The Levels of Serum Serotonin Can Be Related to Skin and Pulmonary Manifestations of Systemic Sclerosis.

Background and Objective: The most prominent feature of systemic sclerosis (SSc), besides vasculopathy and autoimmune disorders, is excessive fibrosis. Serotonin affects hemostasis and can induce vasoconstriction, which is presumed to be one of the pathophysiological patterns in SSc that leads to fibrosis. Our aim was to explore the possible association of serotonin with some of the clinical features of SSc in our cohort of patients. Materials and Methods: We measured serotonin levels in sera of 29 female SSc patients. Patients were 41-79 years old, their average disease duration was 9 years. Serotonin values were analyzed in correlation with clinical and laboratory parameters, such as modified Rodnan skin score (mRSS), digital ulcers (DU), and spirometry parameters-forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and lung diffusion capacity of carbon monoxide (DLCO). Statistical analyses were performed using statistical software Statistica. Results: We found correlation of serotonin level with mRSS (r = 0.388, p = 0.038). The highest values of serotonin were documented in patients with refractory DU, but this was not statistically significant. We also found a negative correlation between serotonin and FVC (r = -0.397), although it did not reach the level of significance (p = 0.114). Conclusions: Our study suggests that levels of serum serotonin could affect the course of skin fibrosis and partially restrictive pulmonary dysfunction in patients with SSc. We assume that serotonin might have influence on several features of SSc, but more studies are needed to reveal those relations.

Extremely rare coincidence of non-radiographic axial spondyloarthropathy HLA-B27 positive and Stiff Person Syndrome--rheumatologist point of view.

Stiff Person Syndrome (SPS) is a rare autoimmune neurological disorder characterized by progressive stiffness and rigidity of truncal muscles accompanied with co-contraction of agonist-antagonist muscles. Our 51-year-old female patient was presented for the first time to physiatrists in 2006 and diagnosed with axial-spondyloarthropathy (SpA) HLA-B27 positive. SPS was diagnosed 7 years after initial symptoms. SPS should be taken into consideration in HLA-B27 positive patients if stiffness of paravertebral and abdominal muscles progresses during SpA therapy.

Relationship between interleukin-6 and cardiac involvement in systemic sclerosis.

OBJECTIVES: To explore the relationship between IL-6 levels and echocardiographic abnormalities, and N-terminal probrain natriuretic peptide (NT-proBNP) levels in SSc patients and to correlate tested parameters with European Scleroderma Activity (EUSTAR) score. METHODS: This case-control study included 31 SSc patients with preserved left ventricular ejection fraction (LVEF) and 32 matched healthy controls. Serum IL-6 and NT-proBNP levels were measured and subjects were evaluated by conventional and pulsed-wave tissue Doppler echocardiography. RESULTS: The level of IL-6 was significantly increased in patients with SSc (3.2 vs 2.2 pg/ml, P < 0.001). SSc patients had significantly lower values of LV systolic (7.7 vs 9.25 cm/s, P < 0.001) and early diastolic (8.7 vs 10.3 cm/s, P = 0.014) myocardial velocities and higher E/e' (9.04 vs 7.37, P = 0.001) ratio, although there was no between-group difference according to LVEF (68% vs 65%, P = 0.248). On evaluating the right ventricle there was no significant between-group difference in systolic tricuspid annular velocity (13 vs 13.9 cm/s, P = 0.105), but the peak early diastolic velocity was significantly lower (11.7 vs 13.6, P = 0.044) and E/e' was significantly higher (4.3 vs 3.38, P = 0.008) in SSc patients. IL-6 level showed correlation with LV mean e' (r = -0.57, P = 0.001), E/e' (r = 0.55, P = 0.001) and NT-proBNP (r = 0.52, P = 0.003). EUSTAR score correlated with LV E/e' (r = 0.48, P = 0.006), mean e' (r = -0.67, P < 0.001), mean s' (r = -0.51, P = 0.004), NT-proBNP (r = 0.60, P < 0.001) and IL-6 (r = 0.79, P < 0.001). CONCLUSION: IL-6 level is increased in patients with SSc and significantly correlates with LV diastolic dysfunction, NT-proBNP and EUSTAR score. These results support the role of IL-6 in the development of cardiac disease in SSc patients.

The Croatian Primary Sjögren's Disease Oral Health Study: Oral Status and Oral Health-Related Quality of Life.

To determine salivary flow rate, oral and periodontal status, oral health-related quality of life (OHRQoL), objective and subjective indexes, and serum antibody reactivity in patients with primary Sjögren's disease (pSD). Thirty-one patients with pSD and 31 control subjects participated in this cross-sectional, single-center study. The unstimulated whole salivary flow rate (UWSFR) and stimulated whole salivary flow rate (SWSFR), salivary pH, DMFT index (DMFT = D-decayed, M-missing, F-filled tooth), periodontal pocket depth (PPD), clinical attachment level (CAL), interincisal distance, OHRQoL, objective European League Against Rheumatism (EULAR) SS Disease Activity Index (ESSDAI) and subjective (EULAR SS Patient Reported Index (ESSPRI), 6-items-VAS-SS (Visual Analog Scale), Profile of Fatigue) indexes were analyzed. The patients with pSD had a blood sample taken in the morning between 7 and 10 a.m. for comprehensive laboratory analysis. Patients with pSD had statistically significant lower UWSFR (0.20 vs. 0.90 mL/min) and SWSFR (0.56 vs. 1.64 mL/min) values compared with control subjects (p < 0.001, Mann-Withney U test). Salivary pH value of pSD patients was significantly lower compared with control subjects (6.00 vs. 7.00; p < 0.001, Mann-Whitney U test). The mean DMFT index of patients with pSD compared to control subjects was not statistically significant (23.74 ± 7.28 vs. 20.77 ± 5.73; p = 0.08, t-test). Interincisal distance was significantly decreased in the pSD group compared with control subjects (43.80 ± 0.38 vs. 47.60 ± 0.50; p = 0.003, t-test). The prevalence of periodontitis was similar in patients with pSD and control subjects (83.9% vs. 77.4%; p = 0.35, λ2 test). The mean Oral Health Impact Profile (OHIP-49) total score was statistically significantly higher in pSD patients compared with control subjects (32.00 vs. 8.00; p < 0.001, Mann-Whitney U test). Patients with pSD have decreased salivary flow and salivary pH, poor oral health, decreased interincisal distance, high prevalence of periodontitis, and worse OHRQoL. These findings highlight the need for a multidisciplinary approach to the management of patients with pSD that includes physical and psychological aspects of the disease.

Association of inflammatory biomarkers and disease activity with subclinical myocardial dysfunction in psoriatic arthritis.

We examined the role of adipokines and pro-inflammatory cytokines in psoriatic arthritis-associated subclinical myocardial dysfunction, and the relationship between these variables and psoriatic arthritis (PsA) disease activity. Fifty-five PsA patients without cardiovascular risk factors and 25 controls underwent standard and speckle tracking echocardiography with global longitudinal strain (GLS) calculated. Standard anthropometric data and Disease Activity in Psoriatic arthritis (DAPSA) scores were recorded, with low disease activity defined as DAPSA ≤ 14 and moderate and high disease activity DAPSA > 14. Standard biochemical tests, adiponectin, resistin, leptin, tumor necrosis factor (TNF) alfa, interleukin 17 A (IL-17A), B lymphocyte chemoattractant (BLC), and monokine induced by intereferon gamma (MIG) were analyzed. Median age was 53.0 (46.0-61.0), median PsA duration 6.0 (4.0-13.0) years and median DAPSA score 25.5 (13.0-41.5). Lower GLS, tricuspid annular plane systolic excursion (TAPSE) and left ventricular ejection fraction (LVEF) were found in moderate and high PsA disease activity compared to low PsA disease activity and controls. PsA patients with GLS < 20 had higher body mass index (BMI), DAPSA score and uric acid levels, and lower adiponectin levels. Although patients with GLS < 20 had higher IL-17A levels, it was not statistically significant (P = 0.056). However, when we included healthy controls and analyzed differences based on a GLS cut-off of 20% in the entire population, the difference in IL-17A became statistically significant, 0.17 pg/mL (0.06-0.32) vs. 0.43 pg/mL (0.23-0.65), P = 0.017. The association between DAPSA score and GLS and IL-17 remained significant in multivariate analysis. Moreover, the association between GLS and IL-17 and adiponectin was significant after adjustment for age and BMI. Patients with moderate and high PsA disease activity have reduced myocardial function, lower adiponectin, and higher IL-17A levels.

Salivary Flow Rate and Oral Status in Patients with Primary Sjögren's Syndrome and Diffuse Cutaneous Systemic Sclerosis: A Cross-Sectional Study.

Determination of salivary flow rate and oral status in patients with primary Sjögren's Syndrome (pSS) and diffuse cutaneous systemic sclerosis (dcSSc) and comparison with control subjects. Thirty-one pSS patients, 28 dcSSc patients, and 28 control subjects participated in this single-center, cross-sectional study. Unstimulated whole salivary flow rate (UWSFR) and stimulated whole salivary flow rate (SWSFR), salivary pH, DMFT index (D-decayed, M-missing, F-filled tooth), periodontal pocket depth (PPD), clinical attachment level (CAL), interincisal distance, and OHRQoL (oral health-related quality of life) were analyzed in all three groups of subjects. Primary SS and dcSSc patients had statistically significant lower values of UWSFR (0.20; 0.38 vs. 0.91 mL/min) and SWSFR (0.56; 0.70 vs. 1.64 mL/min) compared with control subjects (p < 0.001, Kruskal-Wallis test). Salivary pH values were statistically significantly lower in pSS and dcSSc patients compared with control subjects (6.00; 6.25 vs. 7.00, respectively) (p < 0.001, Kruskal-Wallis test). The DMFT index of dcSSc patients was higher (28.50) and statistically significant compared to control subjects (20.00) (p = 0.01). The prevalence of periodontitis was the same in pSS and dcSSc patients and control subjects (p = 0.384). Primary SS and dcSSc patients had a statistically significant decreased interincisal distance compared to control subjects (43.80; 38.00 vs. 48.00) (p = 0.003 and p < 0.001, respectively). Primary SS and dcSSc patients show decreased UWSFR and SWSFR, salivary pH values closer to an acidic medium, higher DMFT index, higher prevalence of periodontitis, decreased interincisal distance, and poorer OHRQoL, i.e., poor oral and periodontal health.

Association of HLA-DRB1 alleles with rheumatoid arthritis in Split-Dalmatia County in southern Croatia.

OBJECTIVE: The aim of this study was to investigate the distribution of HLA-DRB1 alleles in patients with rheumatoid arthritis (RA) in the Sinj Region (SR) and the rest of the Split-Dalmatia County (SDC) in Croatia and to determine their relationship with disease severity. METHODS: A total of 74 RA patients and 80 healthy controls from the SR, and 74 RA patients and 80 healthy controls from the rest of the SDC were genotyped using sequence-specific oligonucleotide primed PCR. High-resolution typing of HLA-DRB1*04 alleles was performed using the single specific primed polymerase chain reaction (PCR-SSP) method. Serum anti-CCP, rheumatoid factor, C­reactive protein, and erythrocyte sedimentation rate were measured in all RA patients, whereas disease activity was assessed by DAS-28 and functional status by the Health Assessment Questionnaire Disability Index. RESULTS: The HLA-DRB1*04 allele was more frequent in patients with RA from the SR than that in patients from the rest of the SDC (18.2% vs. 9.5%; P = 0.014), whereas the HLA-DRB1*15 allele was more frequent in patients with RA from the rest of the SDC than in patients from the SR (16.2% vs. 7.4%; P = 0.010). Shared epitope (SE) positive patients from the SR had significantly higher serum anti-CCP and RF antibody levels (P = 0.014 and P = 0.004, respectively), higher disease activity (P = 0.043), and worse functional status (P < 0.001), than SE-positive patients from the rest of the SDC. CONCLUSION: The observed higher incidence of more severe forms of RA in the SR in comparison to the rest of the SDC might be associated with the higher incidence of HLA-DRB1*04 allele in the SR.

Are the anti-cyclic citrullinated peptide antibodies independent predictors of myocardial involvement in patients with active rheumatoid arthritis?

OBJECTIVES: The anti-CCP antibodies are specific serological markers of RA, especially the aggressive course of joint disease. It has been postulated that the chronic inflammatory state is underlain by cardiovascular (CV) disease and that a higher level of anti-CCP antibodies is implicated in CV risk. The aim of the study was to assess: (i) the possible impact of anti-CCP antibodies on left ventricular diastolic dysfunction; and (ii) the possible differences in the effects of DASs on diastolic dysfunction. METHODS: The study included 80 RA patients (70 females and 10 males) with no clinically evident CV disease, or concomitant diseases, and 80 matched healthy controls. Upon clinical and laboratory evaluation, all subjects underwent M-mode, two-dimensional and colour Doppler echocardiographic examination. RESULTS: Isovolumetric relaxation time (IVRT) prolongation as the first sign of diastolic dysfunction was present in 36.25% of RA patients and in 15% of control subjects. IVRT was found to correlate with anti-CCP antibody titre (r = 0.382, P = 0.002) and modified DAS including CRP [DAS-28-CRP(4v)] (r = 0.204, P = 0.039). On multivariate linear regression analysis, anti-CCP antibody titre showed significant correlation with IVRT, while the ratio of early and late transmitral wave (E/A ratio) independently correlated with age and DAS-28-CRP(4v). CONCLUSIONS: Anti-CCP antibody is an important marker, independently associated with impaired left ventricular relaxation and the DAS-28-CRP(4v) is a more sensitive predictor of cardiac involvement in the RA than the DAS-28 variant including the ESR.

Low dose intravenous immunoglobulin in addition to cyclophosphamide in systemic sclerosis : Single centre experience.

AIM: Systemic sclerosis (SSc) is a rare chronic disease characterized by pathologic collagen deposits in the skin and internal organs. Although it is considered to be an autoimmune disease, immunosuppressants have a limited effect on severe SSc. Intravenous immunoglobulins (IVIG) have shown favorable effects in patients with SSc by suppressing the action of profibrotic cytokines, so they could have additional effect on standard treatment such as cyclophosphamide (CYC). This article presents the immunomodulatory effect of low-dose IVIG in addition to CYC in the treatment of severe SSc in this center during the last 9 years. METHODS: This retrospective observational study analyzed the medical documentation of nine patients with SSc treated with low-dose IVIG (0.4 g/kg and month) together with intravenous CYC (600 mg/m2 and month). The therapeutic effect on lung and skin manifestations was assessed. RESULTS: Of the patients one had interstitial lung diseases (ILD), two had progressive skin diseases, and six had a combination of skin and lung involvement. The best results were achieved in skin changes, where complete healing of digital ulcers (DU) was recorded in every reported case. A decrease in the modified Rodnan skin score (mRSS) was noted in three patients and increased diffusion capacity of the lungs for carbon monoxide in another three patients. CONCLUSION: The results of the study suggest that IVIG may be an additional treatment option together with CYC for patients for whom other therapies have failed, but further studies on the exact role of IVIG in the treatment of severe SSc are required.

Dietary Habits in Patients with Systemic Lupus Erythematosus.

Patients with systemic lupus erythematosus (SLE) are often interested in which diets to follow. Our aim was to investigate which dietary habits were common among our patients, and which of them were in correlation with laboratory parameters of disease activity, such as complement values and 24-h proteinuria. This study included 76 patients with SLE in clinical remission with a 6-month flare free period. They completed a specialized, self-administered, 23-item food frequency questionnaire about their weekly dietary habits. Basic anthropometric data, levels of C3 and C4, and 24-h proteinuria were recorded and analyzed with respect to their dietary habits. The majority of patients had a normal body mass index of 18.5-25 kg/m2, and worked out regularly. The most frequently consumed foods reported by the patients were fruits, milk, vegetables, meat, pasta, rice, and bread. Decreased values of C3 were found in 34 (44.7%) patients, and decreased values of C4 in 28 (36.8%) patients. Decreased values of C3 were found in patients who often consumed meat (P = .015), and decreased values of C4 in patients who often consumed fast food (P = .043). Patients who often consumed fast food demonstrated a decreasing trend of C3 (P = .060), and patients who often consumed fried food had a decreasing trend of C4 (P = .051). Significant correlation between daily proteinuria and dietary habits was not found. Dietary habits can influence the disease course of SLE. Our study confirms that decreased levels of complement compounds C3 and C4, which are possible predictors of disease activation, are associated with frequent consumption of low quality proteins and food rich in calories.

Biomarkers of skin and lung fibrosis in systemic sclerosis.

Introduction: Excessive fibrosis is the hallmark of systemic sclerosis (SSc) and numerous experts are investing efforts into identifying parameters that could predict disease course and prognosis. Here, we review the available and potential biomarkers of lung and skin fibrosis in SSc.Areas covered: Specific autoantibodies are important for the determination of clinical subsets of SSc, making them routine in clinical practice. Physical parameters, such as modified Rodnan skin score (mRSS) and pulmonary function tests are standardized in evaluating the skin and lung involvement. High resolution computed tomography is the gold standard for SSc-related interstitial lung disease (ILD) diagnostics, as well as progress evaluation. Nowadays, the main focus is on specific autoantibodies, various genetic pathways, and different cytokines. In addition to the profibrotic role of interleukin 6 and transforming growth factor-ß, newer studies stress on glycoprotein Krebs von den Lungen-6 (KL-6), surfactant protein-D (SP-D) and chemokine (C-C motif) ligand 18 (CCL18) as potential biomarkers of skin and lung fibrosis in SSc.Expert opinion: Skin and lung biomarkers in SSc frequently mirror the typical signs of fibrosis, overlapping sporadically. There is an urgent need for better diagnostic distinction and evaluation; therefore, further investigations are critical to establish more suitable biomarkers of SSc.

Expression of apoptotic and proliferation factors in gastric mucosa of patients with systemic sclerosis correlates with form of the disease.

Despite high prevalence of patients with gastric disease in systemic sclerosis (SSc), its pathogenesis is still poorly understood. We immunohistochemically analysed biopsies of gastric mucosa (GM) in 5 controls and 15 patients with different forms of SSc: limited cutaneous (lc), diffuse cutaneous moderate (sys1) and severe (sys2). The number of positive cells was analysed by a Kruskall-Wallis test, P < 0.05 was considered statistically significant. Percentage of proliferating (Ki-67 positive) cells was highest in sys1 (3% in superficial and 4,6% in deeper parts of GM), which dropped to 1% in sys2. Percentage of α-smooth muscle actin (α-SMA) positive cells was 5% in controls, 9% in superficial GM, while in deeper GM rose from 7% to 19% in sys1 and sys2, thus indicating increased myofibroblast population. Caspase-3 positive apoptotic cells characterized 1,5-2% of controls, 8% of superficial and 6% of deeper GM cells in sys1. In sys2, apoptosis affected 50% of surface epithelial and gland cells and 30% of deeper glands, and correlated with increased fibrosis and decreased syndecan-1 expression. Our data demonstrate that sys1 is the most "active" proliferating form of SSc. Sys2 characterize collagen deposition, surface epithelium defects, extensive apoptosis and low proliferation, GM atrophy and loss of function.

Association between vitamin D, oestradiol and interferon-gamma in female patients with inactive systemic lupus erythematosus: A cross-sectional study.

Objectives To investigate possible associations between 25-hydroxyvitamin D3 (25(OH)D3), oestradiol (E2) and IFN-gamma (IFNγ) in female patients with inactive systemic lupus erythematosus (SLE). Methods Female patients with inactive SLE and age-matched healthy controls were recruited into this cross-sectional study. Serum concentrations of 25(OH)D3, E2 and IFNγ were measured by radioimmunoassay with gamma-counters and enzyme-linked immunosorbent assay. Results 36 patients and 37 controls were enrolled. In patients with SLE, the concentration of 25(OH)D3 was lower and E2 was higher compared with controls. In vitamin D deficient (i.e., 25(OH)D3≤20 ng/ml) patients, IFNγ was 150% higher compared with patients with 25(OH)D3>20 ng/ml and controls. The concentration of E2 was higher in all patients compared with controls independently of the vitamin D level. A difference was found between patients and controls in the correlation of 25(OH)D3 with E2 and a positive correlation was found between E2 and IFNγ in all participants. Conclusions Our results suggest that E2 may have a strong modulating effect on vitamin D function which is significant only at low concentration of E2.

Association of low socioeconomic status and physician assessment of disease severity with oral health-related quality of life in patients with systemic sclerosis: a pilot study from Croatia, a country in transition.

OBJECTIVE: This study was performed to identify a possible association of the clinical parameters of systemic sclerosis (SSc) and the socioeconomic status (SES) with oral health-related quality of life (OHrQoL) as measured by the Oral Health Impact Profile 49 (OHIP 49), taking into account the effect of educational level (as a proxy of SES) on oral health. METHODS: Subjects were recruited from the Croatian SSc Center of Excellence cohort. Detailed dental and clinical examinations were performed according to standardized protocols. The associations of OHrQoL with disease characteristics and socioeconomic status were examined. RESULTS: Thirty-one consecutive patients with SSc were enrolled (29 women; mean age, 56.45 ± 13.60 years). OHIP 49 scores were significantly correlated with disease activity and severity. Furthermore, OHrQoL was positively correlated with skin involvement as evaluated by the modified Rodnan skin score. Impaired OHrQoL was positively correlated with the severity of general, skin, gastrointestinal, and joint/tendon involvement. The OHIP 49 score differed between patients who were positive and negative for anti-topoisomerase I antibody. Higher OHIP 49 scores were detected in patients with lower SES (primary school educational level). CONCLUSION: Collaboration between rheumatologists and dental professionals is required to improve dental care and oral health outcomes of SSc.

[Etanercept (Enbrel)--our experiences]. / Etanercept (Enbrel)--nasa iskustva.

Rheumatoid arthritis (RA) is a chronic, systemic disease. Female patients outnumber males in a ratio of 3:1. Cytokines and immune cells networks have been identified as important mediators in the pathogenesis and perpetuation of inflammation in RA. This information has been successfully used into the development of new and significantly more effective treatments, for example anticytokines agents. The goal in managing RA is to achieve remission. We report five patients with RA successfully treated with etanercept.