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МЕДИЦИНСКИЕ НАУКИ
616.72-007.24-092.19-008.9-08-053
Voloshyna L.O.
к. med.n., associate professor of internal medicine HSEI «Bukovinian State Medical University», Chernivtsi, Ukraine
Smiyan S.I.
d. med.n., professor, department of internal medicine №2 SHEI «Ternopil State Medical University I.Ya. Gorbachevskogo» Ternopil, Ukraine
Doholich O.I.
assistant at department of propedeutics of internal medicine HSEI «Bukovinian State Medical University», Chernivtsi, Ukraine
EVOLUTION OF VALUES OF THE GROWTH TRANSFORMING FACTOR BETA-1 AND INFLAMMATORY MARKERS IN PATIENTS WITH OSTEOARTHRITIS DEPENDING ON THE
AGE COMORBIDITY AND TREATMENT
Abstract
Objective - To study age aspects of comorbidity in patients with OA and evolution of TGF-Ы values and inflammatory markers in the course of three-month standard treatment.
Material and methods. Clinical observations were conducted in 90 patients aged 37-76 with OA at the first-third radiographic stage by Kellgren-Lawrence (K-L). Methods: clinical, immune-enzyme, biochemical, instrumental.
Results. It has been established that patients with OA aged under 50 had the I—II degree oligoostearthritis by K-L, 2-3 comorbid diseases with moderate manifestations. In patients aged 51-60 the manifestations of ОА became systemic and moderate, there were 4-5 age comorbid diseases in more than two systems. After 60 years the manifestations were more systemic and severe, the patients had the second, mainly the third radiographic stage by K-L, there were 6-8 comorbid diseases which were dominated by cardiovascular and metabolic diseases.
In all age groups of patients we noted a progressive increase of TGF-Ы and markers of inflammation which was characterized by a good reversibility in the treatment of OA patients aged under 50 years and progressive deterioration of reversibility of investigated parameters with age growing signs of OA and comorbid processes, especially in patients over 60 years. The most negative impact on the signs of torpidity of reverse changes was observed in the comorbid second and third degree obesity, diabetes type 2, and the third radiographic stage of OA by K-L.
Conclusions. In patients suffering from OA the changes in their joints become more systemic and pronounced with age as well as the number and severity of comorbid diseases. These phenomena are accompanied by a progressive increase in TGF-Ы levels and those of inflammatory markers, characterized by an increasing resistance to reversibility of changes during the treatment.
Key words: osteoarthritis, comorbidity, transforming growth factor - beta1, inflammatory markers, treatment.
Topicality. Comorbidity is recognized as one of the key problems of modern medicine [1, 4, 7]. Osteoarthritis (OA) is the most common age-dependent progressive joint disease of mainly degenerative-dystrophic nature and with an inflammatory component that significantly affects the quality of life of patients and causes major financial expenditure for the state [2]. This disease is characterized by one of the highest rates of comorbidity [2, 7]. Most of comorbid diseases in patients with OA are also characterized by low levels of non-specific inflammatory processes implemented primarily through the cytokine link of regulation [9]. At different stages of OA and comorbid processes the imbalance of pro- and anti-inflammatory cytokines in such situations have different degrees of severity and reversibility during the treatment, which has not been sufficiently investigated at the current stage [2, 9].
Among the cytokines the transforming growth factor B (TGF-fi:) is the main polyfunctional growth factor which regulates cellular proliferation and differen-
tiation, processes of tissue repair, including the articular cartilage, it is a key factor of regulation and remodeling the extracellular matrix, production and degradation of connective tissue; it is also an inhibitor of pro-inflammatory cytokines and regulates the migration of leukocytes to the inflammation nidus [3, 5, 6, 8, 10, 11].
In this context, a study of changes in TGF-B parameters during the treatment of patients suffering from OA with different levels of age-related comorbid processes is considered important.
Objective. To study age aspects of comorbidity in patients with OA and evolution of TGF-B1 values and inflammatory markers in the course of three-month standard treatment.
Materials and methods. Clinical observation was conducted in 90 patients with OA at the first-third radiographic stage by Kellgren-Lawrence (K-L) in the period of acute attacks. Age range of patients was within 37-76 years, the dominant contingent were women (71 individuals constituting 78.90%), duration of OA - 319 years. The diagnosis of OA was made by EULAR
y
criteria [14], that of comorbid diseases was made according to the recommendations of leading European professional associations and confirmed by appropriate specialists. OA patients received standard treatments: nonsteroid anti-inflamatory drugs (NSAIDs), chondroprotectors, gastroprotectors, a local treatment on the joints and, by the recommendations on comorbid processes, antihypertensive, anti-ischemic, antioxidant, antidiabetic (if necessary) as well as lipid-lowering agents. The studies were approved by the local committee on bioethics. All the patients gave an informed consent to participate in the study.
The levels of TGF-M in the blood were studied using solid-phase ELISA (sets by Bender MedSystems, Austria) according to the manufacturer's instructions on
According to Table 1 one can see that in the age group of 50 years there was a minimum level of comorbid diseases (2-3 disease with moderate or minimal symptoms, and in 4 out of 17 patients comorbid processes were not found). Clinically OA manifest itself by lesions in 1-2 groups of articulations (oligo osteoarthritis of radiographic stages I-II by K-L). In the age group 51-60 years 4-5 comorbid diseases in two or more body systems with more pronounced symptoms were stated. OA in them was manifested by greater regularity (mainly polyosteoarthritis of the second, less frequently the third radiographic stages). In the patients with OA aged over 60 years there were as many as 6-8 comorbid diseases, most of them had more pronounced symptoms, OA manifested itself by
the analyzer «StatFax 300" (USA). We also studied inflammatory markers in the blood - C-reactive protein (CRP), fibrinogen and peripheral blood indices by means of conventional methods. The patients were examined at the time of hospitalization, after one and three months of treatment.
To compare the studied blood parameters, we examined 30 practically healthy volunteers (Healthy Volunteers) (HV) of representative age and sex.
The materials were processed statistically using the application package «Microsoft Excel", version 7.
Results. Age features of comorbid processes in patients with OA were studied by dividing the contingent into three age groups: under 50 years, 51-60 years and over 60 years. Materials are presented in Table 1.
Table 1
polyosteoarthritis but it was mainly that of the third, less frequently of the second radiographic stage by KL. Clinical manifestations and a course of OA at the age under 50 years were mild, after 50, especially 60 years they were moderate ones with a clear tendency to progression. All groups of patients experienced dominated lesions in supporting joints, as to the comorbid diseases, they were progressive with age cardiovascular disease and those of metabolic nature (obesity, diabetes).
In the context of the identified age features of comorbid processes and development of OA in the dinamics of treatment we studied the changes in TGF-M level and that of inflammatory markers (Table 2).
Age features of poly- and comorbid diseases in patients with osteoarthrosis (n, %)
Nosology Age group 50 years n=17 Age group 51-60 years n=32 Age group over 60 years n=41
Without comorbid diseases 4 (23,53%) - -
I degree arterial hypertension 5 (29,41%) 3 (9,37%) 2 (4,88%)
II degree arterial hypertension - 14 (43,75%) 31 (75,61%)
IHD, moderate forms - 4 (12,5%) 10 (24,39%)
IHD, severe forms ( with heart failure or arrhythmia) - - 4 (9,76%)
I degree obesity 3 (17,65%) 6 (18,75%) 3 (7,32%)
II-III degree obesity - 9 (28,12%) 28 (68,29%)
Diabetes mellitus type 2 - 2 (6,25%) 8 (19,51%)
Steatohepatosis - 11 (34,37%) 29 (70,73%)
Cerebral forms of the I-II degree atherosclerosis - 3 (9,37%) 6 (14,63%)
Gastritises, duodenitises 8 (47,06%) 18 (56,25%) 25 (60,97%)
Cholecystitises 7 (41,18%) 20 (62,50%) 30 (73,17%)
Pancreatitises - 7 (21,87%) 11 (26,83%)
Enterocolonopathies - 6 (18,75%) 15 (36,58%)
Notes: IHD - ishemic heart disease
Notes:
*- reliability of the difference between the values in the group compared to those in HV is (p<0,05-0,001); ** - reliability of the difference between the values in the group before and after one month treatment is (p<0,05);
# - reliability of the difference between the values before and after a three-month treatment is (p<0,05-0,01); nr - the difference between values before and after the treatment is not reliable;
• - reliability of the difference between the values in the group of patients < 50 years.
Table 2.
Evolution of levels of the transforming growth factor ß1 and inflammatory markers in the blood of pa_tients with OA depending on age comorbidity and treatment during 1-3 months_
Parameters under study TGF-ßi ng/ml CRP mg/l Fibrinogen, g/l Blood leucocytes, x _ C /1 ESR, mm/h
Practically healthy individuals, n=30 (Healthy Volunteers) 31,6±3,25 2,8±0,22 3,4±0,28 6,4±0,33 7,2±0,43
<50 years, minimal comorbidity, n=17 Before treatment 39,56±2,26* 6,4±0,48* 4,1±0,36 7,3±0,36* 8,4±0,36
After treatment After 1 month 35,24±2,54 nr 4,03±0,26*# 3,8±0,32 6,2±0,48 7,6±0,74
After 3 months 32,1±2,14# 3,1±0,28# 3,5±0,22 nr 6,4±0,52 6,6±0,36
51-60 years, moderate comorbidity, n=32 Before treatment 45,8±3,12* 8,8±0,56* 4,7±0,34* 9,4±0,42*^ 16,6±1,14^
After treatment After 1 month 40,64±3,32 nr 7,2±0,43*# 4,3±0,32* 7,2±0,64** 10,8±1,16*/**
After 3 months 38,6±2,5 nr 5,1±0,32*# 3,8±0,28# 6,8±0,38# 8,6±0,62# •
>60 years, severe comorbidity, n=41 Before treatment 49,83±3,81*^ 10,2±0,62*^ 5,2±0,37* 11,24±0,82*^ 18,4±0,94*^
After treatment After 1 month 44,2±3,32*та 8,4±0,46*^nr 4,8±0,34* 8,2±0,78** 14,2±0,66*/**^
After 3 months 40,8±3,14*та 6,2±0,41*-# 4,1±0,32# 7,1±0,43# 10,4±0,62№
On analysing the data obtained in the age groups (see Table. 2) it was found that patients with OA at the age of 50 years had a significant increase in levels of TGF-M and CRP during exacerbations, but indicators of fibrinogen, leukocytes in peripheral blood and erythrocyte sedimentation rate (ESR) were within the reference values. Within one month of treatment the level of TGF-M showed a clear tendency to improve, and after three months the decline was reliable and its figure was not different from that in HV. CRP dynamics was more demonstrative and it correlated better with the clinical picture of OA: after one month the decline was reliable, although the CRP level was still elevated compared to the HV.
In the age group of patients aged 51-60 years suffering from OA, TGF-M was unreliably higher than in patients under 50 years, it was reliably higher than in HV, the downward trend was sluggish both after one and after three months of treatment. However, CRP levels significantly decreased as early as after one month of treatment and continued to decline, although in the third month of treatment it was reliably higher than in HV. In this age group we also noted a reliable increase of fibrinogen with a torpid tendency to decrease during the treatment. A similar trend was found regarding the dynamics of peripheral blood leukocytes on ESR.
In patients with OA over 60 years TGF-fi 1 was reliably increased, even relatively to the group of patients under 50 years in all stages of the research. Its dynamics to reversibility was worse than in the patients from the
age group 51-60 years. The increase of CRP and fibrinogen was more significant, but their dynamics to reversibility was better than TGF-M and three months after the treatment it was reliably better than before the treatment. The same feature was noted in the dynamics of leukocytes and ESR levels in the blood (see. Table 2).
It should be noted that the dynamics of CRP, fibrinogen, white blood cells and ESR rates reflected clinical regression of OA symptoms better than the dynamics of TGF-M in all groups of observation. Individual analysis of TGF-M parameters in patients with various manifestations of comorbid processes showed that they were the highest and with a very low reversibility during the treatment in patients with the second and third degree obesity, the second degree arterial hypertension (AH), with diabetes mellitus (DM) as well as with the third radiographic stage of changes in the joints and osteophytosis.
Discussion. The research showed that the level of TGF-M can not be considered as a reliable marker of OA or its progression. This opinion was expressed by A.E. Nelson et al [12]. Patients with OA and numerous age-related comorbid processes may have other sources of its origin. It is known that this factor can be produced by megacaryocytes, platelets, monocytes, endothelial cells, fibroblasts, Kupffer cells, and also can be of arthrogenous origin [3, 8]. However, increasing TGF-M in OA is considered to be appropriate, since it prevents the articular cartilage from destruction and contributes to its restoration, though showing side
у
effects, such as formation of osteophytes and fibrosis in other joint structures [6, 10]. Therefore, in the last decade, a considerable attention has been paid to a creation and intraarticular injection of medications, especially those with blood platelets and with enriched content of TGF-B1. [5, 11, 15].
The increase in TGF-B1 and torpidity to its reversibility during the treatment of OA patients against the background of comorbid diseases is one of the evidences of their pathophysiological interdependence [13]. Playing multifaceted and multifunctional regulatory role in maintaining protective processes from the cell to tissue and organ levels with the simultaneous multiple pathological processes, its level should probably be increased to varying degrees. As for the arthritic joint damage the feasibility of raising TGF-B1 level regarding repair of cartilage structures is more important than future delayed formation of osteophytes which has not acquired a sufficient evidence [11]. Researching the evolution of TGF-B1 parameters during the treatment of OA against the background of comorbid processes combined with routine markers of inflammation helps to understand better the pathophysiological essence of their interdependence, predictive value of each of them and their importance as criteria for evaluating the effectiveness of treatment.
Conclusions:
1. Age progression of osteoarthritis in patients is accompanied by adding age comorbid diseases, mainly of cardiovascular system and metabolism which also tend to progress.
2. With the progression of osteoarthritis and age comorbid processes, in the blood of such patients there is a gradual increase of TGF-fi: and inflammatory markers rates which is characterized by their worse reversibility in the course of a long treatment, proportional intensity of the symptoms of osteoarthritis and comorbid processes.
3. Severe metabolic diseases such as the II and III degree obesity, type 2 diabetes as well as OA (polyosteoarthritis) of the third radiographic stage are characterized by the most pronounced negative impact on the reversibility of dynamics of TGF-B1 and inflammatory markers rates during the treatment and might be markers of unfavorable foreseen trends.
Prospects for further research may be in the direction of studying the impact of new generations of phytochondroprotective and anti-inflammatory drugs on the results of treatment of patients with OA, including signs of disorders in the production of TGF-Ы and markers of inflammation.
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