[Autoimmunity and autoinflammation in pathogenesis of immunoinflammatory diseases].

Rheumatic diseases relate to the group of the immunoinflammatory diseases (IID), in pathogenesis of which have a value both autoimmune and autoinflammatory processes. AIM: To present the heterogeneous pathogenesis of inflammation in IID. MATERIALS AND METHODS: It is inspected 260 patients (pts) with IID: 242 pts with systemic autoimmune diseases (SAD): 65 systemic lupus erythematosis, 50 systemic sclerosis, 127 systemic vasculitides (SV) and 18 patients with autoinflammatory diseases (AID): 8 Behcets disease, 2 periodic disease, 5 familial cold fever, 2 idiopathic lobular panniculitis and 1 relapsing polychondritis. Is carried out a study of complement, antigen of von Willebrand factor (FW:AG), antinuclear antibodies, antibodies to DNA, anti-endothelial antibodies, antibodies to topoizomeraze I (anti-Scl-70), antineutrophilic cytoplasmic antibodies (ANCA), anticardiolipin antibodies (aCL IgG and aCL IgM), cryoglobulins, VS, CRP. RESULTS: SAD were characterized by the synthesis of wide antibodies spectrum. As the basic serological marker at the screening it follows to consider antinuclear antibodies (75%). Practically in all groups it took place hypcomlemetemia with reduction of C3 and C4 complement. With systemic lupus erythematosis are revealed antibodies to DNA (71%), with ANCA-associated SV-ANCA (94%), aKL (14%); with SSD aScl-70 (17%). At Wegener granulomatosis ANCA are determined in 94% patients in the active stage. It is noted correlation ANCA with the index of the clinical activity of vasculitis. In the remaining SV groups ANCA were separated in the single cases. Cryoglobulins are noted in all patients with cryoglobulinemic vasculitis. aCL IgG and aCL IgM were the markers of antiphospholipid syndrome. Аnti-endothelial antibodies had significant oscillation spectrum. High indices FW:AG are noted with all above nosologic forms indicated, especially with Wegener granulomatosis and vasculitis hemorrhagic. Among the laboratory tests of inflammatory activity should be considered the determination of VS, CRP and FV:AG, which is also considered the marker of vascular wall defeat. Is given clinical characteristic and changes in the laboratory indices at AID: Conclusion.Isolation from the group IID of patients with AID serves as indication for a genetic study of this contingent with the approval of use for their treatment of biological therapy. Isolation from the group SAD patients with AID serves as indication for a genetic study of this contingent with the approval of use for their treatment of biological therapy.

[Cerebral perfusion, arterial hypertension and endothelial dysfunction in rheumatoid arthritis]. / Mozgovaia perfuziia, arterial'naia gipertenziia i éndotelial'naia disfunktsiia pri revmatoidnom artrite.

To study the relationship between cerebral perfusion with arterial hypertension (AH) and the state of endothelium in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: Seventy-eight patients with RA were divided into two groups: with- and without AH.The functional methods included ultrasonic duplex angioscanning and dopplerografy of the extracranial and intracranial arteries of the head and neck and daily 24 hour monitoring of arterial blood pressure (BP). C-reactive protein (CRP), vascular endothelial adhesion molecule type 1 (sVCAM-1), von Willebrand Factor antigen (vWF AG), interleukin-8 (Il-8), rheumatoid factor (RF) IgG, endothelin-1 (ET-1) were determined by immunoenzyme analysis and velocity of sedimentation (VS). The dysfunction of endothelium was evaluated by calculation of the number of desquamated endotheliocytes cells (DE). RESULTS: AH occurred in 46 (59%) patients. Cerebral hypoperfusion was observed in patients with RA in whom the reduction in the high-speed indices of blood flow were correlated with BP increase. There were negative correlations between the linear speed of blood flow on the common carotid arteries and average day and night systolic BP, average day and night diastolic BP, indices of time systolic BP and diastolic BP and avariability of BP. The same results were established for the intracranial arteries: inverse correlations between the linear speed on the anterior cerebral arteries and average day systolic BP. The signs of endothelial dysfunction represented by significant differences among the indices of activation of endothelium in RA patients in comparison with the control group were shown. Content of ET-1, sVCAM-1, vWF AG, Il-8, CRP was higher in RA. The number of DE was significantly higher as well. These indices showed significant differences depending on RA activity. Correlation analysis revealed that the markers of endothelium activation sVCAM-1, vWF AG were positively correlated with the indices of immune inflammation. CONCLUSION: An increase in the activity of inflammatory process in RA leads to endothelial dysfunction, which contributes to the increase in the peripheral vascular resistance of cerebral arteries, reduction in the high-speed indices of blood flow, growth of BP variability and the increase in load by pressure.

[Endothelial damage and circadian blood pressure profile in rheumatoid arthritis].

AIM: To study the influence of the state of endothelium on the daily profile of arterial pressure (AP) in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: In 70 RA pts carried out C-reactive protein (CRP), vascular endothelial adhesion molecule type 1 (sVCAM-1), antigen von Willebrand Factor (AG WF), interleukin-8 (Il-8), rheumatoid factor (RF), IgG, endotheline-1 (ET-1), number of desquamated endotheliocytes cells (DE), VS, activity of renin by immunoenzyme analysis. The dysfunction of endothelium was evaluated by calculation of DE. The functional methods included the daily monitoring of arterial pressure (AP). RESULTS: Arterial hypertension (AH) occurred in 40 (57.1%) pts. RA pts are revealed the signs of endothelial dysfunction, about which significant differences among the indices of activation of endothelium in comparison with control group testify. ET-1, sVCAM-1, vWF AG, Il-8, CRP content was higher in RA pts. Reliably above there was a number of DE. Reliable differences according to these indices depending of RA activity were discovered. With conducting of correlation analysis it is revealed, that markers of the activation of endothelium: sVCAM-1, vWF AG positively correlated with increasing RF IgG and indices of the immune inflammation: CRP, and DE number. In patients suffering from RA, showed signs of endothelial dysfunction. The positive correlation between endothelial damage and daily profile of AP show the relationship of these processes. CONCLUSION: Positive correlations between the damage of endothelium and disturbance of AP daily profile testify about the interrelation of these processes.

[Clinical and morphological characteristics of systemic vasculitides: contribution of professor N.E. Yarygin into the solution of the problem]. / Kliniko-morfologicheskaia kharakteristika sistemnykh vaskulitov: vklad professora N.E. Iarygina v reshenie problemy.

The article deals with the role of Professor N.E. Yarygin in studying the clinical and morphological characteristics of systemic vasculitides and is dedicated to the 70th anniversary of the Yaroslavl State Medical University.

[Systemic vasculitides: some debatable aspects of the problem].

A new nomenclature of systemic vasculitides (SV) and current approaches to their treatment have necessitated the discussion of some debatable questions on this condition. The paper gives the data of examining 325 patients with different forms of SV, followed up in the Interregional Consulting Center for SV patients, and the results of testing the American College of Rheumatology classification criteria for SV and the authors' criteria, by taking into account the International Chapel Hill Consensus Conference, USA (1994 and 2011) guidelines for CV nomenclature. It discusses the etiological factors and pathogenetic components of SV, morphological aspects, and relationships between the local and systemic forms of SV. The findings were compared with the data available in the literature. It is concluded that differentially diagnostic criteria for CV should be elaborated to specify the stage of the disease, the activity and use of adapted therapy regimens.

[Specific features of hypertension in patients with systemic lupus erythematosus].

AIM: To study the specific features of the development and course of hypertension in patients with systemic lupus erythematosus (SLE). SUBJECTS AND METHODS: A total of 106 age- and sex-matched patients, including 47 with SLE and 55 with hypertensive disease (HD), were examined. In all the patients, plasma renin levels were determined; serum von Willebrand factor antigen concentrations were estimated; desquamated endothelial cell counts were calculated; and 24-hour blood pressure (BP) monitoring (BPM) and Doppler ultrasound of carotid arteries performed. RESULTS: In the patients with SLE and hypertension compared to those with HD, the mean diastolic BP (DBP) was 86.5 (79.5-93.5) mm Hg versus 80.5 (77-90) mm Hg (daytime) and 78 (69-91.5) mm Hg versus 72.5 (64-78) mm Hg (nighttime) (p < 0.05), and there was also a decrease in daily DBP index (5 [0.5-15]% versus 11 [7.5-18]% (p < 0.02)). The plasma renin levels were 1.67 (0.78-2.47) and 0.49 (0.25-0.81) ng/ml/h in the patients with SLE and in those with HD, respectively, p = 0.04 and 0.42 (0.36-0.47) ng/ml/h in the control group (p = 0.0001). An atherosclerotic vascular lesion was found in 52 and 32% of the patients with SLE and those with HD, respectively. The von Willebrand factor antigen levels were 1.63 (0.81-3.36) and 0.29 (0.23-2.8) IU/ml in these patients, respectively (p = 0.04). The plasma circulating endothelial cell counts were also significantly higher in the patients with SLE and hypertension than in those with HD (8 [7-10] x 10(4)/l and 5 [3-8] x 10(4)/l (p < 0.01). CONCLUSION: The patients with SLE and hypertension show a high rate of its hyper-renin states, a propensity for nocturnal hypertension, an increase in DBP, and obvious vascular endothelial regulatory dysfunction.

[Academician V.A. Nasonova's role in the study of systemic vasculitides].

Article is dedicated to academician V.A.Nasonova contribution to the development of clinic, diagnostics and treatment of systemic vasculitides].

[System of microcirculation, markers of vascular wall damage and systematicity of the process in rheumatic diseases].

The work was aimed at studying the interrelationship of the microcirculation system and the parameters of endothelial activation with markers of inflammatory process activity in rheumatic diseases (RD). We carried out a comprehensive examination of a total of 330 patients presenting with systemic diseases of connective tissue (SDCT), rheumatoid arthritis (RA) and systemic vasculitis (SV). Studying microcirculation included impregnation of filmy preparations according to the V.V. Kupriyanov technique and biomicroscopy of the conjunctiva of the eyeball. We also determined markers of endothelial activation and lesion of vascular wall, indices of activity of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and vasculitis clinical activity index (VCAI), common carotid artery intima-media thickness (CCA-IMT), biopsy materials of the musculocutaneous flap, of the operational and autopsy materials. Determining the indices of microcirculation showed that first of all the process involves postcapillaries and venules which are dilated, becoming tortuous, with the formation of microaneurysms and stellate venules. Capillaries, postcapillaries and venules were found to contain parietally located small-grained conglomerates of blood platelets and thrombocytic masses plugging up the lumens of microvessels. Intravascular alterations were characterized by the presence of erythrocyte aggregates, stases, microthrombovasculitis, «sludge¼ phenomenon, and a decrease in capillary blood flow. Extravascular changes included perivascular haemorrhages. In arterioles and precapillaries the inflammatory process manifested itself by swelling, dystrophy and desquamation of endothelial cells, plasmatic impregnation of the walls, luminal thrombosis followed by the development of severe sclerosis and glialinosis. The morphological study showed the presence of destructive alterations in the vascular wall, fibrinoid necrosis, and infiltration-proliferative cellular reaction. The most pronounced changes in the autoimmune inflammation markers had place in RA and systemic lupus erythematosus (SLE). We revealed increased indices of inflammatory process activity such as interleukin-8, C-reactive protein (CRP). We also revealed the signs of endothelial dysfunction, manifesting itself as a statistically significant (p<0.01) increase in concentrations of the soluble vascular cell adhesion molecule (sVCAM-1), von Willebrand factor antigen (VWFA), the number of desquamated endotheliocytes (DE). Also observed was a clear-cut dependence of the level of endothelial activation markers from the degree of the processes activity. We revealed a positive correlation between the level of CRP, IgG RF, the level of sVCAM-1 and the number of DE. The levels of interleukin-8, sVCAM-1 and VWFA were elevated in patients with RD. Increased activity of the disease was accompanied by impairments at the level of the microcirculatory bed, an increase in the concentration of inflammation markers and indices of endothelial dysfunction.

[Systemic vasculitides: diagnostic stages].

AIM: To present systemic vasculitis (SV) diagnostic stages. SUBJECTS AND METHODS: Immunological and hemostatic parameters were determined, vascular scanning, histological and immunomorphological studies were performed in 360 patients. RESULTS: The main diagnostic searching stages were presented, which could reveal the key clinical signs of vasculitis and systemacy of the process, differentiate primary and secondary vasculitides, conduct clinical and instrumental studies, detect specific markers of vascular wall injury, perform a morphological study of biopsy specimens, identify the major pathogenic components of vascular bed lesion, define the possible etiology and form of vasculitis, and make a nosological diagnosis. CONCLUSION: The proposed diagnostic steps will be able to specify the nosological form of SV and the activity of the process and to define approaches to pathogenetic therapy.

[Endothelial dysfunction in rheumatic patients].

Aim - to investigate the relationship between indicators of endothelium activation and markers of inflammatory activity, in rheumatic patients. The study, involved 112 patients including 34 with systemic lupus erythematosus (SLE) and 78 with rheunmatoid arthritis (RA) aged from 19 to 62 years. The markers of endothelium activation, indices of inflammatory activity and correlation between them were investigated Patients with RA and SLE exhibited disturbed endothelial fimction, increased level of soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Wlllebrand factor antigen (Ag:vW), desquamated endotheliocytes (DE) in comparison with control (p<0, 1). Interleukin-8 (IL-8) levels in RA and SLE were significantly higher than in a control: 412,8 pg/ml, 331,1 pg/ml, 208 pg/ml respectively (p < 0,01). Significant positive correlation between RA and SLE activity scores (estimated from DAS28 and SLAM/SLEDAI respectively) and market's of endothelial dysfimction (sVCAM-I, Ag:vW DE) was documented Correlation co-efficients were R = 0, 82, 0,80 and 0,85 respectively, p < 0, 01 for RA patients; R = 0,64, 0, 69 and 0, 61, p < 0, 01 for SLE patients (SLAM); Spirmnen s coefficients 0,64, 0,53 and 0,81, p < 0,01 Jbr SLE patients (SLEDAI). Levels of endothelial dysfunction markers in RA and SLE patients increased with increasing indices of inflammatomy activity. Increased levels oflL-8, sVCAM-1, Ag:vW DE in patients with RA and SLE lead to the damage of endothelium.

[Myocardial remodeling in systemic lupus erythematosus and systemic scleroderma].

AIM: To define the significance of myocardial remodeling and its association with the activity of an inflammatory process in systemic lupus erythematosus (SLE) and scleroderma systematica (SDS). SUBJECTS AND METHODS: One hundred and sixty-seven patients, including 102 with SLE and 65 with SDS, were examined. Intracardiac hemodynamic parameters were estimated by ultrasonography on an Acuson 128 XP/10 computed sonography system, by using 3.5-MHz frequency ultrasound transducers in accordance with the standard procedure recommended by the American Echocardiography Association (1987). The Systemic Lupus Activity Measurement (SLAM) and European Consensus Lupus Activity Measurement (ECLAM) scales were used to estimate the activity of SLE and its stages in SDS. RESULTS: In patients with rheumatic diseases (RD), the spectrum of heart changes varied from latent diastolic dysfunction (DD) to the development of myocardial remodeling with signs of chronic heart failure. Examination of the types of myocardial remodeling in the patients with RD revealed all 4 geometric cardiac model types. There was a normal cardiac model in 59.2%, eccentric left ventricular (LV) hypertrophy in 18.4%, concentric hypertrophy in 19.5%, and concentric remodeling in 2.9%. In SLE, the disease activity determined the magnitude of LV hypertrophic processes (r = 0.57; p = 0.005) and DD (r = -0.43; p = 0.023). In the patients with SDS, the high activity was also associated with LV hypertrophy (r = 0.52; p = 0.015), but DD was primarily determined from the duration of disease (r = -0.44; p = 0.024). The patients with RD had LV DD no matter whether hypertension was present or absent. CONCLUSION: There is evidence for myocardial remodeling and intracardiac hemodynamic disorders in SLE and SDS and their association with the activity of the process.

[Autoimmune inflammation and heterogeneity of arterial hypertension in rheumatic patients].

The lecture presented hereinafter deals with the present-day evidence concerning interrelationships between arterial hypertension and immune inflammation in rheumatic diseases. The development of arterial hypertension, atherosclerosis, and chronic cardiac insufficiency (heart failure) in autoimmune processes is conditioned by not only classical risk factors but also by immunoinflammatory pathogenetic mechanisms of these diseases. Recently, there have appeared reports concerning the interrelationship between the activity of rheumatic diseases and the character and progression of arterial hypertension, as well as detecting elevated contents of CRP and some other cytokines, particularly tumour necrosis factor-alpha, in blood of hypertensive patients.

[VIII International Conference <« Systemic Circulation, Microcirculation And Haemorheology> (from angiogenesis to central circulation)].

From June 10th -14th, 2011, Yaroslavl played host to the traditional VIII International Conference (from angiogenesis to central circulation) with a school for young scientists. The reports discussed cellular and molecular mechanisms of changes in the microrheological properties of RBCs and WBCs. as well as a role of a series of signal compounds and their receptors in regulation of angiogenesis.Also presented were the results of using new methods of investigations such as atomic-power microscopy, computer-assisted video-biomicroscopy of vessels of bulbar conjunctiva, bioimpedance spectroscopy.Some works examined the effect of drugs and certain chemical compounds on microrheological properties of RBCs, as well as peculiarities of haemorheological indices in certain conditions:obesity, ischaemic heart disease on the background of arterial hypertension, myocardial infarction, in nephrological patients, in various types of stress, systemic lupus erythematosus, sickle-cell anaemia, chronic obstructive pulmonary disease.Some works were dedicated to acute impairments of cerebral circulation both in experimental and clinical conditions.A large aspect of the Conference's work touched upon physiological and pathophysiological mechanisms of alterations in the systemic circulation and microcirculation. A separate division of the Program was called ,Haemostasis, thromboses and haemorheology: points of interactions. There was also a master-class: ,Study of molecular signalling pathways of erythrocytes associated with alteration in their microrheologicalproperties

[Inflammation and arterial hypertension in rheumatic diseases].

The development of atherosclerosis, arterial hypertension, and chronic heart failure associated with autoimmune processes is underlain not only by classical risk factors but also by immuno-inflammatory pathogenetic mechanisms of these conditions. There are reports suggesting correlation between activity of rheumatic diseases, the character and progression of arterial hypertension, elevated blood levels of C-reactive protein and certain cytokines, e.g TNO-alpha. The present review discusses the currently available data on the relationship between AH and immune-mediated inflammation in patients with rheumatic diseases.

[Methotrexate-induced changes in the concentration of antibodies to mutaded citrullinated vimentin in blood serum of patients with rheumatoid arthritis].

AIM: To study effects of methotrexate on the titer of antibodies to mutated citrullinated vimentin (anti-MCV) and ascertain possibility of using this marker for control of treatment results and choice of individual effective dose of the drug. MATERIAL AND METHODS: A 12-month trial included 76 patients with verified rheumatoid arthritis (RA). Methotrexate per os was given in a dose 7.5-10 mg/week to 44 (57.9%) patients, 25 patients received no basic therapy. Anti-MCV (IU/ml) were detected with commercial chemicals made in Germany (ORGENTEC). RESULTS: RA patients given methotrexate doses 7.5 and 10 mg/week and untreated with basic anti-inflammatory drugs showed no significant differences by basic clinical and device parameters, level of anti-MCV at primary examination and 12 months later. CONCLUSION: Anti-MCV titer cannot be used for control of efficacy of methotrexate treatment in doses 75 and 10 mg/week, choice of individual effective doses.

[Anticitrullin antibodies--modern markers of rheumatoid arthritis].

Modern diagnosis of rheumatoid arthritis (RA) is based on the ARA criteria with seropositivity detection by the rheumatoid factor (RF). In a clinically evident stage of the disease this factor is highly sensitive and specific (about 90%), but in early RA efficacy of this diagnosis is considerably less. RF-IgM phenotype has limitation: frequent detection of this factor in the absence of RA and unstability of RF-IgM phenotype. Therefore, it is necessary to search for new serological criteria of RA diagnosis at early stage of the disease. Proteins containing citrullin appear only in the course of posttranslation modification of arginin residues. This fact gave rise to an original, available for clinical practice method of enzyme immunoassay for detection of antibodies to cyclic citrullinized (ACCP)--filaggrin derivative with synthetic cyclic citrullinized peptide serves as antigenic substance. According to the results of different studies, ACCP specificity in early RA diagnosis is more than 80%, combination of ACCP with ESR, RF-IgM, CRP, morning stiffness--more than 90%. As specificity of combination of these autoantibodies is almost 100%, their simultaneous determination is indicated in patients with undifferentiated arthritis for specification of the diagnosis. ACCP and antibodies to modified citrullinized vimentin (AMCV) significantly correlate with RA activity, are prognostic factors of rapidly progressive course and can be used for the disease prognosis at its early stage. Present-day data on comparative specificity and sensitivity of ACCP and AMCV are not certain and need further study.

[Rheumatic diseases and atherosclerosis: a role of rheological and microcirculatory impairments].

The lecture deals with the present-day views on the role of an inflammatory component in the development of atherosclerosis and accelerated formation of atherosclerotic lesions in autoimmune-aetiology vasculitis syndromes characteristic of rheumatic diseases. Both processes are typically manifested by lesions of the vascular wall in the form of inflammation, thrombosis, necrosis, and subsequent sclerotic alterations. The common links of the pathogenesis of these processes are associated with immune-system impairments, rheological and microcirculatory disorders, endothelial dysfunction, atherosclerosis, and dyslipoproteidaemia.

[Arterial hypertension in patients with systemic connective tissue diseases and hemorrhagic vasculitis].

AIM: To study the specific features of 24-hour blood pressure (BP) profile and its association with plasma renin activity in patients with systemic connective tissue diseases and hemorrhagic vasculitis (HV). SUBJECTS AND METHODS: One hundred patients aged 22 to 58 years, including 45 patients with systemic lupus erythematosus (SLE), 25 with scleroderma systematica (SDS), and 30 with HV, were examined. A control group included 30 healthy individuals. 24-hour BP profile, renal function, and plasma renin activity were studied. RESULTS: Arterial hypertension (AH) was revealed in 53% of patients. AH occurred in 62% of patients with SLE, in 40% of those with SDS, and in 50% of those with HV. In patients with systemic connective tissue diseases and HV, the 24-hour BP profile was characterized with increases in the mean values and indices of pressure load and with a predominance of subjects with inadequate decreases in nocturnal BP (non-dippers), and with the higher values of its variability in the presence of elevated plasma renin concentrations in patients with SLE. In all the patients, the elevation of BP and its circadian dynamics depended on the renal functional status that correlated with the activity of a systemic inflammatory process. CONCLUSION: The patients with systemic connective tissue diseases and HV were found to have prognostically poor types of 24-hour BP profile (night-peaker, non-dipper), the magnitude of which elevation depended on renal function and plasma renin activity.