[Autoimmunity in rheumatology: A review].

Autoimmunity and autoinflammation, co-potentiating pathological processes, are considered within the "immune-inflammatory" continuum (continuity with a variety of elements), reflecting the close relationship between the innate and acquired immune responses. Autoimmunity is the leading pathogenetic mechanism for a specific type of human chronic inflammatory disorders - autoimmune diseases, affecting more than 10% of people in the general population. Advances in molecular biology, pharmacogenetics, and bioinformatics provided the background for individualizing therapy for systemic autoimmune rheumatic diseases within personalized medicine. Studying the immunopathogenesis mechanisms, improving diagnostics, interpreting the molecular taxonomy, and developing approaches to the prevention and personalized therapy of systemic autoimmune rheumatic diseases are the priority issues of modern medicine.

[Systemic lupus erythematosus and antiphospholipid syndrome: past, present, future].

Immune-inflammatory (autoimmune and autoinflammatory) rheumatic diseases are widespread severe chronic inflammatory diseases and also "models" for studying the fundamental mechanisms of pathogenesis and approach to pharmacotherapy of other diseases associated with autoimmunity and/or autoinflammation. Uncontrolled inflammation leading to hypercoagulation forms the basis of "thromboinflammation", which is considered a universal pathogenetic mechanism of organ involvement in immune-inflammatory rheumatic diseases, as well as in COVID-19 and atherosclerotic vascular lesions (atherothrombosis). Thrombo-inflammatory mechanisms play a crucial role in systemic lupus erythematosus and antiphospholipid syndrome. Russian rheumatology, under the leadership of academician Valentina Alexandrovna Nasonova, greatly contributed to the research of these disorders. This article addresses the current view about the overlapping pathogenetic mechanisms of thrombosis in systemic lupus erythematosus and antiphospholipid syndrome, the relevance of these studies during the COVID-19 pandemic, and the prospects for antithrombotic and anti-inflammatory therapy.

[Subclinical atherosclerosis of the carotid arteries in patients with rheumatoid arthritis with low cardiovascular risk].

AIM: To evaluate the detection rate of subclinical carotid atherosclerosis in rheumatoid arthritis (RA) patients with low cardiovascular risk (CVR). MATERIALS AND METHODS: The study included 182 RA patients with low CVR (mSCORE<1%) and no established cardiovascular diseases and a control group comprising 100 people. Atherosclerotic lesion of the carotid arteries was assessed using Doppler ultrasound of the carotid arteries and was determined by the detection of atherosclerotic plaque (ASP) - the local increase in the thickness of the intima-media complex (IMT) >1.5 mm. RESULTS: Carotid ASP were observed more frequently in RA patients with low CVR than in the control group (17% versus 8%; p=0.02). The frequency of ASP in RA patients with low CVR did not depend on the disease's stage or activity and ongoing therapy. In RA, the detection of subclinical atherosclerosis was associated with traditional risk factors: carotid ASP were detected 4 times more often in men than in women (48% versus 12%, p<0.01); carotid IMT correlated with age (R=0.46), body mass index (R=0.17), LDL-C level (R=0.20), systolic blood pressure (R=0.17); p<0.05 in all cases. According to a multivariate model, in RA, the risk of developing ASP increased in the presence of dyslipidemia (odds ratio - OR 2.97; 95% confidence interval - CI 1.36-6.49; p=0.006) and arterial hypertension (OR 2.16; 95% CI 1.03-4.54; p=0.04). In RA patients with carotid ASP, sCD40L level was associated with carotid IMT (R=0.32; p=0.04) and cholesterol concentration (R=0.39; p=0.01). CONCLUSION: Subclinical atherosclerotic lesions of the carotid arteries were observed in 24% of RA patients with low cardiovascular risk and were detected almost 2 times more often than in the control group. In RA patients with low CVR, the risk of developing carotid ASP increased by 2-3 times with concomitant hypertension and dyslipidemia. The carotid IMT was associated with traditional risk factors - age, gender, lipid levels and blood pressure indicators, in cases of detection of ASP - with an immunoinflammatory marker - sCD40L.

[Comparative assessment of sensitivity and specificity of three variants of classification criteria for systemic lupus erythematosus in a cohort of Russian patients].

BACKGROUND: The clinical and serologic heterogeneity of systemic lupus erythematosus (SLE) presents challenges for diagnosis, particularly in the earliest stages of the disease when there are insufficient signs to make a reliable diagnosis. AIM: To make a comparative assessment of sensitivity and specificity of various classification criteria of SLE on a cohort of patients of Nasonova Research Institute of Rheumatology. MATERIALS AND METHODS: A total of 252 patients were included in the study; 152 (60%) of 252 patients had reliable SLE (mean age 36 [29.5-46] years, duration of disease 9 [3.4-19] years). Of 252 patients, 26 (11%) had PAPS (mean age 36.5 [31-42] years, duration of disease 4.6 [1-10.4] years). Systemic sclerosis was diagnosed in 74/252 (29%) patients, (mean age 51.5 [42-59] years, duration of disease 9 [5-16] years). The quality of the classification function of the criteria was assessed by ROC analysis. RESULTS: SLE was diagnosed in 131 (86%) of 152 patients using the American College of Rheumatology - ACR)-1997 criteria, in 145 (95%) using the The Systemic Lupus International Collaborating Clinics (SLICC) 2012 criteria, and in 144 (94.7%) using the European League Against Rheumatism (EULAR)/ACR 2019 criteria. ANF positivity was the least statistically significant of all signs in relation to the diagnosis of SLE. The area under the curve (AUC) for ANF≥1/160 titers was AUC 0.654 for the ACR-97 criteria, AUC 0.616 for the SLICC-12 SLE criteria, and AUC 0.609 for the 2019 EULAR/ACR criteria. ROC analysis of the relationship between the number of criteria/points and a reliable diagnosis of SLE revealed a high diagnostic accuracy - the AUC for all SLE criteria was greater than 0.940. In the ROC analysis of patients with SLE and PAFS, indicating the number of diagnostic criteria, sensitivity was 86% for ACR-1997, 95% for SLICC-2012, 95% for EULAR/ACR 2019, and specificity was 100, 62 and 62%, respectively. CONCLUSION: The classification criteria SLICC-2012 and EULAR/ACR 2019 are more sensitive for the diagnosis of SLE in the Russian population, and the criteria ACR-1997 are more specific. All three variants of the SLE classification criteria have sufficient sensitivity and specificity for their use in real clinical practice.

[A new integral enthesial-comorbididity index of psoriatic arthritis activity].

AIM: To develop an integral index of psoriatic arthritis (PsA) activity. MATERIALS AND METHODS: 117 patients with PsA (M/F - 63/54) were included. Patients' age 44±11 years, psoriasis (Ps) duration - 213±153 months, PsA duration - 73.4±78.5 months. Patients underwent standard clinical examination of PsA activity: tender (out of 68) and swollen (out of 66) joint counts (TJC, SJC), LEI, tenderness of the plantar fascia (PF), skin lesion severity (BSA), presence of nail Ps, body mass index (BMI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), DAPSA, FACIT-F. Parametric and nonparametric statistic methods, correlation and ROC analysis were used. RESULTS: Mean DAPSA was 38±21, TJC - 14.2±10.6, SJC - 10.6±8.3, ESR - 30.5±29.5 mm/h, CRP - 23.3±29 mg/l, LEI - 1.2±1.5, FACIT-F - 32±11, BMI - 27.4±6.2 kg/m2. The following significant positive correlations were revealed: between DAPSA and BMI, patients' age, ESR, PsA and Ps duration, TJC, SJC, LEI, presence of PF enthesitis, skin lesion severity, presence of nail Ps. A negative correlation between FACIT-F and male sex was found. Based on the predictive model of parameters, the Entesial-Comorbid Index of PsA (ECIPsA) was created: 3.81×LEI+13.72×PF+0.54×Age-0.25×FACIT-F+7.36×BSA+7.94×PsA duration+5.5×Nail Ps+0.32×BMI-3.52, namely LEI - Leeds Enthesial Index; PF - pain in the PF; patient's age; FACIT-F - fatigue scale; BSA<3%=0, ≥3%=1; PsA duration≤2 years=0, >2 years=1; presence of nail Ps=1, absence=0; ECIPsA≥28 corresponds with high PsA activity according to DAPSA≥28. ROC analysis of sensitivity and specificity of the prognostic model demonstrated high correctness of the index: the area under the ROC curve was 0.768, 95% confidence interval (0.624-0.913). CONCLUSION: The new PsA activity index corresponds to the existing ones and takes into consideration the clinical heterogeneity and comorbidity of the disease.

[Hypogonadism syndrome in men with inflammatory joint diseases: A review].

Most rheumatic diseases are characterized by sexual dimorphism both in prevalence and in the characteristics of the clinical course. Increased production of pro-inflammatory cytokines that accompanies inflammatory joint diseases may be accompanied by a decrease in the level of male sex hormones, and vice versa, the presence of hypogonadism in men increases the risk of developing certain rheumatic diseases. The review presents data on the relationship between testosterone deficiency and major inflammatory joint diseases, as well as the effect of testosterone replacement therapy on their manifestations.

Different Clinical Relevance of Anti-Citrullinated Protein Antibodies in RA Patients.

The objective of the study was to find a potential relationship between ACPAs and disease activity, bone destruction, and ACPA responses to various therapeutic regimens. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA, and 142 patients had an advanced stage of the disease. 77 (85.6%) patients with early RA were highly positive for anti-CCP, and 29 (70.7%) patients were highly positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 (r = 0.4; p = 0.04). As for advanced RA, 78 (80.4%) patients were high-positive for anti-CCP, and 70 (79.5%) were high-positive for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r = 0.4; p = 0.02), as well as CDAI (r = 0.4; p = 0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0-122.0)) were found in pts highl-positive for anti-MCV (n = 79), compared to low-positive/negative (n = 27) patients (57.0 (31.0-88.0); p < 0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment. Anti-MCV levels correlated with inflammatory activity and development of bone destruction and decreased in pts on treatment. Anti-CCP was less responsive and showed minor changes during treatment; therefore, its thorough monitoring was not feasible.

Are the Goals of Therapy Achievable in Patients with Rheumatoid Arthritis Receiving Upadacitinib in Real Clinical Practice?

The aim of the study was to evaluate the effectiveness of UPA in RA patients in real clinical practice after 3 and 6 months of therapy. The study included 63 RA patients with high activity of the disease. Activity was assessed according to the DAS28(ESR), DAS28(CRP), SDAI, CDAI; functional ability to HAQ; quality of life to the EQ-5D; disease activity according to the patient's RAPID-3 index; the level of depression and anxiety to the HADS scale. The effectiveness of therapy was evaluated after 3 (n = 45) and 6 (n = 31) months of UPA therapy. Remission or low activity of the disease by 3 months of therapy was achieved by most patients: remission of 69.8% of patients, low activity of the disease-16.3% of patients. Moderate or high activity persisted in 13.9% of patients. By the 6th month of UPA therapy, the number of remissions reached 90%, low activity 3.3%, moderate activity persisted in 6.7% of patients, high activity of the disease was not in any patient. 20% improvement in function was achieved in 71.8% of patients by the 3rd month of therapy and in 77.8% by the 6th month of treatment; the difference in average HAQ values by the 3rd month of therapy was 0.38 points, by the 6th month-0.58 points. After 3 months of follow-up, 31.1% of patients continued taking GC, by 6 months-24.2%. The dose of GC was reduced from an average of 7.23 to 5.6 mg/s. The percentage of patients requiring NSAIDs decreased from 95.2 to 35.6% and 33.3%, respectively. DMARDs continued to be received by 75.6% of patients by 3 months and 69.7% by 6 months of follow-up. Achieving remission or low activity of the disease in patients with RA receiving UPA in real clinical practice is possible in most patients. A rapid decrease in inflammatory activity is accompanied by a significant improvement in the functional state and quality of life of patients. UPA therapy reduces the need for the use of NSAIDs and reduces the dose of GC in a third of patients.

Contributing Factors of Diabetes Mellitus among Patients with Gout (Results of the Long-Term Prospective Study).

It is assumed that the risk of developing type 2 diabetes mellitus (T2DM) in patients with gout is influenced by both generally accepted risk factors and factors related to gout. The aim of the study was to evaluate the impact of various risk factors for T2DM in patients with gout. A total of 444 patients (49 women, 395 men) ≥18 years old with gout and without DM were included. The duration of observation was 5.66 [2.69; 7.64] years. To identify the factors associated with the risk of developing T2DM, multivariate logistic regression was used, which included sex; T2DM in relatives; insufficient physical activity; unbalanced diet; age  ≥ 45 years; ≥4 attacks per year; presence of tophi; BMI ≥30 kg/m2; allopurinol, febuxostat, glucocorticoids, diuretics, metformin, colchicine; GFR < 60 mL/min/1.73 m2; serum uric acid level (sUA) ≥ 420 µmol/L and  ≥ 480 µmol/L. T2DM developed in 108 (24.3%) patients. According to the multivariate model, the presence of ≥4 attacks of arthritis per year increased the risk of T2DM (OR = 5.23; 95% CI: 2.98-9.19; p = 0.0001); presence of tophi (OR = 2.61; 95% CI: 1.50-4.54; p = 0.001); sUA ≥ 480 µmol/L (OR = 2.26; 95% CI: 1.02-5.00; p = 0.144); diuretics (OR = 2.35; 95% CI: 1.19-4.64; p = 0.014). Febuxostat (OR = 0.31; 95% CI: 0.11-0.84; p = 0.022) and metformin (OR = 0.49; 95% CI: 0.21-1.16; p = 0.107) reduced the risk of developing T2DM. Risk of T2DM in patients with gout is associated with high incidence of arthritis attacks, MK ≥ 480 µmol/L, hypertension, diuretic use, and febuxostat and metformin reduces risk.

Anti-topoisomerase 1 Antibody Level Changes after B Cell Depletion Therapy in Systemic Sclerosis.

The aim of our study was to assess the relationship between the changes of antinuclear autoantibodies (ANAs) and autoantibodies to topoisomerase 1 (anti-Topo 1) in systemic sclerosis (SSs) patients on rituximab (RTX) therapy. The prospective study included 88 patients (73 women) with a mean age of 47 (17-71) years. The mean disease duration was 5.9 ± 4.8 years. The mean follow-up period was more than 2 years (27 (12-42) months). We documented a statistically significant change in skin score, the disease activity index, improvement of pulmonary function and reduction of mean dose of prednisolone after RTX treatment. There was a significant decrease in the number of patients with high levels of ANA and overall decrease of the ANA and anti-Topo 1 levels. A moderate positive statistically significant correlation was found between ANA and anti-Topo 1 (r = 0.403). In the group of patients positive for anti-Topo 1 there were a more pronounced depletion of B lymphocytes, significantly higher increase in forced vital capacity and diffusion capacity, decrease in the disease activity index, compared with patients negative for anti-Topo 1. We observed the decline in the level of ANA and anti-Topo 1 in SSc patients after RTX therapy, and it was correlated by an improvement of the main outcome parameters of the disease. Therefore, anti-Topo 1 positivity could be considered as a predictor of a better response to RTX treatment, especially in SSc patients with hyperproduction of anti-Topo 1.

Global Antiphospholipid Syndrome Score (GAPSS) in Patients with Systemic Lupus Erythematosus.

The Global Antiphospholipid Syndrome Score (GAPSS) is a tool proposed to quantify the risk of clinical manifestations associated with antiphospholipid antibodies (aPL) and certain cardiovascular risk factors. To validate GAPSS in a cohort of patients with systemic lupus erythematosus in Russia. 115 patients with SLE were included in the study, including 51 (44%) patients with systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS), 14 (12%) SLE patients with aPL, and 50 (44%) patients with SLE. There was a history of thrombosis in 58 (50%) out of 115 patients; of them, 14 (24%) had arterial thrombosis, 29 (50%) had venous thrombosis, and 15 (26%) had combined thrombosis. Pregnancy against the background of the disease occurred in 43 women included in the study. Of them, 29 (67%) had obstetric pathology. Patients with thrombosis and obstetric pathology had a GAPSS score of 7.17 ± 5.64 versus 4.48 ± 4.55 without these manifestations (p = 0.0003). There was a significant association between GAPSS levels and thrombosis: patients with thrombosis had a GAPSS of 7.31 ± 5.70, those without thrombosis-4.00 ± 4.81 (p = 0.001). GAPPS values were higher in arterial thrombosis compared to venous thrombosis (10.40 ± 25.30 versus 5.82 ± 5.28, p = 0.01). GAPSS levels  ≥ 6 and  ≥10 were analyzed to select GAPSS values at which a high risk of recurrent thrombosis and/or obstetric pathology could be indicated. All GAPSS levels had a significant association with clinical manifestations of APS. The quality of GAPSS by ROC analysis showed an area under the curve (AUC) for GAPSS of 0.697. GAPSS can be used to assess the risk of recurrence or development of thrombosis and/or obstetric pathology in patients with SLE in the Russian Federation. The GAPSS ≥6 values should be used to stratify patients with SLE into high risk group for recurrence of vascular complications. Further prospective follow-up is needed to confirm the value of GAPSS.

Antibodies to Domain I ß2-Glycoprotein 1 in Patients with Antiphospholipid Syndrome and Systemic Lupus Erythematosus.

The role of antiphospholipid antibodies (aPL), which are not included in the Sydney diagnostic criteria, in antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) is poorly understood. The aim of this study was to determine the clinical significance of IgG antibodies for domain 1 of ß2-glycoprotein 1 (ß2-GP1), IgG anti-ß2-GP1DI, in patients with APS with and without SLE. The study included 187 patients with APS with or without SLE, 49 patients formed the comparison group, and 100 apparently healthy individuals formed the control group. IgG/IgM antibodies to cardiolipin (aCL) and IgG/IgM anti-ß2-GP1 were determined by enzyme immunoassay (ELISA) in patients with or without APS, and IgG anti-ß2-GP1DI was determined by chemiluminescence assay (CLA) in all patients and controls. IgG anti-ß2-GP1DI was detected in 37 (71%) of 52 patients with primary APS (PAPS), in 6 (50%) of 12 patients with probable APS, in 42 (71%) of 59 patients with SLE + APS, in 17 (26%) of 64 patients with SLE, in 1 (2%) of the comparison group, and in none of the control group. IgG anti-ß2-GP1DI was significantly associated with PAPS and SLE + APS compared with the patients with SLE (p = 0.0002 and 0.0001, respectively). The association of IgG anti-ß2-GP1DI with clinical manifestations of APS (thrombosis (p = 0.001) and obstetric pathology (p = 0.04)) was detected. There was a significant association of IgG anti-ß2-GP1DI with arterial thrombosis (p = 0.002) and with late gestational obstetric pathology (p = 0.01). High specificity of IgG anti-ß2-GP1DI depending on the diagnosis and clinical manifestations of APS despite low sensitivity was noted: specificity was 84% for thrombosis, 94% for obstetric pathology, and 89% for APS. Isolated IgG anti-ß2-GP1DI positivity was reported in 2% of 50 aPL-negative patients and was not associated with APS manifestations. The frequency of IgG anti-ß2-GP1DI detection was higher in the patients with APS compared to the patients with SLE, comparison group, and control (p < 0.05). Positive IgG anti-ß2-GP1DI values were significantly associated with thrombotic complications and with obstetric pathology (p = 0.002 and p = 0.01, respectively). Specificity of IgG anti-ß2-GP1DI for APS and its clinical manifestations (thrombosis and obstetric pathology) was higher than sensitivity (89, 94, and 84%, respectively).

[Janus kinase inhibitors in immunoinflammatory rheumatic diseases].

Despite great advances in the diagnosis and treatment of immunoinflammatory rheumatic diseases, which have led to a significant improvement in the prognosis in many patients, the fundamental medical problems of this pathology the restoration of the quality of life and the reduction of mortality to the population level are far from being resolved. This served as a stimulus for the study of new approaches to the pharmacotherapy of IVRD, one of which is associated with the use of low molecular weight chemically synthesized drugs that inhibit intracellular "signaling" molecules Janus kinase. Modern advances regarding the use of Janus kinase inhibitors in the treatment of immunoinflammatory rheumatic diseases and COVID -19 are considered.

[The burden of progression of psoriatic arthritis. All-Russian register data].

BACKGROUND: Psoriatic arthritis (PsA) is a complex immune-mediated disease in which a third of patients with psoriasis (PsO) have a inflammatory lesion of both the musculoskeletal system (peripheral joints and axial structures) and extra-articular manifestations (dactylitis, enthesitis, nail PsO, uveitis and inflammatory bowel disease). AIM: To assess the burden of PsA progression in real practice according to the Russian register of PsA patients. MATERIALS AND METHODS: Seven hundred thirty seven M/F=350 (47.5%)/387 (52.5%) patients with PsA from the Russian register of PsA patients were included. Mean age 47.412.7 yrs., duration of PsO 200.6158.9 mo., PsA 79.681.9 mo. All patients were divided into 2 groups by PsA duration: 1st gr 36 mo 288 (39.1%) and 2nd gr 36 mo 449 (60.9%). All patients underwent standard clinical examination of PsA activity. Tender (68) and swelling (66) joint count (TJC, SJC), DAPSA, LEI, tenderness of the plantar fascia, PsO BSA (%), PASI, HAQ-DI, PsAID-12, BMI (kg/m2), ESR (mm/h), CRP (mg/l) and comorbidities by ICD-10 were evaluated. Parametric and non-parametric methods of statistical analysis were used. All p0.05 were considered to indicate statistical significance. RESULTS: In patients with PsA duration 36 mo we found significant prevalence of erosions by X-Ray, axial PsA, BMI30 kg/m2, HAQ-DI1, PsAID-124, arterial hypertension, metabolic syndrome and overall comorbidity (p0.05). There were no significant differences between groups in PsO severity by BSA3%, PASI1, LEI1, TJC, SJC, dactylitis, ESR30 mm/h, CRP10 mg/l, DAPSA, diabetes mellitus, hyperlipidemia, coronary heart disease and liver damage (p0.05). Сonclusion. Long-standing stage PsA is associated with erosions, axial PsA, worst health related quality of life, functional disability and increased cardio-metabolic disorders and overall comorbidity. Our results support the idea to start bDMARDs at early stage of PsA, it can improve better outcomes.