Introduction. Cutaneous Lupus Disease Area and Severity Index (CLASI) and its modified version, the Revised Cutaneous Lupus Erythematosus Disease Areas and Severity Index (R-CLASI) are tools for quantifying skin and mucosal lesions in patients with both cutaneous lupus erythematosus and its systemic variant. Evaluation of the scales of activity and skin damage in systemic lupus erythematosus (SLE) is associated with the need to stratify their quantitative characteristics. The Cutaneous Lupus Disease Area and Severity Index (CLASI) and its modified version the Revised Cutaneous Lupus Erythematosus Disease Area and Severity Index (R-CLASI) are a tool for quantifying skin and mucosal lesions in patients with both cutaneous lupus erythematosus (CLE) and its system version.Objective. To validate the indexes of objective assessment of skin activity and damage CLASI and R-CLASI in the Russian cohort of patients with systemic lupus erythematosus and compare it with dermatological assessments of the quality of life.Material and methods. The study included 55 patients with SLE with various types of skin and mucosal lesions, the median age was 30.0 [26.0; 40.0] years, the duration of the disease was 7.0 [3.0; 14.0] years. To assess the active (reversible) lesion and irreversible skin damage, the CLASI and R-CLASI indexes were used, for the general assessment of activity and damage in SLE, the SLEDAI-2K and SLICC/ACR DI were used.Results. The most common variant of skin lesions in patients with SLE is acute cutaneous lupus erythematosus (ACLE) – 45%, as well as alopecia, which occurs in 62% of cases. The median activity index for CLASI was 5.0 [2.0; 11.0], and R-CLASI was 7.0 [3.0; 18.0]; the median damage index for CLASI was 5.0 [2.0; 11.0], and R-CLASI was 2.0 [0.0; 7.0]. A significant relationship was revealed between the medians of CLASI and R-CLASI scores depending on the degree of activity according to SLEDAI-2K (Systemic Lupus Erythematosus Disease Activity Index) and the damage Index (DI) in SLE (SLICC/ACR DI, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) when recalculating these indexes only for skin and mucous lesions. According to the ROC analysis, the CLASI and R-CLASI skin activity and damage indices showed high sensitivity (CLASI activity index – 98%, R-CLASI – 93%, CLASI and R-CLASI damage index – 91%) and specificity (CLASI activity index – 64%, R-CLASI – 71%, CLASI and R-CLASI damage index – 86%).Conclusion. To assess the severity of skin and mucosal lesions in patients with SLE in the Russian Federation, it is reasonable to use the CLASI and R-CLASI indices. The CLASI and R-CLASI indices reflect the level of activity and severity of skin lesions, with higher values of these indices indicating more severe skin lesions and a significant impact on the overall well-being of SLE patients. Patients with high values of these indices often experience feelings of embarrassment, discomfort, difficulty in performing daily tasks, and limitations in social life. To assess the severity of skin and mucous lesions in patients with SLE in the Russian Federation, it is advisable to use the CLASI and R-CLASI indexes.

Antineutrophil cytoplasmic antibody-associated systemic vasculitis (ANCA-SV) is a group of rare and potentially severe systemic diseases. The search for reliable methods to assess ANCA-SV activity remains relevant. Among the indicators of neutrophil activation that have emerged in clinical practice, the level of serum calprotectin (CLP) stands out, which can be a marker for monitoring vasculitis activity and identifying patients at risk of disease relapse. Objective: to determine serum CLP levels in patients with ANCA-SV. Material and methods. The study group comprised 64 patients (37 with granulomatosis with polyangiitis, 11 with eosinophilic granulomatosis with polyangiitis and 16 with microscopic polyangiitis) aged 18 years and older with a confirmed diagnosis of ANCA-SV. The control group consisted of 30 healthy individuals. ANCA-SV activity was determined using the BVAS index; high activity corresponded to a BVAS value of >3. Damage was assessed using the VDI index. Depending on ANCA-SV activity, patients were divided into two groups: high activity group (group 1, n=33) and low activity group (group 2, n=31). In addition to the generally accepted indicators, serum CLP levels were assessed in all patients with ANCA-SV and healthy donors. Results and discussion. Statistically significant differences (p<0.001) were found in CLP levels in patients with ANCA-SV in groups 1 and 2. A significant correlation was found between CLP concentration and leukocyte count, neutrophil count, neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII). Blood CLP levels in ANCA-SV were associated with creatinine levels and not with glomerular filtration rate and urinary sediment. Although CLP concentration depended on disease activity, it did not correlate with acute phase indicators, including ESR and CRP concentration. Conclusion. Serum CLP concentration is significantly higher in patients with active ANCA-SV and is related to NLR and SII inflammatory indices, so we consider the possibility of using this indicator to assess disease activity.

Aim. To evaluate the levels of MPO-DNA complex in patients with systemic lupus erythematosus (SLE) and its association with the presence of lupus nephritis (LN). Materials and methods. The study included 77 patients with SLE, of whom 30 had SLE without anti phospholipid syndrome (APS), 47 had SLE with APS, and 20 were healthy individuals serving as the control group. The MPO-DNA complex in the serum was investigated using ELISA. Results. The levels of MPO-DNA complex in serum were significantly higher in patients with SLE compared to healthy controls (p=0.001). Among the patients with SLE, 30 (39%) had elevated levels of MPO-DNA complex. The presence of elevated MPO-DNA complex was significantly associated with the presence of a history of LN (p=0.009). Moreover, among the patients included in the study, 20 had active LN, and patients with elevated MPO-DNA complex levels were more likely to have active LN than patients without elevated MPO-DNA complex concentrations [12 (40%) of 30 vs 8 (17%) of 47, χ2=5.029; p=0.034]. An association was found between elevated levels of MPO-DNA complex and the presence of proteinuria, hematuria, cellular hematic/granular casts and aseptic leukocyturia. A direct correlation of MPO-DNA complex with SLEDAI-R was found in patients with active LN (rs=0.497; p=0.026). Conclusion. Elevated levels of MPO-DNA complex were detected in 39% of patients with SLE. These patients had a higher prevalence of LN in their medical history and at the time of inclusion in the study. The correlation between MPO-DNA complex levels and the activity of LN according to SLEDAI-R indicates the potential role of MPO-DNA complex as a biomarker for assessing the activity of renal damage in SLE.

An Erratum to this paper has been published: https://doi.org/10.1134/S1607672923050046

Objective: to assess the level of serum calprotectin (CLP) in Behcet's disease (BD).Material and methods. The study included 90 patients with BD (35 women and 55 men) and 30 healthy controls (22 women and 8 men). The mean age of the BD patients was 32 [26; 37] years, that of the control subjects was 30 [25; 37] years. Serum CLP levels were measured with an enzyme immunoassay using a reagent kit from Bulhmann Laboratories AG (Switzerland). Results and discussion. CLP levels were statistically significantly higher in patients with BD compared to healthy controls (median 4.08 [2.81; 7.25] vs. 2.86 [2.15; 3.92] μg/ml; p=0.003). Elevated serum CLP levels were found in 23 (26%) of the 90 patients with BD. Patients with high CLP levels were more likely to have active uveitis (odds ratio, OR 4.741; p=0.011), pustulosis (OR 3.41; p=0.044), arthritis (OR 13.89; p=0.014) and high BD activity (OR 3.195; p=0.029). A direct correlation was found between CLP level and BDCAF activity index (rs=0.415, p<0.0001), CRP (rs=0.466, p <0.0001) and ESR (rs=0.357, p=0.001).Conclusion. Serum CLP levels are elevated in patients with BD and are associated with high disease activity, active uveitis, pustulosis and arthritis.

Assessment of systemic lupus erythematosus (SLE) activity is important to determine the efficacy of treatment and to decide on further therapy. Russian-language versions of activity indices are needed to meet the needs of Russian-speaking patients and clinicians and to facilitate the use of these tools in clinical practice. An important step in this direction is the adaptation of the EASY-BILAG index, which is used to more accurately assess disease activity and select appropriate therapy in patients with SLE.

Нейтрофилы – это клетки врожденной иммунной системы, которые длительное время рассматривались только как первая линия защиты организма от чужеродных веществ. С открытием способности нейтрофилов к образованию внеклеточных ловушек (англ. neutrophil extracellular traps, NETs) в процессе нетоза (формирования NETs) расширилось представление о вкладе нейтрофилов в развитие патологии человека. В настоящее время гиперактивация нейтрофилов с повышенным высвобождением NETs рассматривается как важный механизм в патогенезе многих воспалительных, аутоиммунных заболеваний, а также тромбозов. Болезнь Бехчета и антифосфолипидный синдром (АФС) – модели хронической тромбовоспалительной патологии. В обзоре представлены современные представления о вкладе нетоза в развитие гиперкоагуляции, тромбозов при болезни Бехчета и АФС. Neutrophils are the cells of the innate immune system, which were for a long time considered only as the first line defense against allogeneic substances. The idea of neutrophils contribution to human pathology expanded with the discovery of neutrophils ability to form neutrophil extracellular traps (NETs) during NETosis (NETs formation). Neutrophil hyperactivation with increased NETs release is now considered an important mechanism in the pathogenesis of multiple inflammatory and autoimmune diseases, as well as thrombosis. Behcet’s disease and antiphospholipid syndrome (APS) are the models of chronic thromboinflammation. The review presents current views on NETosis contribution to hypercoagulability, as well as thrombosis in Behcet’s disease and APS.

Citrullinated histone H3 (CitH3) is a specific marker for NETosis; its role in determining the clinical and laboratory manifestations of systemic lupus erythematosus (SLE) remains to be elucidated. Objective : To evaluate the role of CitH3 in the development of clinical and laboratory manifestations in patients with SLE with and without an-tiphospholipid syndrome (APS). Material and methods . The study included 30 patients with SLE and 39 with SLE+APS, including 51 (73.9%) women and 18 (26.1%) men. The median age of the patients was 36 [32; 46.5] years. The control group consisted of 26 healthy individuals. SLE activity was assessed by the SLEDAI-2K index. Patients were divided into two groups: 41 patients with moderate and high SLE activity (SLEDAI-2K ≥6) were included in the first group, and 28 patients with low activity or remission (SLEDAI-2K <6) were included in the second group. CitH3 content in blood serum was determined by enzyme immunoassay using a set of reagents for the assay of CitH3 (BlueGene Biotech, China) according to the manufacturer's instructions. Results and discussion . CitH3 content in blood serum was significantly higher in SLE than in the control group (p=0.048). High blood serum CitH3 content was associated with moderate and high SLE activity (p=0.039). CitH3 concentration was inversely correlated with lymphocyte count but was not related to immunological parameters. Increased CitH3 levels were associated with photosensitivity, while lower levels were associated with a history of serositis. There were no significant differences between blood serum CitH3 levels in patients with SLE and SLE+APS (p=0.39). Conclusion . The concentration of a specific marker for NETosis, CitH3, is increased in patients with SLE, and this increase is associated with moderate and high disease activity.

Behcet's disease (BD) is a systemic vasculitis of unknown etiology, characterized by damage of vessels of any type and caliber, manifested by recurrent ulcerative process in the oral cavity and genital organs, eye damage, joints, gastrointestinal tract, central nervous system and other organs involvement. The pathogenesis of the disease is complex. The contribution of both innate and adaptive immune responses is noted. A feature of BD is hyperactivation of neutrophils and neutrophilic infiltration of affected tissues.The review presents data from studies related to the assessment of the main functions of neutrophils in this disease.

We presented two clinical cases with clinical manifestations of antiphospholipid syndrome (APS) and ankylosing spondylitis (AS). The peculiarity of these cases is the onset of diseases in childhood, as well as the presence of not only extra-skeletal manifestations, but also complications or manifestations of other pathology. In the first case, it was thrombosis of the superficial veins of the lower limbs with the development of postthrombotic syndrome. In the second case, aortic valve defect, as a result of aortitis with a dilatation of the ascending aorta, which led to aortic valve replacement and its subsequent dysfunction because of thrombosis of the valve prosthesis. The frequency of detection of antiphospholipid antibodies (aPL), APS and thrombosis in AS is discussed. The role of tumor necrosis factor α (TNFα) inhibitors in the induction of aPL synthesis and the development of APS in patients with AS is considered either. Separately, we discussed the role of TNFα inhibitors, which are the main drugs in the treatment of ankylosing spondylitis, in the induction of aPL synthesis and the development of APS. Data on the occurrence of aPL, the reasons for the development of thrombosis in APS and the role of TNFα inhibitors remains incomplete. Perhaps the combination of APS and AS is an underestimated problem, and the information available in the literature does not reflect the real numbers. It is obvious that further research is needed to improve the treatment of patients with AS with thrombosis.

Antiphospholipid syndrome is an acquired autoimmune thrombophilia characterized by the development of recurrent vascular thrombosis of any caliber and type or obstetric pathology and the mandatory identification of persistently positive antiphospholipid antibodies. The main drug in the treatment of patients with antiphospholipid syndrome is warfarin. The role of direct-acting oral anticoagulants in the treatment of antiphospholipid syndrome remains controversial. The article discusses modern data on the place of direct-acting oral anticoagulants in the treatment of antiphospholipid syndrome.

Antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are autoimmune diseases. In recent years, APS has been considered as an autoimmune thrombo-inflammatory disease. It has been established that clinical manifestations of APS can persist, progress over time, or debut during an adequate anticoagulant therapy and, in some cases, require administration of immunosuppressive drugs, which indicates the role of autoimmune inflammation in their development. The formation of extracellular neutrophil traps (neutrophil extracellular traps, NETs) is one of the connecting links of inflammation and thrombosis. Netosis is the process by which activated neutrophils in the extracellular space form netlike structures (NETs). This review examines the role of neutrophils and netosis in the pathogenesis of APS and SLE.

The paper deals with an update on biologically active additives (BAAs) and emphasizes their role in normalizing and/or improving the functional status of organs and systems, including the gastrointestinal tract microflora, in reducing the risk of diseases, etc. It gives data on the consumption and turnover of BAAs, definitions and classifications of this group of substances, the basic documents governing the control of their production and promotion in different countries and in Russia. Undenatured type II collagen (UC-II® ) that is made from the chicken sternal cartilage and is a component of Sustaflex is considered as an example of the BAA that is compliant with good medical practice regulations. The therapeutic properties of UC-II® have been confirmed in clinical trials. The paper describes the mechanism of action of the BAA, evidence for its efficacy and safety, and the possibility of its administration for the prevention and combination treatment of knee osteoarthritis (OA) and its use as an alternative treatment for OA.

Rheumatoid arthritis (RA) is characterized by a progressive course with the formation of joint deformities and the development of severe functional disorders. The most favorable conditions for changing the course of the disease emerge in the first months after its onset. Methotrexate (MTX) occupies a leading position in the treatment of RA. There is a need to develop tools that will be able to predict the efficacy and tolerability of MTX at the earliest stages of RA treatment. The concentration of active metabolites of MTX is considered as a potential biomarker that enables one to predict what response to therapy with this drug will be.The paper analyzes the most relevant works devoted to the study of the concentration of active MTX metabolites polyglutamates (MTX PGs) in patients with RA. It is shown that the presented studies do not cover all the possibilities of therapeutic drug monitoring, in particular the determination of the levels of MTX PGs in mononuclear cells over time. Further investigation is needed to develop an objective approach to prescribing MTX in RA patients.

Therapeutic control of the methotrexate (MT) polyglutamates (MTPG) level in erythrocytes can be an objective marker of the effective dose of MT prescribed for rheumatoid arthritis (RA).Objective: to assess the relationship between the level of MTPG in red blood cells and efficacy of the MT dose used by RA patients.Subjects and methods. The study included 60 patients with RA (44 women and 16 men over 18 years) who met the criteria of the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) 2010 and received MT ≥20 mg/week subcutaneously for ≥12 weeks. The patients were divided into two groups of comparable age, sex, alcohol intake, number of smokers, body mass index (BMI), depending on the presence (group 1; n=30) or absence (group 2; n=30) of the effect of MT, according to the EULAR efficacy criteria (DAS28). The concentration of MTPG (total MTPG and metabolites of MTPG 1, 2, 3, 4, 5) was determined in erythrocytes by high-performance liquid chromatography with mass spectrometric detection.Results and discussion. It was found that the levels of total MTPG and MTPG1, 2, 3, 5 in erythrocytes did not differ in groups of responders and nonresponders, and the dose of MT was comparable in both groups. At the same time, the level of MTPG4 in the first group was significantly higher (26.4±6.1 nmol/l; p=0.023) than in the second one (22.1±6.8 nmol/l). Analysis of the ROC curve showed that the values of MTPG4 <22.5 nmol/l corresponded to the absence of effect of MT. The area under the curve was 0.672 (95% confidence interval 0.536–0.808 (p=0.022), sensitivity 77%, specificity 53.3%.Conclusion. For effective treatment of patients with RA MT dose should provide MTPG4 level in red blood cells ≥22.5 nmol/l.

Objective: to analyze the reasons for discontinuation of traditional disease-modifying antirheumatic drugs (tDMARDs), biologic agents (BAs), and tofacitinib (TOFA) in patients with rheumatoid arthritis (RA) in real clinical practice.Patients and methods. The authors carried out a retrospective analysis of the data of the patients treated with tDMARDs, BAs, and TOFA, who had been included by the physicians of the V.A. Nasonova Research Institute of Rheumatology (RIR) in the all-Russian register of patients with RA (Group 1) in January 1, 2016 to November 1, 2018, the data of a pharmacology history (information about inefficacy (IE) and adverse reactions (ARs) due to the use of tDMARDs and BAs) in RA patients admitted to the V.A. Nasonova RIR during 2011–2016 for high-tech medical care (Group 2).Results. The main reasons for discontinuation of tDMARDs, BAs, and TOFA were found to be their IE and ARs.Discussion. 20% of patients with early RA never achieve not only remission, but also minimal disease activity, despite the introduction of current guidelines for its treatment. It is believed that one of the potential causes of resistance to treatment in RA is the IE of traditionally used drugs, which is mediated by transporters (ABCB1 and ABCG2) that reduce their concentrations, causing outflow from the intracellular space. The great importance of these transporters in RA is that their substrates are widely used drugs, such as methotrexate, leflunomide, sulfasalazine, aminoquinoline drugs, and prednisolone. The function of ABCB1 and ABCG2 is shown to be increased in patients with active RA, i.e. the disease activity is closely related to this phenomenon.Conclusion. IE and ARs are the most common reasons for discontinuation of tDMARDs, BAs, and TOFA in patients with RA; further investigations are needed to clarify their possible mechanisms.Objective: to analyze the reasons for discontinuation of traditional disease-modifying antirheumatic drugs (tDMARDs), biologic agents (BAs), and tofacitinib (TOFA) in patients with rheumatoid arthritis (RA) in real clinical practice.Patients and methods. The authors carried out a retrospective analysis of the data of the patients treated with tDMARDs, BAs, and TOFA, who had been included by the physicians of the V.A. Nasonova Research Institute of Rheumatology (RIR) in the all-Russian register of patients with RA (Group 1) in January 1, 2016 to November 1, 2018, the data of a pharmacology history (information about inefficacy (IE) and adverse reactions (ARs) due to the use of tDMARDs and BAs) in RA patients admitted to the V.A. Nasonova RIR during 2011–2016 for high-tech medical care (Group 2).Results. The main reasons for discontinuation of tDMARDs, BAs, and TOFA were found to be their IE and ARs.Discussion. 20% of patients with early RA never achieve not only remission, but also minimal disease activity, despite the introduction of current guidelines for its treatment. It is believed that one of the potential causes of resistance to treatment in RA is the IE of traditionally used drugs, which is mediated by transporters (ABCB1 and ABCG2) that reduce their concentrations, causing outflow from the intracellular space. The great importance of these transporters in RA is that their substrates are widely used drugs, such as methotrexate, leflunomide, sulfasalazine, aminoquinoline drugs, and prednisolone. The function of ABCB1 and ABCG2 is shown to be increased in patients with active RA, i.e. the disease activity is closely related to this phenomenon.Conclusion. IE and ARs are the most common reasons for discontinuation of tDMARDs, BAs, and TOFA in patients with RA; further investigations are needed to clarify their possible mechanisms.