Impaired endothelial function in patients with undifferentiated connective tissue disease: a follow-up study.

OBJECTIVE: In this study the alteration of endothelial function, arterial stiffness and autoantibodies was investigated in patients with UCTD. METHODS: Thirty-one patients with UCTD were included in this prospective study. All the patients remained in the UCTD stage during the average 3.8 years follow-up period. The onset of UCTD was denoted as UCTD1, while the end of the follow-up period was called UCTD2. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), autoantibodies [such as anti-SSA, anti-SSB, anti-DNA, anti-RNP, anti-CCP, aCL, anti-oxidized low-density lipoprotein (oxLDL) and AECA], von Willebrand factor antigen, thrombomodulin (TM), endothelin 1 (ET-1) and lipid parameters were measured. RESULTS: In the UCTD1 stage, high-sensitivity CRP (hsCRP) and endothelial cell activation and/or damage markers such as TM, ET-1 and AECA levels were significantly higher compared with controls (controls vs UCTD1: hsCRP, P < 0.0001; TM, P = 0.001; ET-1, P < 0.0001). In the UCTD2 stage, the carotid IMT increased (UCTD1 vs UCTD2, P = 0.01) and FMD further deteriorated (UCTD1 and UCTD2, P = 0.001). In UCTD2 there was a close correlation between the carotid IMT, and duration of the disease (r = 0.612, P < 0.001), the level of TM (r = 0.673, P < 0.001) and anti-oxLDL (r = 0.800, P < 0.001). CONCLUSION: Our data suggest that the presence of inflammation and autoantibodies provoke endothelial cell activation and/or injury in UCTD patients. The persistent endothelial dysfunction may provoke the development of atherosclerosis. FMD was found to be the most sensitive marker for arterial stiffness, and the increase of IMT clearly indicated the existence of preclinical atherosclerosis in UCTD patients.

Progressive divergent shifts in natural and induced T-regulatory cells signify the transition from undifferentiated to definitive connective tissue disease.

The objectives of the study is to determine clinical signs and distribution of peripheral T-cell subsets, B cells and T regulatory cells in patients with undifferentiated connective tissue disease (UCTD) and during the development toward well-established connective tissue diseases (CTD). The methods include 46 patients with UCTD were followed and investigated for differentiation into defined CTDs for 2 years. Cell subsets were determined on the basis of cell surface markers, intracellular cytokine production by flow cytometry and serum cytokine levels by ELISA. The results are as follows: 45.6% of UCTD patients developed into a defined CTD. The number and percentage of activated T cells, memory T cells and NKT cells were increased in patients compared with controls. In addition, in patients with UCTD, the percentage of CD4+/IFN gamma+ T(h)1 was significantly higher compared with controls and further increased in patients that developed CTDs. The percentage and absolute number of CD4+CD25+Foxp3+ regulatory T cells (Tregs) were diminished in UCTD patients compared with healthy controls, while the number of CD4+/IL-10+ Tregs increased. The conclusions are Overproduction of IFN gamma and the decrease of natural (Foxp3+) Tregs seem to be characteristic features of UCTD patients. The increased IL-10 production of CD4+ T cells might be a compensatory suppressive mechanism; however, it is probably not able to balance the overproduction of IFN gamma and the observed decrease of Foxp3+ Tregs. The shift toward T(h)1 with increased IFN gamma production in patients with UCTD combined with the degree of immunoregulatory disturbances characterized by the progressive divergent shifts in natural and induced T-regulatory cell populations signify the transition from undifferentiated to definitive CTD.

[Undifferentiated connective tissue disease]. / Nem differenciált collagenosis 2009-ben.

Evolution of immunopathological diseases is usually slow and progressive. Non-differentiated collagen disease (NDC) or the term "undifferentiated connective tissue disease" (UCTD) represents a stage of disease where clinical symptoms and serological abnormalities suggest autoimmune disease, but they are not sufficient to fulfill the diagnostic criteria of any well-established connective tissue disease (CTD) such as systemic lupus erythematosus (SLE), Sjögren's syndrome, mixed connective tissue disease (MCTD), systemic sclerosis (SSc), polymyositis/ dermatomyositis (PM/DM) or rheumatoid arthritis (RA). 30-40 percent of patients presenting undifferentiated profile develops and reaches the stage of a well defined systemic autoimmune disease during five years follow up, while 60 percent remains in an undifferentiated stage.In the stage of NDC, immunoregulatory abnormalities and endothelial dysfunction are present. In conclusion, NDC represents a dynamic state, and it is important to recognize the possibility of a progression to a definite systemic autoimmune disease.

Balneotherapy in elderly patients: effect on pain from degenerative knee and spine conditions and on quality of life.

BACKGROUND: Balneotherapy is an established treatment modality for musculoskeletal disease, but few studies have examined the efficacy of spa therapy in elderly patients with degenerative spine and joint diseases. OBJECTIVES: To assess the effects of balneotherapy on chronic musculoskeletal pain, functional capacity, and quality of life in elderly patients with osteoarthritis of the knee or with chronic low back pain. METHODS: The 81 patients in the study group underwent a 1 day course of 30 minute daily baths in mineral water. Changes were evaluated in the following parameters: pain intensity, functional capacity, quality of life, use of non-steroidal anti-inflammatory or analgesic drugs, subjective disease severity perceived by the patients, investigator-rated disease severity, and severity of pain perceived by the patients. We analyzed the results of 76 subjects as 5 did not complete the study. RESULTS: Compared to baseline, all monitored parameters were significantly improved by balneotherapy in both investigated groups. Moreover, the favorable effect was prolonged for 3 months after treatment. CONCLUSIONS: This study showed that balneotherapy is an effective treatment modality in elderly patients with osteoarthritis of the knee or with chronic low back pain, and its benefits last for at least 3 months after treatment.

Diastolic function of the heart in mixed connective tissue disease.

The authors examined the right and left ventricle functions in patients with mixed connective tissue disease (MCTD) by Doppler echocardiography. Of 51 patients, 20 had temporary pulmonary arterial hypertension in their case history. According to our knowledge, this is the first study examining the use of Doppler echocardiography and tissue Doppler technique in MCTD patients. Of 51 MCTD patients, 20 had pulmonary arterial hypertension (PAH) in the past 2 years. Diameters of the right and left ventricle, systolic and diastolic blood pressure were measured both in the 51 MCTD patients and in the 30 control subjects (mean age 54.8+/-6.2 years in the case of patients and 54.2+/-8.8 years in the case of control subjects). To estimate the global ventricle functions, the myocardial performance index--as described by Tei et al. (J Am Soc Echocardiogr 6:838-874, 1996)--was applied, which reflects the ratio of the sum of the isovolumetric contraction and relaxation time as compared to the ejection time. The 20 MCTD patients with PAH received cyclophosphamide therapy for 1 year beside the pulse corticosteroid (CS) therapy. In the case of MCTD patients without PAH, different treatments were used: 12 out of 31 patients were treated with sulfasalazine, 5 of whom received a combination of CS and methotrexate, and 14 took nonsteroid antiinflammatory drugs. In the case of the 51 MCTD patients (20 with PAH and 31 without PAH), diastolic function disorder of the left ventricle was detected; the diastolic Ee/Aa velocity quotient of the lateral mitral anulus was lower (p<0.01), and the mean deceleration time was longer (p<0.001) than that of the control group. The Tei index demonstrated the damage of the global ventricle function. The Tei index of the right ventricle indicated global failure of the right ventricle function in the case of MCTD patients complicated with PAH (Tei index 0.36+/-0.07 in MCTD with PAH and 0.28+/-0.04 in MCTD without PAH, p<0.001). The right ventricle function of MCTD patients without PAH was no different from that of the control group. In the case of patients with MCTD, signs of the disorder of the left ventricle diastolic function were observed. Our results suggest that the global impairment of the left ventricle function is the consequence of the disease itself and not the side effect of the treatment. In the case of MCTD patients complicated with PAH, the signs of the right ventricle function impairment proved to be permanent.

[When does an autoimmune disease begin? Importance of the early diagnosis]. / Mikor kezdodik egy autoimmun betegség? A korai diagnosztikára való törekvés jelentosége.

In autoimmune diseases, such as type I diabetes mellitus, systemic autoimmune diseases and the early phase of rheumatoid arthritis, before the development of a definitive disease, clinical and laboratory alterations can be observed. Being aware of these symptoms is crucial both for family practitioners and specialists, handling autoimmune and early arthritis patients. The early recognition and prognosticating of the disease and sending the patient immediately to a specialist will lead to the exponential improvement of the patient's life expectancies and will also help to avoid complications. The need for special diagnostics, care and treatment made the development of national immunological and rheumatological centers imperative, where sufficient experience and professional knowledge helps the proper medical attendance.

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), Sjögren'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.

High prevalence of oesophageal involvement in patients with undifferentiated connective tissue disease using radionuclide oesophageal transit scintigraphy.

AIM: To look for the frequency of oesophageal dysfunction using radionuclide oesophageal transit scintigraphy in 145 patients with undifferentiated connective tissue disease (UCTD); to seek the correlation between the clinical/laboratory data and scintigraphic alterations; and to determine predictive value of radionuclide oesophageal transit scintigraphy for evolution to established connective tissue disease (CTD). METHOD: One hundred and forty-five patients with UCTD were examined by 99mTc-DTPA oesophageal transit scintigraphy. The intraoesophageal transport of the radiopharmaceutical was followed and imaged by a gamma camera, a series of 128 x 128 images were stored and evaluated. The correlation between the scintigraphic data and clinical and laboratory parameters was analysed statistically. RESULTS: Unequivocally positive scintigraphy, indicative of motor abnormality was found in 46% of patients (66), 71% (47) of whom were totally asymptomatic. Significant correlation was found between the presence and severity of scintigraphic alterations and antinuclear antibodies, the anti-beta2GPI, IgM, IgG, the aCL antibody positivity, and the skin symptoms. Scintigraphic positivity was significantly more frequent in patients evolving to definitive CTD (P = 0.0178), and abnormal scan predisposed to transition into the definitive CTD (odds ratio, 2.292; CI, 1.610-4.525). Its cumulative positive predictive value was found to be 43% and cumulative negative predictive value 73% with regard to the development of a definitive CTD. CONCLUSION: Our results show that scintigraphic alterations together with clinical and laboratory alterations can help the clinician in the prediction of final outcome.

[Endothelial dysfunction and early atherosclerosis in non-differentiated collagenosis]. / Endotheldiszfunkcó és korai atherosclerosis nem differenciált collagenosisban.

INTRODUCTION: The most common systemic autoimmune diseases, as the rheumatoid arthritis (RA) and the systemic lupus erythematosus (SLE) are associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality. The authors' aim was to determine the endothelial dysfunction and the accelerated atherosclerosis in patients with undifferentiated connective tissue disease (UCTD), in a preliminary phase of defined connective tissue diseases. PATIENTS AND METHODS: Twenty-two UCTD patients and twenty age and sex-matched controls were included. Using high-resolution B-mode ultrasound, the authors' measured the intima-media thickness (IMT) of the common carotid artery (CCA), and the diameter of brachial artery at rest, during reactive hyperemia, and after sublingual glyceryl trinitrate administration. The clinical, the demographical status and the serological profile of UCTD patients were also assessed. RESULTS: There was no significant difference between the groups considered to the traditional risk factors. The endothelium dependent vasodilatation was significantly impaired in UCTD patients as compared to the controls (5.3 +/- 3.03% vs. 8.85 +/- 4.02%, P < 0.002). The authors' have not found significant difference between the two groups either at the endothelium independent vasodilatation or at the CCA-IMT. CCA-IMT correlated significantly with the age (R = 0.819, p < 0.001) and with the anti-DNA antibody levels (R = 0.563, P < 0.008). CONCLUSIONS: The endothelium-dependent vasodilatation of patients with UCTD is reduced before development of a defined connective tissue disease and the potential anti-atherogenic treatment. The endothelium dependent vasodilatation is a more sensitive method to determine an early atherosclerotic process. The authors' found moderate correlation between the CCA-IMT and the anti-DNA antibody levels.

[Interstitial lung disease in mixed connective tissue disease]. / Interstitialis légzoszervi betegség kevert kötooszöveti betegségben.

INTRODUCTION: The authors analyzed the incidence of interstitial lung disease in mixed connective tissue disease. They were seeking an answer to the following problems: the nature of the pathological course of mixed connective tissue disease complicated by and the therapy to be used in interstitial lung disease. PATIENTS AND METHODS: 179 patients were followed up during a period of 15.9 +/- 6.1 years. Interstitial lung disease was diagnosed using high resolution computed tomography. The diagnosis of interstitial lung disease was not obvious in 5 patients thus open lung biopsy was performed, which confirmed common interstitial pneumonitis. The patients were followed-up, and the data of computed tomography and respiratory function tests were detected 6 months, and then 4 years after the acute lung disease complicated by mixed connective tissue disease. RESULTS: Out of the 179 mixed connective tissue disease patients 96 (53.6%) had interstitial lung disease. The onset of interstitial lung disease was the most frequent in the 2-4 years of the disease. Four years after the first appearance of interstitial lung disease severe fibrosis was diagnosed in 24 patients (25%). A honey comb formation in the lung developed only in one patient. For the treatment of interstitial lung disease, corticosteroid treatment had to be combined with cyclophosphamide in 51 cases. In 4 patients (24%), pulmonary arterial hypertension evolved 2-4 years following interstitial lung disease. The high pulmonary arterial pressure decreased using pulsed corticosteroid treatment, cyclophosphamide, prostacyclin analogue, anticoagulants therapy and the 4 patients stay alive. The pulmonary arterial hypertension was caused by obliterative vasculopathy. CONCLUSION: Pulmonary involvement is found in more than half of the patients with mixed connective tissue disease. Early diagnosis of interstitial lung disease is possible by computed tomography. Interstitial lung disease can be treated by the combination of corticosteroids and cyclophosphamide. The authors were the first to detect the coexistence of interstitial lung disease and pulmonary arterial hypertension in mixed connective tissue disease. Subsequent respiratory alterations in these patient necessitate regular patient follow up.

Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review.

Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities. In systemic autoimmune conditions, a quantitative and qualitative impairment of regulatory T cells has been shown previously, and in parallel, a relative dominance of pro-inflammatory Th17 cells has been introduced. Moreover, the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD. Additionally, we depict a cytokine imbalance, which give raise to a biased T cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of interleukin (IL)-6, IL-12, IL-17, IL-23, and interferon (IFN)-γ were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression toward serious systemic autoimmune diseases. Moreover, the early targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage.

[Undifferentiated connective tissue disease: clinical and serological profile of 578 patients followed for five years: disease course, prognosis and therapy]. / Nem differenciált collagenosisban szenvedó betegek ötéves követésével nyert megfigyelések: 578 beteg klinikai és immunszerológiai sajátossága, kórlefolyás, terápia.

INTRODUCTION: Evolution of immunopathological diseases is usually slow and progressive. The term the undifferentiated connective tissue disease (UCTD) is used to describe the phase preceding a defined connective tissue diseases (CTD). AIMS: The objective of this work was evaluate the clinical and serological profile of patients with UCTD, who had been followed between 1994-1999. They have investigated the frequency and the type the developed autoimmune diseases from UCTD. PATIENTS: A total of 578 UCTD patients were evaluated. RESULTS: In 143/578 patients (24.7%) with the UCTD differentiated to systemic connective tissue diseases (28 systemic lupus erythematosus, 26 mixed connective tissue disease, 19 progressive systemic sclerosis, 3 polymyositis/dermatomyositis, 45 Sjögren syndrome, and 22 systemic vasculitis). 86.7 percent (124/143) of the systemic connective disease developed in first two years of UCTD. The condition of 435/578 (75.2%) remained UCTD after 5 years, among them in 82 patients with UCTD was regression of the symptoms. The presence of the fever and anti-DNS antibodies correlated with SLE (P = 0.0104, Fisher exact test), arthritis/arthralgia and anti-RNP antibodies with MCTD (P = 0.0302), Raynaud phenomenon and ANA positivity with PSS (P = 0.0144), xerostomia/xerophtalmia and anti-SSA/SSB antibodies with Sjögren syndromes (P = 0.0144). CONCLUSIONS: The UCTD in our patients seem to represents an dynamic phase, one part of the patients show progression to definite connective tissue diseases, one part show regression, and on part of the patients stay in UCTD phase.

[Evaluation of survival in mixed connective tissue disease (MCTD)]. / Túlélés kevert kötószöveti betegségben (MCTD).

INTRODUCTION: 179 patients with mixed connective tissue disease (MCTD) were follow-up, and the cause of death was analyzed in 12 died patients. PATIENTS AND METHODS: The survival of 179 patients with MCTD was evaluated by using Kaplan-Meier's method. Clinically and immunological data of the patients were analyzed between 1 and 25 years follow-up period (mean: 13.1 +/- 5.5 years). RESULTS: The five-year survival rate was 96.4%, 10-year survival rate was 93.9%, and the 15-year survival rate was 89.6%. The cause of death was pulmonary hypertension in 5 patients, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in 3 cases, infection in 3 cases (hepatitis C virus induced hepatic coma in 2 patients, Staphylococcus sepsis in one patient), and on one patient myocarditis. The pulmonary hypertension was the most serious prognostic factor. CONCLUSION: In patients with MCTD the pulmonary hypertension with endothelial cells proliferation and microangiopathy developed very quickly, and there was progressive and therapy resistant statement. The secondary virus and bacterial infections may develop in the patients who were followed-up the long term period. Their survival rate was better than the data in the literature. This fact may cause genetic-demographic factors, and the sequential follow-up of the patients.

Increased levels of anti-heat-shock protein 60 (anti-Hsp60) indicate endothelial dysfunction, atherosclerosis and cardiovascular diseases in patients with mixed connective tissue disease.

Heat-shock protein 60 (Hsp60) has been shown to provoke inflammation, and anti-Hsp60 may facilitate the development of atherosclerosis. In this study, we have investigated 30 patients with mixed connective tissue disease (MCTD) and assessed anti-Hsp60 and their relationship to cardiovascular diseases (CVD). Out of 30 patients with MCTD, 15 had CVDs. Anti-Hsp60 antibody was determined by enzyme-linked immunosorbent assay. Since endothelial dysfunction and accelerated atherosclerosis are characteristic to MCTD, a wide array of MCTD-, endothelial dysfunction- and CVD-associated parameters was investigated: serum lipid levels, paraoxonase activity (PON1), rich nuclear ribonucleoprotein U1 (anti-U1RNP), anti-endothelial cell antibodies, anti-cardiolipin and anti-ß2-glycoprotein I antibody isotypes (anti-CL and anti-ß2GPI), endothelin-1 (ET-1) levels, also intima-media thickness (IMT), a quantitative indicator of atherosclerosis. In MCTD, anti-Hsp60 antibody levels were significantly higher than in healthy individuals (p < 0.02). MCTD patients with CVD had significantly higher levels of anti-Hsp60 compared to MCTD without CVD (p = 0.001). Patients with MCTD had significantly lower high-density lipoprotein cholesterol (p = 0.02) and PON activity (p < 0.001), and significantly increased systolic (p < 0.0002) and diastolic (p < 0.001) blood pressure compared to healthy individuals. Anti-U1RNP levels (p < 0.002) and IMT were higher in patients compared to controls (p = 0.002). The CVD-positive MCTD patients had increased anti-Hsp60 (p < 0.0013), anti-CL IgG (p = 0.0005), ET-1 serum concentration (p < 0.05) and IMT levels (p < 0.001) compared to MCTD patients without CVD. Anti-Hsp60 showed a strong correlation with anti-oxLDL (r = 0.36, p = 0.01) and serum ET-1 (r = 0.62, p < 0.001) and negative correlation with PON activity (r = -0.47, p = 0.01). Anti-Hsp60 indicates endothelial injury, CVD, and can function as a novel atherosclerotic risk factor, also a valuable diagnostic marker in patients with MCTD.

Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies - novel tool for diagnostics and patient follow-up.

Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes. The intricate interplay and fine balance of pro- and anti-inflammatory processes drive, whether inflammation and eventually organ damage will occur, or the inflammatory cascade quenches. In the early and late, as well as inactive and active stages of autoimmune diseases, different cellular and molecular patterns can dominate in these patients. However, the simultaneous assessment of pro- and anti-inflammatory biomarkers aids to define the immunological state of a patient. A group of the most useful inflammatory biomarkers are cytokines, and with increasing knowledge during the last decade their role have been well-defined in patients with autoimmune diseases and immunodeficiencies. Multiple pathological processes drive the development of autoimmunity and immunodeficiencies, most of which involve quantitative and qualitative disturbances in regulatory cells, cytokine synthesis and signaling pathways. The assessment of these biomarkers does not aid only in the mechanistic description of autoimmune diseases and immunodeficiencies, but further helps to subcategorize diseases and to evaluate therapy responses. Here, we provide an overview, how monitoring of cytokines and regulatory cells aid in the diagnosis and follow-up of patients with autoimmune diseases and immunodeficiencies furthermore, we pinpoint novel cellular and molecular diagnostic possibilities in these diseases.

Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders.

A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.

Clinical course, prognosis, and causes of death in mixed connective tissue disease.

OBJECTIVE: To study the survival rate and prognostic indicators of mixed connective tissue disease (MCTD) in a Hungarian population. METHODS: Two hundred eighty patients with MCTD diagnosed between 1979 and 2011 were followed prospectively. Clinical features, autoantibodies, and mortality data were assessed. Prognostic factors for survival were investigated and survival was calculated from the time of the diagnosis by Kaplan-Meier method. RESULTS: A total of 22 of 280 patients died: the causes of death were pulmonary arterial hypertension (PAH) in 9 patients, thrombotic thrombocytopenic purpura in 3, infections in 3, and cardiovascular events in 7. The 5, 10, and 15-year survival rates after the diagnosis was established were 98%, 96%, and 88%, respectively. The deceased patients were younger at the diagnosis of MCTD compared to patients who survived (35.5 ± 10.4 vs 41.8 ± 10.7 yrs; p < 0.03), while there was no difference in the duration of the disease (p = 0.835). Our cohort study showed that the presence of cardiovascular events (p < 0.0001), esophageal hypomotility (p = 0.04), serositis (p < 0.001), secondary antiphospholipid syndrome (p = 0.039), and malignancy (p < 0.001) was significantly higher in the deceased patients with MCTD. The presence of anticardiolipin (p = 0.019), anti-ß2-glycoprotein I (p = 0.002), and antiendothelial cell antibodies (p = 0.002) increased the risk of mortality. CONCLUSION: Overall, PAH remained the leading cause of death in patients with MCTD. The prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD. The presence of antiphospholipid antibodies raised the risk of mortality.

Vitamin D deficiency and connective tissue disease.

Recently, the evidence linking vitamin D status as a potential environmental factor affecting autoimmune disease prevalence continues to accumulate. Beyond that the traditional known metabolic activities, vitamin D has been shown to modulate the immune system and has anti-inflammatory properties. The immune-regulatory role of vitamin D affects both the innate and adaptive immune responses contributing to the immune-tolerance of self-structures. Vitamin D deficiency skews the immunologic response towards loss of tolerance. Serum levels of vitamin D have been found to be significantly lower in several autoimmune or immune-mediated diseases than in the healthy population. Experimental animal models and clinical studies show that 1,25-dihydroxyvitamin D3 or vitamin D receptor (VDR) agonists can either prevent or suppress symptoms of type 1 diabetes, experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erthyematosus and inflammatory bowel disease. The heading aims at reviewing the complex immune-regulatory role of vitamin D from the cellular and humoral level through animal models of autoimmune rheumatic diseases and representing the known contribution of vitamin D in the pathogenesis of connective tissue diseases. Increased vitamin D intakes might reduce the incidence and severity of autoimmune disorders besides reducing the rate of osteoporotic bone fracture.