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The article discusses the importance of ultrasound examination of the salivary glands in Sjogren’s disease for the diagnosis, as well as for assessing the activity of the disease. The characteristics of the main ultrasound changes in the salivary glands and the pathogenetic reasons of these changes are given. The results of studies of the dynamics of changes in ultrasound parameters both in patients not receiving treatment and in the presence of various methods of therapy are presented. The paper also provides basic data on the role of ultrasound in the differential diagnosis of diseases involving the salivary glands.

Objective: to determine the frequency, spectrum and severity of liver affection in anti-centromere antibodies (ACA) positive patients with primary Sjogren's syndrome (pSS).Patients and methods. 119 ACA-positive patients with pSS were included in the study, 37 (31%) of them had signs of liver damage, 3 of these patients were excluded from the study (2 had cholelithiasis, 1 had viral hepatitis B). Signs of autoimmune liver damage were found in 34 (28.6%) patients, most of them were seropositive for antimitochondrial antibodies (AMA). The diagnosis of primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. In 5 (14.7%) patients the cause of cholestasis remained unspecified.Results and discussion. AMA were found in 73.5% of patients, elevated serum IgM levels – in 57.6%. Clinically liver damage in most cases was characterized by an asymptomatic, slowly progressive course without a dramatic increase of symptoms over time. Liver cirrhosis was found in 14.7% of patients. According to clinical, laboratory and morphological manifestations, PBC was diagnosed in 21 patients, 4 of them also had a cross syndrome with AIH. AMA-negative PBC was found in 3 patients and isolated AIH – in 1. In most cases, histological stage I of PBC was detected. During follow-up, median of 7 years (range from 2 to 15 years), in 7 patients with stage I PBC and in 7 AMA-positive patients without functional liver disorders no clinical, laboratory or instrumental progression of liver damage was noted. In this regard, it was suggested that these patients have epitheliitis of the biliary ducts as manifestation of glandular affection in pSS, and not true PBC.Conclusion. Autoimmune liver lesions are detected in 28.6% of ACA-positive patients with pSS, most (41.2%) of them develop epitheliitis of the biliary ducts as pSS manifestation or a combination of pSS with PBC (with the same frequency), less often PBC / AIH cross syndrome is diagnosed. PBC / pSS-related epitheliitis of the biliary ducts in ACA-positive patients is characterized by a slowly progressive asymptomatic course in most cases and rarely leads to the development of liver cirrhosis.

Objective: to compare clinical and laboratory manifestations in 2 groups of patients with primary Sjogren’s syndrome (pSS): with and without anticentromere antibodies (ACA); compare the incidence, clinical and laboratory characteristics of lymphomas in these two groups.Materials and methods. We examined 119 patients with ACA-positive pSS (pSS-ACA+). pSS was diagnosed based on Russian 2001 criteria, systemic sclerosis (SSc) – criteria ACR/EULAR 2013. To diagnose liver diseases, the level of transaminases, alkaline phosphatase and antimitochondrial antibodies (AMA) was determined, as well as liver biopsy. The diagnosis of primary biliary cholangitis (PBC) was established according to the recommendations of the American Association for the Study of Liver Diseases, the Russian Gastroenterological Association and the Russian Society for the Study of the Liver. Lymphomas were diagnosed according to histological, immunohistochemical and molecular studies of affected organs biopsies, according to the classification of the World Health Organization. A combination of pSS and SSc was diagnosed in 37 patients, and they were excluded from further analysis. We compared clinical and laboratory features in patients with pSS-ACA+ (n=82) and ACA-negative pSS (pSS-ACA–, n=64) and characterized lymphomas in the pSS-ACA+ (n = 14) and pSS-ACA– (n=10) groups.Results and discussion. In patients with pSS-ACA+, a later age of disease onset was revealed, the duration of the disease before lymphoma development did not differ. In patients with pSS-ACA+, we found a lower frequency of rheumatoid factor (RF), antibodies to Ro (anti-Ro) and La (anti-La), decreased C3-complement, hypergammaglobulinemia, increased IgG concentration, CRP, increased ESR, leukopenia and anemia. 51.2% of patients with pSS-ACA+ were seronegative for anti-Ro, anti-La and RF. Patients with pSS-ACA+ had a higher frequency of AMA and elevated IgM. The incidence of cryoglobulinemia and paraproteinemia did not differ. The frequency of recurrent parotitis in pSS-ACA+ was significantly lower, there were no differences in the frequency and severity of other signs of salivary and lacrimal gland damage. PBC and epitheliitis of the biliary ducts in patients with pSS-ACA+ were detected significantly more often. Damage to the peripheral nervous system, lungs, hypergammaglobulinemic purpura, arthralgia and autoimmune thyroiditis were significantly more often detected in the group of patients with pSS-ACA–. In the pSS-ACA+ group, Raynaud’s phenomenon was significantly more frequent, mainly with scleroderma-type capillaroscopic abnormalities. There was no difference in the frequency of other signs characteristic of SSc. MALT lymphomas were diagnosed in the study groups with the same frequency. Patients with lymphomas in the pSS-ACA+ group were characterized by significantly higher laboratory activity. All patients with lymphomas in both groups showed persistent parotid salivary gland enlargement. Lymphomas in both groups developed in patients with late stage salivary and lacrimal gland damage, systemic manifestations of pSS in both groups were rare.Conclusion. pSS-ACA+ is an independent subtype of pSS, which has a number of significant clinical and laboratory differences from the “classic” variant of the disease. ACA in pSS are associated with a low frequency of anti-Ro, anti-La, and RF, as well as an increased risk of PBC and limited SSc. MALT lymphomas in the pSS-ACA+ and pSS-ACA– groups developed with the same frequency and were associated with the progression of glandular damage, regardless of the presence of systemic manifestations.

Aseptic necrosis of bone is a serious disease that, if detected early and with adequate therapy, can be cured. Late diagnosis and lack of therapy leads to rapid joint destruction and patient disability. The proposed draft guidelines are a part of the National Clinical Guidelines for Aseptic Bone Necrosis (Osteonecrosis). Purpose of the study was creating an algorithm for diagnosing and treating osteonecrosis based on assessment of the level of evidence of literature data. The Guidelines reflect aspects of the clinical, instrumental and laboratory examination of patients with osteonecrosis, treatment options depending on the localization of the process and stage of the disease.

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.

Objective: to study the clinical and laboratory features of patients with anticentromere antibody (ACA) positive Sjö gren’s syndrome (SjS); to assess the spectrum of autoantibodies in patients of this group; to determine the frequency with which the SjS patients who are highly positive for ACA, meet the international classification criteria for SjS and systemic sclerosis (SS); to reveal the incidence of MALT lymphomas in this patient group; to estimate the incidence of primary biliary cirrhosis (PBC)/biliary lesions as part of autoimmune epithelitis in SjS in this patient group.Material and methods. A total of 83 patients with ACA positive SjS were comprehensively examined at the V.A. Nasonova Research Institute of Rheumatology during the period 2012 to 2018. The inclusion criteria were con formity to the 2001 Russian SjS criteria and a high ACA level. MALT lymphomas were diagnosed on the basis of histological and immunohistochemical studies and polymerase chain reaction-based determination of B-cell clonality in the biopsy samples of affected organs according to the World Health Organization classification of Hematopoietic Tumors. The diagnosis of PBC/biliary lesions was made on the basis of histological and immunohistochemical studies of liver biopsy specimens.Results and discussion. The investigation revealed low detection rates for anti-Ro antibodies (32.5%), anti-La antibodies (7.2%) and rheumatoid factor (RF) (21.7%), which were typical for the classical SjS immunophenotype), increased ESR (14%), leukopenia (7%), hypergammaglobulinemia (17.6%), elevated levels of IgG (9.5%) and IgA (18.7%), and hypocomplementemia (16.1%) in the ACA positive SjS patients. Despite the low detection rate of RF, 15 (18%) patients in this group developed MALT lymphomas: 14 patients had salivary gland MALT lymphoma and one patient had tonsil MALT lymphoma with peripheral lymph node involvement (generalized marginal zone lymphoma). Also, the patients of this group showed high detection rates for AMA antibodies (34.6%), increased IgM level (29.7%) and a higher risk for PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS (14.5%). AMA-antibodies were absent in only two patients who were diagnosed with liver disease according to biopsy specimens. Nervous system and renal lesions, antiphospholipid syndrome, rheumatoid arthritis, hypergammaglobulinemic purpura, and cryoglobulinemic vasculitis were much less common and sporadic. Also ACA-positive SjS patients often have Raynaud’s phenomenon (54.9%) with scleroderma-type capillaroscopic changes (68%) and a limited form of SS (24%) according to the 2013 ACR criteria.Conclusion. ACA-positive SjS is a subtype of the disease, which is significantly different from the classic one in a number of clinical and laboratory signs and characterized by an increased risk for SS, MALT lymphomas, and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS which in some cases leads to the underdiagnosis of SjS. ACA should be considered as pathogenetically related to SjS autoantibodies; and all patients who are seropositive for ACA should be examined for SjS and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS regardless of whether they have SS or not, as well as complaints of dry mouth and eyes. Patients with significantly enlarged salivary glands should undergo biopsy to rule out or confirm MALT lymphoma before initiating hormonal, antilymphoproliferative, and anti-B-cell therapy.

Osteoarthritis (OA) and other large joint diseases remain an unsolved problem of modern orthopedics and rheumatology. The use of intra-articular injections of various drugs, including hyaluronic acid, is widespread in both our and foreign countries; however, the efficiency of treatment is not always sufficient, despite its high cost. One of the most effective and inexpensive methods for treating OA is intra-articular ozone therapy that has recently become widespread. The ability of ozone to suppress joint inflammation, to improve blood supply, including that to the subchondral bone, and to reduce pain is considered to be the main advantages of this method. The safety and low risk of adverse reactions allow ozone to be used in a wide range of patients.

The paper describes a clinical case of a female patient with bacterial sialadenitis. The specific features of this case are sialadenitis concurrent with serum monoclonal secretion, as well as the absence of the effect of previous antibacterial therapy. The author describes basic directions in the differential diagnosis of sialadenitis, which requires that rheumatic, granulomatous, and tumor diseases should be ruled out.

IgG4-related disease (IgG4-RD) is a systemic immune mediated condition that is characterized by the formation of tumor-like fibroinflamma-tory foci in different organs and by the elevation of serum and tissue IgG4 levels in the majority of patients. The pathogenesis of the disease, including the role of IgG4, has not been established exactly. Serum and tissue IgG4 hypersecretion is a nonspecific sign and occurs in many rheumatic, infectious, and malignant diseases. Objective : to determine the range of nosological entities associated with the increase in serum IgG4 levels, as well as the frequency and nature of this increase in patients with IgG4-RD. Patients and methods . The results of all serum IgG4 measurements carried out in the Laboratory of Immunology and Molecular Biology of Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, in 2017—2018 were analyzed. Serum IgG4 parameters were separately estimated in 52 patients with verified IgG4-RD according to the universal diagnostic criteria proposed by H. Umehara et al (2011). Results and discussion . In 2017—2018, a total of247patients were tested for serum IgG4 levels. The latter were elevated in 76 (30.8%) patients, but only 28 (36.8%) were diagnosed as having IgG4-RD. Along with IgG4-RD, antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) were characterized by increased serum IgG4 levels. The highest median IgG4 level was found in patients with a verified diagnosis of IgG4-RD: 6.31 vs 3.2, 3.22, and 2.69 g/L in ANCA-associated vasculitis, RA, and SLE, respectively. In 52 patients with IgG4-RD, the IgG4 level >1.35 g/L was found in 88% of cases. The median serum IgG4 level was 3.45 g/L (2.1; 11.4). The highest level was observed in patients with generalized lymphadenopathy and in those with IgG4-related sialoadenitis and dacryoadenitis (Mikulicz disease). The serum IgG4 level was positively correlated with the number of affected organs (Spearman's correlation coefficient, 0.39; p=0.0056, Student's t-test). All the patients showed a tendency towards decreasing serum IgG4 levels during treatment regardless of its clinical response; however, the levels returned to normal only in 73% after 12 months of treatment. Conclusion . The increased serum and tissue IgG4 concentration is not specific, but at the moment it is the only disease marker available in clinical practice. To correctly interpret the diagnosis, it is necessary to assess the entire set of clinical manifestations, imaging data, and morpholopathological findings.

This case is the first description of the successful anti-B-cell therapy with rituximab in a patient with Sjogrenʼs syndrome and neuromyelitis optica spectrum disorder in Russia. This article contains the literature data on clinical manifestations and methods of the diagnosis of neuromyelitis optica spectrum disorder. Furthermore, contemporary view on the pathogenesis of the combination of this disease with Sjogrenʼs syndrome are presented here.

Objective. To reveal changes of CD+CD25+FoxP3+ T-regulatory cells (T-reg) number in pts with systemic lupus erythematosus (SLE) receiving rituximab and to assess relationship T reg content with changes of disease activity and serum autoantibodies level during treatment. Material and methods. 12 pts with definite SLE were included. Pts were examined before treatment, after 1, 3 and 6 months. Besides routine laboratory tests anti-double-stranded DNA antibodies, B lymphocytes and T reg cells number was evaluated with flow-cytometry. SLE activity was assessed with SLEDAI 2K scale. Rituximab 500 mg was administered every week iv during 4 weeks. 4 pts received combined treatment with cyclophosphan. Results. Mean age of pts was 30,5±9,8 years (Me 31 years, varied from 18 to 49 years), disease duration varied from 7 to 148 months. T reg number before treatment was not decreased and did not correlated with anti-DNA antibodies level. T reg markers (Foxp3+, CD25+, CD4+CD25+) changes and values of SLE activity on SLEDAI 2K after the end of treatment correlated with presence of clinical response to treatment with rituximab in 3 months. Binary logistic regression model including 4 above mentioned predictors in total allows predicting correctly clinical response to therapy in 83% of cases. Conclusion. Changes of CD25+, CD4+CD25+, CD4+CD25+FoxP3+ T-cells number immediately after the end of treatment with rituximab correlated with clinical effect of the treatment and determined subsequent response to anti-B cell therapy.

Aim: TO assess the effects of rituximab (RTM) therapy on clinical and morphologic activity of lupus nephritis (LN). Material and methods: The study included 45 patients with confirmed diagnosis of systemic lupus erythematosus (SLE), unaffected by previously received standard therapy with glucocorticoids (GCs) and cytostatics. The disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K); to assess the LN activity we used the SLICC RA/RE index. Forty-five patients with LN were given puncture renal biopsy prior to prescribing RTM; 16 patients had repeated renal biopsy 1 year and more after beginning the anti-B-cell therapy. LN was graded histologically in accordance with the WHO classification (2003) with indices of activity (AI) and chronicity (CI). Results: The predominant number of patients had class III - IV of LN. The repeated renal biopsies demonstrated that LN had undergone a transition into a more favourable morphologic class, which was associated, in most of these cases, with a positive therapeutic effect. The follow-up dynamics showed a statistically significant reduction of AI (p=0.006), and no statistically significant changes in the CI (p = 0.14). Conclusion: The long-term follow-up in the study has showed that repeated courses of anti-B-cell therapy with RTM have a positive effect both on SLE activity and generally on the renal process. The reduction of the morphologic class of LN as assessed in the repeated renal biopsies is a convincing proof for this. Eleven out of 16 patients experienced transition of the morphologic class into a more favourable type, which in most cases was combined with lower AI (p = 0.006). We found no evidence of increase in the CI (p = 0.14).

CD4+CD25+ regulatory T cells (Tregs) play an important role in maintaining tolerance to self-antigens controlling occurrence of autoimmune diseases. Recently, it has been shown that the transcription factor forkhead box P3 (FoxP3) is specifically expressed on CD4+CD25+ T cells. FoxP3 has been described as the master control gene for the development and function of Tregs. We characterized CD4+CD25+CTLA-4+FoxP3+ T cells in 43 patients with systemic lupus erythematosus (SLE). Twenty of them comprised a group of newly admitted patients with the first manifestations of the disease, and the second group included patients that were treated with cytostatics and steroids. The results revealed a significant decrease in CD4+CD25+ and CD4+CD25high T cells numbers in patients from group I compared with control and group II patients. Coexpression of FoxP3 on CD4+CD25+ T cells was significantly reduced in both groups regardless the therapy. The ability of Tregs to suppress proliferation of autologous CD8+ and CD4+ T cells was significantly reduced in both groups of patients compared to healthy donors. Our data revealed impaired production of Tregs in SLE patients that can be partly restored by conventional treatments.

Objective. To evaluate the efficacy and safety of rituximab (RTM) treatment in the long-term follow-up of patients with systemic lupus erythematosus (SLE) refractory to standard therapy. Material and methods. RTM therapy was prescribed to 97 SLE patients with high disease activity and insufficient effica- cy of using high doses of glucocorticoids (GC) and cytostatics. The median follow-up time (25th; 75th percentiles) was 18 [12; 36] months. The most common clinical manifestations of SLE included nephritis (62%), skin lesion (33%), and lesion of the nervous system (22.7%). The clinical assessment of the SLE activity was carried out using the SLEDAI-2K activity index. In assessing the therapy efficacy, the following concepts were used: the partial response (PR), complete response (CR), and flare. Flare was classified as moderate (MF) and severe (SF) using the SLE flare index (SFI). Results. Immediately after RTM therapy, depletion of B-cells was determined in 78% of the patients with SLE. During the 6-year follow-up, the effect of RTM therapy was achieved in 84% of the patients after repeated courses of RTM (CR – 56%, PR – 28%). In total, flares were observed in 24 (24.7%) patients; the median interval from RTM administration to flare was 12 [12; 24] months. In the long-term follow-up, the decline in the SLEDAI-2K index, normalization of laboratory test values, and the decrease in the daily GC dose were noted. Most patients tolerated well both the first and repeated courses of RTM therapy. Conclusion. According to the results of the long-term follow-up, RTM therapy is a highly effective method to treat SLE patients with the ineffectiveness of previously conducted standard therapy with GC and cytostatics. Good tolerance of RTM treatment has been noted; no increase in risk of infectious complications or adverse reactions has been found.