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Objective: to study clinical and laboratory features in patients with anticentromere antibody (ACA)-positive SjЪgren's disease (SD), as well as the sensitivity of different methods for determination of ACA, and to elaborate an algorithm for differential diagnosis in ACA-positive patients.Patients and methods. The V.A. Nasonova Research Institute of Rheumatology followed up 136 patients who were highly positive for ACA. The investigators used the 2001 Russian criteria for the diagnosis for SD; the 2013 ACR/European League Against Rheumatism (EULAR) criteria for that of scleroderma systematica (SDS); the guidelines of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association, and the Russian Society for the Study of the Liver for that of primary biliary cholangitis (PBC)/biliary duct epitheliitis in the presence of SD. Lymphomas were diagnosed by biopsies of affected organs according to the WHO classification. SD was diagnosed in 119 patients; SDS in 49 cases (37 with SDS concurrent with SD and 12 with isolated SDS), PBC/biliary duct epitheliitis in 23 (all cases with PBC/biliary duct epitheliitis concurrent with SD and/or SDS); 5 patients were excluded from the investigation. Further analysis included 131 ACA-positive patients. The patients were divided into three groups: SD (n=82 or 62.6%); SD+SDS (n=37 or 28.24%); SDS (n=12 or 9.16%).Results and discussion. Autoantibodies to centromere peptide (CENP) A and CENP-B in the same titers were detected in all ACA-positive patients, regardless of diagnosis. Comparative analysis of three patient groups revealed no statistically significant differences in the frequency of laboratory deviations. The signs characteristic of classical SD (rheumatoid factor (RF)), anti-Ro and anti-La antibodies, leukopenia, higher ESR values, hypergammaglobulinemia, and elevated IgG/IgA levels) were found in a small proportion of patients. The frequency and severity of glandular manifestations did not differ in SD and SD + SDS. PBC/biliary duct epitheliitis was present in 17.5% of ACA-positive patients (in most antimitochondrial antibody-positive cases); no statistically significant differences in its frequency were found between the groups. Other extraglandular manifestations in SD and SD + SDS were identified in a smaller number of patients. All sclerodermic spectrum manifestations were more common in SD and SD + SDS than in BS. Pulmonary arterial hypertension was not diagnosed in any patient from the SD group. MALT lymphomas were detected in 19 ACA-positive patients. Those were present only in BS patients and absent in the SDS group. MALT lymphomas developed in the first 10 years after the onset of SD. The transformation of MALT lymphoma into diffuse large B-cell lymphoma was observed in 2 patients. The main signs of lymphomas in SD patients were persistent parotid salivary gland enlargement, decreased levels of complement C4 and peripheral blood CD19+ cells, as well as cryoglobulinemic vasculitis, serum monoclonal secretion, lymphoid infiltration in the minor salivary glands (a focus score of >4), and severe damage to the salivary and lacrimal glands.Conclusion. ACA-associated SD is an independent disease subtype characterized by an increased risk for SDS, PBC, and MALT lymphomas and by a low frequency of the systemic manifestations and laboratory signs characteristic of classical SD. Regardless of the detected type of antibodies and the presence or absence of extraglandular manifestations, damage to the salivary and lacrimal glands progresses in SD, which often leads to lymphomas; therefore, the therapy that may prevent this complication should be initiated as soon as possible after SD diagnosis. The lymphoproliferation signs identified in this investigation should be taken into account in all ACA-positive patients with SD for the early diagnosis of lymphoid tumors before therapy is prescribed. An algorithm for differential diagnosis in seropositivity for ACA is presented. Determination of autoantibodies to CENP-A and CENP-B does not allow the differential diagnosis in ACA-positive patients.

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.

In 1980, the American College of Rheumatology proposed the first criteria as tentative for the diagnosis of scleroderma systematica (SDS). These criteria were aimed at revealing the comprehensive picture of mainly the diffuse form of the disease. They could not timely make a diagnosis in the low manifestive forms of the disease or virtually reveal its early stages that were most therapeutically promising. The review traces the evolution of approaches to diagnosing SDS and considers the novel classification criteria elaborated to select patients for epidemiological surveys and clinical trials. They include 8 parameters, each having scores. Skin thickening on both hands above the metacarpophalangeal articulations was highest (9 scores). The clinical variants of skin thickening on the fingers as its swelling (2 scores) or sclerodactyly (4 scores) are estimated from the maximum scores, as digital ischemia (sores, 2 scores; cicatricles, 3 scores). Teleangiectasias and characteristic capillaroscopic changes, as well as leading lung injury (pulmonary hypertension and/or interstitial lung disease) are rated as 2 scores each. Three scores are added to the total amount when Raynaud's syndrome is present and SDS-specific (anti-Scl-70, anti-centromere, and anti- RNA polymerase III) autoantibodies are detected. The patients gaining a total of 9 scores or more are classified as having definite SDS. Testing the novel criteria on a validation sample of 405 people showed that their sensitivity and specificity were 91 and 92%, respectively.

Objective: to estimate the informative value and reproducibility of ultrasound study (USS) in interstitial lung disease (ILD) in patients with scleroderma systematica (SDS) and to compare ultrasound lung comet (ULC) scores with the data of multislice spiral computed tomography (MSCT) of the lung and its function tests. Subjects and methods. Forty patients with SSD and ILD were examined. According to the extent of lung injury, the patients were divided into two groups: 1) 12 patients with significantly pronounced changes (>20% lung involvement, as evidenced by MSCT); 2) 28 patients with just noticeable changes (

Esophageal lesion is a characteristic visceral manifestation of scleroderma systematica (SDS). Sclerodermic esophagitis complications, such as ulcers and Barretts esophagus (BE), bring a threat to life and require active and long-term therapy. Objective: to evaluate the incidence, clinical symptoms, and endoscopic picture of esophageal pathology in patients with SDS, as well as the efficiency of therapy with proton pump inhibitors (PPIs). Subjects and methods. Three hundred and fifty-six patients (women, 92.6%; men, 7.4%) aged 47.8±19.7 years with SDS and 1018 patients (women, 89.0%; men, 11.0%) aged 44.1±16.3 years with rheumatoid arthritis (RA) were examined. Out of them, 66.7 and 52.6% took glucocorticoids (GC), 21.6 and 82.9% received nonsteroidal antiinflammatory drugs (NSAIDs), 13.2 and 0% had D-penicillamine, 15.7 and 56.5% had cytotoxic drugs, and 23.7 and 8.7% had PPIs, respectively. All the patients underwent endoscopic study of the upper gastrointestinal tract. Results. The subjective symptoms of esophageal pathology were in 64.0 and 33.9% of the patients with SDS or RA, respectively (p < 0.001). Dysphagia and retrosternal pain were observed in 10.1 and 7.0% of the patients with SDS, respectively, and in only 1.7% of the patients with RA. Endoscopy revealed mucosal hyperemia in 27.4 and 1.5% of the patients, erosive esophagitis in 21.9 and 2.2%, and esophageal ulcers in 4 (1.1%) and 0%, respectively (p = 0.000). Esophageal mucosal biopsy was performed in 92 of the 356 patients with SDS, which could identify BE (intestinal metaplasia) in 19 (20.1%) cases. There was a significant correlation between the clinical symptoms of the esophagus and the endoscopic signs of erosive esophagitis (p = 0.001). There was no relationship between esophageal pathology, age, and the use of drugs (NSAIDs, GC, cytotoxic drugs). Erosive esophagitis and BE were detected in 35.0 and 36.8% of the SDS patients (n = 90) during their regular use of PPIs. All 4 patients with esophageal ulcers regularly took PPIs. Conclusion. Esophageal pathology is noted in the majority of patients with SDS and in only individual patients with RA. BE is a common complication of SDS, which requires a regular endoscopic examinations in all patients with this disease. PPIs are not always rather effective, which determines it necessary to use large doses of these drugs or combination therapy.

Objective. To compare disease history data and clinical and laboratory parameters in patients with scleroderma systematica (SDS) with high-resolution computed tomography (HRCT)-verified interstitial lung lesion (ILL) versus those without lung involvement. Subjects and methods. An examination was made in 138 patients with SDS who had been consecutively admitted in 2006-2008, female/male ratio, 124 : 14; limited : diffuse : mixed forms, 78 : 40 : 20; mean age, 47±13 years; median disease duration, 6 (2.5 11) years. The history data (occupational hazards, smoking, respiratory diseases) and clinical manifestations of SDS and laboratory data were studied. The diagnosis of ILL was established on the basis of chest HRCT. Results. According to HRCT data, the signs of varying ILL were found in 82% of the patients with SDS. The duration of SDS was similar in the patients with and without lung involvement; but the latter were younger at the time of disease onset. There were no significant differences between the groups compared in history data, clinical forms of SDS, the frequency of involvement of visceral organs and systems. Crepitation was heard only in the patients with ILL. The frequency of respiratory manifestations increased with a larger number of the involved lung segments. The prevalence of ILL was found to be positively correlated with age at the onset of SDS (r=0.29; p

Scleroderma systematica (SDS) is a disease in which vascular diseases underlie the pathogenesis and presented by diverse clinical manifestations. Raynaud's syndrome and digital ulceration are the most common symptom of the diseases, which influences the quality of life in patients and requires continuous drug therapy. The paper discusses the recent European guidelines for the management of this manifestation of SDS. The proposed recommendations cannot unfortunately be realized in full measure now due to the unavailability of some drugs. The authors give their clinical experience with therapy for the vascular manifestations of SDS.

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.