EVALUATION OF CLINICAL RESPONSE AND LEPTIN LEVEL AT THE PATIENTS WITH KNEE OSTHEOARTHRITIS TREATED WITH MUD

IONESCU Elena Valentina MD, Prof. SUTA Maria MD, PhD, Assoc. Prof. PETCU Lucian, PhD

1. Ovidius University Constanta, Romania. 2. Balneal and Rehabilitation Sanatorium Techirghiol Drd. Elena-Valentina Ionescu Balneal and Rehabilitation Sanatorium Techirghiol 34-40 Victor Climescu Street Techirghiol, Constanta P.C. 906100 Tel. +40723166950 Fax +40241735705 E-mail: elena_valentina_ionescu@yahoo.com

ABSTRACT

It is well known that the pathogenic mechanism of osteoarthritis is still

incompletely understood. However, during its study, various risk factors have been identified. One of them is obesity, which plays an important role, both by its mechanical role, and through numerous biologically active substances that the fat tissue secretes. One of them is the leptin, that has gained valences in recent years, being increasingly important in this context. A group of patients suffering of knee osteoarthritis have been studied both in terms of clinical response quantified by visual analogous scale for pain and the serum level of leptin at the application of
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peloidotherapy. All patients were hospitalized in Balneal and Rehabilitation Sanatorium from Techirghiol for a period of two weeks. At all patients were evaluated clinical response and serum level at leptin after natural treatment with sapropelic mud. During this period, significant decreases were registered for both parameters. Key words: knee osteoarthritis, visual analogous scale for pain, leptin, peloidotherapy.

INTRODUCTION
Osteoarthritis is characterized by a progressive loss of articular cartilage accompanied by new bone formation and synovial proliferation that may culminate in pain, loss of joint function, and disability. A variety of etiologic risk factors and pathophysiologic processes contribute to the progression of the disease and serve as targets of behavioral and pharmacologic interventions. Knee osteoarthritis represents the most frequent localization of arthritis and the most common arthropathy arthritis of the knee, representing over 50% of the causes of knee pain [1]. One of the proven risk factors is obesity in knee osteoarthritis. Numerous studies demonstrate the association between body weight and symptoms, systemic inflammation and cartilage turnover of the knee [2,3]. WAT (white adipose tissue) has been found to produce cytokines and other molecules (leptin, adiponectin, rezistin, visfatin, etc), but the study of their role is yet in early stages [4]. Several adipokines like leptin and adiponectin are reported to be responsable for inflammation and cartilage degradation in osteoarthritis associated with obesity or cardiovascular conditions [5]. The theory that WAT may be an active factor in whole body homeostasis rather than just a fat deposit became eligible in 1994 with the discovery of leptin [6]. Since then, there have been discovered more than 50 adipocytokines, and more and more new adipokines are being discovered, like chemerin, lipocalin 2 or serum amyloid A3 [7]. Moreover, a recent study attempted to determine the role of infra patellar fat pad and subcutaneous adipose tissue of the knee, revealing that soluble mediators derived from infra patellar fat pad could contribute to pathophysiological processes in the osteoarthritis knee joint [8]

Leptin is a 16 kDa non-glycosylated peptide hormone belonging to the class I cytokine super-family. It is mainly produced by adipocytes, and leptin levels are directly correlated with WAT mass. In osteoarthritis, leptin production is higher in osteoarthritic human cartilage than in normal cartilage. Major effects of leptin on the immune system and in the vascular system are: acts proinflammatory, increases in T-cell activation and cytokine release proliferation, promotes Th1 response, increases NK cell activation, releases macrophage activation and cytokine (TNF-, IL6, etc)[9,10], induces endothelial dysfunction, increases blood pressure.[11] Thermal mud is a therapeutic agent widely used in the treatment of arthritic processes. The therapy with mud has remained mysterious, unknown and full of surprises even today, although it has been used with therapeutic purposes since ancient time. The purpose of this study is to determine if sapropelic mud from Techirghiol could influence the evolution of knee osteoarthrosis.

MATERIAL AND METHODS:

The core aim of this study is first to evaluate the benefits of rehabilitation using visual analogous scale for pain and the secondly, to evaluate serum level of leptin using peloidotherapy after 10 procedures of mud applications in knee osteoarthritis. We use as material: sapropelic mud (as hot mud baths heated to 38 degrees) and mineral water of Techirghiol lake (heated to 35 degrees), all devices which are needed in a specific hydro-thermotherapy, electrotherapy, kinetotherapy and massage, blood samples, specific kits for the determination of human leptin using Elisa technique and program SPSS 12.0 for statistical analysis.

The object of the study was a group of patients between 40 and 80 years old, diagnotized with knee osteoarthritis, who signed the consent forms for being part of this study and who were hospitalized in march 2010 in Balneal and Rehabilitation Sanatorium from Techirghiol. Inclusion criteria is knee osteoarthritis diagnosed according to ARA criteria Exclusion criteria are: blood sedimentation rate >40 Age between 40-80 dermatological diseases (chronic or acute), including skin integrity damaged cardiovascular, respiratory, digestive, neurological, nefrological sever diseases. cancers presence of inflamatory disease steroidian and nonsteroidian antiinflamatory treatmentat at least 4 weeks before the admision in this study. arthroplasty, arthroscopic surgery at least 3 mounth before study intra/periarthicular administration of corticosteroids solutions at least 6 weeks before study or hyaluronic solution at least 6 mounth before. opioid treatement at least 4 weeks before phisiotherapy, acupuncture, Trans-cutaneous electrical nerve stimulation, massage, kinetotherapy at least 4 weeks before sedative, hypnotics, anticonvulsant, muscle relaxant treatment at least 2 weeks ago.

The blood samples were harvested from 36 patients in the first day, before they started therapy, but 4 patients were excluded because they presented a higher value of blood sedimentation rate (VSH) than 40. This was not revealed at the initial examination, therefore only 32 patients were included in this study. During the second examination, after 10 days of treatment, none of the patients was withdrawn from the study.

The study batch was submitted to 10 sessions of mud baths, electrotherapy (3-4 different types/day), massage (1 session/day) and kinetotherapy (1 session/day). A Visual Analogue Scale for pain (VAS) is a measurement instrument that tries to measure level of pain and cannot easily be directly measured. Operationally, VAS is usually a horizontal line, 10 cm in length, marked with value from 1 to 10 (1 represents no pain and 10 represents very severe pain).The patient marks on the line the point that they feel represents their perception of their pain. Patients filled in the appreciation form of pain level (visual analogous scale for pain) both in the first day and after 10 days of treatment. Also, the blood samples were taken from all patients before they started balneotherapy and at the end of the cure.

RESULTS After analyzing the data obtained on the study lot, the values were introduced in tables and then statistically analyzed and processed. In the end all the data gathered is presented as graphical representation. Demographic characteristics of the lot align existing data in literature, even if its small, from a total of 32 patients, 9 were men and 23 woman (table I)
Cumulative Percent 28.1 100.0

Frequency Valid Male Female Total 9 23 32

Percent 28.1 71.9 100.0

Valid Percent 28.1 71.9 100.0

Table I-Sex distribution

Figure 1 shows that patients varied between 40 and 80 years, and the distribution by age group reveals a largest number of patients included (18 patients), which is in the range of 50-60 years old. 5

20

15

10
Frequency

18

5
8 4 2

0 (40-50] (50-60] (60-70] (70-80]

age

Fig.1-Age distribution

I considered VAS 1 the value of pain which was recognized by the patient at the initial moment ( first day of study, before balneophysical therapy) and VAS 10 the value of pain registered after ten days of treatment. The results for VAS 1, can be found in the following figure (fig.2), according to each parameter taken into consideration. From the total of 32 patients, 2 of them gave the value 2, 1 the value 4, 12 the value 5, 4 the value 6, 6 the value 7, 5 the value 8, 1 the value 9 and 1 the value 10.

12 10 8 6
Frequency

12

4
6

2
2

4 1

0 2

10

VAS 1

Fig.2-VAS 1

After 10 days of treatment, VAS values were: 2 patients gave value 1, 5 patients value 2, 7 patients value 3, 3 patients value 4, 6 patients value 5, 3 patients value 6, 3 patients value 7 2 patients value 8 and 1 patient value 9. As you can see none of the patients gave value 10 after the treatment.( fig.3)

7 6 5 4
7

3
Frequency

6 5 3 3 3 2 1

2 1 0 1 2 3 4 5 6 7 8 9
2

VAS 10

Fig. 3- VAS 10

Applying the normality tests, we discovered that that for VAS1, p value is 0.033, and for VAS 10 is 0045. In both cases p <0.05, therefore the assumption of normality of distribution is not accepted .( Table II)

Kolmogorov-Smirnov(a) Statistic VAS 1 VAS 10 .188 .172 df 32 32 Sig. .005 .018 Statistic .927 .949

Shapiro-Wilk df 32 32 Sig. .033 .045

a Lilliefors Significance Correction Table II- Tests of Normality

Because the condition of normality is not satisfied, we will make use of nonparametric Wilcoxon test for dependent samples (pairs) in order to find out if there are any significant differences between average values of VAS measured at times 1 and 10. (Table III, IV)
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N VAS 1 VAS 10 32 32

Mean 6.02 4.34

Std. Deviation 1.762 2.149

Minimum 2 1

Maximum 10 9

Table III- Descriptive Statistics

N VAS 10 VAS 1 Negative Ranks Positive Ranks Ties Total 22(a) 3(b) 7(c) 32

Mean Rank 14.16 4.50

Sum of Ranks 311.50 13.50

a VAS 10 < VAS1 b VAS10 > VAS1 c VAS10 = VAS1 Table IV- Wilcoxon Signed Ranks Test

For the visual analogous scale for pain (VAS), negative rank differences reveal that, in this case, the average value on VAS scale at the study batch has decreased compared to the initial moment. (VAS 10 < VAS 1; M10 = 4.34 < M1 = 6.02). (fig.4)

p = 0.001 < = 0.05 Fig. 4- VAS-scale decreased the average value from baseline

Regarding serum levels of leptin, I considered leptin1 the value which is taken before the start of treatment and leptin 10 as being the value after 10 days of treatment. Applying the normality tests, it is revealed that that for leptin 1, p value is 0.006, and for Leptin 10 is 0003. In both cases p <0.05 , therefore the assumption of normality of distribution is not accepted.( Table V)

Kolmogorov-Smirnov(a) Statistic Leptin1 Leptin 10 .185 .123 df 32 32 Sig. .007 .200(*) Statistic .899 .889

Shapiro-Wilk df 32 32 Sig. .006 .003

* This is a lower bound of the true significance. a Lilliefors Significance Correction Table V- Tests of Normality

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Because the condition of normality is not satisfied, we will make use of nonparametric Wilcoxon test for dependent samples (pairs) in order to find out if there are any significant differences between average values of leptin measured at times 1 and 10. A significant decrease of plasma leptin levels has been found at the experimental group after 10 sessions of mud baths. Negative rank differences reveal that, in this case, the average value of leptin has decreased compared to the initial moment. (Leptin 10 < Leptin 1; M10 = 24.98, M1 = 30.1)(fig.5)

p = 0.008 < = 0.05 Fig.5- Leptin decreased the average value from baseline

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DISCUTIONS

Following the results we have obtained after 10 days of complete balneophysical treatment, the level of pain described by the patients has decreased, this fact being statistically relevant. Considering the fact that the patients were treated only with sapropelic mud, electro therapy massage and kinetotherapy, and none of them received anti- inflammatory or painkiller and Rehabilitation medication, it is certified that the natural treatment provided in Balneal sapropelic mud from Techirghiol has proven its therapeutic value. Researchers demonstrated that leptin is involved in the pathogenic mechanism of knee osteoarthritis, due to its pro inflammatory action; this discovery confirms the significant role that leptin has in the pathogenic mechanism of knee osteoarthritis. According to these studies,a low level of leptin decreases inflammation and therefore pain.

Sanatorium Techirghiol is very efficient in knee osteoarthritis management. Once again, the

CONCLUSIONS

The complex balneo-physical treatment from Techirghiol Sanatorium is considered to be relevant in the evolution of knee osteoarthritis, rising the quality of patients life. This is achieved by decreasing inflammation, protecting articular cartilage. Also, removal / reduction of pain and inflammatory pathophysiological is related to mud bath, as well as improvement of joint function and reduced muscle and prevention / correction side. The data suggests that mud bath therapy influences also adipokines. This may reveal the fact that they have a role in osteoarthrosis pathomechanism, and encourage further investigation in order to evaluate mud bath therapy. Even if the study is limited by a small number of patients, it can be stated that adipokines will soon be pivotal to pharmacotherapeutic approaches to obesity-induced inflammatory diseases.

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