF, LF, and VLF and significantly higher SDNN, CAB, TI, and LF/HF in patients of Group I.

The next stage of the study was to conduct a correlation analysis between the HRV and QOL indicators, as well as the manifestations of AD, laboratory activity of AS in the groups.

Correlation analysis revealed significant (p<0.05) relationships between individual spectral components of HRV and indicators of psycho-emotional status, as well as components of QOL (physical and psychological) in patients with AS with ADSDS (Table 4). A direct correlation of medium strength was established between VLF, TP with PH, MH, VP, which confirms a strong predominance of sympathetic influences in this category of patients.

In Group II of the examined subjects, reliable correlations between the studied indicators were not established. However, a tendency to form correlations between TP and chronic fatigue, decreased mood was noted. In Group I, the correlations between the above indicators were reliable and stable.

When performing a correlation analysis between the spectral characteristics of HRV and the laboratory activity indices of AS in Group I, the following significant relationships were found: moderate negative relationships between TP, HF, VLF, and laboratory data (CRP, ESR, UA and fibrinogen levels), moderate direct correlation between the CP level and TP, HF, and VLF. A direct correlation was established between the LF/HF indicator and CRP, ESR, UA, fibrinogen levels, and reliable negative relationships with the blood calcium level and CP. The data are presented in Table 5.

When conducting a similar correlation analysis in Group II, weak correlation relationships were established between TP, VLF, and the level of CRP and fibrinogen. The results are presented in Table 6.

Discussion

According to the conducted study, all the patients with AS with ADSDs (59.8% of the total number of patients examined) showed signs of AD. The obtained results are similar to those of other studies, where the frequency of ADSD in patients with AS varies from 25% to 60%, and the ANS imbalance is aggravated by increased anxiety and depressive disorders [6][7]. Chronic pain, typical for patients with AS, has a common neurochemical substrate with depressive disorders (serotonergic and noradrenergic insufficiency), which contributes to a stereotype of pain behavior in the patient, as well as an increase in emotional, vegetative, and behavioral reactions; increased anxiety contributes to a change in the SNS tone, increases pressor reactions and the release of catecholamines, and leads to ANS imbalance. The severity of these reactions directly depends on the high level of stress and the tension of regulatory mechanisms which aggravate negativistic patterns of thinking and form the vicious circle of chronic stress, thereby affecting the chronification of pain and a decrease in QOL [22].

In a study by Peláez-Ballestas et al., patients with AS (according to the SF-36 questionnaire) had decreased social adaptation and negativistic emotions caused by pain syndrome [23]. The author of the present research found that patients with AS with ADSDs were characterized by even lower life activity, decreased social adaptation, and a lower mental health indicator than patients with AS without ADSDs, which generally affected the total indicators of physical and psychological health.

According to the results, in patients with AS with ADSDs, in comparison with patients with AS without ADSDs, a highly reliable decrease in the enzymatic activity of CP (t = 3.48; p <0.001) and an increase in UA indicators (t = 3.14; p = 0.002) were revealed, which indicates a more rapid depletion of the antioxidant potential in this category of patients and the progression of their immunoinflammatory activity. This is consistent with the data of other researchers presented in the literature [24].

The HRV indices recorded in patients with ADSDs indicate increased sympathetic influences (increased LF/HF ratio, low TP) and reflect the predominance of the defensive component in the structure of vegetative provision, which is consistent with the literature data [8][11], according to which an increase in anxiety is accompanied by a decrease in the HRV level in general and an increase in the SNS tone, and is regarded as a sign of the loss of “functional flexibility” of vegetative regulation, that is, a decrease in the ANS ability to adaptively restructure in response to various external stimuli and homeostatic changes. Low TP indices, largely due to the high-frequency component (HF), as well as a decrease in the duration of R-R intervals (Mo), recorded in patients with ADSDs, are regarded by us and other authors [9] as indicating a decrease in resistance to psycho-emotional stress and indicating a deterioration in the orienting component in cognitive activity. Thus, in addition to the general decrease in spectral power, the contribution of various regulatory levels to the activity of the cardiac system also changes in emotional disorders.

The present research reveals negative correlations between the HRV indices and markers of clinical and laboratory activity, which were stronger in the group of patients with signs of ADSDs than in patients with AS without ADSDs, which indicates a significant role of depression in enhancing immune inflammation and does not contradict the results of other authors [9][19].

Moreover, a correlation analysis showed reliable relationships between the indices of antioxidant potential (UA and CP) and autonomic regulation (TP, HF, and LF/HF) in the group of patients with ADSD, which confirm increased ANS imbalance with the dominance of its sympathetic link against the background of decreased antioxidant defense factors in patients with signs of ADSDs.

Conclusion

In the study, all patients with ADSDs showed signs of AD. Patients with AS with ADSDЫ are characterized by low vital activity and mental health, decreased adaptation to social functioning, and depletion of the potential. Deterioration of the HRV indices in this category of patients is accompanied by the prevalence of the sympathetic link of the ANS and decreased resistance to psycho-emotional stress with a predominance of the defensive component in the structure of vegetative provision. Further study is required on the relationship between changes in vegetative homeostasis indices and laboratory markers of inflammation against the background of immune inflammation in this category of patients.