FRONTIERS
Currently, strong evidence has been obtained for the fundamental role of pathological activation of B cells in the pathogenesis of immunoinflammatory (autoimmune) rheumatic diseases (IMRD), and drugs that specifically modulate the function or cause depletion of various subpopulations of B cells and plasma cells are considered a promising direction. pharmacotherapy of these diseases. of particular interest is belimumab (BLM), a human monoclonal antibody (mAb) (IgG1λ) to BAFF (B cell-activating factor belonging to the TNF family), which is the first “targeted” biological drug specially developed for the treatment of systemic lupus erythematosus (SLE). The efficacy and safety of BLM in SLE in adults and children, including lupus nephritis, in combination therapy with rituximab, steroid-sparing effect, the ability to prevent irreversible damage to internal organs dictate the need for its wider application in clinical practice.
PROBLEMS OF RHEUMATOLOGY DURING THE 2019 CORONAVIRUS PANDEMIC
In patients with immune-mеdiated (autoimmune) rheumatic diseases (IMIRD), there are a number of factors (advanced age, uncontrolled inflammation, initially irreversible damage to internal organs, comorbid pathology, genetic and other factors) that can potentially lead to an increase in “sensitivity” to SARS-CoV -2 (severe acute respiratory syndrome coronavirus-2) and concomitant viral and bacterial infections, an increase in the risk of a severe course of COVID-19 (coronavirus disease 2019), a decrease in the effectiveness of therapy for both IMIRDs and COVID-19. An important area of pharmacotherapy for IMIRDs and other autoimmune diseases is associated with the use of anti-B-cell drugs, primarily rituximab (RTX), which is a chimeric (mouse/human) monoclonal antibody (mAb) to the CD20 antigen of B cells. At present, in Russia, the RTM biosimilar, acellbia (BIOCAD), is widely used, which is not inferior to RTX in terms of efficiency and safety. The problems of anti-B-cell therapy during the COVID-19 pandemic in relation to the risk of infection, severe course and insufficient effectiveness of vaccination against SARSCoV- 2 are considered. According to the recommendations of the Association of Rheumatologists of Russia, a more rigorous assessment of indications for induction and maintenance therapy of RTX therapy and harmonization of the timing of drug administration and vaccination is required.
ORIGINAL RESEARCH
The JAK inhibitor tofacitinib (TOFA) blocks the intracellular signaling pathway that activates the synthesis of cytokines and mediators involved in the development of pain and central sensitization (CS), which determines the rapid analgesic effect. However, it is not clear how pain reduction is associated with achieving low activity in rheumatoid arthritis (RA).
The aim of the study was to assess the relationship between the early clinical response to tofacitinib and a decrease in rheumatoid arthritis activity after 3 and 6 months.
Material and methods. The study group consisted of 88 RA patients (age – 53±11.5 years; 79.3% of women) who received basic anti-inflammatory drugs (59.5% – methotrexate, 19.8% – leflunomide) and who were prescribed TOFA in a dose 10 mg/day. Seropositivity for rheumatoid factor was 89.8%; the value of the DAS28 index is 5.2±1.2. The severity of pain was assessed using the Brief Pain Inventory questionnaire, the neuropathic component of pain (NCP) – using the PainDETECT questionnaire, signs of CS – using the Central Sensitization Inventory (CSI) questionnaire in the early stages after the administration of TOFA, RA activity – using the DAS28-CRP index after 3 and 6 months.
Results. The mean severity of pain at baseline was 5.3±2.0 on the visual analogue scale (VAS); 51.1% of patients had signs of CS (CSI>40), 15.9% had NCP (PainDETECT>18). 7 days after the start of therapy, there was a significant decrease in pain – to 4.1±1.8 according to VAS (p<0.05) and CS – 40.4±13.5 to 36.5±12.5 according to CSI (p=0.01). After 28 days, the effect was even more significant: the level of pain according to the VAS was 2.8±1.6 (p=0.000), the NCP decreased from 11.8±5.6 to 6.8±3.1 (p=0.000), CS – up to 31.6±13.9 (p=0.000). The value of the DAS28-CRP index after 3 and 6 months was 3.7±1.3 and 3.6±1.2, respectively. The number of patients with pain relief ≥50% after 28 days was 59.9%, low RA activity after 3 months. (DAS28-CRP≤3.2) was acieved in 64.4% of patients. There was a clear correlation between the number of patients with a pain reduction of ≥50% at 28 days and the number of patients who achieved low RA activity at 3 and 6 months. (rS=0.548, p=0.000 and rS=0.790, p=0.000). 6 patients dropped out of the study due to inefficiency or social reasons. No serious adverse reactions were noted.
Conclusions. The use of the JAK inhibitor TOFA allows achieving a quick analgesic effect and reducing the signs of CS. An early clinical response to TOFA (pain relief) predicts a decrease in RA activity after 3 and 6 months of therapy.
Objective. To study the relationship between the level of calprotectin (CP) and RA activity, the level of acute phase reactants, proinflammatory cytokines, chemokines and growth factors, to assess its dynamics during rituximab (RTM) biosimilar therapy.
Material and methods. 20 patients with RA were examined. All patients received 2 intravenous infusions of RTM (Acellbia®) at a dose of 600 mg with an interval of 2 weeks against the background of methotrexate therapy. The level of CP in blood serum was measured by ELISA.
Results. Before starting DAS28 (5.6 [4.9–6.8]), SDAI (27.17 [23.08–39.9]) and CDAI (26.6 [22.25–37.0]) corresponded to the high disease activity. A decrease in disease activity was noted after 12 and 24 weeks of therapy: the DAS28 value was 4.28 [3.24–4.75] and 4.14 [3.11–4.66], respectively (p<0.05). Before the start of therapy, patients with RA had a higher CP level compared with healthy donors 9.68 (4.5–21.5) and 2.39 (1.52–4.45) μg/ml, respectively (p<0.05). Against the background of RTM therapy, there was a decrease in the CP level 12 weeks after the first infusion of the drug in the group as a whole by 26.5% from the initial level, among patients with moderate/no effect of therapy – by 32.7% from the initial level.
Conclusion. The CP level significantly decreases during therapy and can be used to monitor the effectiveness of therapy. The predictive value of this laboratory parameter requires further study.
Objective. To clarify the frequency of insulin resistance (IR) in patients with systemic lupus erythematosus (SLE), traditional and associated with rheumatic disease risk factors for its development, to assess the possibility of using the Finnish Type 2 Diabetes Risk Assessment Score (FINDRISC) questionnaire to detect IR.
Material and methods. The cross-sectional study included 49 patients with SLE (46 women, 3 men) without diabetes mellitus and hyperglycemia, observed at the V.A. Nasonova Research Institute of Rheumatology in 2019–2020. The median age of the patients was 40 [33; 48] years, the duration of the disease was 3.0 [0.7; 8.0] years. Glucocorticoids (GC) were received by 41 (84%) patients, hydroxychloroquine – by 38 (78%), immunosuppressive drugs – by 10 (20%), biological agents – by 5 (10%). The glucose and fasting immunoreactive insulin levels were examined, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was calculated in all patients. HOMA-IR value ≥2.77 corresponded to IR. Traditional risk factors for type 2 diabetes and the risk of its development in the next 10 years in patients with SLE were assessed using the Russian version of the FINDRISC questionnaire.
Results. The median HOMA-IR level in SLE patients was 1.7 [1.2; 2.5]. IR was detected in 10 (20%) of 49 patients with SLE. Patients with and without IR were comparable in terms of sex, age, duration and activity of SLE, therapy, and type 2 diabetes traditional risk factors. BMI, WC and insulin levels were higher in patients with IR. HOMA-IR correlated with body mass index (BMI) (r=0.6; p<0.001), waist circumference (WC) (r=0.5; p<0.001), risk categories for developing type 2 diabetes according to FINDRISС (r=0.3; p=0.03), SLEDAI-2K index (r=–0.4; p<0.01), C3 complement levels in serum (r=0.3; p=0.04) and the duration of GC therapy (r=0.3; p=0.03).
Conclusion. IR was diagnosed in 20% of SLE patients without a history of diabetes and with normal fasting glucose in venous blood. The lower SLE activity, the longer GC intake in patient, the higher the HOMA-IR index was detected in him. However, the IR appearance was reliably associated only with an increasing BMI and WC. The use of the FINDRISC questionnaire, which allows to stratify respondents in the general population by the risk of developing type 2 diabetes mellitus, did not help to identify SLE patients with IR.
The frequency of vascular calcification in patients with osteoarthritis (OA) and calcium pyrophosphate crystal deposition disease (CPPD) has not yet been studied, and the role of calcium crystals (basic and pyrophosphates) in the development of calcification is also unknown.
Objective. Determine the presence and degree of calcification of the coronary vessels in patients with calcium pyrophosphate crystal deposition disease and osteoarthritis of the knee joints with no clinical signs of cardiovascular diseases.
Materials and methods. One-stage, single-center study, performed by the “case – control” method. The main group – 20 patients with CPPD, the comparison group – 20 patients with OA of the knee joints. Inclusion criteria: age from 18 to 65 years; absence of clinical signs of cardiovascular disease at the time of examination and indications of a history of cardiovascular accidents. Exclusion criteria: unsigned informed consent; pregnancy; breastfeeding; other rheumatic disease; cancer; high and very high cardiovascular risk on the SCORE scale. The survey included an assessment of anthropometric data, blood pressure (BP), lipid profile, serum levels of glucose, creatinine, uric acid, C-reactive protein, vitamin D, osteoprotegerin, parathyroid hormone, and the levels of magnesium, phosphorus, and total calcium were studied. All patients underwent multispiral computed tomography with determination of calcium count and the number of affected arteries. To calculate the coronary score, the A.S. Agatston et al.
Results and discussion. Most of the parameters in the compared groups did not differ. When assessing the calcification of the coronary arteries according to the A.S. Agatston et al. 9 (45%) patients with CPPD and 8 (40%) patients with OA had a coronary calcium score >1. Quantitative indicators of calcium score can correspond to coronary artery stenosis ≥20% in 8 (40%) patients with CPPD and in 5 (25%) patients with OA according to J.A. Rumberger et al. The serum level of osteoprotegerin was significantly higher in patients with a calcium score ≥27 according to J.A. Rumberger et al. (p=0.04). Calcification was detected in 9 (56%) of 16 patients with serum vitamin D levels <30 ng/ml and in 8 (33%) of 24 patients with serum vitamin D levels >30 ng/ml.
Conclusions. In patients with an initially low cardiovascular risk, the probability of a combination of chondrocalcinosis and cardiovascular calcification is 45%, in OA it is 40%. The risk factors for coronary calcification in patients with CPPD and OA should be studied further.
Standard radiography in direct projection is the “gold standard” in the diagnosis of hand osteoarthritis (HOA). However, the currently clinically most severe “erosive” or “inflammatory” phenotype of HOA is characterized by the presence of inflammatory symptoms such as bone marrow lession (BML), synovitis and tenosinovitis, which are not visible on the radiograph by the nature of the study due to the low optical density. In addition, X-ray examination is planar and has no possibility of multiplanar visualization. This dictated the need to search for a more informative visualization technique in HOA.
Aim – to compare the sensitivity and specificity of standard radiography and magnetic resonance imaging (MRI) techniques in determining the symptoms of osteoarthritis (OA) of the distal interphalangeal (DIP), proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the right hand; to determine the indications for the appointment of MRI in patients with HOA.
Materials and methods. The study included 64 women with clinically verified diagnosis of HOA according to ask criteria. For the first time, X-rays of the joints of the right hand in the anterior-posterior projection and MRI were performed for each of them. Each patient completed the AUSCAN questionnaire. X-rays were described according to the Kellgren and Lawrence systems, magnetic resonance imaging was analyzed according to the modified OHOA system. The sensitivity and specificity of the methods were compared based on the detection of 4 symptoms detected by radiography and MRI: joint space narrowing (JSN), osteophytes (OP), erosions and subluxations. The average age of the patients was 65.28±6.82 years, the age of onset was 48.81±7.73 years, the duration of the disease was 15.0 (10.0–19.5) years.
Results. Both methods showed approximately equal identification JSN symptom in DIP and PIP, 95% definition JSN in MCP. OP were detected in 88% of patients in DIP according to radiography and in 95% – using MRI (p>0.05). In PIP OP were observed in 70% of patients on radiographs and in 86% on magnetic resonance imaging, in MCP – in 45% and 66% of cases, respectively. Erosion in DIP were found in 41% of patients according to MRI and 34% as a result of X-ray examination, in PIP – in 27% and 13% of cases, in MCP – in 60% and 8% of cases, respectively. Subluxations were determined in DIP 23% on radiographs in 31% of cases by MRI, in PIP – in 8% and 6% (p>0.05), in MCP subluxations almost never met – in 3% of cases by conventional radiography.
Conclusions. MRI in HOA can be used in the detection of erosive process, differential diagnosis with other diseases of the joints, determination of inflammatory changes in the hands and assessment of their severity, but has no significant advantages over standard radiography in determining the symptoms of degenerative-dystrophic nature (JSN and OP). Subluxations of the MCP joints are not typical for the HOA.
Microcirculatory (MC) disorders in systemic sclerosis (SS) are an important part of pathogenesis, morphogenesis, determine the clinical picture of the disease, the severity of the patient’s condition and prognosis. The authors draw attention to a direct method for studying microcirculatory disorders – conjunctival biomicroscopy (CBM). The use of improved equipment for conducting CBM and the survey algorithm allows at the present stage to improve the quality of the data obtained, to simplify and standardize the CBM procedure, to record and analyze new MC predictors.
The study of the correlations between MC changes identified in CBM in patients with SS, with the data of the clinical picture, will make it possible to determine a limited set of the most significant MC parameters, simplify the analysis of primary CBM data and take a fresh look at the CBM method, rethinking its diagnostic capabilities SS, which determined the aim of this study.
Materials and methods. In 48 patients suffering from SS (mean age 51±1.7 years), MC was studied by the direct method – conjunctival biomicroscopy. Quantitative parameters of MC are compared with the clinical manifestations of SS by the methods of linear Pearson correlation and Spearman non-linear correlation. The critical value of the level of statistical significance in testing null hypotheses was taken to be 0.05.
Results. The main clinical manifestations of SS: the duration of the disease (months), skin count (points), the activity of the disease (points), the duration of skin syndrome (months) and the duration of vascular syndrome (months) showed statistically significant linear and non-linear correlation with seven MC parameters: the value of the arteriolo- to-venule ratio (AVR), five parameters characterizing the density of capillaries on the bulbar conjunctiva and the average diameter of capillaries.
Conclusion. A limited set of the most informative MC signs in the form of AVR and the number of capillaries in various areas of the temporal section of the bulbar conjunctiva greatly simplify the interpretation of CBM data and allow a new look at the diagnostic capabilities of the “old” method in SS. A promising direction, in our opinion, is the further study of the indicated MC parameters and the identification of possible correlations with the data of laboratory, instrumental methods of research and assessment of the dynamics of the indicated MC parameters in case of SS.
Primary Sjogren’s syndrome (pSS) is one of the most frequent among the connective tissue diseases. Histological examination of the minor salivary gland (MSG) is important diagnostic method. The currently established histological criteria for pSS do not have absolute sensitivity and specificity, which makes the search for additional morphological hallmark relevant.
Aim – to study of the qualitative and quantitative composition of cellular populations inflammatory infiltrates in MSG pSS patient with the assessment of additional diagnostic criteria for disease based on the data obtained.
Subjects and methods. The study included 55 patients with a diagnosis of pSS according to the criteria of ACR/ EULAR 2016. The control group consisted of 18 healthy volunteers. A MSG biopsy was performed all subjects for histological and immunohistochemical studies with a quantitative assessment of CD3+, CD4+, CD8+, CD20+, CD21+, CD68+, CD138+ cells. Statistical data analysis was performed using the Statistica 10.0 for Windows (StatSoft Inc., USA). For comparison of quantitative traits, the Mann – Whitney U-test was used. To determine the diagnostic threshold of the number of a ROC analysis was performed. An operating characteristic curve was plotted. The area under the curve (AUC), diagnostic specificity, diagnostic sensitivity, diagnostic accuracy, likelihood ratio of the positive and negative results of the test were calculated. The construction of classification models, including the number of different cell types, was carried out using linear discriminant analysis.
Results and discussion. The number of CD3+, CD4+, CD8+, CD20+, CD138+ cells in 4 mm2 (area of section) was significantly higher in the pSS group. The largest AUC were observed for the quantitative evaluation of CD3+ cells – 0.88 [95% confidence interval (CI): 0.80–0.96] and CD8+ cells – 0.87 [95% CI: 0.79–0.95], which at the specified diagnostic thresholds corresponded to the sensitivity of 70.9% [95% CI: 57.86–81.23] and 65.45% [95% CI: 52.25–76.64], specificity of 94.4% [95% CI: 74.24–99.72] and 100% [95% CI: 82.41–100], respectively. The CD21+ follicular dendritic cells were detected only in MSG of pSS group. AUC for quantitative assessment of these cells was 0.65 [95% CI: 0.52–0.78], sensitivity 29.1% [95% CI: 18.77–42.14] and specificity 100% [95% CI: 82.41–100]. Using the method of discriminant analysis, we designed classification models that included various combinations of the studied markers. The highest AUC among all possible combinations was observed for the decimal logarithms of the number of CD3+ and CD68+ cells – 0.92 [95% CI: 0.85–0.98], which for a given diagnostic threshold corresponded sensitivity – 81.82% [95% CI: 69.67–89.81], specificity – 94.4% [95% CI: 74.24–99.72].
REVIEWS AND LECTURES
The article discusses the importance of ultrasound examination of the salivary glands in Sjogren’s disease for the diagnosis, as well as for assessing the activity of the disease. The characteristics of the main ultrasound changes in the salivary glands and the pathogenetic reasons of these changes are given. The results of studies of the dynamics of changes in ultrasound parameters both in patients not receiving treatment and in the presence of various methods of therapy are presented. The paper also provides basic data on the role of ultrasound in the differential diagnosis of diseases involving the salivary glands.
The paper discusses the results and substantiates the effectiveness of pharmacotherapy for osteoarthritis of the knee joints using a dietary supplement Cartilox, which includes five active substances (type II collagen peptide, Boswellia serrata extract, curcuminoids, piperine and hyaluronic acid).
PEDIATRIC RHEUMATOLOGY
The complexity of diagnosing and predicting the course of TNF-receptor-associated periodic syndrome TRAPS determines the importance of studying the dependence of clinical manifestations on the variant of genetic mutation and the presence of modifier genes. We observed 5 children with an identified diagnosis of TRAPS. It was established that the disease onset in most cases is defined as a juvenile arthritis with systemic onset. Genetic variants with the replacement of cysteine residues are associated with an early debut and an aggressive course, the c.362G> A p.R121Q mutation is associated with an erosive damage to the spine. The case of a favorable course of TRAPS in siblings with a newly detected mutation is described. The development of urgent complications of TRAPS was revealed when basic therapy with canakinumab was canceled.
ORTHOPEDIC RHEUMATOLOGY AND REHABILITATION
Introduction. Hallux rigidus (HR) is a common source of forefoot pain, which leads to progressive loss of range of motion in the first metatarsophalangeal (MTP1) joint and pathologically affects biomechanics of the whole lower limb. HR is characterized by degeneration of the articular surfaces of MTP1 joint with the formation of bone growths, cysts and erosions, osteochondral defects and loose bodies. The frequency of occurrence of HR is 1 in 40 adults older than 50 years, and this localization of osteoarthritis is the most common among all joints of the foot. The aim of this article is to improve the results of conservative treatment of HR through the use of physical rehabilitation methods, such as manual therapy, therapeutic exercises and foot orthotics.
Materials and methods. This study included retrospective cases of 24 patients (28 feet), who underwent a single course of conservative treatment of HR at the European Clinic for Sports Traumatology and Orthopedics (ECSTO) of the European Medical Center (EMC) since January 2014 to December 2018. The patients’ mean age was 51 years (range, 41 to 69 years). Median time between the beginning of treatment and final examination was 26 months (interquartile range from 17 to 36 months). Patient satisfaction, VAS pain scale, AOFAS and FAAM questionnaires and MTP1 dorsiflexion were evaluated in this study.
Results. According to AOFAS scale, we obtained 18% (5/28) of excellent, 78% (22/28) of good, 4% (1/28) of fair and no poor results. Median AOFAS score significantly increased from 58.5 points before treatment to 87.0 points on the final examination (p<0.05). Median FAAM daily activity subscale showed 98% of functional outcome with median subjective score of 95%, median FAAM sports score was 97% and median subjective sports score rate was 90%. Patient’s satisfaction at the final examination was “excellent” in 57% (16/28), “good” in 39% (11/28), “fair” in 4% (1/28) of cases and no poor results were obtained. Median VAS pain scale decreased from 5 points before treatment to 1 point at the final examination (p<0.05). Median angle of the MTP1 dorsiflexion significantly increased from 23° before treatment to 30° on the final examination (p<0.05).
Conclusion. Described approach of the conservative treatment of HR is an effective method of treatment of early stages of the disease with high patient satisfaction rate and functional outcome.
CLINICAL OBSERVATIONS
The clinical picture of lobular panniculitis associated with damage to the pancreas can vary widely, accompanied by damage to the joints and internal organs, which complicates the diagnosis of the disease. A clinical observation of a torpid course of lobular panniculitis with total damage to organs and systems is presented, which clearly illustrates the difficulties of differential diagnosis and therapy that arise in real therapeutic practice.
ТЕЗИСЫ VIII СЪЕЗДА РЕВМАТОЛОГОВ РОССИИ С МЕЖДУНАРОДНЫМ УЧАСТИЕМ «РЕВМАТОЛОГИЯ 2021: МУЛЬТИДИСЦИПЛИНАРНЫЕ И МЕЖДИСЦИПЛИНАРНЫЕ ПРОБЛЕМЫ», ПОСВЯЩЕННОГО 30-ЛЕТИЮ ОБРАЗОВАНИЯ ОБЩЕРОССИЙСКОЙ ОБЩЕСТВЕННОЙ ОРГАНИЗАЦИИ «АССОЦИАЦИЯ РЕВМАТОЛОГОВ РОССИИ»
ISSN 1995-4492 (Online)