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Aim of the work – to compare the frequency of upper respiratory tract (URT) involvement in patients with ANCAassociated vasculitides (AAV), to reveal its main clinical and radiological patterns and to estimate their association with the serological profile (ANCA presence and type).Material and methods. This retrospective study evaluated 369 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The enrolled patients were diagnosed with AAV according to the ACR criteria, CHCC classification (2012) and EMA algorithm. Patients with URT manifestations underwent standard ENT assessment and X-ray/CT. Serum ANCA levels were measured by ELISA.Results. URT involvement was diagnosed in 280 (75.9%) patients with AAV. It was significantly more common amongthe patients with GPA (86.4%) and EGPA (85.5%) compared with the MPA group (29.2%) (pConclusion. The frequency and patterns of upper respiratory tract manifestations depend both on the nosologic form of AAV and type of ANCA. Localized forms of URT involvement can be observed in patients with GPA and are closely associated with absence of ANCA, which determines the need for especially high suspicion level.

The available evidence suggests that mortality from coronavirus disease 2019 (COVID-19) in males is higher than in females.1Pradhan A Olsson PE. Sex differences in severity and mortality from COVID-19: are males more vulnerable?.Biol Sex Differ. 2020; 11: 53Crossref Scopus (0) Google Scholar In a recent cross-sectional study, de Lusignan et al. evaluated the absolute excess risk (AER) of mortality and excess mortality rate (EMR) in the UK from a COVID-19 sentinel surveillance network in people aged 45 years and above.2de Lusignan S Joy M Oke J et al.Disparities in the excess risk of mortality in the first wave of COVID-19: Cross sectional study of the English sentinel network.J Infect. 2020 Aug 25; (Online ahead of print): 4817https://doi.org/10.1016/j.jinf.2020.08.037Abstract Full Text Full Text PDF Scopus (0) Google Scholar The AER in mortality was calculated by comparing mortality for weeks 2 to 20 this year with mortality data from the Office for National Statistics (ONS) from 2018 for the same weeks. The absolute excess mortality was approximately 2 deaths per 100 person years in the first wave of COVID-19, whereas the EMR for male gender, compared with female, was 1.4 (95% confidence interval [CI] 1.35–1.44, p

In a retrospective study, we evaluated factors associated with the early development of septic shock in patients with severe COVID-19.We collected medical records of the intensive care unit patients submitted by the local COVID-19 hospitals across Russia to the Federal Center for the Critical Care at the Sechenov First Moscow State Medical University (Sechenov University). Septic shock in crticially ill patients requiring mechanical ventilation was defined as a need in vasopressors to maintain blood pressure.We studied 1078 patients with severe COVID-19 who were admitted to the intensive care units for respiratory support. There were 611 males and 467 females. The mean age was 61.013.7 years. Five hundred twenty five medical records (48.7%) were received from the Moscow hospitals, 159 (14.7%) from the Moscow region, and 394 (36.5%) from the hospitals located in 58 regions of the Russian Federation. In 613 (56.9%) patients, diagnosis of SARS-CoV-2 infection was confirmed by PCR, and in the other cases it was established on the basis of the clinical picture and the results of the chest CT scan. Septic shock developed in 214 (19.9%) of 1078 patients. In the logistic regression model, the risk of septic shock in patients older than 50 years was higher than in patients of a younger age (OR 2.34; 95% CI 1.533.67; p0.0001). In patients with more severe SARS-CoV-2 infection, there was an increase in the prevalence of cardiovascular diseases, including coronary heart disease and atrial fibrillation, type 2 diabetes and malignant tumors. The risk of septic shock in patients with three or more concomitant diseases was higher than in patients without any concomitant chronic diseases (OR 1.76; 95% CI 1.762.70).The risk of septic shock in patients with acute respiratory distress syndrome induced by SARS-CoV-2 is higher in patients older than 50 years with concomitant diseases, although a severe course of the disease is also possible in younger patients without any concomitant disorders.Цель. Анализ факторов, ассоциированных с ранним развитием септического шока у больных с тяжелым течением COVID-19. Материалы и методы. В исследование включены данные всех пациентов, проконсультированных до 1 мая 2020 г. на базе Федерального дистанционного консультативного центра анестезиологии и реаниматологии на базе ФГАОУ ВО Первый МГМУ им. И.М. Сеченова (Сеченовский Университет). Критерием септического шока считали снижение артериального давления, требовавшее введения вазопрессорных средств. Результаты. В исследование включены 1078 пациентов, 611 (56,7%) мужчин и 467 (43,3%) женщин. Средний возраст составил 61,013,7 года; 525 (48,7%) заявок на консультацию получены из стационаров Москвы, 159 (14,7%) Московской области, 394 (36,5%) лечебных учреждений в 58 регионах Российской Федерации. У 613 (56,9%) больных диагноз SARS-CoV-2-инфекции подтвержден с помощью полимеразной цепной реакции, а в остальных случаях установлен на основании клинической картины и результатов компьютерной томографии органов грудной клетки. Развитие септического шока отмечено у 214 (19,9%) из 1078 больных. В логистической регрессионной модели риск его развития у пациентов старше 50 лет выше, чем у больных более молодого возраста (отношение шансов 2,34; 95% доверительный интервал 1,533,67; р0,0001). У пациентов с более тяжелым течением SARS-CoV-2 отмечалось увеличение частоты сердечно-сосудистых заболеваний в целом, ишемической болезни сердца, фибрилляции предсердий, сахарного диабета 2-го типа, частота злокачественных опухолей выше. Риск развития септического шока у пациентов с тремя и более сопутствующими заболеваниями оказался выше, чем у пациентов без сопутствующих болезней (отношение шансов 1,76; 95% доверительный интервал 1,762,70). Заключение. Риск развития септического шока у пациентов с острым респираторным дистресс-синдромом, вызванным SARS-CoV-2, выше у пациентов старше 50 лет, страдающих несколькими сопутствующими заболеваниями, хотя тяжелое течение заболевания возможно и у более молодых людей без какой-либо сопутствующей патологии.

To evaluate the efficacy of earlier and late tocilizumab (TCZ) infusion, that is, prior to and after initiation of mechanical ventilation, in reducing mortality in a cohort of patients with severe COVID-19 pneumonia who required support in the intensive care unit (ICU).

Background There are reports of circulating antineutrophil cytoplasmic autoantibodies (ANCA) in patients with immunoglobulin A (IgA) nephropathy with an uncertain pathogenic role. Aim of the work To present the findings of myeloperoxidase (MPO) ANCA-positive patients amid a different course of IgA nephropathy with crescents and to discuss the efficacy of immunosuppressive therapy. Case presentation Two cases of IgA nephropathy associated with positive ANCA are reported and a review of the literature data is presented. The first patient presented with a progressive nephropathy and significantly impaired renal function at baseline, whereas in the second patient renal function remained stable over 10 years, despite the recurrent exacerbations of the disease. Both patients had extrarenal manifestations (joint pain and/or anemia) and elevated markers of inflammation (erythrocyte sedimentation rate, C-reactive protein) that are not typical features for IgA nephropathy. In the first case, immunosuppressive therapy with corticosteroids and cyclophosphamide resulted in improvement of kidney function. The second case showed the potential efficacy of rituximab as an induction remission and maintenance therapy for ANCA-positive IgA nephropathy. Conclusion Whether the association of IgA nephropathy with ANCA positivity is coincidental or constitutes a novel entity remains debated. Circulating ANCA can be found in patients with IgA nephropathy. They can be truly pathogenic and contribute to kidney damage and may induce overt systemic vasculitis or at least extrarenal signs and symptoms. ANCA-positive IgA nephropathy can respond to immunosuppressive regimens, including rituximab, similar to patients with ANCA-associated vasculitis (AAV).

Background: Fabry disease (FD, OMIM #301500) is a rare, progressive, X-linked, inherited genetic disease caused by a functional deficiency of lysosomal α-galactosidase, leading to the accumulation of glycosphingolipids in virtually all of the body’s cell types and fluids. Patients with rare genetic diseases and non-specific symptoms often experience substantial diagnostic delays, which can negatively impact the prompt initiation of treatment. If FD is not treated specifically, end organ damage (such as chronic renal failure, hypertrophic cardiomyopathy with arrhythmia, and strokes) impairs quality of life and reduces life expectancy. Patients and Methods: For 83 consecutive patients with FD referred to the Russian reference center for lysosomal storage diseases, family trees were built and genetic testing (cascade genotyping) was offered to family members. Results: The pathogenic GLA variant associated with FD was identified for all 83 probands. Family testing using cascade genotyping enabled the identification of 165 additional cases of FD among the tested 331 at-risk family members. Discussion: This is the first study to have described family screening in a large Russian cohort of patients with FD and chronic kidney disease. Raising awareness of FD among clinicians is important for earlier diagnosis and specific treatment.

ObjectiveTo investigate the occurrence of cardiovascular events (CVEs) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, China, Turkey, Russia, the United Kingdom, and the USA.MethodsPatients with a definite diagnosis of AAV who were followed for ≥ 3 months and had sufficient documentation were included. Data on myocardial infarction (MI) and stroke were collected retrospectively from tertiary vasculitis centers. Univariate and multivariate Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs.ResultsOver a median follow-up of 62.0 months (IQR 22.6-100.0), CVEs (mostly MIs) occurred in 245 (10.7%) of 2286 patients with AAV, with a higher frequency in China and the UK. On multivariate regression analysis, older age (55-64.9 yrs, HR 2.93, 95% CI 1.99-4.31), smoking (HR 1.98, 95% CI 1.48-2.64), Chinese origin (HR 4.24, 95% CI 3.07-5.85), and pulmonary (HR 1.50, 95% CI 1.09-2.06) and kidney (HR 3.02, 95% CI 2.08-4.37) involvement were independent variables associated with a higher occurrence of CVEs.ConclusionWe showed that geographic region and both traditional and disease-specific (kidney involvement in particular) factors were independently associated with CVEs. Proper assessment and management of modifiable cardiovascular (CV) risk factors are essential for prevention of CV morbidity in patients with AAV.

This non-randomized controlled study aimed to assess the efficacy of tofacitinib in reducing the risk of invasive mechanical ventilation or death in patients with COVID-19. Patients with COVID-19 associated with reduced oxygen saturation, increased C-reactive protein (≥50 mg/L), and/or persisting fever were recruited. Tofacitinib was administered in addition to standard of care therapy. Study outcomes were evaluated separately in the groups of patients with oxygen saturation at rest ≤93% and >93%. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox regression analysis adjusted for inverse propensity score weighting. Overall, 384 patients with COVID-19 (212 males; median age 60 years) were included in our study and were treated with tofactinib (n=131) or standard of care alone (n=253). The percentages of patients who started mechanical ventilation or died during hospitalization in the tofacitinib and control groups were 12.5% (9/72) vs. 14.1% (26/185) among patients who required respiratory support (HR 0.92, 95% CI 0.33-2.56), and 1.7% (1/59) vs. 4.4% (3/68) in those with normal oxygen saturation (HR 0.83; 95 CI 0.07-9.44). Tofacitinib did not reduce the risk of invasive mechanical ventilation or death in patients with COVID-19, although the analysis of these outcomes favored tofacitinib.

Objective To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. Methods Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. Results Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15–60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR Conclusion Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

Background and Aims Despite significant progress in treatment of ANCA-associated vasculitis (AAV), at least 20% of patients with renal involvement develop end-stage renal disease (ESRD). Histopathologic classification by Berden et al, which addresses only glomerular pathology, has been used to predict renal outcome in ANCA-assoicted glomerulonephritis (ANCA-GN) since 2010.1 In 2018 Brix et al proposed ANCA renal risk score (ARRS), which combines assessment of morphological (percentage of normal glomeruli, tubular atrophy and interstitial fibrosis) and clinical parameters (estimated glomerular filtration rate) to predict probability of ESRD.2 The aim of our study was to compare clinical utility of these two methods. Methods In our retrospective study we enrolled 57 patients with ANCA-associated vasculitis, diagnosed according to Chapel Hill Consensus Conference (2012) definition and/or American College of Rheumatology (1990) criteria, with histologically proven renal involvement. There were 14 (24.6%) males and 43 (75.4%) females, median age at AAV onset was 48 (33; 57) years. Fifty-one (89.5%) patients were ANCA-positive. Eight (14.0%) patients were diagnosed with renal-limited AAV. Median Birmingham vasculitis activity score (BVAS v.3) at onset was 16 (13; 19). In each case ANCA-GN class was established according to Berden classification: focal (>50% normal glomeruli); crescentic (>50% cellular crescents); mixed (50% globally sclerotic glomeruli). ARRS at onset was also retrospectively assessed and all patients were divided into three groups depending on the risk of ESRD: low risk (0 points), intermediate risk (2 to 7 points), or high risk (8 to 11 points). Thirteen patients (22.8%) developed ESRD after a median of 12 (6.5; 28) months. Renal survival rates were assessed by Kaplan-Meier method and compared by log-rank test. Results Among the 57 patients seven (12.3%) had focal, 10 (17.5%) – crescentic, 24 (43.2%) – mixed, and 16 (28.1%) – sclerotic ANCA-GN class according to Berden et al classification. 1- and 3-year renal survival rates were the highest (100% and 100% respectively) in focal, and the lowest in sclerotic class (67% and 50.2% respectively). 1- and 3- year renal survival was similar in crescentic (80% and 80% respectively) and mixed (80.6% and 80.6% respectively) classes (Fig. 1A). The differences were not statistically significant (Log-rank (Mantel-Cox) p = 0.17). Then we retrospectively re-evaluated all cases according to ARSS: 12 cases were classified as low-risk, 27 – as medium risk, 18 – as high risk. One-year and three-year survival rates were 100% and 100% in low-risk group, 86.1% and 74.2% in medium risk group, 50.6% and 50.6% in high risk group (Figure 1B). The differences were statistically significant (Log-rank (Mantel-Cox) p=0.003). Conclusion In our limited group of patients ANCA renal risk score classification provided better and more clear stratification of patients in terms of ESRD prediction than Berden classification. ARRS is a simple and valuable tool for assessment of renal survival prognosis which can contribute to personalized approach to the management of AAV.

Background and Aims End-stage renal disease (ESRD) is associated with significant morbidity and mortality among patients with Fabry disease (FD). The aim of our study was to evaluate impact of renal failure on overall survival of patients with FD. Method We recruited 117 adult (>18 years) patients with FD that was confirmed by enzymatic and genetic studies. ESRD was defined according to the KDIGO guidelines (2012). Kaplan-Meyer analysis and Log Rank test were used to estimate overall survival of patients with FD. Results Thirty-seven (36 males and 1 female) of 117 patients had ESRD. Thirty-three of them were treated with chronic hemodialysis, whereas four patients have undergone renal transplantation. Among patients with ESRD eleven (29.7%) patients died at the median age of 43 (37; 46) years. All deceased patients were males. The median time from dialysis initiation to death was 32 (6; 67) months. The causes of death included sudden cardiac death (n=9), stroke (n=1) and peritonitis (n=1). Only 2 deceased patients received enzyme replacement therapy over 3 and 11 months. There were deaths only in the ESRD group (Table). There was a decline in survival function after the age of 30 years in patients with ESRD. In Kaplan-Meyer analysis overall survival was 51.2 years (95% Confidence interval 47.7-54.7) and was lower in patients with ESRD (Log Rank (mantel-Cox) χ2=17.5, df 1, р Conclusion ESRD was the major factor associated with low survival of patients with FD in Russia. One out of every 3 dialysis patients died in 5 years after dialysis initiation.

Fabry disease (FD) is a severe lysosome storage disease caused by congenital deficiency of the enzyme α-galactosidase A and characterized by the risk of renal failure combined with cardiovascular and CNS complications. According to the currently available information, the early start of enzyme replacement therapy (ERT) leads to a significant improvement in patient’s condition.The aim of the studyis to assess whether the timely ERT prevents severe FD complications and to calculate the number of prevented cases as depending on the time of ERT start.Materials and methods. The proposed model is based on the published results on patients with FD, receiving agalsidase alpha as ERT (no data for agalsidase beta was found). The expected number of cases with life-threatening complications was calculated for different starting timepoints and durations of the ERT.Results. In patients with FD, continuous ERT during five years reduces the number of serious cardiovascular and renal complications by 25%. An early start of ERT makes it possible to additionally (as compared with a late start) prevent the complications in more than 20% of cases.Conclusion. The early initiation of RPT in patients with FD can significantly reduce the occurrence of severe lifethreatening complications, increase the patients’ survival and improve their quality of life.

Cornea verticillata is the typical sign of ocular involvement in Fabry disease and manifests by the whorl-like, linear opacities in the inferior part of the cornea. Aim. To study the frequency of cornea verticillata in patients with Fabry disease and it’s relation to the severity of the disease and the types of mutation in the GLA gene. Materials and methods. We studied 69 adult (over 18 years) patients with a classic form of Fabry disease that was confirmed by enzymatic and molecular genetic studies. There were 39 males and 30 females. The median age was 39 years [30.0; 50.0]. The severity of Fabry disease was assessed using the Mainz Severity Score Index (MSSI) with a maximum value of 76 points. Depending on the MSSI score, patients were classified into mild (40) clinical categories. Results and discussion. At least one classic symptom of Fabry disease was present in 88.4% of patients. The majority of patients had the missense mutations of the GLA gene. Cornea verticillata was found in 65.2% of patients and occurred with a similar frequency in males (56.4%) and females (76.7%; p=0.07). Cornea verticillata was the single classic symptom of Fabry disease in only 4.9% of cases, while the rest of the patients presented with angiokeratoma, neuropathic pain and/or hypohidrosis. The frequency of classic symptoms of Fabry disease, as well as renal disease (with the exception of terminal chronic renal failure), brain and heart damage was similar in patients with and without cornea verticillata. Median MSSI scores were also similar in patienths with and without cornea verticillata (20.0 and 18.5 points, respectively; p=0.92). Similar results were obtained in males (26.5 and 30.0 points, p=0.97) and females (16.0 and 16.0 points, p=0.45). The frequency of cornea verticillata did not differ in patients with different types of mutations in the GLA gene. Conclusion. Cornea verticillata occured in 65% of adult patients with Fabry disease, was usually accompanied by the other classic symptoms of the disease, and was not associated with the severity of the disease.

Goodpasture’s disease (anti-GBM disease) is a rare small vessels vasculitis characterized by the presence of autoantibodies directed against the glomerular basement membrane (GBM) and alveolar basement membrane. Common feature of anti-GBM disease is a combination of rapidly progressive glomerulonephritis and alveolar hemorrhage (pulmonary-renal syndrome). We present a case of atypical disease course in a young male patient who developed alveolar hemorrhage without renal failure. The only symptom of renal involvement was isolated hematuria. Plasmapheresis combined with immunosuppression (cyclophosphamide and corticosteroids) was effective. We present a review of state-of-art data on the pathogenesis and disease course of anti-GBM disease.

Microscopic polyangiitis (MPA) is the form of ANCA-associated vasculitis, characterized by pulmonary and kidney damage. This article discusses a case of severe MPA in a young patient and is focused on the modern diagnostic and treatment approaches. The authors also review different clinical courses and outcomes of MPA.

Background:There is increasing evidence that the complement system, in particular the alternative pathway, plays a crucial role in the pathogenesis of ANCA-associated vasculitis (AAV) [1]. Efficacy of C5a receptor antagonists indicates that chemoattraction mediated by C5a plays a key role in the inflammatory process observed in AAV [2]. Another promising research object are regulatory proteins such as factor B [3].Objectives:To study complement activation via the alternative pathway in patients with active ANCA-associated vasculitis.Methods:59 patients with newly diagnosed (n=35) or relapsing GPA or MPA (n=24) were enrolled in this prospective study. Median BVAS v.3 at the time of AAV onset was 16.5 (9.5; 20). In 28 patients activation of complement was reassessed during sustained remission (BVAS v.3 = 0) after a median of 16 months. Thirty six age-and gender-matched healthy volunteers comprised the control group. Levels of complement components (C3, C5, C3a, C5a, vitronectin, factor B and factor P) were measured by ELISA (Cloud Inc.). Data were not normally distributed, therefore, values are given as medians and IQRs and nonparametric statistical tests were used.Results:The concentrations of C5, C3, vitronectin and CFB were significantly higher in patients with active AAV than control group. There were no significant differences in the levels of factor P in patients with active AAV and control group (388000 (371960; 417150)) vs 416000 (400200; 437000), ng/ml, p >0.05) (Fig. 1).Fig 1.Concentration of complement components in patients with active AAV and healthy controls (*pSerum level of C5a and C3a were higher in patients with active AAV than in healthy controls (22.9 (14.4; 33.0) vs 3.0 (0.35; 6.73), ng/ml, pThe levels of complement components were similar in PR3-ANCA and MPO-ANCA disease, and severe and non-severe AAV. C5a/C5 and C3a/C3 ratios were not influenced by disease activity, severity or ANCA type.After immunosuppressive treatment concentrations of C5, C3, and their activated products, C5a, C3a significantly decreased (Fig. 2). However, concentrations of regulatory proteins such as factor B, factor P and vitronectin were unaffected. Interestingly, that there was no significant difference in MAC levels before and after immunosuppressive treatment (24646 (15342; 46681) vs 20057.4 (19709.3; 41477.6), mAU/ml, p=0.925).Fig 2.Concentration of complement components in patients with active disease and remission (*pConclusion:The complement system plays an important role in AAV. While treatment affects some component, some remain unchanged and are not dependent on AAV severity or ANCA serotype.References:[1]Jennette JC, Xiao H, Hu P. Complement in ANCA-Associated Vasculitis. Seminars in Nephrology 2013; 33 (6): 557 – 564[2]Schreiber A, Xiao H, Jennette JC et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 2009; 20(2): 289-298.[3]Gou SJ, Yuan J, Chen M et al. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 2013; 83(1): 129-137.Disclosure of Interests:Anastasiia Zykova Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Nikolai Bulanov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Andreas Kronbichler Grant/research support from: This work was supported by unrestricted grant from the Austrian Society of Rheumatology., Evgeny Gitel: None declared, Oxana Novikova: None declared, Mayra Bulanova: None declared, Elizaveta Safonova: None declared, Sergey Moiseev Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow

To the Editor: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) form a group of necrotizing small-vessel vasculitides characterized by the presence of ANCA against either proteinase 3 (PR3) or myeloperoxidase (MPO). ANCA have a key role in the pathogenesis of AAV, inducing excessive activation of neutrophils, which results in injury to small vessels1. ANCA can target other neutrophil-derived molecules, among them lysosome-associated membrane glycoprotein 2 (LAMP-2). LAMP-2 is a glycosylated membrane protein expressed in lysosomes and on the surface of neutrophils and glomerular cells2. Antibodies against LAMP-2 were originally detected in cases with active AAV and pauci-immune crescentic glomerulonephritis3. Subsequent experimental studies showed that passive immunization with rabbit IgG to recombinant LAMP-2 or active immunization with recombinant FimH (a bacterial adhesion protein present in gram-negative bacteria and sharing 1 epitope of LAMP-2) can induce pauciimmune crescentic glomerulonephritis in rats, thus supporting the pathogenicity of anti–LAMP-2 antibodies4. Patients with active AAV defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥ 3 were included in our study. Serum concentration of anti–LAMP-2 antibodies was determined using … Address correspondence to Dr. S. Moiseev, Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Rossolimo, 11/5, Moscow, 119435, Russia. E-mail: avt420034{at}yahoo.com

Fabry disease (FD) is a rare lysosomal storage disorder characterized by severe complications in young patients. The aim of the study was to determine predictors of clinical outcomes in patients with FD. Methods The diagnosis of FD was confirmed by enzymatic and genetic studies. The outcomes included death and a composite of end-stage renal disease (ESRD), cardiac (clinically significant arrhythmia and cardioverter/pacemaker implantation) and cerebrovascular (transient ischemic attack, stroke) events. Cox regression model was used to examine the risk of clinical outcomes. Results One hundred adult patients (65 males and 35 females, median age 40 [32; 50.8] years) with a definite diagnosis of FD were enrolled in our study. The majority of patients had classic phenotype (94.2%) and missense mutations in the GLA gene (69.0%). Forty-seven patients (38 males and 9 females) experienced clinical outcomes which included arrhythmias in 10 patients (atrial fibrillation in 8 of thems), ESRD in 33 patients, and cerebrovascular events in 8 patients. The median age of the first outcome was 39 (32; 49) years. In males, the outcomes occurred more frequently than in females (58.5% vs. 25.7%, respectively, p=0.002). Eleven males died at the median age of 43 (37; 46) years. All of them had ESRD. The most frequent cause of death was sudden cardiac death (n=9). Left ventricular myocardial mass index (LVMMI) was higher among patients with outcomes than in patients without outcomes (153 g/m2 [102; 203] vs. 92 g/m2 [78; 122], respectively, p300 mg/day (HR 1.29 [1.04; 1.59], p=0.022) were associated with a higher risk of a composite outcome after adjustment for gender and age. Albuminuria>300 mg/day (HR 1.57 [1.05; 2.35], p=0.029) and LVMMI (HR 1.006 [1; 1.012], p=0.038) were predictors of death after adjustment for gender. However, this effect has been lost after adjustment for hemodialysis duration. The type of mutation in the GLA gene was not a predictor of clinical outcomes. Conclusion Left ventricular myocardial mass index was a predictor of clinical outcomes in patients with FD. Poor prognosis in our cohort was related to ESRD that accounted for all deaths.

Tocilizumab (TCZ), a recombinant monoclonal antibody against the interleukin (IL)-6 receptor, has been proposed as a potential therapy for severe SARS-CoV-2 pneumonia based on observational studies.1 Recently, a strategy involving a course of high-dose glucocorticoids, followed by TCZ if needed (in 43% of patients), was shown to improve mortality in patients with rapid respiratory deterioration plus elevation of at least two out of three biomarkers (C reactive protein (CRP), ferritin and/or D-dimer).2 Nevertheless, a short-term use of TCZ is not free from serious adverse events, and the efficacy data, although promising, are preliminary.3 The timing of anti-inflammatory treatments in relation to the stage of disease seems to be important in patients with COVID-19.4 Therefore, the objective of our retrospective study was to assess the efficacy of earlier and late intravenous TCZ, that is, prior to and after initiation of mechanical ventilation, respectively, in reducing mortality in a cohort of patients with severe COVID-19 pneumonia who required support in intensive care unit (ICU). In March 2020, the Russian Ministry of Health set up a Federal Center at the Sechenov University (Moscow) to provide virtual support for the ICU physicians caring for patients with COVID-19.5 All local COVID-19 hospitals were proposed to submit medical records of critically ill patients via secure network to the Federal Center giving urgent advice on the critical care management. For this study, we selected consecutive ICU patients whom TCZ administration was recommended given the presence of bilateral …

Background:The role of ANCA type is well established for the risk of relapses of ANCA-associated vasculitis (AAV). However their association with renal involvement and its outcomes is less well understood.Objectives:To assess clinical and morphological features of ANCA-associated glomerulonephritis (ANCA-GN) and renal survival in ANCA-negative patients, proteinase-3-ANCA (pr3-ANCA) positive and myeloperoxidase-ANCA (MPO-ANCA) positive patients.Methods:We enrolled 53 patients with AAV, diagnosed according to Chapel Hill Consensus Conference (2012) definition and/or ACR (1990) criteria, with histologically proven renal involvement. There were 13 (24.5%) males, median age at onset was 48 (33; 57) years. Seven patients were ANCA-negative (13.3%), 17 (32.0%) patients were pr-3-ANCA positive and 29 (54.7%) patients were MPO-ANCA-positive. ANCA-associates glomerulonephritis (ANCA-GN) class was established according to Berden et al classification.1We retrospectively assessed ANCA renal risk score (ARRS) at disease onset.2Twelve patients (22.6%) developed end-stage renal disease (ESRD) after a median of 12 (6.5; 28) months. Renal survival rates were assessed by Kaplan-Meier method and compared by log-rank test.Results:The only significant difference was median BVAS score which was significantly higher in pr3-ANCA-positive (18 (17;20)) than in MPO-ANCA positive patients (15 (12; 18), p=0.012). Creatinine levels, eGFR, percentage of glomeruli with crescents, global sclerosis, and interstitial fibrosis and tubular atrophy didn’t depend on the presence of ANCA or type of the antibodies. The proportion of patients with focal, crescentic, mixed of sclerotic class of ANCA-GN was similar in all groups. There was no significant difference in the numbers of patients with low, medium or high risk of ESRD according to ARRS. One- and three-year renal survival rates were similar in ANCA-negative (81.7% and 60.0% respectively) and ANCA-positive patients (84.2% and 74.6% respectively, Figure 1A). One-year and three-year survival rates were higher in MPO-ANCA-positive (84.4% and 84.4% respectively) than in pr3-ANCA-positive patients (73.1% and 50.1% respectively), however the difference was not statistically significant (Figure 1B).Figure 1.Kaplan-Meier curves showing renal survival in ANCA-positive and ANCA-negative patients (A), and pr3-ANCA-positive and MPO-ANCA-positive patients (B)Conclusion:Our small study indicates that clinical and morphological features of renal involvement, as well as renal survival are similar in ANCA-negative and ANCA-positive patients and don’t depend on the type of ANCA.References:[1]Berden AE, Ferrario F, Hagen EC, et al. Histopathologic Classification of ANCA-Associated Glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628–1636.[2]Brix RB, Noriega M, Tennstedt P, et al. Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int. 2018;94(6):1177-1188.Disclosure of Interests: :Nikolai Bulanov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Ekaterina Stolyarevich: None declared, Anastasiia Zykova: None declared, Elizaveta Safonova: None declared, Elena Shchegoleva: None declared, Ekaterina Kuznezova: None declared, Mayra Bulanova: None declared, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Sergey Moiseev Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow

Aim. To evaluate clinical features and outcomes of renal involvement in patients with microscopic polyangiitis (MPA). Materials and methods: We enrolled 99 patients with MPA, diagnosed in accordance with the algorithm of the European Medicines Evaluation Agency (EMEA) and the Chapel Hill consensus conference definition (2012). Serum creatinine (sCr), estimated glomerular filtration rate (eGFR), hematuria and proteinuria were estimated. Frequency of rapidly progressive renal failure (a twofold increase in the sCr level in ≤3 months) was regarded as the clinical equivalent of rapidly progressive glomerulonephritis (RPGN). Results and discussion. Renal involvement was present in 92 (92.9%) patients. RPGN developed in 51 (55,4%) patients. The most common features of kidney involvement were hematuria and subnephrotic proteinuria. Arterial hypertension was revealed in 32 (34.7%) patients and was associated with RPGN (p

Background Fabry disease (FD) is a rare X-linked storage disease resulting from the deficient activity of the lysosomal a-galactosidase A (AGAL) and leading to a progressive accumulation of glycosphingolipids in a wide range of cell types throughout the body, including kidney, heart and nervous system. Certain manifestations of FD can mimic those of rheumatic diseases. Objectives To evaluate the occurrence and the possible causes of diagnostic errors in patients with FD in rheumatology practice. Methods We retrospectively studied the medical records of 82 adult patients with definite FD (low or absent AGAL activity, pathogenic mutation in the GLA gene, typical clinical symptoms in patient and/or his relatives, results of kidney biopsy). There were 55 males and 27 females aged of 18 to 69 years (median 3829; 48 years). Results Seventy two of 82 patients (87.8%) had a history of classic phenotype of FD from childhood or adolescence. The typical manifestations included neuropathic pain that was related to heat and fever (65/82; 79%), angiokeratoma (37/82; 45%), anhydrosis/hypohydrosis (44/82; 53.6%), and cornea verticillata (40/62; 64.5%). However, there was a significant delay to diagnosis of up to 51 years (median 189; 27 years). Moreover, diagnosis was established by nationwide screening in dialysis units in 22/82 (26.8%) patients or by family screening in 34/82 (41.4%) patients. At the time of diagnosis, patients usually presented with a clinical picture of systemic disease with mild to moderate proteinuria with or without impairment of kidney function (70/82; 85.4%), left ventricular hypertrophy (56/82; 68.3%), white matter lesions on brain MRI (38/72; 52.8%), and/or a history of stroke (15/82; 18.3%). Twenty six of 82 patients (31.7%) previously had at least one diagnosis of rheumatic disease (Table 1). The common causes for referral to rheumatologist were skin rash and neuropathic pain. In 6 of 26 patients (23.1%), the latter was initially misdiagnosed as joint pain. The possible causes of diagnostic errors included also ‘genuine’ arthralgia (6/26; 23.1%), episodes of unexplained fever (13/26; 50%), Raynaud phenomenon (2/26; 7.7%), and the laboratory markers of inflammation (11/26; 42.3%). Conclusions Practicing rheumatologists should be aware of FD, given a high occurrence of diagnostic errors. The clues to correct diagnosis include a history of typical symptoms (i.e. neuropathic pain, angiokeratoma, hypohydrosis) from childhood or adolescence and/or the presence of typical manifestations in family members. Notably, FD can initially present as an autoinflammatory disorder with episodes of joint pain and unexplained fever associated with the laboratory markers of inflammation. Disclosure of Interest None declared

Background The role of polymorphisms of hemostasis genes in venous thromboembolic events in ANCA-associated vasculitides. Objectives To evaluate the role of polymorphisms of hemostasis genes in the risk of VTEs in AAV patients and to the clinical features of AAV. Methods We studied 85 patients with AAV [69 with granulomatosis with polyangiitis (GPA), 11 with microscopic polyangiitis (MPA), 5 with eosinophilic granulomatosis with polyangiitis (EGPA)] diagnosed according to CHCC 2012 classification. There were 34 males and 51 females, aged of 5545;63 years. Duration of follow-up was 74.0 (36.5;120.3) months. Coagulation genes polymorphisms MTHFR 677 C/T (rs1801133), FV 1691 G/A (rs6025), FII 20120 G/A (rs1799963), FGB 455 G/A (rs1800790), PAI-1 675 5G/4G (rs1799889), ITGA2 807 C/T (rs1126643), ITGB3 1565 T/C (rs5918), FVII 10976 G/A (rs6046), FXIII 103 G/T (rs5985) were evaluated by real time polymerase chain reaction. VTEs (deep vein thrombosis, pulmonary embolism) were identified by ultrasonography and chest computed tomography, respectively. We used score system, according to which the presence of each minor allele was assigned one point. Results We retrospectively detected 12 (14.1%) VTEs in 85 patients with AAV, including 5 (7.2%) in GPA, 4 (36,4%) in MPA and 3 (60,0%) in EGPA. There were no significant differences in the prevalence of alleles of the each gene in patients with and without VTE (figure 1). However, the combination of integrin A2 (ITGA2 807 C/T), plasminogen activator inhibitor-1 (PAI-1 675 5 G4G), fibrinogen (FGB 455 G/A) and FVFV 1691 G/A) polymorphisms was associated with a significantly higher occurence of VTE in patients with AAV (p=0.007) (table 1). We observed a higher risk of lung involvement in carriers of methylenetetrahydrofolate reductase gene (MTHFR 677 C/T) polymorphism (p=0.007, OR 4.305 (95% CI 1.55 to 11.98), and an earlier AAV onset in patients with FXIII 103 G/T polymorphism (47.0 vs 50.0 years, p=0.049) Conclusions The combination of several genetic polymorphisms of hemostasis system is associated with an increased prevalence of VTE in AAV patients. The association between MTHFR 677 C/T and FXIII 103 G/T alleles and clinical features of AAV warrants further studies in the larger cohorts of patients. Acknowledgements The study was conducted in the framework of Government Assignment of Lomonosow Moscow State University. Disclosure of Interest None declared

Background Many patients with eosinophilic granulomatosis with polyangiitis (EGPA) lack a “vasculitic” phenotype and/or are ANCA negative. Recently, the Groupe d’Etudes et de Recherche sur les Maladies Orphelines Pulmonaires developed a revised nomenclature for EGPA and proposed to differentiate it from hypereosinophilic asthma with systemic (nonvasculitic) manifestations (HASM). Objectives To evaluate the occurrence of genuine polyangiitis and HASM in a cohort of patients with EGPA. Methods We retrospectively studied the medical records of patients with EGPA that fulfilled the classification criteria of the American College of Rheumatology. Patients with genuine vasculitis were identified by at least one of the following criteria:1 definite vasculitis feature as defined: biopsy-proven necrotizing vasculitis of any organ, biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis, alveolar haemorrhage, palpable purpura, myocardial infarction due to proven coronary arteritis;2 strong surrogate of vasculitis as defined: haematuria associated with red casts or ≥10% dysmorphic erythrocytes, or haematuria and 2+proteinuria on urinalysis related to the systemic disease; and any organ manifestation other than ENT or bronchopulmonary manifestation associated with leukocytoclastic capillaritis and/or eosinophilic infiltration of the arterial wall;3 mononeuritis multiplex;4 ANCA with at least one extra-thoracic non-ENTmanifestation of disease. Results We followed 68 patients with EGPA for a mean ±SD of 6.3±6.5 years (587.7 patient-years). There were 19 males and 49 females. Their mean ±SD age was 49.5±13.8 years. In 18 patients (26.5%) with EGPA diagnosis was revised in favour of HASM using the new criteria (table 1). Notably, 19 of 50 patients (38%) with genuine polyangiitis were ANCA-negative but have histological evidence or clinical signs (rapidly progressive glomerulonephritis in 1, mononeuritis multiplex 7, palpable purpura in 5) of definite vasculitis. The majority of patients in both groups were females of similar age at disease onset. The occurrence of constitutional symptoms, except myalgia, nasal involvement, cardiovascular and pulmonary manifestations did not differ between patients with genuine polyangiitis and HASM. However, patients with EGPA usually required more intensive immunosuppressive treatment, including cyclophosphamide, while monotherapy with moderate to high dose corticosteroids was adequate for the majority of patients with HASM. Table 1 Clinical and demographic characteristics of patients with genuine EGPA and HASM Conclusions At least a quarter of patients with EGPA classified according to the ACR criteria do not have genuine polyangiitis. The revised criteria of EGPA and HASM may have a significant value for choosing treatment options. Disclosure of Interest None declared

Objectives We evaluated the frequency of clinical and CT features of lung damage in patients with microscopic polyangiitis (MPA). Methods We enrolled 97 patients with MPA, that was diagnosed according to CHCC2012. The median age at disease onset was 50.7±16.6 (M±SEM) years, the median duration of follow-up was 47.6±47.5 (M±SEM) months. 64 (66.0%) patients were ANCA-MPO-positive, 24 patients (24.7%) were ANCA-PR-3-positive, and 9 (9.3%) patients had undifferentiated ANCA. Diffuse alveolar haemorrhage (DAH) was diagnosed by the presence of dyspnea, hemoptysis, anaemia and pulmonary infiltrates on chest CT. Results Lung damage was diagnosed in 77 (79.4%) patients. 43 (55.8%) patients had pulmonary damage at the disease onset, while 34 (44.2%) patients developed signs of lung involvement within 8.0±4.1 (M±SEM) months. At baseline, the median pulmonary BVAS was 4.2; 6 The interstitial changes occurred in more than half of cases at the onset of the disease. The most frequent CT-patterns included pulmonary infiltrates (n=49) and ground-glass opacity (n=39) (table 1). DAH developed in 30 (30.9%) patients, among them 15 (15.5%) had DAH at the onset of the disease. The pulmonary fibrosis was the most common CT-pattern at the end of follow-up (52 patients). Notably, interstitial damages at the onset of disease were associated with the development of fibrotic changes (OR=4.7, 95% CI 1.7–12.9) and bronchiectasis (OR=9.8, 95% CI 1.2–78.3) at the end of follow-up. The median of pulmonary VDI was 1 (0;4) at the end of the follow up. PR-3-positive group had higher occurrence of consolidations at the end of the follow-up as compared to patients with anti-MPO-antibodies (53.8% versus 16.0%, p=0.023). The pulmonary fibrosis was the most common CT-pattern at the end of follow-up (52 patients). Notably, interstitial damages at the onset of disease were associated with the development of fibrotic changes (OR=4.7, 95% CI 1.7–12.9) and bronchiectasis (OR=9.8, 95% CI 1.2–78.3) at the end of follow-up. The median of pulmonary VDI was 1 (0;4) at the end of the follow up. PR-3-positive group had higher occurrence of consolidations at the end of the follow-up as compared to patients with anti-MPO-antibodies (53.8% versus 16.0%, p=0.023). Conclusions In patients with MPA, the CT signs of interstitial damage were usually reversible. However, they predicted a higher incidence of lung fibrosis and bronchiectasis at the end of follow-up. DAH occured in one third of patients with MPA. Disclosure of Interest None declared

To assess the significance of determining the serum and urinary concentrations of monocyte chemotactic protein-1 (MCP-1), kidney injury molecule-1 (KIM-1), and type IV collagen in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) to estimate the activity of renal involvement in AAV.78 patients (32 men and 46 women) (median age 55 (45; 61) years) with AAV were examined. The patients were divided into 3 groups according to the AAV activity estimated using the Birmingham vasculitis activity Score (BVAS): 1) 25 patients with active ANCA-associated glomerulonephritis (GN); 2) 26 patients with active AAV without renal involvement; 3) 27 patients in sustained AAV remission. The serum and urinary concentrations of the markers were measured by enzyme immunoassay.The urinary concentration of all 3 biomarkers was higher in patients with renal involvement (Group 1); the differences in the levels of MCP-1 and type IV collagen were statistically significant as compared to Groups 2 and 3 (p0.01), while that in KIM-1 level was only in Group 2. There were statistically significant correlations between the urinary concentration of these biomarkers and the traditional GN activity indices (erythrocyturia, daily proteinuria (DPU), total BVAS scores that reflect renal involvement, as well as serum creatinine levels and estimated glomerular filtration rate (p0.05). ROC curve analysis showed that the urinary MCP-1 excretion of ≥159 pg/ml had the highest (92%) sensitivity and urinary type IV collagen excretion of ≥3.09 µg/l had the highest (86%) specificity in assessing the activity of ANCA-associated GN. At the same time, their diagnostic value increased in terms of a combination of DPU and ESR (96% sensitivity, 84.9% specificity).The urinary excretion of MCP-1, KIM-1, and type IV collagen reflects the severity of local renal inflammation in AAV patients and a study of these indicators is a promising diagnostic tool for assessing the activity of ANCA-associated GN.Цель исследования. Оценка значения определения в сыворотке крови и моче больных с ассоциированными с антинейтрофильными цитоплазматическими антителами (АНЦА) васкулитами (ААВ) концентрации моноцитарного хемотаксического фактора 1-го типа (MCP-1), молекулы повреждения почек 1-го типа (KIM-1) и коллагена IV типа в оценке активности поражения почек при ААВ. Материалы и методы. Обследовали 78 пациентов с ААВ - 32 мужчины и 46 женщин, медиана возраста 55 (45; 61) лет. Больных разделили на 3 группы в зависимости от активности ААВ, оцененной по величине Бирмингемского индекса активности васкулита (BVAS): 1-я - 25 пациентов с активным гломерулонефритом (ГН), ассоциированным с АНЦА (АНЦА-ГН), 2-я - 26 пациентов с активным ААВ без поражения почек, 3-я - 27 пациентов с длительной ремиссией ААВ. Концентрацию маркеров в сыворотке крови и мочи определяли методом иммуноферментного анализа. Результаты. Концентрация в моче всех 3 биомаркеров выше у пациентов с поражением почек (1-я группа), причем различия по уровню MCP-1 и коллагена IV типа статистически значимы по сравнению со 2-й и 3-й группами (p0,01), в то время как по уровню KIM-1 - только со 2-й группой. Выявлены статистически значимые корреляции между концентрацией в моче этих биомаркеров и традиционными показателями активности ГН - эритроцитурией, суточной протеинурией (СПУ), суммарной оценкой по BVAS, отражающей поражение почек, а также уровнем креатинина в сыворотке крови и расчетной скоростью клубочковой фильтрации (p0,05). Анализ построенных ROC-кривых показал, что наибольшей чувствительностью в оценке активности АНЦА-ГН обладал уровень экскреции с мочой MCP-1159 пг/мл (92%), наибольшей специфичностью - уровень экскреции с мочой коллагена IV типа3,09 мкг/л (84,9%). При этом их диагностическая ценность повышалась при сочетании с СПУ и СОЭ (чувствительность 96%, специфичность 84,9%). Заключение. Уровень экскреции с мочой MCP-1, KIM-1 и коллагена IV типа отражает выраженность локально-почечного воспаления у больных ААВ, и исследование этих показателей является перспективным диагностическим инструментом для оценки активности АНЦА-ГН.

Objectives We assessed the frequency, clinical features and prognosis of renal involvement in granulomatosis with polyangiitis (GPA) and current treatment approaches. Methods We performed a retrospective analysis of 234 patients with GPA, diagnosed according to Chapel-Hill Consensus Conference 2012 classification, 81 male and 153 female, aged 53 (41; 62) years. 54 patients (23.1%) had localized GPA. 174 (74.4%) were ANCA positive. Median follow up was 61.5 (32; 105) months. 103 patients (44%) had a history of renal involvement. Frequencies of proteinuria, hematuria, hypertension, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI) and chronic kidney disease (CKD) grades were analyzed. Results In 25 patients (24.3% of 103) renal involvement developed at disease onset, the other 78 patients (75.7%) developed glomerulonephritis after a median of 3 (1; 12) months. Hematuria was present in 94 (91.3%), proteinuria in 85 patients (82.5%), nephrotic syndrome in 11 patients (10.7%), hypertension in 31 patients (30.1%). Rapidly progressive glomerulonephritis (RPGN) defined by the doubling of serum creatinine within ≤3 months developed in 29 patients (28.2% of 103). Myeloperoxidase-ANCA-positive patients (n=12) developed RPGN significantly more often than proteinase-3-ANCA-positive patients (n=78): 7 (58.3%) vs 22 (28.2%) (p=0.0499). 11 (10.7%) patients developed AKI, stage 3 being the most common (in 8 patients). 40 (38.8%) patients exhibited indolent renal disease course, i.e. without worsening of renal function. By the end of the follow-up, 33 (32.0%) patients were diagnosed with CKD grade 3b-5, among them 11 patients (10.7%) developed end-stage renal disease (ESRD). 6 patients (5.8%) died. As the first line induction therapy all patients received corticosteroids in combination with cyclophosphamide in 93 patients (90.3%), rituximab (RTX) in 3 patients (2.9%), mycophenolate mofetil in 7 patients (6.8%). RTX was used for remission induction in 27 (26.2%) patients due to refractory or recurrent disease. During follow-up, 74 patients (71.8%) developed one or more severe relapses with a relapse rate of 0.27 per patient-year. 50 (48.5%) patients had renal relapses (0.096 per patient-year). Conclusions Prevalence of renal involvement in the studied group was lower than expected, most likely because of a large proportion of patients with localized GPA. Our study showed that RPGN was not the most common feature of renal involvement. Almost 40% of patients developed indolent course of kidney disease. Nevertheless one third of patients developed CKD G3B or worse by the end of the follow up. Despite effective induction therapy with high-dose corticosteroids, cytotoxic agents and/or RTX relapses, both renal and extrarenal, are frequent. Disclosure of Interest None declared

Granulomatous orbital cellulitis is one of the most common ocular manifestations of granulomatosis with polyangiitis (Wegener's). The process is often refractory to conventional immunosuppressive therapy and requires a more radical treatment approach. However, surgical experience with this type of patients is limited. There have been just a few reported cases of orbital decompression in such patients and many authors have doubted the appropriateness of the procedure, since it is associated with a high risk of potentially fatal complications. Our experience demonstrates the feasibility and effectiveness of orbital mass removal as to pain relief and exophthalmos reduction.Одним из самых частых офтальмологических проявлений гранулематоза с полиангиитом (Вегенера) является гранулематозное воспаление орбитальной клетчатки. Зачастую такое поражение рефрактерно к стандартной консервативной иммуносупрессивной терапии и требует более радикальных методов лечения. Однако опыт хирургического лечения таких пациентов ограничен. В литературе описаны единичные случаи декомпрессии орбиты у таких больных и их целесообразность оспаривается многими авторами с учетом высокого риска развития потенциально фатальных осложнений. Наш пример демонстрирует возможность и эффективность удаления орбитальных масс с целью уменьшения болевого синдрома и экзофтальма.

To the editor, In the excellent study recently published in the Annals of the Rheumatic Disease ,1 Damoiseaux et al showed a high diagnostic performance of antigen-specific immunoassay for the detection of myeloperoxidase (MPO) and proteinase 3 (PR3) antineutrophil cytoplasmic antibodies (ANCAs). These data challenge the role of indirect immunofluorescence in the ANCA testing algorithm. In our centre, we have discarded ANCA indirect immunofluorescence more than a decade ago. Therefore, new data showing the feasibility of screening by antigen-specific immunoassay have a particular value for us. In the recent series of 284 patients with ANCA-associated vasculitides, we have detected ANCAs by this approach in 96.9% of patients with microscopic polyangiitis (MPA) but only in 72.7% of patients with granulomatosis with polyangiitis (GPA) (table 1). The latter result can be explained by a relatively high occurrence of localised GPA in our series,2 since a rate of ANCA positivity reached 92.2% in patients with renal GPA. View this table: Table 1 Results of ANCA testing in 284 patients with ANCA-associated vasculitis, n (%) ANCA testing should be performed only in the clinical context since PR3-ANCA and MPO-ANCA can be found in the other conditions …

Background Kidney involvement is common in ANCA-associated vasculitis (AAV), but early detection of glomerulonephritis often presents a challenge. Objectives We evaluated diagnostic significance of urinary levels of kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (uMCP-1) and type IV collagen (uCollagenIV) and serum levels of MCP-1 (sMCP-1) and CollagenIV (sCollagenIV) and their relationship with nephritis activity and prognosis in AAV. Methods We enrolled 78 patients with AAV, diagnosed according to CHCC2012 definition (GPA=48, MPA=19, EGPA=11), 32 male, 46 female, aged 55 (45;61). To assess disease activity and kidney involvement we measured proteinuria, hematuria, serum creatinine (SCr), eGFR (CKD-EPI), BVAS and VDI. Urinary and serum concentrations of biomarkers were measured by ELISA. Results 28 patients had active renal AAV (35.9%, group 1), 26 had active nonrenal AAV (33.3%, group 2) and 24 were in long-term remission (30.8%, group 3). Median urinary levels of all biomarkers in active renal AAV were significantly higher than in groups 2 and 3 (Table), and did not depend on age and nosological form of AAV. Urinary excretion of all molecules was comparable in groups 2 and 3. There was a significant difference in sMCP-1 levels only between groups 1 and 3. sCollagenIV levels were similar in all groups. Significant positive correlations were found between urinary excretion of all biomarkers and features of nephritis activity: hematuria, proteinuria, renal component of BVAS (all p sMCP-1 level showed no association with signs of nephritis activity, but had a positive correlation with CRP and total BVAS (p ROC-analysis showed that uMCP-1≥159 pg/mL identified renal involvement with sensitivity 89%, specificity 67% (AUC 0.80). uKIM-1≥2283.3 pg/mL had similar sensitivity (92%) and lower specificity (58%), AUC 0.76. uCollagenIV≥3.09 mcg/L showed the worst sensitivity (57%), but the highest specificity (86%), AUC 0.76. Conclusions Urinary excretion of all biomarkers was significantly increased in active renal vasculitis. We suggest that uKIM-1 and uMCP-1 levels reflect local renal inflammation, while elevated uCollagenIV is likely to represent both glomerular basement membrane damage and activation of renal fibrogenesis. Limited specificity or sensitivity of individual urinary biomarkes may justify their combined use to identify active renal AAV. In contrast serum MCP-1 and CollagenIV only show a weak correlation with overall inflammatory activity and kidney dysfunction respectively, but have no association with nephritis activity. Disclosure of Interest None declared

Objectives Our aim was to assess frequency, clinical features and prognosis of renal involvement in microscopic poliangiitis (MPA) and used treatment modalities based on experience of Clinic of Nephrology, Internal and Occupational diseases in Moscow, Russia. Methods We performed a retrospective analysis of 61 patients with MPA, diagnosed according to Chapel-Hill Consensus Conference 2012, 23 male and 38 female, who were followed over a median of 29 (11;74) months. 58 patients (95.1% of 61) had a history of active renal vasculitis. Rapidly progressive glomerulonephritis (RPGN) was defined by the doubling of serum creatinine in ≤3 months. Acute kidney injury (AKI) and chronic kidney disease (CKD) stages were diagnosed according to KDIGO 2012 definition. Results In 43 patients (74.1%) renal involvement developed at the onset of the disease. Other 15 (25.9%) developed glomerulonephritis after a median of 7 (6;14) months. All patients had active urinary sediment; hematuria was present in 55 (94.8% of 58) patients; 8 patients (13.8%) developed nephrotic syndrome. Nephrogenic hypertension was present in 27 (46.5%) patients. RPGN developed in 35 patients (60.3% of 58), 6 of them (17.1%) also had nephrotic syndrome. During follow up 12 patients (20.7%) developed AKI, stage 2 was diagnosed in 5 patients, stage 3 in 7 patients. In 9 patients (15.5%) AKI developed during their first admission to the hospital. Renal involvement was confirmed by kidney biopsy in 9 cases (15.3% of 59). By the end of the follow-up CKD stage 1 was diagnosed in 9 (15.5%), stage 2 in 13 (22.4%), stage 3A in 9 (15.5%), stage 3B in 12 (20.7%), stage 4 in 10 (17.3%) patients and only 5 (8.6%) developed end-stage renal disease (ESRD). Three more patients were likely to develop ESRD, but they died before it could be diagnosed according to KDIGO criteria. ESRD developed in 9 (8;13) months from the onset of the disease. A total of 4 patients (6.8%) died. As the first line induction therapy all patients received corticosteroids (CS), 51 (87.9%) – cytotoxic agents, predominantly cyclophosphamide (90.3% of 51), and 4 (6.9% of 58) – rituximab (RTX). Plasmapheresis was used in 13 (22.4%) patients. Complete remission was achieved in 40 (69%) patients who received cytotoxic agents and/or CS, 14 (24.1%) developed partial remission, in 4 (6.9%) remission was not achieved. During follow up 18 patients received RTX for remission induction due to refractory disease in 12 (66.7%), severe relapses in 2 (11.1%) and/or CS and cytotoxic agents side effects or intolerance in 8 (44.4% of 18) patients. Thirteen (72.2% of 18) patients achieved complete remission on RTX, 3 (16.7% of 18) achieved partial remission, in 2 (11.1%) RTX was ineffective. 29 patients (50%) developed one or more severe relapses during follow-up; corresponding to a relapse rate of 0.186 per patient per year. Renal relapses developed in 21 (36.2%) patients, with a renal relapse rate of 0.105 per patient per year. Conclusions Our research revealed considerably lower prevalence of ESRD and fewer lethal outcomes in patients with MPA when compared with the published data. Nevertheless more than a half of patients develop RPGN during the course of the disease, and 46.6% have CKD stage 3B or worse by the end of the follow up. Despite effective induction therapy with high-dose CS, cytotoxic agents and/or RTX relapses, both renal and extrarenal, are frequent. Disclosure of Interest None declared