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The complex role of vitamin D in autoimmune diseases.

Vitamin D, besides having well‐known control functions of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune‐homeostasis. The immune‐regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune‐tolerance of self‐structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases. The administration of vitamin D in these animals leads to improvement of immune‐mediated symptoms. Moreover, in human autoimmune diseases, such as multiple sclerosis, or rheumatoid arthritis the pathogenic role of vitamin D has been described. The review aims at describing the complex immune‐regulatory role of vitamin D from the cellular level through autoimmune animal models and depicting the known contribution of vitamin D in the pathogenesis of human autoimmune diseases.

Association of systemic and thyroid autoimmune diseases.

Objective: There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) with systemic autoimmune diseases. Methods: One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjogren’s syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated. Results: Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90-, 160-, 220-, 556-, 176- and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively). Conclusion: Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.

Vitamin D deficiency in undifferentiated connective tissue disease

IntroductionBoth experimental and clinical data provide evidence that vitamin D is one of those important environmental factors that can increase the prevalence of certain autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The aim of the present study was to investigate the prevalence of vitamin D insufficiency in patients with undifferentiated connective tissue disease (UCTD).MethodsPlasma 25(OH)D3 levels in 161 UCTD patients were measured in both summer and winter periods. Autoantibody profiles (antinuclear antibody, anti-U1-ribonucleoprotein, anti-SSA, anti-SSB, anti-Jo1, anti-Scl70, anti-double-stranded DNA, anti-centromere, anti-cardiolipin, rheumatoid factor, and anti-cyclic citrullinated peptide) and clinical symptoms of the patients were assessed.ResultsPlasma levels of 25(OH)D3 in UCTD patients were significantly lower compared with controls in both summer and winter periods (UCTD summer: 33 ± 13.4 ng/mL versus control: 39.9 ± 11.7 ng/mL, P = 0.01; UCTD winter: 27.8 ± 12.48 ng/mL versus control: 37.8 ± 12.3 ng/mL, P = 0.0001). The presence of dermatological symptoms (photosensitivity, erythema, and chronic discoid rash) and pleuritis was associated with low levels of vitamin D. During the average follow-up period of 2.3 years, 35 out of 161 patients (21.7%) with UCTD further developed into well-established connective tissue disease (CTD). Patients who progressed into CTDs had lower vitamin D levels than those who remained in the UCTD stage (vitamin D levels: CTD: 14.7 ± 6.45 ng/mL versus UCTD: 33.0 ± 13.4 ng/mL, P = 0.0001).ConclusionsIn patients with UCTD, a seasonal variance in levels of 25(OH)D3 was identified and showed that these levels were significantly lower than in controls during the corresponding seasons. Our results suggest that vitamin D deficiency in UCTD patients may play a role in the subsequent progression into well-defined CTDs.

Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases.

Angiogenesis, the formation of new vessels, is important in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. Chemotactic cytokines termed chemokines mediate the ingress of leukocytes, including neutrophils and monocytes into the inflamed synovium. In this review, authors discuss the role of the most important angiogenic factors and angiogenesis inhibitors, as well as relevant chemokines and chemokine receptors involved in chronic inflammatory rheumatic diseases. RA was chosen as a prototype to discuss these issues, as the majority of studies on the role of angiogenesis and chemokines in inflammatory diseases were carried out in arthritis. However, other systemic inflammatory (autoimmune) diseases including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjögrens syndrome (SS), mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM) and systemic vasculites are also discussed in this context. As a number of chemokines may also play a role in neovascularizaton, this issue is also described here. Apart from discussing the pathogenic role of angiogenesis and chemokines, authors also review the regulation of angiogenesis and chemokine production by other inflammatory meditors, as well as the important relevance of neovascularization and chemokines for antirheumatic intervention.

Isotype distribution and clinical relevance of anti-β2-glycoprotein I (β2-GPI) antibodies: importance of IgA isotype

The aim of this study was to evaluate the prevalence of IgG, IgA and IgM anti‐β2‐GPI antibodies in anti‐phospholipid syndrome (APS), and to establish the clinical significance of IgA type antibodies compared with the other isotypes. Anti‐β2‐GPI antibodies were measured in the sera of 70 patients by solid‐phase enzyme immunoassay in γ‐irradiated polystyrene plates coated with human purified β2‐GPI. Thirty‐three out of the 70 patients were classified as having APS: three of them had primary, and 30 had secondary APS related to systemic lupus erythematosus (SLE). The remaining 37 patients had SLE without APS. Anti‐β2‐GPI antibodies of IgG, IgA and IgM isotypes were present in 84.8%, 59.3% and 51.5% of patients with APS. Both the frequency and the level of each isotype were significantly higher in patients with APS. This association was very strong for IgA (P = 0.0004 for the antibody frequency and P < 0.0001 for the antibody level), as well as for IgG type antibodies (P < 0.0001 and P < 0.0001), whereas it was weaker for IgM (P = 0.01 and P = 0.04). A strong relationship was demonstrated between increased IgA anti‐β2‐GPI antibody levels and a history of venous thrombosis, thrombocytopenia, heart valve disease, livedo reticularis and epilepsy. IgG anti‐β2‐GPI antibodies were associated with the presence of lupus anticoagulant (LA) in addition to the main features of APS. However, antibodies of IgM isotype were related only to thrombocytopenia and heart valve disease. We recommend the evaluation of anti‐β2‐GPI antibodies of IgA isotype in addition to IgG in patients with clinical suspicion of APS.

Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment.

Numerous autoimmune-inflammatory rheumatic diseases have been associated with accelerated atherosclerosis or other types of vasculopathy leading to increased cardio- and cerebrovascular disease risk. Traditional risk factors, as well as the role of systemic inflammation including cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. The characteristics of vasculopathies may significantly differ depending on the underlying disease. While classical accelerated atherosclerosis has been associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or spondyloarthropathies (SpA), obliterative vasculopathy may rather be characteristic for systemic sclerosis (SSc) or mixed connective tissue disease (MCTD). Antiphospholipid antibodies have been implicated in vasculopathies underlying SLE, antiphospholipid syndrome (APS), RA and MCTD. There is also heterogeneity with respect to inflammatory risk factors. Cytokines, such as tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) and immune complexes are primarily involved in arthritides, such as RA, SpA, as well as in SLE. On the other hand, autoantibodies including anti-oxLDL anti-cardiolipin and anti-β2GPI are rather involved in SLE- and APS-associated vasculopathies. Regarding the non-invasive assessment of vascular function, endothelial dysfunction, overt atherosclerosis and vascular stiffness may be indicated by brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and aortic pulse-wave velocity (PWV), respectively. These abnormalities have been described in most inflammatory rheumatic diseases. While ccIMT and stiffness are relatively stable, FMD may be influenced by many confounding factors. In addition to traditional vasculoprotection, immunosuppressive agents including corticosteroids, traditional and biologic DMARDs may have significant vascular and metabolic effects. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides have just been published, and similar recommendations in connective tissue diseases are to be developed soon.

Vitamin D insufficiency in a large MCTD population

OBJECTIVES The aim of the present study was to evaluate the vitamin D status in patients with mixed connective tissue disease (MCTD) and to determine which clinical symptoms, laboratory parameters and endothelial cell markers are associated with low vitamin D levels. METHODS 125 female MCTD patients and 48 age- and sex-matched healthy controls were enrolled in the study. The clinical symptoms, autoantibodies (anti-U1-RNP, anti-cardiolipin - anti-CL and anti-endothelial cell antibody - AECA), serum cytokines (IFN-γ, IL-6, IL-12, IL-23, IL-17 and IL-10), soluble endothelial cell markers (endothelin, thrombomodulin - TM, and von Willebrand factor antigen - vWFAg) and serum lipids (total cholesterol, triglyceride, LDL-C, HDL-C, apolipoprotein A1, and apolipoprotein B) were investigated for an association with vitamin D levels by univariate and multivariate statistical analyses. RESULTS The mean vitamin D levels were significantly lower in MCTD patients, as compared with the control group (26.16±13.50ng/ml vs. 34.92±9.64ng/ml; p<0.001). In laboratory parameters, vitamin D levels were inversely associated with serum IL-6 (p<0.001), IL-23 (p=0.011), IL-10 (p=0.033) cytokine levels, TM (p=0.001) and endothelin (p=0.033) levels. Low vitamin D levels were also significantly associated with carotid artery intima media thickness (p<0.001), fibrinogen (p=0.010), total cholesterol (p=0.042) and ApoA1 (p=0.004) levels. Among the clinical symptoms, the cardiovascular involvement showed an inverse correlation with vitamin D status in MCTD (p<0.001). CONCLUSIONS The prevalence of vitamin D insufficiency is high in patients with MCTD. We assume that vitamin D insufficiency along with inflammatory parameters and lipid abnormalities may provoke cardiovascular events.

Plasma Endothelin Correlates With Antiendothelial Antibodies in Patients With Mixed Connective Tissue Disease

BACKGROUND Elevated circulating levels of the vasoactive peptide endothelin-1 have been reported in various cardiovascular disorders. Because these conditions are frequently associated with endothelial dysfunction and damage and the vasoconstrictor effect of endothelin-1 is believed to be produced at the local vascular level, it is uncertain whether circulating endothelin-1 is a causal factor in enhanced vascular tone or instead a marker of endothelial injury. METHODS AND RESULTS We tested whether elevated immunoreactive endothelin-1 could be detected by radioimmunoassay in plasma and whether endothelin-1 levels correlated with antiendothelial autoantibodies in patients with mixed connective tissue disease. Venous blood samples were collected from 21 patients in the morning after an overnight fast and before medication. The plasma immunoreactive endothelin-1 level was 2.7 +/- 0.5 pg/mL (range, 1.1 to 5.2 pg/ml; n = 9) and 7.3 +/- 1.5 pg/mL (range, 2.8 to 20.7 pg/mL; n = 12) in patients who had no antiendothelial antibodies and in patients with antiendothelial antibodies, respectively. These latter values were significantly (P < .001) increased compared with 10 age-matched healthy volunteers (2.0 +/- 0.3 pg/mL; range, 0.5 to 3.0 pg/mL). Plasma endothelin-1 level strongly correlated with antiendothelial antibodies (rs = .836, n = 21, P < .001), whereas there was no correlation between age, systolic and diastolic blood pressures, antinuclear antibodies, and duration of the disease and endothelin-1 values. The incidence of Raynauds phenomenon and angina did not differ significantly in patients with low and high endothelin-1 levels. CONCLUSIONS This study showed that mixed connective tissue disease is associated with elevated plasma immunoreactive endothelin-1 and that endothelin-1 levels significantly correlate with antiendothelial autoantibodies. These findings suggest that increases in plasma endothelin-1 concentration may be secondary to vascular injury and do not necessarily represent enhanced susceptibility to vasoconstriction.

Clinical and Immunoserological Characteristics of Mixed Connective Tissue Disease Associated with Pulmonary Arterial Hypertension

We investigated the clinical characteristics and immunoserological alterations in patients with mixed connective tissue disease (MCTD) associated with pulmonary arterial hypertension (PAH). Anti‐U1RNP autoantibodies, anti‐endothelial cell antibodies (AECA) and serum thrombomodulin (TM) as well as von Willebrand factor antigen (vWFAg) concentrations were measured in 25 patients with MCTD associated with PAH and in 154 MCTD patients without PAH. The results showed that the probability of survival was lower in MCTD patients with PAH than in the 154 MCTD‐non‐PAH patients (5‐year survival rate in MCTD with PAH: 73%, versus 96% in MCTD‐non‐PAH; P < 0.01). AECA were more frequently present in the sera of MCTD patients with PAH than in MCTD‐non‐PAH (P < 0.001). Serum TM and vWFAg levels were higher in MCTD‐PAH patients than in MCTD‐non‐PAH patients (TM: P < 0.001; vWFAg: P < 0.001). Significant correlation was noticed between the quantity of AECA and TM level (r = 0.466) as well as the quantity of AECA and vWFAg level (r = 0.550). In conclusion, our results suggest that in MCTD the presence of AECA and endothelial cell activation may play a role in the development of PAH and in the maintenance of obliterative vascular processes.

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.