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Scleroderma systemitica (SDS) is an autoimmune connective tissue disease characterized by excessive fibrosis of the skin and viscera. SDS is prone to be chronic and progressive, is accompanied by the deterioration in quality of life and working ability and has an unfavorable prognosis. Interstitial lung disease (ILD) is one of the most common causes of death due to SDS. The lecture deals with the clinical and laboratory instrumental features of ILD in SDS. SDS-associated ILD occurs in 65–80% of patients and is highly diverse in the degree of severity and the tendency to progression. In the majority of patients, the fibrous process in the lung occurs in the early years of the disease, is limited and progresses slowly. Severe lung damage with rapid progression develops only in 10–15% of cases. Evaluation of lung damage in SDS includes pulmonary function tests, lung diffusing capacity determination, Doppler echocardiography analysis, multispiral computed tomography (MSCT) of the chest, bronchoalveolar lavage, lung biopsy with morphological examination of its specimens, as well as right heart catheterization. The best technique for detecting ILD is MSCT, as chest radiography has a low sensitivity in the early stages of the disease. IPL is treated in accordance with the 2017 ACR/EULAR guidelines; the leading role is played by immunosuppressive drugs, such as cyclophosphamide and mycophenolate mofetil. Antifibrotic drugs (pirfenidone, nintedanib) are being tested now .

The review deals with the problem of antibody production in scleroderma systematica (SDS), with a focus on antiribonucleoprotein (RNP) antibodies: frequency, structure, and clinical associations. SDS is a progressive polysyndromic disease with characteristic lesion of the skin, locomotor apparatus, viscera (heart, lungs, digestive tract, and kidneys), and common vasospastic disorders as Raynaud's syndrome, the basis for which are the processes of connective tissue disorganization with a predominance of fibrosclerotic changes and vascular pathology as peculiar endarteritis obliterans. The presence of antibodies to different autoantigens is a distinguishing feature of SDS. Among the patients who meet the classification criteria for SDS, there is a subgroup of patients who are not found to have SDS-specific antinuclear antibodies, but have antibodies to soluble nuclear autoantigens, namely, antibodies to RNP. This type of autoantibodies is described in various systemic connective tissue diseases: systemic lupus erythematosus, dermatomyositis, polymyositis, and SDS. The detection rate of anti-RNP antibodies in SDS varies from 5 to 30% in different ethnic groups. In addition, positivity for anti-RNP antibodies is a characteristic feature of mixed connective tissue disease. A more detailed study of anti-U1-RNP antibody-positive patients with SDS, by identifying a new subtype of SDS, comparing, and searching for dissimilarities of anti-U1-RNP antibody carriers from other well-described phenotypes of SDS, is of interest today. This problem is relevant, by taking into account the personalized approach to following up patients, which is actively being elaborated in rheumatology.

Interleukin 6 (IL-6) is one of the key cytokines that are involved in inflammation and that has pleiotropic properties. Diverse effects of IL-6 result from the transmission of an intracellular signal in two ways: via direct binding to a membrane receptor having a molecular mass of 80 kDA (a classical way) or absorption of the IL-6 complex with its soluble receptor on another transmembrane receptor – gp-130 (trans-signaling). Different signaling pathways lead to various consequences. The classical way of signal transmission activates mainly protective and regenerative processes; trans-signaling has a proinflammatory potential. The review gives schemes of signal stimuli and shows that IL-6 and its receptors are a dynamic intricately organized regulatory system that can adapt to stress-induced homeostatic changes. It considers in detail evidence suggesting the effect of IL-6 on the development and maintenance of a number of systemic sclerosis (SS)-specific pathogenetic disorders, such as the activation of the endothelium, the development and maintenance of inflammation, and excessive deposition of extracellular matrix components in tissues. Endothelial cell activation during trans-signaling gives rise to an enhanced adhesion molecule expression, chemokine release, and further production of IL-6. Excessive secretion of the latter may initiate a fibrosing process and favor the further development of pathological conditions. Autoimmune disorders theoretically associated with IL-6 overproduction occur in SS. Elevated blood IL-6 concentrations in SS are related to disease clinical parameters, such as activity, severity, worse prognosis, and reduced survival. Taken together, the data presented suggest that IL-6 blocking may have a therapeutic potential in SS. The first clinical data on successfully using the IL-6 receptor antagonist tocilizumab to treat SS are given.

To study the frequency and magnitude of a reduction in bone mineral density (BMD) and its association with clinical parameters in patients with scleroderma systematica (SDS).Fifty-six postmenopausal women aged 45-71 years (58.1±7.1 years) with a valid diagnosis of SDS and 44 age-matched healthy women were examined. Dual-energy X-ray absorptiometry (Hologic QDR 4500, Waltham, MA) was performed in all the included patients to measure BMD in the lumbar spine (L(I)-L(IV)), femoral neck, and proximal femur.The patients with SDS and the healthy women showed no differences in body mass index (BMI) (24.7±4.6 and 25.7±3.5 kg/m(2), respectively) and postmenopause duration (9.6±6.4 and 9.5±7.0 years, respectively); menopause occurred earlier in the patients with SDS than in the healthy women (46.9±3.6 and 49.7±3.0 years, respectively (p0.001). The patients with SDS versus the controls had a significantly lower BMD in the lumbar spine (0.821±0.121 and 0.861±0.092 g/cm(2); р0.05), femoral neck (0.620±0.129 and 0.736±0.112 g/cm(2); p0.0001), and proximal femur (0.736±0.148 and 0.884±0.124 g/cm(2); р0.0001). Osteoporosis (OP) was detected in 29 (52%) of the 56 patients and in only 5 (11%) of the 44 control women (р0.0001). The patients with diffuse SDS displayed a much greater reduction in BMD in all the regions than those with circumscribed SDS. BMD was significantly lower in the patients treated with glucocorticosteroids (GCS) than in the untreated ones. In the control group, BMD was associated with age, duration of menopause, and BMI. In the patients with SDS, BMD was correlated with BMI and inversely correlated with duration of menopause, and the magnitude of a BMD reduction was closely related to disease duration. The patients also showed an inverse correlation of BMD with the daily dose of GCS.The postmenopausal women with SDS were found to have a lower BMD in 80% of cases. In this category of women, the reduction in BMD was significantly commoner and more pronounced than in the age-matched healthy women. Low BMI, diffuse SDS, disease duration, and GCS use are risk factors for reduced BMD and OP.Цель исследования. Изучить частоту и выраженность снижения минеральной плотности костной ткани (МПКТ) и ее связь с клиническими параметрами в российской популяции больных системной склеродермией (ССД). Материалы и методы. Обследовали 56 женщин в постменопаузе в возрасте 45-71 (58,1±7,1) года с достоверной ССД и 44 сопоставимых по возрасту здоровых женщин. Всем включенным в исследование проводили двухэнергетическую рентгеновскую абсорбциометрию (Hologic QDR 4500, Waltham, MA) поясничного отдела позвоночника (LI-LIV), шейки бедренной кости (ШБК) и проксимальной части бедренной кости. Результаты. Между больными ССД и здоровыми женщинами не наблюдалось различий по индексу массы тела - ИМТ (24,7±4,6 и 25,7±3,5 кг/м2 соответственно) и длительности постменопаузы (9,6±6,4 и 9,5±7,0 года соответственно); у больных ССД отмечался более ранний возраст наступления менопаузы (46,9±3,6 и 49,7±3,0 года соответственно; p0,001). МПКТ во всех исследованных отделах у больных ССД достоверно меньше, чем в контрольной группе (0,821±0,121 и 0,861±0,092 г/см2 в поясничном отделе позвоночника, р0,05; 0,620±0,129 и 0,736±0,112 г/см2 в ШБК; p0,0001; 0,736±0,148 и 0,884±0,124 г/см2 в проксимальном отделе бедренной кости, р0,0001). ОП выявлялся у 29 (52%) из 56 больных и только у 5 (11%) из 44 женщин контрольной группы (р0,0001). У больных с диффузной ССД во всех участках отмечалось значительно большее снижение МПКТ, чем при лимитированной ССД. МПКТ у больных, принимавших глюкокортикостероиды (ГКС), достоверно меньше, чем у больных, которым не проводилось лечения ГКС. В контрольной группе МПКТ ассоциировалась с возрастом, длительностью менопаузы и ИМТ. У больных ССД наблюдалась корреляция МПКТ с ИМТ и обратная связь с длительностью менопаузы, а выраженность снижения МПКТ тесно ассоциировалась с длительностью болезни. У больных наблюдалась обратная связь МПКТ с суточной дозой ГКС. Заключение. У женщин с ССД в постменопаузе в 80% случаев выявляется снижение МПКТ. Снижение МПКТ у женщин этой категории достоверно более частое и более выраженное, чем у здоровых женщин соответствующего возраста. Факторами риска снижения МПКТ и ОП у больных ССД женщин являются низкий ИМТ, диффузная форма ССД, длительность болезни, прием ГКС.

Objective: to study the efficiency and tolerance of rituximab (RTM) treatment in patients with scleroderma systematica (SDS) with interstitial lung injury (ILI). Subjects and methods. The trial included 27 patients (26 women and 1 man) (mean age 45.7±13.0 years), with diffuse (n=13) and circumscribed (n = 14) forms and a disease duration of > 5 years in 63%. All the patients underwent chest computed tomography; examination of external respiratory function, including forced vital capacity (FVC) and diffusing capacity of the lung (DCL), as well as echocardiographic study. The efficiency of the treatment was evaluated from changes in FVC, skin score, and disease activity index. The indicators were compared prior to the treatment and one year after the first administration of RTM. The latter was injected with premedication (125–500 mg of methylprednisolone intravenously) 500–1000 mg per administration. The mean dose of RTM was low and amounted to 1.3 g per year. Results. As estimated by the physician, good, satisfactory, no effects were seen in 81.5, 14.8, and 3.7% of the patients, respectively. There was a significant increase in mean FVC one year after the first administration of RTM and a reduction in the total activity of the disease, including skin syndrome. DCL was substantially unchanged in the entire group. In the diffuse and circumscribed forms of the disease, FVC increased significantly and to the same extent. A clinically significant increase in FVC (by 11%) was achieved in patients with a disease duration of ≤5 years and mild lung injury. In people with a more than 5-year disease duration, FVC was initially decreased to a greater extent and the treatment-induced increase was only 3.7%. A significant and permanent decline in peripheral blood B lymphocytes was noted when both the standard dose (2 g) of RTM and its lower doses (0.5–1 g) were administered. RTM treatment was well tolerated, but complicated by mild intercurrent infections in 11% of cases within the first 2 months after RTM administration. Conclusion. The findings substantiate the indications for RTM use primarily in the early stage of the disease. The admittedly low doses of RTM have an inadequate effect if the disease is long-lasting. Further study of dosage regimens for RTM is required within the framework of controlled trials.

Objective: to study the specific features of regulation of peripheral vascular tone and their association with the endothelial structure and function of large vessels in patients with scleroderma systematica (SDS). Subjects and methods. The investigation enrolled 25 patients with SDS (mean age, 47±2.6 years; mean disease duration, 8.3+1.7 years) and 15 apparently healthy individuals matched for age and gender. Comprehensive examination involved laboratory and instrumental studies, laser Doppler study to evaluate endothelium-dependent and endothelium-independent vasodilation, as well as applanation tonometry calculating the pulse wave velocity and augmentation index. Results. All the patients were found to have impaired peripheral vascular responsiveness as compared to the controls. The examination established a relationship between the magnitude of endothelium-dependent vasodilation and the stiffness index of large vessels. There was no association between endothelium-independent vasodilation and vascular elasticity parameters.

Objective: to study the efficacy and safety of the endothelin 1 receptor inhibitor traclir in patients with pulmonary hypertension (PH) asso ciated with systemic connective tissue diseases. Subjects and methods. The study included 4 patients: 3 with scleroderma systematica and 1 with exanthematous lupus erythematosus. The diagnosis of PH was established on the basis of right heart catheterization data and after exclusion of all its other causes of HP. In addition to hemodynamic evaluation, the female patients underwent echocardiography (EchoCG), lung function tests, 6-minute walk test, and blood biochemical study (determination of uric acid levels). Traclir was given in a dose of 62.5 mg twice in the first 4 weeks of the study and then in a dose of 125 mg twice for the subsequent 12 weeks. Every 4 weeks, the levels of transaminases were monitored and a pregnancy test was carried out in patients of fertile age. Results. After 16-week intake of the drug, all the female patients were found to have obvious positive changes as a longer 6-min walk test distance and two female patients had improvement in the functional class of PH. Estimation of hemodynamic parameters suggested a posi tive effect in all the female patients, as confirmed primarily by an increase in cardiac index and a reduction in pulmonary vascular resist ance. According to EchoCG data, there was a substantial increase in tricuspid annular plane systolic excursion; other parameters had no informative value. During traclir therapy, there was also an increase in lung diffusion capacity and a reduction in uric acid levels. There were no adverse events throughout the trial. Conclusion. Thus, the experience with traclir used in patients with PH associated with systemic autoimmune diseases suggests its high effi cacy and safety.

Interstitial lung diseases (ILD) are a common manifestation of scleroderma systematica (SSD) that along with pulmonary arterial hypertension remains the leading cause of death in this nosological entity. As of now, cyclophosphanum remains the only immunosuppressant recommended by the European League against Rheumatism for the treatment of ILD in SSD. The paper analyzes the papers providing evidence for the efficacy of cyclophosphanum in ILD in patients with SSD. It also considers the regimens and duration of treatment with cyclophosphanum, ways of evaluating its efficacy and effects on extrapulmonary manifestations of SSD. It is concluded that cyclophosphanum has a positive, predominantly stabilizing, effect on the course of ILD in SSD.

AIM: To evaluate the short-term efficacy of the nonselective endothelin receptor antagonist bosentan in the treatment of pulmonary hypertension (PH) associated with diffuse connective tissue diseases (CTD), as well as its effect on survival in both monotherapy and in combination with other PH-specific agents/MATERIAL AND METHODS: The study included 20 CDT-associated PH patients who had been hospitalized in 2009-2013. All the patients had valid diagnoses of scleroderma systematica (SDS) (n=18) or systemic lupus erythematosus (SLE) (n=2). Bosentan was given in an initial dose of 62.5 mg/day twice for 4 weeks, then 125 mg/day twice/RESULTS: Eighteen patents completed therapy at 16 weeks. One patient with Functional Class (FC) IV PH associated with SDS died after 10 weeks of treatment because of PH progression; bosentan was discontinued in another patient following 4 weeks because of the enhanced activity of transaminases. The patients who had completed the investigation showed a significant FC decrease (from 2.9±1.0 to 2.4±1.0 following 16 weeks; р=0.03), an increase in 6-minute walking distance (from 298±140 to 375±94 m; р