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BACKGROUND: Microcirculatory dysfunction in patients with diabetes mellitus leads to tissue trophic insufficiency, reduction of adaptation reserves. It is possible to perform lifetime assessment of structural and functional changes in the microcirculation system by laser Doppler flowmetry. The presence of microcirculatory disorders is established in eyelids in chronic blepharitis and meibomian gland dysfunction. The article presents the results of the study concerning the peculiarities of neoangiogenesis as a mechanism of development of chronic blepharitis and meibomian gland dysfunction in diabetes mellitus (DM).AIM: to reveal the peculiarities of microcirculatory disorders of the eyelid in chronic mixed blepharitis in patients with type 2 diabetes mellitus (T2DM).MATERIALS AND METHODS: The study was conducted in 57 patients: 37 patients with chronic mixed bilateral blepharitis and a verified diagnosis of T2DM (group 1, n=74 eyes, average age 69.5 ± 7.5 years; subgroup 1a, n=38 eyes — patients with T2DM and glycated hemoglobin average level (HbA1с) 6.7±1.2; subgroup 1b, n=36 eyes — patients with T2DM and HbA1с average level 8.2±1.3) and 20 patients with chronic mixed bilateral blepharitis without signs of DM (group 2, n=40 eyes, mean age 67.2±4.3 years). Laser Doppler flowmetry was performed on the device «LAZMA MC-1».RESULTS: In patients with chronic blepharitis against the background of T2DM the development of ischemia of the eyelid tissue with increasing tension of functioning of the regulatory systems of microcirculation blood flow and lymph flow was detected, and in persons without DM — venous stasis with moderate inhibition of vasomotor, respiratory and dominance of cardiac oscillations of blood flow, as well as insufficiency of neurogenic oscillations of lymph flow. In this case in 1a subgroup the dominance of neurogenic oscillations of blood flow was revealed, in 1b - myogenic. Microcirculatory changes of lymph flow in the 1b subgroup were more pronounced in comparison with the 1a subgroup.CONCLUSION: The results proves the negative influence of T2DM on the microcirculatory bed of patients with chronic mixed blepharitis. The disorders detected by laser Doppler flowmetry vary depending on the HbA1с.

Background. Excessive evaporation of the tear film can lead to damage to the corneal nerve fibers and cause the occurrence of chronic neuropathic pain that mimics dryness. Laser confocal microscopy of the cornea allows you to record morphological changes in the nerve fibers of the cornea and can be a diagnostic tool for finding the substrate of neuropathic pain.Aim. To study and compare the structural changes of corneal nerve fibers in patients with burning eye syndrome and dry eye disease.Materials and methods. 54 patients (108 eyes) aged 20–35 years were examined: 17 patients (34 eyes) with a verified diagnosis of mild and moderate dry eye disease were the first group, 17 patients (34 eyes) with burning eye syndrome were the second group. The third group (control) consisted of 20 volunteers (40 eyes) of the same age, who did not have any somatic and eye diseases. The criterion for exclusion from the study was the presence of clinical signs of blepharitis and dysfunction of the meibomian glands in patients and individuals of the control group. In all patients, the number of blinking movements and the completeness of eyelid closure were determined, the Norn test and the Schirmer I test were performed. For an objective assessment of corneal nerve fibers, laser confocal microscopy of the cornea was used on a Heidelberg Retina Tomograph III device with a rostock corneal module.Results. The lowest values of the anisotropy coefficient of the corneal nerve fibers directivity were recorded in the group of patients with burning eye syndrome (2.605), which indicates the greatest changes in the structure of the nerve fiber in this group. There was no significant negative correlation between the value of the Norn sample, the number of blinking movements, and the value of the anisotropy coefficient of the corneal nerve fibers orientation in the group of patients with burning eye syndrome (r = –0.45, p = 0.07 and r = –0.45, p = 0.07). There was a statistically significant (p >0.05) increase in the number of inflammatory Langerhans cells, the length and density of their processes in the groups of burning eye syndrome and dry eye disease compared with the group of healthy volunteers.Conclusion. The method of laser confocal microscopy of the cornea can be used to detect changes in corneal nerve fibers associated with the occurrence of neuropathic pain syndrome.

During long term follow up (median 10 years) of 412 patients with primary Sjogren's syndrome (pSS) 46; (11,2%) women developed non-Hodgkin's lymphoma (NHL). Median pSS duration before development of NHL was 17 years. 43 (93,3%) patients had B-cell and 3 (6,7%) - T-cell NHL. All types of NHL were present except precursor cell lymphomas. Diffuse large B-cell lymphoma (LBCL) (39%) and MALT lymphomas (21%) prevailed. Nodal NHL with extranodal involvement (52,2%) were the most frequent. Nodal (21,8%) and extranodal (26%) lymphomas were less frequent. The most frequent target organs in lymphoproliferative disease (LPD) were lymph nodes (74%), salivary glands (45,5%), lungs (26%), bone marrow (19,5%), liver (17,5%), spleen (13%), lachrymal glands (6,5%). Waldeyer's throat ring (4%), oral cavity mucous membrane, ovary and brain (2%) were involved rarely. Immunoglobulin-secreting variant of lymphoma was revealed in 53,7% of cases. LPD developed predominantly in patients with systemic features and late stage of pSS. Significant increase of parotis, mixed monoclonal cryoglobulinemia, generalized lymphadenopathy, presence of more than 5 focuses of lymphoid infiltration in small salivary glands biopsies and thrombocytopenia were predictors of NHL development in pSS (p

Introduction. The availability of an objective assessment of the microcirculatory bed is possible when examining the vessels of the conjunctiva. This is especially true in individuals who have had COVID-19 and have diseases associated with endothelial dysfunction.Aim. To study the microcirculation in the conjunctiva after a new coronavirus infection caused by the SARS-CoV-2 virus.Materials and methods. 83 patients with a history of coronavirus infection were examined. Patients were divided into 2 groups depending on the presence or absence of comorbidities. Group 1 patients (n = 42) with post-COVID changes in the conjunctiva (severe injection of the eyeball, chemosis, microhemorrhagia, folliculosis of the tarsal and bulbar conjunctiva, the presence of a nodular formation (conflicts), slight edema of the corneal epithelium) and a history of concomitant diseases: arterial hypertension, diabetes, coronary heart disease, atherosclerosis. Group 2 patients (n = 41) with no history of concomitant diseases and similar post-COVID changes in the conjunctiva. The control group consisted of healthy volunteers without a history of coronavirus infection (n = 30). All subjects underwent laser Doppler flowmetry of the bulbar conjunctiva 3, 6, 12 months after the coronavirus infection.Results and discussion. In comparison with the control group of persons after 3 months, microcirculatory disorders were detected in both groups (group 1 – subcompensated, group 2 – decompensated). In group 1, after 6 months and 12 months, violations persisted in the subcompensation stage, which were accompanied by an increase in the intensity of the functioning of the regulatory systems of the microcirculation: the M index corresponded to normal values, and the values of σ and Kv were above the norm. After 6 months in group 2, compensation of microcirculatory disorders was noted (indicators M, σ, Kv were normal), which persisted even by 12 months of observation.Conclusion. The data obtained indicate that in patients with concomitant endothelial dysfunction, the processes of restoration of the microvasculature are slowed down.

The prevalence of diabetes mellitus has increased in recent decades. The most common ophthalmic manifestations of diabetes mellitus are retinopathy, epitheliopathies, corneal erosion and dry eye syndrome, the symptoms of which are more pronounced than in people without diabetes. The meibomian glands, which are the producer of various lipids, participate in the formation of the lipid layer of the tear film, which prevents the evaporation of the water-mucin phase and ensures the preservation of homeostasis of the ocular surface. Meibum is a lipid-rich secret produced by fully differentiated meibocytes. Impaired insulin secretion, insulin resistance, absolute insulin deficiency, as well as hyperglycemia, potentiate the development of oxidative stress and a cascade of metabolic changes, leading to a change in the anatomical and functional state of the meibomian glands, which affects the qualitative and quantitative secretion. Cytological abnormalities, as well as the structure of the excretory ducts of the meibomian glands in patients with long-term diabetes mellitus, were established using the method of laser scanning microscopy. Using the method of mass spectrometry, it is possible to determine the patterns of changes in the chemical composition of meibum in patients with diabetes mellitus. The data obtained can become one of the criteria for predicting the course, reflect the degree of compensation and / or progression of diabetes mellitus.

Introduction. World statistics indicate an increase in patients, including young people, suffering from dry eye disease (DED). Along with exogenous factors, the development of DED depends on a genetic predisposition. Changes in the expression of genes PTPN22, TRIM21, directly or indirectly affecting the T-cell link of immunity, leads to overproduction of cytokines and, as a consequence, damage to the ocular surface.This study aimed to design a diagnostic panel of genetic markers to determine the risk for DED of various etiologies development.Materials and methods. The study included 154 patients with autoimmune diseases with and without established DED. With a diagnosis of rheumatoid arthritis (RA) n = 79 and primary Sjogren’s syndrome (PSS) n = 75. The control group consisted of 100 people without ophthalmic diseases, 31 patients with exogenous DED. In this study, we use melting curve analysis to confirm the results of the association analysis for polymorphic markers in genes.Results. The prognostic value of the predisposing genotypes of the TRIM21 gene of the markers rs915956 and rs7947461 with the risk of DED in the presence of RA (p ≤ 0.001), the marker rs4144331 at the tendency level (p ≤ 0.1) was determined. The risk of developing DES against the background of PSS is associated with the presence of the predisposing genotypes of the TRIM21 genes, the rs4144331 marker, and the PTPN22 rs33996649 marker (p ≤ 0.001). The association of polymorphic markers of the TRIM21 rs7947461 gene and the PTPN22 gene of the rs33996649 marker (p ≤ 0.01) with the risk of developing exogenous DED was established.Conclusions. The predisposing genotypes were identified and the associations of polymorphic markers of the TRIM21, PTPN22 genes were established. A diagnostic panel of genetic markers has been created to predict DED of various etiologies.

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.

Introduction. Dry eye syndrome (DES) is a multifactorial disease of the ocular surface, characterized by changes in its homeostasis and accompanied by ocular symptoms, the etiology of which is associated with destabilization of the tear film, hyperosmolarity, inflammation, damage to the structures of the ocular surface and neurosensory disorders.Objective. To study the effect of a drug containing plastoquinonyldecyltriphenylphosphonium bromide (PDTP, SkQ1) on dynamics of osmolarity and reparative properties of the cornea.Materials and methods. The study included 23 patients (46 eyes) aged 23 to 49 years. All patients presented complaints of dryness, burning sensation, cramps and discomfort in the eyes, increased sensitivity with instillation of drops, periodic blurred vision. Patients underwent standard and special ophthalmic examinations. The patients were divided into two groups comparable in gender and quantitative composition.Results. Based on the results of the examination at the starting visit, all patients were diagnosed with DES mild or moderate study. After one week of therapy, a significant decrease in subjective complaints was noted patients who received the drug with PDTF. All patients tolerated the drug well. In the group of patients who received a tear replacement therapy with hypromellose, in most patients, while complaints of dryness persist, decreased a feeling of pain in the eyes. A month later, complaints persisted only in patients of this group, but their intensity was known significantly reduced compared to the visit after a week. Against the background of therapy with the drug with PDTP, significant improvement of the Schirmer test, Norn test and corneal staining, as well as with the help of a in vivo confocal microscopy shows a decrease in the number of Langerhans cells.Conclusion. The results obtained indicate a positive effect of PDTP on the structure of the ocular surface even with its short-term use due to its keratoprotective and anti-inflammatory action.

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature. Aim.To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs). Materials and methods.In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD. Results.Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs. Conclusion.pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

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 identify clinical and morphofunctional changes in the lacrimal gland in sarcoidosis.Material and methods. Ultrasonography was conducted in 53 patients (106 eyes) with a verified diagnosis of systemic sarcoidosis (7 men and 46 women) whose age was 31 to 72 years.Results. Different types of lacrimal gland structural changes in sarcoidosis were detected. Comparing the acoustic and functional findings revealed a high correlation (r > 0.7) between these parameters as vascularization index, a reflex component of tear secretion, and the presence of tubular structures. Types of changes in the acoustic structure of the lacrimal glands were identified, which were designated as edematous and polymorphic changes, as well as atrophic changes with a necrotic component.Conclusion. The findings can be used to diagnose lacrimal gland changes in patients suffering from sarcoidosis.

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.

Aim: to propose diagnostic algorithm of IgG4-related disease (IgG4-RD). Materials and methods. One center retrospective research. 52 pts with IgG4-RD were included. The diagnosis was proved histologically and immunohistochemically. 48 out of 52 pts received treatment. Treatment included one of the following schemes (along with low oral glucocorticoids): rituximab monotherapy, cyclophosphamide monotherapy or their combination. Results. The mean age was 47.4±5.9 years, the mean age of the disease onset was 43.9±16.0 years. Median time before the diagnosis was 24 months. The most often sites of IgG4-RD were lacrimal (63.5%), salivary (46.2%) glands, lungs (48%), lymph nodes (34.6%) and retroperitoneum (17.3%). In clinical picture the leading complain was organ enlargement, but not its dysfunction. Pain was characteristic for retroperitoneum localization. In 56.8% of pts with IgG4-related syalo - and/or dacryoadenitis there was association with ear - nose - throat organs affection. In 4 pts (7.7%) IgG4-RD was combined with some malignant disease, including MALT-lymphoma of lacrimal glands. Irreversible organ damage as an IgG4-RD outcome had 15.4% of pts. The main laboratory markers of IgG4-RD were ESR elevation (38.5%), blood eosinophilia (9.6%), immunological disturbances (serum total IgG and IgG4 elevation, IgE elevation, antinuclear antibodies, rheumatoid factor detection, hypocomplementemia). Serum IgG4 level >1.35 g/l was elevated in 88% of pts and correlated with the number of affected organs (Spearman correlation coefficient 0.39, Student’s test, р=0.0056). Monoclonal serum secretion and B-cell clonality in the tissue was detected in 4 (23.5%) out of 17 pts, but not all of them had both signs. Conclusion. Based on the analysis of clinical and laboratory characteristics of IgG4-RD a diagnostic algorithm was proposed that enhances the detection and examination of the patients with suspected IgG4-RD.

Objective: to identify the main types of lymphoma with the onset of involvement of the major salivary glands (MSGs), which are encountered in rheumatologic practice, and to evaluate the efficiency of minimally invasive incisional biopsies of the MSGs/lacrimal glands in the diagnosis of different diseases affecting the parotid, submandibular, sublingual, and lacrimal glands.Patients and methods. A total of339patients (291 women and 48 men) aged 18 to 78 years (median age, 55 years) with MSG involvement were examined at the V.A. Nasonova Research Institute of Rheumatology in 2004 to 2017. Minimally invasive incisional biopsies of the parotid, submandibular salivary (SMSG), and lacrimal glands were carried out to verify the diagnosis.Results and discussion. Different variants of hematological malignancies with MSG involvement were diagnosed in 187 (55%) patients; nonneoplastic diseases were in 152 (45%) patients. Primary tumors with the onset of MSG involvement were detected in 52 (15.3%) patients. Hematologic malignancies were diagnosed in 32 (61.5%) cases and 20 (38.5%) patients had various benign neoplastic or infectious diseases with MSG involvement. The prevailing hematologic malignances with MSG involvement were non-Hodgkin lymphomas (NHL), indolent MALT-lymphomas in 12 (23%) patients, follicular lymphomas in 6 (11.5%), and AL-amyloidosis affecting the SMSG in 9 (17.3%). The diagnosis was morphologically verified using minimally invasive incisional biopsy of the salivary/lacrimal glands; in all cases, the biopsy was informative for full morphopathological examination and diagnosis verification.Conclusion. Minimally invasive incisional biopsy of the MSG/lacrimal glands should be actively used in dentistry, rheumatology and blood oncology hospitals for verification of nosological diagnoses when the MSG and lacrimal glands are involved. A sufficient number of tissues obtained using these techniques allows one to abandon severe surgical interventions (partial and complete parotidectomy, SMSG removal, and orbitotomy) currently used for diagnostic purposes in various types of hospitals.

The effectiveness of topical application of various drugs in ophthalmology is no more than 3 % due to the presence of anatomical and physiological barriers. The therapeutic effect accomplishment is possible with increasing concentration or multiplicity of drug use. The article presents the results of the development of a new type of therapeutic contact lens for the deposition of medications in order to shorten the periods of treatment and to obtain a result without repeated manipulation. The quantitative evaluation of the drug content in the lens is given. The dynamics of the release of the drug substance from the lens was determined by the method of spectrometry. Practically complete elimination of the drug from the soft contact lens (SCL) depot (both on the outer and inner surfaces of the lens) is observed on the 13-14 day. With the help of the chromatography method, the absence of drug diffusion from saturated SCL during storage in buffer solutions was proved. The design features of the lens: a depot with a drug on the external and / or internal surface of the therapeutic SCL allow for a dosed and directed effect on various structural components of the oculer surface. The presence of a transparent optical center allows maintaining high visual functions. If it is necessary to prolong therapy, it is possible to re-saturate the same SCL with a drug substance.

Purpose: to study the possibilities of laser Doppler flowmetryin assessing the effectiveness of treatment of chronic Demodex blepharitis. Material and methods. The study included 33 patients (66 eyes), divided into the main and the control groups, identical in gender and age structure. The main group consisted of 16 patients (32 eyes) with chronic Demodex blepharitis. The control group included 17 patients (34 eyes) with no signs of changes in the structures of the anterior eye segment. In addition to the standard ophthalmologic examination, the patients underwent an eyelid skin microcirculation examination (using the Analyzer of peripheral blood and lymph flow LASMA MC-1 and laser diagnostic complex LASMA MC, produced by LASMA firm). The patients of the main group used Dexodem Phyto cream gel for 45 days, whereupon, after 1.5 months, an efficacy control examination was performed. Results. In the main group, typical microcirculatory disorders - arterial hyperemia of the upper eyelid and lower eyelid ischemia, and insufficient activity of the lymph of the upper eyelid - were revealed prior to treatment. After treatment, positive changes were clinically observed. Microcirculation parameters, including the perfusion and the amplitude-frequency spectrum of blood flow of both eyelids approached the normal values, and the activity of the lymphatic system improved. Conclusion. The laser Doppler flowmetry enables the examination of blood flow and lymph flow in inflammatory diseases of the eyelids, in particular blepharitis, and may be considered as an objective method of treatment effectiveness evaluation // Russian ophthalmological journal. 2017; 10 (2): 62-6. (in Russian). doi: 10.21516/2072-0076-2017-10-2-62-66.

Purpose of the study. To provide demographic, clinical, laboratory, ultrasound, radiological, morphological/ immunomorphological phenotype of IgG4-related ophthalmic diseases, which allowsmaking a differential diagnosis with granulomatous, autoimmune, inflammatory, endocrine and hematologic diseases affecting the eye and orbits. Materials and methods. From 2004 to 2016 108 (78.2%) of the 138 patients were diagnosed with non-tumoral lesions of eye and orbits. In 48 patients (35%) at admission and 5 patients in the follow were diagnosed IgG4-related ophthalmic disease. In the analysis of 82 (f-44, m-38) patients with IgG4-related disease, localization of lesions in orbit observed in 53 (f-36, m-17) and it was the most frequent involvement in patients with IgG4-related disease (64.5%). Only 7 patients had isolated IgG4-related ophthalmic disease, whereas 46 patients (87%) had involvement of 2-7 locations, as a manifestation of IgG4-related systemic disease.During the examination, the average age of patients with IgG4-related ophthalmic disease was 47.5 years (19-73 years). Median time to diagnosis was 52.8 months before 2004 and 36 months 2004-2016. Results. We noted the predominance of females in the ratio 2: 1 inthe group of patients with IgG4-related ophthalmic disease. Edema of the eyelids, nasal congestion (55-60%), tumor-like formations of the upper eyelids and increased lacrimation prevailed at the onset of the disease, whereas such functional impairment like limited mobility and pain in eyeballs, exophthalmos, ptosis and diplopia appeared later at 15-38% with a loss visual acuity in one case. Bilateral lesion (86%), mainly affecting the lacrimal glands (93.5%), infiltration of the extraocular muscles (83.5%) and retrobulbar tissue with a thickening of the optic nerve in one third of patients were the main localizations IgG4-related ophthalmic disease. Clinical symptoms were accompanied by the appearance of moderate inflammatory activity (38%), increased levels IgG (44%), IgG4(88%) and IgE (61%). Indicators of autoimmune disorders observed in 6-22% of patients, most often in patients with simultaneous involvement of the salivary glands. Significant lymphoplasmacytic infiltration (94%) with a ratio of plasma cells (IgG4/IgG) secreting IgG4> 40% (90%) with fibrosis formation (94%) and follicle formation (71%) with a moderate amount of eosinophils (34%) were the major morphological / immunomorphological manifestations of IgG4-related ophthalmic disease. Signs of vasculitis and obliterative phlebitis were found in a small amount of patients. Conclusion. Determination of elevated levels of IgG-4 / IgE in patients with edema, pseudotumor of the eyelid, sinusitis and increase of the palpebral lobe of the lacrimal gland suggests the presence of IgG4-related ophthalmic disease. Minimally invasive incisional biopsy of lacrimal glands and salivary glands followed by morphological / immunomorphological research is needed for the correct diagnosis. Diagnostic orbitotomy in ophthalmic hospitals in such cases is inexpedient, since it leads to the development of dry eye. Massive lymphoplasmacytic infiltration with IgG4 / IgG ratio more than 40%, advanced fibrosis in biopsiesof the orbits tissue or salivary glands when combined lesions are required for the making the diagnosis of IgG4-related ophthalmic disease.

The authors have described the world’s first case of necrotizing sarcoid granulomatosis (NSG) in a 22-year-old woman with the clinical presentations of acute abdomen, which are associated with abdominal lymph nodal infiltration and necrosis, obvious constitutional disturbances (fever, nocturnal sweats, and significant weight loss), high inflammatory activity (anemia, leukocytosis, high erythrocyte sedimentation rates and C-reactive protein levels), the gradual appearance of splenic and hepatic necrotic foci, and infiltration into the lung and lacrimal glands with the development of unilateral uveitis. The patient underwent five surgical interventions, several needle biopsies for recurrent abdominal syndrome, and long-term antibiotic treatment for presumed sepsis, which had caused drug-induced hepatitis. Bacteriological examination of blood, puncture samples, and removed abdominal cavity tissues, serological tests, and immunomorphogical study of biopsy samples and removed tissues yielded negative results for the presence of bacterial, fungal, and tuberculosis infections. NSG was diagnosed on the basis of the systemic nature of the lesion, the presence of granulomas with severe abdominal lymph nodal necrosis and necrotizing granulomatous/lymphocytic vasculitis in the mesentery and removed spleen, as well as the absence of granulomas in the spleen, appendix, and biopsy materials of the liver, colonic mucosa, and parotid gland. Fludarabine therapy was first used in world practice due to the inefficient treatment with high-dose glucocorticoids and cyclophosphamide and to a disease relapse when reducing their doses. The paper gives a detailed review of the literature on the clinical, laboratory, radiological, and morphological manifestations of the disease, which allow the differential diagnosis of NSG with different variants of granulomatous lesions. Based on the 5-year follow-up of the patient and on the analysis of clinical, laboratory, radiological, and morphological changes, the authors uphold the concept that the disease is an independent nosological entity: necrotizing angiitis with sarcoid reactions, rather than the entity of nodular or classic sarcoidosis.

The paper describes Russia’s first diagnosed case of Erdheim—Chester disease (systemic histiocytosis) in a 65-year-old man who has been long treated for Ormond’s disease (idiopathic retroperitoneal fibrosis). It also gives the data available in the literature on the pathogenetic components of these diseases and on the similarity of many clinical, laboratory, and morphological characteristics of these two immunoinflammatory diseases and covers the issues of their differential diagnosis. Invasive procedures with a careful morphological/immunomorphological examination of biopsy specimens obtained from affected tissues are shown to be necessary for accurate diagnosis.

IgG4-related disease (IgG4-RD) is a systemic immune-related disease that may involve the pancreas, liver, retroperitoneal space, biliary tract, salivary and lacrimal glands, eye socket, lung, and kidney. In term of pathomorphogenesis, it is a fibroinflammatory disease manifesting as a tumor-like lesion of organs, elevated serum IgG4 levels, and a morphofunctional substrate – the development of marked fibrosis and lymphoplasmacytic infiltration in the tissues with the high content of IgG4-positive plasma cells. The detection of a tumor-like nodule frequently leads to that the patients with IgG4-RD undergo major traumatic surgery for presumed cancer. At the same time, a number of investigations show the association of IgG4-RD with the development of cancer and lymphoproliferative diseases. The paper describes two clinical cases: Russia’s first diagnosis of MALT lymphoma of the lacrimal gland, IgG4-positive and IgG4-RD with a rare onset with a destruction focus in the cervical vertebrae, multiple organ dysfunction, B-cell clonality in salivary gland tissue and PIgMκ secretion. It also reviews world literature on the development of lymphoproliferative diseases in the presence of IgG4-RD.

Aim. To provide the demographic, clinical, laboratory, radiological, morphological, and immunomorphological characteristics of IgG4-related sialoadenitis (IgG4-S), which allow the differential diagnosis with neuroendocrine, granulomatous, blood cancer lesions of the salivary gland (SG). Subjects and methods. In the period 2004 to 2014, IgG4-S was diagnosed in 32 (11%) out of 289 patients with significantly enlarged parotid and submandibular glands (PG and SMG). Only 4 (9%) patients had isolated IgG4-related disease (IgG4-D) whereas involvement of a few organs ran as an IgG4-SD systemic disease in 29 (91%) patients. Results. There was a slight preponderance of women with a median onset age of 42 years. Enlargement of the SMG (52.7%), lesions of the nasal cavity and paranasal sinuses (37.2%), and enlargement of the lacrimal gland and orbital pseudotumors (31%) are the most common clinical manifestations at disease onset. A follow-up study indicated that along with involvements of SMG (97%), PG (72%), eye sockets (72%), nasal cavity and paranasal sinuses (56%), one third of the patients were found to have generalized lymphadenopathy, to frequently develop pulmonary, hepatic, pancreatic, renal injuries; and the disease ran within IgG4-SD. The laboratory manifestations were characterized by moderate eosinophilia and elevated blood IgE levels in one-third of the patients and by moderately higher erythrocyte sedimentation rate and hypergammaglobulinemia in 50%. The increased blood level of IgG (84%) and its subclass IgG4 (86.4%) is an indication for further verification of IgG4-D in patients with involvement of the major SG. Immunohistochemical examination, by measuring the concentration of IgG4-secreting plasma cells (PCs), and determination of B-cell clonality in biopsy specimens should be done to verify a diagnosis with IgG4-D. Conclusion. The determination of blood IgG4 (>2 g/l) in patients with considerably enlarged major SG may suggest the presence of IgG4-S. Minimally invasively incised PG and SMG biopsies with their subsequent morphological and immunomorphological examinations should be performed to make an accurate diagnosis. More than 40% of IgG4-secreting PCs detected in SG tissue is evidence to diagnose IgG4-D.

The data on the efficacy of rituximab (RTM) in systemic manifestations of primary Sjogren's syndrome (PSS) are limited by single trials.Objective: to evaluate the efficacy of RTM in patients with the systemic manifestations of PSS.Subjects and methods. RTM therapy was performed in 24 patients with the systemic manifestations of PSS. The mean dose of a RTM for induction therapy cycle was 2±0.3 g. Nine patients received RTM monotherapy and 12 were treated with RTM in combination with cyclophosphan. A complete clinical response was defined as complete disappearance of pre-treatment clinical manifestations; a partial one was interpreted as more than 50% improvements in some signs or cessation of half of the existing signs. A complete immunological response implied normalization of a low baseline C4 level, disappearance of cryoglobulinemia and monoclonal immunoglobulins in serum and/or their light chains in urine; a partial one meant normalization or cessation of more than half of the initial signs. The remaining cases were regarded as no treatment response. A recurrence was considered to be the reoccurrence of at least one pretreatment sign during a 3-month or more follow-up.Results. At 3 months after RTM therapy, a complete or partial clinical response was observed in 71.4% (15/21) and 19% (4/21) of cases, respectively. A complete or partial immunological response was obtained in 50% (10/20) and 25 (5/20) of the patients, respectively. At 6 months, a clinical and immunological recurrence was noted in 25% (5/20) and 33% (6/18) of the patients, respectively. There was a reduction in median ESSDAI from 8 (7–10) (median, 25th and 75th percentiles) to 3 (2–4) at 3–6 months (p

According to orbit computer tomography, lacrimal gland is involved in autoimmune process in 26.8% of patients with Graves’ orbitopathy. A short orbit is a predisposing factor of the lacrimal gland (LG) involvement in the autoimmune process. In addition to increasing of the size of the lacrimal gland, formed thickening of the optic nerve in 1 cm from the eye posterior pole (in 60% of cases), the increase in x-ray density of orbital portions of optic nerve, proved «shortening» of length in axial projection with reliable reduc- tion of length to width ratio (with increase in width at the same time) up to 5.8±0.2 are roentgenological features of this сlinical form. Change of spatial topography in orbit with reduction of the conversion rate was associated with increased rate of optic neuropathydevelopment.

Purpose: to evaluate the efficiency and tolerance of drops replacing tear with hyaluronic acid 0.15% (Hylabak, thea, France) for the treatment of tear film diseases, in particular blepharoconjunctival form of dry eye syndrome.Methods: 32 patients (range 38 to 72 years) with blepharoconjunctival form of dry eye syndrome were treated lubricant Hylabak 2-4 times a day during 7-30 days.Results: After treatment was detected the elimination of complaints in 30 of 32 people, increasing the stability of the tear film (increasing values of the samples Norn test from 7.3 ±0.5 to 10.1±0.6 seconds), as well as normalization of Schirmer test (from 8.8±0.4 to 15.2±0.5 mm).Conclusion: the study was showed high efficacy of lubricant Hylabak and subjective tolerability at blepharoconjunctival form of dry eye syndrome.

The hygienic complex for the eyelids and magnetic field actions were studied in the prophylactic and treatment of the blepharocon- junctival form of dry eye. It was placed the actions with tear’s substitute and antibacterial eye drops got to disappears of the symptoms, restorations of the tear film and improvement quality of live. the hygienic complex involved all eyelids glands but did not injure theeyelids and did not pain in the eyes.

Purpose: to analyze clinical polymorphism of endocrine ophthalmopathy in patients with Graves’ disease.Methods: Clinical and radiological data of 18 cases with clinical manifestations of lacrimal gland increase were analyzed and compared with data retrieved from 50 patients without increasing of lacrimal gland.Results: the characteristics of clinical manifestations of endocrine ophthalmopathy with lacrimal gland increase were presented. this form differs, as the organ of the target, along with orbital fat and/or eye muscles becomes the glandula lacrimalis. A correlation between fact involving, on the one hand, and the intensity and severity of the autoimmune process in orbit, on the other hand were identified.Conclusion: Involvement of this secretion organ in the autoimmune process makes the clinical course of endocrine ophthalmopa-thy more complicated, and leads to eye dry syndrome creation.

AIM: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS)/MATERIAL AND METHODS: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis/RESULTS: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD/CONCLUSION: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4-RD.

IgG4-related diseases are a new nosological entity that encompasses a few previously known diseases. IgG4-related systemic disease is diagnosed if two or more affected organs are detected. This group of diseases has two similar signs: serological (elevated serum IgG4 subclass concentrations) and histological (organ and tissue infiltration from plasmo-cytes secreting IgG4, and eosinophils, and the development of fibrosclerosis and phlebitis obliterans). The paper describes two cases. In one case, a multisystemic disease was observed virtually at its onset whereas in the other this lesion was diagnosed several years after the natural course of the disease.

AIM: To characterize a group of patients with IgG4-related disease (IgG4-RD) in a Russian population and to evaluate the efficiency of rituximab therapy/MATERIAL AND METHODS: In 2009 to 2011, at the Research Institute of Rheumatology, Russian Academy of Medical Sciences, 30 patients (16 men and 14 women; mean age 44 years) were diagnosed with IgG4-RD that was confirmed by determination of serum IgG4 levels and immunohistochemical study of biopsy samples stained for IgG4-positive plasma cells. Seven patients received rituximab therapy/RESULTS: It was assumed at baseline that there were different types of neoplasias in 12 (40%), non-Hodgkin's and Hodgkin's lymphomas in 10 (33.3%), Sjögren's syndrome in 5 (16.7%), and Wegener's granulomatosis in 3 (10%). When 2 or more locations were involved, the condition was regarded as multifocal fibrosclerosis (33.3%). Localized forms were revealed in 20 (66.7%) patients. Among them, the largest number of patients was those who had orbital pseudotumor, Mikulicz's disease, or retroperitoneal fibrosclerosis. The most common sites of involvement were orbits (66.7%), salivary glands (70%) and lymph nodes (36.7%). Comparison of serum IgG4 levels in 28 patients with IgG4-RD, 22 patients with Sjögren's disease, salivary and lacrimal gland lymphomas, and 10 healthy controls showed that the concentration of IgG4 was significantly higher in Group 1 (median 2.6 g/l; IQR 1.22-4.65 (p

AIM: To evaluate the efficacy of rituximab (RT) in cryoglobulinemic vasculitis (CGV) and MALT lymphomas of the parotid gland (PG) in patients with Sjögren's disease (SD). /MATERIAL AND METHODS: RT therapy was performed in 13 patients with SD and CGV and in 17 with SD and PG MALT lymphoma. Eleven patients with SD received RT monotherapy and 19 with this disease had combined therapy with RT and cyclophosphan (CP). RT was used intravenously dropwise at a dose of 500 mg weekly or once every two weeks in combination with intravenous dropwise CP 1000 mg the next day with 4-6 per course. For the diagnosis of MALT lymphomas, all the patients with SD underwent incisional PG biopsy under local anesthesia at the Research Institute of Rheumatology, Russian Academy of Medical Sciences. PG biopsy specimens were histologically and immunohistochemically studied at the Russian Cancer Research Center, Russian Academy of Medical Sciences. In 11 cases, B-cell clonality was identified from immunoglobulin (Ig) heavy chain genes rearrangements, by using polymerase chain reaction at the Hematology Research Center, Ministry of Health and Social Development of the Russian Federation /RESULTS: Cutaneous manifestations of vasculitis disappeared in 75% of cases after monotherapy with RT and in 100% of cases after combination therapy with RT and CP. At 6-month follow-up, a complete response to therapy remained in 25% of the patients after a course of monotherapy and in 83% after combined therapy. Serum monoclonal Ig cryoglobulins and their urinary light chains ceased to be detectable in 75% of the patients in both groups at 3 months. At 6 months, a recurrence of mixed monoclonal cryoglobulinemia was seen in 50 and 43% of cases after monotherapy and combined therapy, respectively. The clinical and laboratory response of cryoglobunemic glomerulonephritis to combined therapy with RT and CP was complete in 60% of cases at 6-month follow-up. After RT monotherapy, the patients with SD and PG MALT lymphoma achieved a complete clinical response in 88%, of whom histological and immunohistochemical reexaminations of PG biopsy specimens revealed no signs of MALT lymphoma in 71% of cases. B-cell clonality remained in the PG biopsy specimens following RT monotherapy. After the combination of RT and CP, a complete clinical response to therapy was observed in 100% of the patients, a complete histological response and a complete molecular one were seen in 83 and 60%, respectively /CONCLUSION: RT showed its efficacy in treating SD patients with CGV and PG MALT lymphomas.

Aim. To analyze clinical and laboratory features of cryoglobulinemic vasculitis (CGEV) associated with HCV infection. Material and methods. We examined 61 patients with clinical manifestation of CGEV in 2006-2011. CGEV was associated with autoimmune diseases in 31 patients (51 %), with HCV infection in 21 patients (34,4 %), essential (idiopathic) cryoglobulinemia in 8 patients (13 %) and lymphoproliferative diseases in 1 patient (1,6 %). 21 patients with HCV-associated CGEV were studied for main clinical and laboratory manifestations of the disease. Kidney and liver involvement was confirmed morphologically and immunomorphologically. Electroneurophysiological investigation evaluated peripheral nervous system involvement. Biopsy of parotid, lacrimal glands, peripheral lymph nodes, splenectomy and bone marrow trephine biopsy with morphological study and immunohistochemistry were used to identify type of lymphoma. Characteristics of monoclonal secretion were assessed with high-resolution electrophoresis in agarose gel with subsequent immunofixation of sera and concentrated urine. Results. Liver involvement was detected in 66 % of patients with HCV-associated CGEV., 34% patients were chronic HCV carriers with persistently normal liver function tests. Common rheumatologic manifestations of HCV-associated CGEV were skin lesions (90%), arthralgia (85%), frequent peripheral nervous system involvement (52%) and glomerulonephritis (38%). Prevalent immunological markers of CGEV associated with HCV were mixed monoclonal cryoglobulinemia with rheumatoid factor activity (62%), rare polyclonal (34%) and olygoclonal (4%) cryoglobulinemia, low levels of С4 compliment fraction (80%). Patients with mixed monoclonal cryoglobulinemia often developed clinical manifestations of Sjögren s syndrome (23 %) and malignant lymphoproliferative diseases (14 %). CGEV is a prognostically adverse sign in HCV infected patients and caused death of 14% patients even in a short period of follow-up (1-2 years).

The authors analyzed the hormonal profile of patients with Graves’ disease and endocrine orbitopathy with or without autoimmune dacryoadenitis. Presented compelling evidence about the role of hormonal imbalance between thyreoglobulines and thyroidstimulating hormones in the development of autoimmune dacryoadenitis. The availability of this kind of imbalance increases the risk of involvement of lacrimal gland in the pathological process with 12.3 % up to 64.3 % in the population with Graves’ disease and endocrine orbitopathy.

The paper describes a case of Mikulicz's disease (MD) in a young woman (aged 19 years) with symmetrical large salivary gland lesion concurrent with the enlarged lacrimal glands. Immunomorphological and molecular studies of parotid gland biopsy specimens revealed the formation of MALT tissue without signs of B-cell clonality of an infiltrate. The diagnosis of lacrimal sac lymphoma was ruled out. MD was diagnosed. The use of rituximab in therapy for MD has first demonstrated a positive result in Russian and worldwide practice.

Aim. To investigate the incidence of MALT-lymphoma in Sjogren's disease by means of biopsy of the enlarged parotid glands. Material and methods. The incisional parotid biopsy was performed in 57 primary Sjogren's syndrome (pSS) patients with existing parotid enlargement. The median age was 54 years (range 19-75 years). The median pSS duration was 7 years (range 1-30 years). The palpable parotid enlargement was defined as grade 1 and massive (visional) enlargement of the parotid glands was defined as grade 2. Histologic and immunohistochemical examinations for diagnosis of lymphoma were made. High resolution electrophoresis and immunofixation were performed for detection of monoclonal immunoglobulins in the serum and their free light chains in the urine. Results. Biopsy of he enlarged parotid glands identified MALT-lymphoma in 37 of 57 (64.9%) pSS patients. Of 37 pSS patients with parotid enlargement of grade 2, diagnosis of MALT-lymphoma was made in 89.2%. Of 20 pSS patients who had parotid enlargement of grade 1, MALT-lymphoma was diagnosed in 20%. In patients with grade 1 enlarged parotid glands MALT-lymphoma was identified only in cases with the presence of monoclonal immunoglobulins in the serum and their free light chains in the urine (3 of 4 patients) or in case of disseminated disease (lymphoma involved regional lymph nodes and soft tissues of the face) - 1 of 4 patients. In patients with grade 2 enlargement of parotid glands MALT-lymphoma located most frequently in affected parotid glands (69.6%). Conclusion. The incisional biopsy of enlarged parotid glands is necessary for detection of MALT lymphoma in pSS patients.

Tsel' issledovaniya. Otsenit' effektivnost' dlitel'noy terapii bolezni Shegrena (BSh) malymi dozami glyukokortikoidnykh (GK) i alkiliruyushchikh tsitotoksicheskikh (ATs) preparatov Materialy i metody. V issledovanie vklyucheno 412 patsientov (406 zhenshchin i 6 muzhchin) s BSh, nablyudavshikhsya v Institute revmatologii v 1975 - 2007 gg. Mediana nablyudeniya - 9 (5-15) let. Sredniy vozrast bol'nykh na nachalo nablyudeniya - 44,8 goda. Mediana dlitel'nosti BSh do pervogo postupleniya - 9 let, mediana vozrasta debyuta BSh - 33 goda. Effektivnost' dlitel'noy terapii malymi dozami GKu 151 bol'nogo (mediana - 10 let), malymi dozami ATsu 147 bol'nykh (mediana - 5 let) otsenena v sravnenii s rezul'tatami lecheniya 94 bol'nykh, poluchavshikh tol'ko «oftal'mologicheskie» i «stomatologicheskie» metody terapii. Rezul'taty issledovaniya. Pokazano, chto terapiya malymi dozami GK i ATs polozhitel'no vliyala na nekotorye zhelezistye i vnezhelezistye proyavleniya zabolevaniya, odnako k snizheniyu veroyatnosti razvitiya limfoproliferativnykh zabolevaniy (r=0,036) i povysheniyu vyzhivaemosti bol'nykh s BSh privodila tol'ko terapiya ATs (r=0,037). Razrabotany i predstavleny metodiki lokal'nogo ispol'zovaniya GK pri tyazhelykh oftal'mologicheskikh i stomatologicheskikh proyavleniyakh BSh. U 150 bol'nykh s BSh s tyazhelymi sistemnymi proyavleniyami predstavleny pokazaniya i protivopokazaniya dlya provedeniya pul's-terapii (PT), kombinirovannoy PT, plazmafereza, krioafereza i dvoynoy fil'tratsii plazmy v sochetanii s kombinirovannoy PT. Pokazano, chto naznachenie malykh doz GK i PT u zhenshchin s BSh s sokhranennym menstrual'nym tsiklom privodit k bolee rannemu nastupleniyu menopauzy i sposobstvuet razvitiyu glyukokortikoidnogo i postmenopauzal'nogo osteoporoza v otdalennye sroki. Otseneny naibolee znachimye pobochnye proyavleniya terapii GK i ATs pri razlichnykh variantakh terapii BSh.

Aim. To specify the risk of severe systemic manifestations and transformation into malignant lymphoma in Sjogren's disease (SD) patients with monoclonal mixed cryoglobulinemia (MMC). Material and methods. A prospective study performed in 1985-1990 included 248 SD patients followed up after the initial detection of monoclonal immunoglobulins (Ig) with serum active rheumatoid factor (RF). The patients' cryoglobulins (CG) were examined. The type of CG was determined by electrophoresis in agarose gel combined with immunofixation and Immunoelectrophoresis with monospecific antisera to heavy and light Ig chains. Biopsies of the lower lip salivary glands and skin were made in all the patients with MMC and 40 patients without CG. The biopsies were studied histologically, histochemically and immunomorphologically. Clinical symptoms and prognosis were studied in all the patients observed in 1985-2000 after the initial diagnosis of MMC. In suspected lymphoma development, histological and immunophenotypical studies of lymph node, bone marrow biopsies, trephine biopsies were made as well as myelograms, Ga-67 scintigraphy, CTofthe thoracic and abdominal cavities. The total of clinical, morphological, immunophenotypical and cytogenetic characteristics of lymphoma was estimated by REAL classification. Results. CG at first examination was detected in 50 (20.2%) of 248 patients with SD. 20 (40%) of 50 patients were diagnosed to have MMC with monoclonal IgM% (19) and IgA (1) in the serum with RF activity. Ten (50%) patients with MMC developed lymphoma after 10.9 ±3.3 years, on the average. In the absence of CG lymphoma developed in 5.5% (p < 0.001). B-cell intoxication in patients with diffuse lymphadenopathy, foci of lymphoid infiltration in the lungs, ulcers of the cms and such indices as stab neutrophilic shift, monocytosis, hypoproteinemia with hypogammaglobulinemia, disappearance of the RF, CG, low CIC level, immunodeficiency of monoclonal Ig and appearance of the protein BJ in the urine are markers of developing large B-cell immunosecreting lymphomas. Highly aggressive diffuse LCL resulted in death of 70% SD patients with MMC; 30% died of immunocomplex cryoglobulinemic vasculitis. 10-15-year survival of SD patients after detection of MMC was 50%, free of CG - 97% (p < 0.001). Conclusion. MMC is a definite serological marker of developing lymphoma and ulcerative-necrotic vasculitis in SD. In detection of MMC in SD patients it is necessary to prescribe early pathogenetically validated treatment before development of life threatening manifestations.

Aim. To examine clinical features of Sjogren's syndrome (SS) and morphological picture of the lesser salivary glands (LSG) in chronic hepatitis С (СНС). Material and methods. The examination of 42 patients with SS and chronic HCV infection (mean age 44.3 ± 13.7 years) has detected signs of chronic hepatitis and hepatic cirrhosis, respectively, in 31 (71.4%) and 11 (26.2%) patients. "Dry syndrome" was diagnosed by criteria of European SS Study Group. LSG biopsy of the lower lip was conducted in 23 (54.7%) of 42 patients. Results. The "dry" syndrome in CHC ran subclinically in 73.8% patients. Apparent symptoms of SS were seen primarily in middle-aged and aged women with CHC history over 10 years. The first signs of SS occurred in 25 (59.5%) patients 2.9+3.1 years prior to diagnosis of hepatic disease. All the patients had xerostomy. Xerophthalmia was recorded 1.5 times less frequently. In 16 (47.1%) patients with CHC "dry eye" and in 6 (17.6%) patients dry keratoconjunctivitis were detected. Pathohistological changes of LSG were diagnosed in 21 (91.3%) of 23 patients with CHC. In the majority of cases (86.9%) the glands exhibited insignificant inflammatory infiltration and advanced fibrosis. LSG in CHC is characterized by fibrosis prevalence over cell infiltration. 83.3% CHC patients had SS and other extrahepatic lesions. SS was most evident in 28.6% CHC patients with cryoglobulinemia. Conclusion. Registration of SS symptoms in CHC patients depends on targeted examination of patients with chronic HCV infection. The severity of the symptoms correlates directly with the infection duration and age of the patient. LSG lesions in CHC patients with SS are characterized by fibrosis predomination over cell infiltration.