[NETosis in lupus nephritis].

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.

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).

[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.

[Mental disorders in patients with systemic lupus erythematosus: association with activity and the course of rheumatic disease].

AIM: To clarify the relationship between the clinical and psychopathological features of mental disorders, clinical and laboratory manifestations of activity and the nature of the course of systemic lupus erythematosus (SLE). MATERIALS AND METHODS: The study included 119 patients - 98 (82.4%) women, mean age 36.5±12.4 years (M±SD) - with a reliable diagnosis of SLE (EULAR/ACR 2019 criteria), 51 (29.5%) of them - with secondary antiphospholipid syndrome - APS (International criteria of 2006). RESULTS: Among patients with SLE a high frequency of anxiety-depressive spectrum disorders (ADSD) and cognitive impairment (CI) was revealed. There was an association of greater severity of depression with high SLE activity index, acute/subacute onset of the disease course according to the classification of V.A. Nasonova, relapsing-remitting and chronic active current disease activity patterns of SLE according to the classification of S. Barr - M. Petri. Anxiety disorders were associated with subacute onset and relapsing-remitting disease activity patterns of SLE and were not associated with SLE activity index. Bipolar disorder was detected more often in patients with chronic SLE. Acute psychosis/delirium was associated with acute onset of SLE. Organic CI was associated with APS, chronic onset and long quiescent disease activity patterns of SLE. The episindrome and schizotypal disorder in patients with SLE are more often caused by concomitant APS. CONCLUSION: Patients with high SLE activity index should be of particular concern to rheumatologists regarding the diagnosis of depressive disorders. Patients with concomitant APS need timely diagnosis and treatment of CI and episindrome in order to improve the prognosis of the disease and the overall quality of life.

[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.

[Antibodies to the phosphatidylserine/prothrombin complex in the diagnosis of antiphospholipid syndrome].

AIM: To determine the significance of antibodies to the phosphatidylserine/prothrombin complex (aPS/PT) in patients with systemic lupus erythematosus (SLE) antiphospholipid syndrome (APS). MATERIALS AND METHODS: A total of 190 patients were included in the study: 123 (64.7%) with reliable SLE and 55 (29%) with PAPS. The control group included 100 relatively healthy subjects of comparable age. All patients were tested for classical aPL as well as IgG/IgM-anti-PS/PT by enzyme immunoassay. RESULTS: Based on the average values of IgG/IgM aPS/PT of the control group, the levels of positivity were allocated mean (M) + 3 or 5 standard deviations (SD): M+3SD and M+5SD. IgG aPS/PT levels above 73.6 U/ml (M+5SD) were more accurate diagnostic, for IgM aPS/PT above 18.0 U/ml. IgG-aPS/PT were detected in 84 (44%) of 190 patients. Levels above diagnostic levels were detected in 68 (65%) of 104 patients with APS (55 with PAPS and 59 with SLE+APS). Thrombosis was significantly more common in patients with IgG aPS/PT compared with patients negative for IgG aPS/PT. Arterial but not venous thrombosis was associated with IgG aPS/PT positivity. CONCLUSION: The frequency of detection of IgG aPS/PT in the examined patients was 44%, IgM aPS/PT 29% and their combination 19% of 190 patients. Half of the patients with probable APS had positive IgG aPS/PT and third IgM aPS/PT. Median IgG aPS/PT were significantly higher in patients with APS compared to patients without APS and the control group. Thrombosis was associated with IgG aPS/PT. Arterial thrombosis was significantly more frequently reported in patients with IgG aPS/PT. The sensitivity of IgG aPS/PT for reliable APS at levels greater than 73.6 units/ml was 59%, specificity 92%, for IgM aPS/PT 35% and 91%, respectively.

Study of antiphospholipid antibodies by enzyme immunoassay and chemiluminescent methods in patients with antiphospholipid syndrome and systemic lupus erythematosus (preliminary data).

Antiphospholipid antibodies (aPL) are a family of different autoantibodies that lead to recurrent vascular thrombosis of any localization and caliber, and/or obstetric pathology - fetal loss. Serological markers of antiphospholipid syndrome (APS) include only three types of aPL - lupus anticoagulant (VA), antibodies to cardiolipin (aCL) classes IgG and IgM, antibodies to ß2-glycoprotein1 (aß2GP1) classes IgG and IgM. Medium and high levels of aCL and aß2HP1 (IgG and / or IgM) were selected as serological markers of APS in the 2006 classification criteria. However, the threshold of values used from low to moderately high levels has not been standardized. aPL standardization issues are still unresolved, resulting in heterogeneous results of the ongoing studies. The aim of the study was to assess the comparability IgG/IgM-aCL and IgG/IgM-ab2GP1 by enzyme-linked immunosorbent assay and chemiluminescent analysis in patients with APS with and without (systemic lupus erythematosus) SLE. The study included 70 patients (49 women and 21 men) with APS, of which 21 (30%) were with primary APS (pAPS) and 49 (70%) with APS in combination with SLE. All study participants underwent determination of IgG/IgM-aCL and IgG/IgM-aß2GP1 by enzyme-linked immunosorbent. A study was performed by the chemiluminescent analysis: IgG/IgM-aCL - in 70 patients; IgG/IgM-aß2GP1 - in 69 patients. Results. According to preliminary data, the determination of IgG-aCL and IgG-aß2GP1 by the chemiluminescent analysis is informative in assessing positivity according to the manufacturer, compared with the enzyme-linked immunosorbent (p < 0.05). However, when taking into account the levels of antibody positivity determined by enzyme-linked immunosorbent, the level of positive values according to chemiluminescent analysis was much higher than the performance of the manufacturer.

[Thrombotic microangiopathy in rheumatology: a link between thrombosis and autoimmunity].

Uncontrolled hypercoagulation and inflammation (thromboinflammation), which are both independent and closely related and amplifying each other pathological processes, form the basis for pathogenesis of a wide range of diseases and complications, including immuno-inflammatory (autoimmune) rheumatic diseases, with the development of potentially fatal injuries of internal organs. Thrombotic microangiopathy is one of the most prominent prototypes of thromboinflammatory pathological conditions. The close link between environmental factors, hemostasis genetic defects and the complement system, inflammation and autoimmunity as pathogenetic mechanisms of microthrombosis draws particular attention to studying thrombotic microangiopathy in immuno-inflammatory rheumatic diseases, primarily systemic lupus erythematosus, antiphospholipid syndrome and scleroderma renal crisis. In future, these studies may be important for expanding the idea of the role of autoimmune mechanisms in pathogenesis of critical hemostasis disorders in human diseases, and for developing new approaches to therapy. Recently, special attention has been paid to the treatment of systemic lupus erythematosus and antiphospholipid syndrome with eculizumab, which is humanized monoclonal IgG2/4k antibody that blocks the complement component C5a and the membrane attack complex (C5b-9) formation, and which is registered for the treatment of atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, as well as severe forms of myasthenia gravis and neuromyelitis optica. Further studies in this direction will create prerequisites for improving the prognosis not only in patients with orphan disorders, but also for widespread human diseases.

[Mental disorders and cognitive impairment in patients with antiphospholipid syndrome].

Mental disorders (mainly anxiety and depressive disorders) and cognitive impairment are often found in patients with antiphospholipid syndrome (APS), but their prevalence, structure, and mechanisms of occurrence are not well researched. The review provides literature data on the frequency, spectrum and possible causes of mental disorders and cognitive impairment in patients with APS, the pathogenetic mechanisms of these disorders (in particular, the important role of antiphospholipid antibodies, stress factors, chronic inflammation), the relationship between APS, mental disorders and as well as cognitive impairment is examined. Special attention is paid to the influence of mental disorders and cognitive impairment on patients adherence to treatment, their quality of life, as well as the particularities of psychopharmacotherapy of mental disorders in patients with APS. The aim of the review is to actualize the interdisciplinary problem of mental disorders and cognitive impairment in patients with APS and the need to introduce a partnership model of care.

[Effectiveness and safety of selective and non - selective factor Xa inhibitors in antiphospholipid syndrome and systemic lupus erythematosus: anti - Xa - activity range].

The aim of the study was to evaluate the anti - Xa - activity (aXa) of selective and non - selective factor Xa inhibitors in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) patients according to clinical implications and laboratory parameters. MATERIALS AND METHODS: Clinical and laboratory data were analyzed retrospectively in SLE and APS patients who protractedly received low weight molecular heparins (LWMH) and selective factor Xa inhibitors fondaparinux and rivaroxaban. The study included 70 patients in the middle age 39 [31; 43] years: 15/70 (21%) - with SLE, 10/70 (14%) - with APS and 45/70 (65%) - with SLE and APS (SLE+APS). All the patients received anticoagulants: 29 patients - nadroparin (98.3 [67.8; 129.5] IU/kg/day), 29 patients - fondaparinux (5 [5; 7.5] mg/day), 3 patients - enoxaparin (1.2 [0.8; 1.5] mg/day) and 9 patients - rivaroxaban (20 mg/day). All the patients signed informed consents. RESULTS: aXa therapeutic range of 0.1-1.5 IU/ml was found in 43/70 (61%) patients, low aXa - in 14/70 (20%) and high aXa - in 13/70 (19%) patients. Patients with low aXa underwent anticoagulant dose correction. There were not any major bleedings and thrombosis relapses in the study. Increased aXa was more common in patients, who took fondaparinux (31%), than in those, who took nadroparin (7%) and rivaroxaban (23%), p=0.02. Patients with enoxaparin had normal aXa range. In the absence of bleeding in SLE and APS patients, received anticoagulants in standardized therapeutic dose, the next factors influenced the aXa range excess: valvular heart disease (VHD) with the 3rd stage of mitral valve insufficiency as a result of aseptic Libman-Sacks endocarditis (odds ratio - OR 9.02, 95% confidential interval - CI [1.53; 53.12], p=0.015), peripheral artery disease in analogy with arteritis obliterans (AO) (OR 6.86, 95% CI [1.25; 37.71], p=0.027), and also triple - positivity of all types of antiphospholipid antibodies (OR 4.93, 95% CI [1.11; 21.99], p=0.036). According to found logistic regression model, aXa range excess risk can be prognosticated by the next formula: Z = -3.98 + 2.2 × VHD (yes-1/no-0) + 1.9 × AO (yes-1/no-0) + 1.6 × Triple - positivity (yes-1/no-0). Classified function value Z=0.39 defines the patients group with aXa range excess. Thus the value Z>0.39 indicates aXa range excess in the absence of bleeding, herewith sensibility is of 77% and specificity is 86%, positive prognostic value is 84.3%. CONCLUSION: In SLE and APS patients the next clinical and immunologic manifestations influenced the aXa therapeutic range excess: peripheral artery disease in analogy with AO, earlier aseptic Libman-Sacks endocarditis with the 3rd stage of mitral valve insufficiency and triple - positivity of all types of antiphospholipid antibodies, that does not need LWMH and fondaparinux dose correction. In contrast, anticoagulant dose reduction can cause clinical symptoms progression. Therapeutic aXa range in such patients should be extended.

[Chronic thromboembolic pulmonary hypertension developed in a female patient with lupus erythematosus and secondary antiphospholipid syndrome]. / Khronicheskaia tromboémbolicheskaia legochnaia gipertenziia, sformirovavshaiasia u bol'noi sistemnoi krasnoi volchankoi c vtorichnym antifosfolipidnym sindromom.

Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the potentially curable forms of pulmonary hypertension, in which pulmonary thromboendarterectomy is the gold standard treatment. However, over the last decade, great attention has been given to a combined therapeutic approach including both drug therapy and surgical treatment and the application of endovascular technologies. This clinical case demonstrates the diagnostic difficulties of CTEPH and the opportunities of a comprehensive approach to therapy for the disease with mandatory assessment of preoperative surgical and medical treatment in order to improve the patient status and to prepare for surgery.

[Anxiety-depressive disorders and stress factors in patients with systemic lupus erythematosus and antiphospholipid syndrome]. / Osobennosti rasstroistv trevozhno-depressivnogo spektra i stressovykh faktorov u bol'nykh sistemnoi krasnoi volchankoi i antifosfolipidnym sindromom.

OBJECTIVE: The aim of this work was to analyze the frequency and, spectrum of mental disorders (MD), and stressful factors, as well as the characteristics of anxiety and depressive spectrum disorders (ADSD) in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). MATERIAL AND METHODS: The study included 155 patients (37 (23.9%) men and 118 (76.1%) women) aged 18 to 69 years ((M±SD) 37.7±12.3 years), including. 61 (39.3%) patients - with a reliable diagnosis of SLE according to the 2019 EULAR/ACR criteria, 48 (30.9%) patients with - SLE with secondary APS and 46 (29.7%) - with primary APS (PAPS), established according to the international criteria of 2006. RESULTS: The majority of the examined patients were found to hadve MD (current MD in 145 (93.5%) patients). ADSD prevailed in all groups: in 58 (95.1%) patients with SLE, in 42 (87.5%) - with SLE with APS and in, 39 (84.8%) - with APS. Patients with SLE were exposed to stressful events in childhood (predominantly parental deprivation) more often than patients with SLE with APS and PAPS were exposed to stressful events in childhood (93.4% versus 81.2% and 69.6%, respectively; predominantly parental deprivation). ADSD in these patients developed mainly in pre-adolescence, with a tendency towards chronic variants without remission, which leads to a greater vulnerability of the patients in this group to stressful events compared with patients with APS (p=0.05). CONCLUSION: When diagnosing and treating MD in patients with SLE and APS, special attention should be paid to the analysis of the history of stressful eventsstress history of patients, which affects the formation of common predisposing and provoking factors, both MD and RD, aggravating their course and prognosis.