Judit Végh

Distinct phenotypes in mixed connective tissue disease: subgroups and survival

The aim of the present study was to assess the autoantibody profile, dominant clinical symptoms and cluster characteristics of different Mixed connective tissue disease (MCTD phenotypes. Two-hundred-and-one patients with MCTD were followed-up longitudinally. Five clinical parameters, Raynaud’s phenomenon, pulmonary artery hypertension (PAH), myositis, interstitial lung disease (ILD), erosive arthritis and five auto-antibodies besides anti-U1RNP, antiendothelial cell antibodies (AECA), anti-CCP, anti-cardiolipin (anti-CL), anti-SSA/SSB and IgM rheumatoid factor (RF) were selected for cluster analysis. The mean age of patients was 52.9 ± 12.4 years and the mean follow-up of the disease was 12.5 ± 7.2 years. Patients were classified into three cluster groups. Cluster 1 with 77 patients, cluster 2 with 79 patients and cluster 3 with 45 patients. In cluster 1 the prevalence of PAH (55.8%; p < 0.001), Raynaud’s phenomenon (92.2%; p < 0.001) and livedo reticularis (24.6%, p < 0.001) was significantly greater than in cluster 2 and 3. In cluster 2, the incidence of ILD (98.7%; p < 0.001), myositis (77.2%; p < 0.001), and esophageal dysmotility (89.8%; p < 0.001) was significantly greater than that in cluster 1 and 3. In cluster 3, anti-CCP antibodies were present in 31 of 45 patients (68.8%) with erosions. Anti-CCP antibodies were present in 37 of 42 patients (88.0%) with erosions. PAH, angina, venous thrombosis was observed in cluster 1 and pulmonary fibrosis in cluster 2, musculosceletal damage, gastrointestinal symptoms and osteoporotic fractures were most frequent in cluster 3. Cumulative survival assessment indicated cluster 1 patients having the worst prognosis. Cluster analysis is valuable to differentiate among various subsets of MCTD and useful prognostic factor regarding the disease course.

Rosuvastatin improves impaired endothelial function, lowers high sensitivity CRP, complement and immuncomplex production in patients with systemic sclerosis - a prospective case-series study

IntroductionWe studied the effect of rosuvastatin on endothelial and macrovascular function, cardiovascular risk factors and the complement pathway in patients with systemic sclerosis (SSc).MethodsAltogether 28 patients with SSc underwent laboratory and complex vascular assessments before and after six months of 20 mg rosuvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery, as well as carotid artery intima-media thickness (ccIMT), carotid-femoral and aorto-femoral pulse wave-velocity (PWV) were analyzed by ECG-synchronized ultrasound. Ankle-brachial index (ABI) was determined by Doppler, and forearm skin microcirculation was assessed by Laser Doppler perfusion monitoring.ResultsBrachial artery FMD significantly improved upon rosuvastatin therapy (2.2% ± 3.3% before versus 5.7% ± 3.9% after treatment, P = 0.0002). With regard to patient subsets, FMD significantly improved in the 21 lcSSc patients (from 2.1% to 5.6%, P = 0.001). In the seven dcSSc patients, we observed a tendency of improvement in FMD (from 3% to 6%, P = 0.25). Changes in PWV, ccIMT and ABI were not significant. Mean triglyceride (1.7 ± 0.97 versus 1.3 ± 0.46 mmol/l, P = 0.0004), total cholesterol (5.3 ± 1.6 mmol/l versus 4.2 ± 1.3 mmol/l, P = 0.0003), low density lipoprotein cholesterol (3.0 ± 1.3 versus 2.2 ± 1.0 mmol/l, P = 0.005) and C-reactive protein levels (CRP) (5.1 ± 5.2 versus 3.4 ± 2.7, P = 0.01) levels significantly decreased after rosuvastatin treatment. Mean C3, C4 and IC levels also decreased significantly as compared to pretreatment values.ConclusionsSix-month rosuvastatin therapy improves endothelial function and lowers CRP, C3, C4 and IC levels indicating possible favourable effects of this statin on the cardiovascular and immune system in SSc.

Regulatory T cells in peripheral blood of patients with mixed connective tissue disease

Objective: To determine the percentage and absolute number of CD4+ regulatory T‐cells (Treg) in 48 patients with mixed connective tissue disease (MCTD). Methods: Data were classified on the basis of the stage of the disease: 17 patients were in the active stage and 31 in the inactive stage. The absolute number of CD4+/intracellular interleukin‐10+ (IL‐10+) and CD4+CD25+high Treg cells was determined by flow cytometry. The percentage of CD4+CD25+high suppressor T‐cells was determined on the basis of Foxp3 expression. Results: The percentage and the absolute number of CD4+CD25+high Treg cells were lower in patients than in healthy controls (p<0.04), and were further decreased in patients with active MCTD and were lower than in the inactive stage (p<0.01). There was an increase in the percentage and absolute number of CD4+IL‐10+ Treg cells in patients with MCTD compared to the healthy controls (p<0.02). The percentage of CD4+IL‐10+ Treg cells was higher in the active stage of MCTD than in the inactive stage of the disease (p<0.005). However, we did not find any significant difference in the absolute number of CD4+IL‐10+ Treg cells between the patients in the active and inactive stages of MCTD. Conclusion: Our results suggest that the decrease in the number of CD4+CD25+high Treg cells in an important factor in the immunoregulatory disturbance in patients with MCTD. We suggest that the increase in the number of CD4+IL‐10+ Treg cells is a compensatory mechanism aiming to restore the balance between type 1 and type 2 cytokines in MCTD.

Catastrophic antiphospholipid syndrome in cancer

Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies resulting in arterial and venous thromboembolism. Apart from primary cases, this syndrome is often associated with autoimmune diseases. Around 50 cases of catastrophic antiphospholipid antibody syndrome have been reported as yet. Authors describe the first case of catastrophic antiphospholipid syndrome associated with gastric cancer. Apart from presenting the clinical case, authors also discuss the possible pathomechanism of this associated disorder including the role of immunological factors, as well as antiphospholipid antibodies.

Sarcoidosis in patients with mixed connective tissue disease: Clinical, genetic, serological and histological observations

The objective of this study was to investigate how the development of sarcoidosis influences the disease course of mixed connective tissue disease (MCTD). The cellular composition of MCTD-associated sarcoidosis granulomas was evaluated and also the disease-accompanying T-cell activation and alterations of the serum cytokine levels were measured before and after the therapy. The HLA-DR specific alleles were also assessed. We present two cases with MCTD coexisting sarcoidosis. Serum concentrations of Th1 and Th2 cytokines were assessed by ELISA. Peripheral blood CD3+ total T-cell numbers, CD4+ and CD8+ T-cell subset were determined by flow cytometry. Furthermore, hematoxylin-eosin staining and immunhistochemistry were performed for histological assessment. HLA-DR specific alleles were determined by using PCR-SSP. Elevated number of activated T-cells and high Th1 cytokine levels were detected, mainly IFN-gamma and TNF-alpha. Histologically, CD4+ and CD8+ T-cells were present in the sarcoidosis infiltrations. The haplotypes were to some extent dissimilar from the HLA-DR genotype from patients with MCTD, or sarcoidosis alone. Sarcoidosis enhances the activation of MCTD, based on the laboratory and clinical findings. Our results show that the inflammation is mainly in the effector phase, while granuloma formation is characteristic of the resolution phase of the disease. The assessment of the cytokine network in sarcoidosis-associated MCTD enables us to select the most effective, individualized therapy protocol for these patients.

348 Immunomodulatory Effects of Extracorporeal Photochemotherapy in Systemic Sclerosis.

Background The aim of the present study was to evaluate the clinical and immunomodulatory effects of extracorporeal photochemotherapy (ECP) in systemic sclerosis (SSc). Methods In the study, we enrolled 16 patients with diffuse cutaneous SSc, who received 12 ECP treatments in total. Skin involvement was assessed by modified Rodnan skin score and high-resolution ultrasonography. Blood samples were taken prior to the first therapy and 6 weeks after each cycle. Samples were also obtained from 16 healthy controls. Lymphocyte subgroups were quantified by flow cytometry, autoantibodies were determined by ELISA technique, and levels of 17 circulating cytokines were measured by multiplex cytokine assay. We used in vitro test to assess the changes in suppressor capability of CD4+CD25+ Treg cells. Results After ECP treatments, the dermal thickness reduced and the mobility of the joints improved. Internal organ involvement did not deteriorate. Initially, patients had lower numbers and percentages of peripheral NKT, Th1, Tr1 and CD4+CD25+ Treg cells, compared to control values. Moreover, the suppressor activity of Treg cells was lower. During the therapy, the values of Tr1 and Treg cells elevated, and the suppressor capacity of Treg cells improved. Initially, patients had higher numbers and proportions of NK and Th17 cells, compared to control values. During the therapy, values of Th17 cells decreased. Levels of CCL2 and TGF-beta decreased, while the concentration of IL-1Ra, IL-10 and HGF increased during ECP. Conclusions ECP contributes to the restoration of the balance between regulatory and effector immune mechanisms, leading to the deceleration of disease progression.