Femoral cartilage thickness in patients with systemic sclerosis: It’s relation to vitamin D

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease of unknown etiology characterized by multiorgan involvement, autoimmune heterogeneous clinical manifestations representing widespread vascular injury and progressive fi brosis of the skin and internal organs [1-3] .The incidence of SSc is about 20 cases per million populations per year and the prevalence is more than 250 patients per million populations in USA [4]. Major organ involvement leads to decreased survival in SSc, however, cardiopulmonary complications being the most frequent causes of disease related death. However, patients with SSc live longer and cardiac deaths are increasing [5]. In the last two decades, the survival of patients with systemic sclerosis (SSc) has signifi cantly improved [6,7]. Nevertheless, SSc can still cause increased disability and reduced quality of life. Hand, tendon and joint involvement are other factors which can cause signifi cant functional disability, leading to consequent disuse and worsening of bone loss in patients with SSc, contributing to a signifi cant impairment in the quality of life of these patients [8-10].


Introduction
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease of unknown etiology characterized by multiorgan involvement, autoimmune heterogeneous clinical manifestations representing widespread vascular injury and progressive fi brosis of the skin and internal organs [1][2][3] .The incidence of SSc is about 20 cases per million populations per year and the prevalence is more than 250 patients per million populations in USA [4]. Major organ involvement leads to decreased survival in SSc, however, cardiopulmonary complications being the most frequent causes of disease related death. However, patients with SSc live longer and cardiac deaths are increasing [5]. In the last two decades, the survival of patients with systemic sclerosis (SSc) has signifi cantly improved [6,7]. Nevertheless, SSc can still cause increased disability and reduced quality of life. Hand, tendon and joint involvement are other factors which can cause signifi cant functional disability, leading to consequent disuse and worsening of bone loss in patients with SSc, contributing to a signifi cant impairment in the quality of life of these patients [8][9][10].
American College of Rheumatology (ACR)/EULAR, 2013 developed a classifi cation criteria assumed to improve sensitivity, which would lead to earlier diagnosis, and it also incorporates the autoantibodies that are commonly used for diagnostic purposes [11]. Vitamin D have been the focus of a growing number of studies in past years, demonstrating their function not only in calcium metabolism and bone formation, but also their interaction with the immune system since vitamin D receptors are expressed in different tissues. Numerous studies have been conducted to study whether vitamin D is Abstract Background: Systemic sclerosis (SSc) is a chronic autoimmune progressive connective tissue disease characterized by widespread vascular, immune and fi brotic changes of the skin and internal organs. Articular cartilage thickness previously investigated in few. Lower levels of vitamin D have been demonstrated in SSc patients and may be related to more sever disease of longer duration and extensive skin involvement. Aim of this study was to compare the levels of vitamin D and femoral cartilage thickness (FCT) in SSc patients with that of controls and to analyze the associations between the (FCT), vitamin D levels and SSc-disease parameters.

Material and Methods:
Twenty fi ve SSc patients diagnosed according to ACR/EULAR-2013 classifi cation criteria and twenty fi ve controls; apparently healthy age and sex matched were studied. Serum levels of 25-hydroxyvitamin D (25[OH] D) were assessed by (ELISA), levels less than ≤ 10ng/ mL are defi ned as defi ciency, while > 10 ng/mL is defi ned as insuffi ciency. The thickness of femoral articular cartilage was measured by ultrasonography (MSU) in patients and controls. Three midpoint measurements were taken from each knee: lateral femoral condyle (LFC), femoral intercondylar area (ICA) and medial femoral condyle (MFC).

Result:
We concluded that SSc patients seem to have thinner femoral cartilage values at all studied sites than that of control. A signifi cant difference was found in measurement of right inter condylar area (p=0.029), right medial condyles (p=0.022), left inter condylar area (p=0.036), left lateral condyle and left medial condyle (p=0.001) between patients and control. Lower levels of vitamin D was signifi cantly found in SSc patients than controls, predominantly among females (p= 0.009) with longer disease duration (p= 0.03) and sever skin involvement (p= 0.0001). Vitamin D was correlated with SSc severity scale as well as thinner femoral cartilage sites studied by MSU, while some sites shown correlation with disease activity parameters. associated with SSc; however, they produced varying results. [12][13][14][15][16][17][18][19][20]. Vitamin D defi ciency has been documented in 80% of SSc patients. Low vitamin D levels in SSc patients are universal and independent of geographic origin or vitamin D supplementation [21,22]. Poor vitamin D status in SSc patients seems to be related to disseminated skin involvement and renal injury that may interfere with vitamin D synthesis. Also, Gastrointestinal involvement and malabsorption of dietary vitamin D in advanced intestinal disease are responsible for low levels of vitamin D [23,24]. Moreover, patients with SSc experience impairment in physical functioning and they are prone to a sedentary lifestyle and diminished sunlight exposure [25].
The association between SSc patients and vitamin D levels might also be explained by the hypothesis that low vitamin D level directly increases the risk of autoimmune disease. Vitamin D has been substantiated to have an antifi brotic effect on fi broblasts, inhibit synthesis of the extracellular matrix and regulate the skin's immune system [26]. Furthermore; vitamin D can increase the activity of anti-inflammatory mediators and decrease the expression of proinflammatory cytokines [27]. Cartilage thinning may occur in Systemic Sclerosis. Vitamin D defi ciency may change the balance of cartilage metabolism via reducing the synthesis of proteoglycan and/or increasing the metalloproteinase activity, leading to cartilage loss [28,29]. The serum human cartilage glycoprotein (HC gp-39), cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase (MMP) levels were found to be elevated in patients with SSc [30]. We aimed to study levels of vitamin D in relation to the femoral cartilage thickness (FCT) in patients with SSc comparing that with controls that were matched for age and sex and to analyze the associations between the (FCT), vitamin D levels, SSc-disease activity and severity scores.

Materials and Methods
Twenty -fi ve SSc patients (25) diagnosed according to the ACR/EULAR-2013 classifi cation criteria for SSc [11], were recruited from attendee of Rheumatology & Rehabilitation Department, Minia University hospital, Egypt; in the period of Nov., 2015 to August, 2016 and enrolled in this cross-sectional study. Excluded patients who known to have other connective tissue diseases overlap, juvenile scleroderma, localized subtype scleroderma and known metabolic diseases. Twenty-fi ve (25); apparently healthy age and sex matched volunteers were included as controls from the same population. Patients' oral and written consent was obtained and the study was approved by a local ethical committee. All subjects (patients and control) had a thorough history taking and clinical examination. Data concerning Vitamin D were reported {sun time exposure, area to be exposed to sun with approximate duration, skin tone and diet}. Assessment of disease severity was evaluated in Ssc patients according to Medsger Disease Severity Index (MDSI) [31], who defi ned severity as the total effect of the disease on organ function. Scales were developed from 0 (no documented involvement) to 4 (end stage disease) for each organ system: general (weight loss in kg), peripheral vascular (digital vascular ischemia), skin (mRSS), joint/tendon, muscle (weakness), gastrointestinal tract, lung, heart, and kidney. We considered a severe disease when the MDSI was superior to 3, according to previous studies. Modifi ed Rodnan skin score (mRSS) was used to determine the extension of the skin involvement, classifying 17 anatomical sites from 0 (no skin involvement) to 3 (severe skin involvement), with maximal score of 51 [32].

Statistical analysis
Analysis of data was completed using SPSS (Statistical program for social science) version 16. Data were expressed as mean±SD for parametric variables and as number and percent for non-parametric variable. Comparison between groups for parametric data was done by unpaired t-test and for nonparametric variables by Mann-Whitney U test. Chi-square (X2) test was used to compare qualitative variables. Spearman's test was used for correlation of non-parametric variables.

Results
Of the twenty-fi ve SSc patients enrolled, women were more prevalent in frequency, represented in 22(88%) and men in only 3(12%

Discussion
Defi cient 25(OH) D serum concentrations were below 10 ng/ ml in 36% and insuffi cient level >10 ng/ml in 64% of the studied SSc patients with no signifi cant difference of limited versus diffuse types. Additionally, vitamin D inversely correlated with SSc-disease severity scales (p=0.03, r=-0.428), Patients with high disease severity state and diffuse skin affection have low serum vitamin D level. Lower signifi cant levels of vitamin D 25(OH) D levels were found among SSc patients than that of the controls (p= 0.007). Similarly, a meta-analysis study of Vitamin D levels in systemic sclerosis patients concluded that, SSc patients exhibited lower vitamin D levels compared with healthy controls. Vitamin D levels of diffused-type SSc patients were signifi cantly lower than those in limited type SSc patients. Unlike us, the severity of clinical features was not associated with the extent of vitamin D defi cit. They hypothesized that SSc patients, especially diffused type, have lower vitamin D levels and that the decrease of vitamin D levels might not be an accelerating factor of SSc severity [23].
In two previous studies for hypovitaminosis D at the same population, the fi rst clinically studied hypovitamoniosis D in Sixty female patients complaining of LBP lasting more than 3 months. Hypovitaminosis D (25 OHD < 40 ng/ml) was found in 49/60 patients (81%) and 12/20 (60%) of controls, with an odds ratio of 2.97. They postulated although many risk factors related to sun exposure, clothing, diet, and pregnancy were signifi cantly correlated with vitamin D levels in patients, only limited duration of sun exposure, contributing 55% to the variance of 25 OHD, limited areas of skin exposed (13%), and increased number of pregnancies (2%), were signifi cant determinants of vitamin D levels in those patients. It was concluded that, despite the sunny climate, hypovitaminosis D is prevalent among Egyptian women, the major determinant of hypovitaminosis D in their patients was limited sun exposure [36].
The second study had the same conclusion that, Hypovitaminosis D is prevalent in the Egyptian females 61.5%. The prevalence and determinants of hypovitaminosis D among Two hundred females aged from 17-76 years with a mean± SD of (38.