Using rheumatology as an example, the paper considers current trends in the development of medical science in the 21st century. It is emphasized that biochemistry,  genetics, and molecular biology are becoming the central research priority site attracting to clinical medicine and rheumatology,  neuroscience  (including cognitive and computational neurobiology, neuroinformatics), and psychology. Modern rheumatology effectively adapts current scientific achievements, which contributes to the significant progress of fundamental  and clinical medicine. Deciphering the key immune mechanisms of the pathogenesis of immune-mediated inflammatory rheumatic diseases (IIRD) has allowed biotechnology techniques to be used to design fundamentally new drugs, such as biological agents, small molecules that are able to selectively affect certain pathogenetic constituents  and to minimize the overall functioning of the immune system. This could substantially enhance the efficiency of treatment for IIRDs,  by achieving a long-term  stable remission in many patients and contributed  to a significant expansion of ideas on human pathology. It is assumed that most promising studies of pharmacotherapy for IIRDs towards personalized medicine will be based on postgenomic technologies, including proteomics,  transcriptomics, metabolomics,  epigenomics, as well as the integrated use of digital methods. 

A diversity of the clinical manifestations of systemic lupus erythematosus (SLE) and its undulating course with alternating remissions and exacerbations make this disease one of the most difficult ones to diagnose, treat, and evaluate the efficiency of therapy.

Despite the fact that the recently developed methods for early diagnosis and procedures for combined pathogenetic therapy and monitoring  the disease course have led to increases in survival rates (≥90%) and life expectancy in patients with SLE, there are still many unsolved problems. In particular,  the treatment for SLE is not yet efficient enough and the activity of the latter cannot be completely controlled.  The relapsing and remitting course of SLE concurrent with comorbidity,  as well as the adverse effects of glucocorticoids  and immunosuppressants contribute to the accumulation of irreversible organ damages.

The paper is devoted to a review of the updated EULAR recommendations for the treatment of systemic lupus erythematosus, which were published in 2019. It presents comments  and debatable issues, by taking into account the Russian recommendations for the treatment of SLE.

Patients with psoriatic arthritis (PsA) have a higher risk of cardiovascular disease (CVD) compared with the general population. Inflammation and traditional CVD risk factors (RFs), including dyslipidemia, make a significant contribution to the development of CVD and their complications in patients with PsA.

Objective: to assess the time course of changes in lipid profile measures in patients with early PsA (ePsA) during adalimumab (ADA) treatment for 3-months.

Subjects and methods. The investigation enrolled 16 patients (11 women, 5 men; median (Me) age, 45.5 years) with early PsA (ePsA) (disease duration, 7.7 months). ADA was administered subcutaneously at doses of 40 mg once every 2 weeks for 3 months. Before and 3 months after the start of ADA therapy, DAS, C-reactive protein levels, and traditional CVD RFs, including lipid profile measures (total cholesterol, TC, low-density lipoprotein cholesterol, LDL-C, triglycerides, TG, high-density lipoprotein cholesterol, HDL-C, and atherogenic coefficient, AC) were estimated. Ten-year risk for fatal CVD was assessed using the SCORE scale.

Results and discussion. Lipid profile disorders mainly associated with elevated LDL-C levels were revealed in 11 (69%) patients; according to the SCORE scale, the total 10-year risk for fatal CVD was low and moderate in 10 (62.5%) and 6 (37.5%) patients, respectively. A correlation was found between the baseline DAS and TG (r=0.53; p<0.05) and AC (r=0.57; p<0.05); between HDL levels and DAS (r=-0.68; p<0.05), and between the number of tender (r=-0.63; p<0.05) and swollen joints (r=-0.65; p<0.05).

Three months after starting ADA Median level of TC increased from 4.9 [4.5; 5.9] to 5.5 [4.9; 6.3] mmol/L (p=therapy, 15 (94%) patients achieved remission of ePSA; one (6%) patient showed a low disease activity. 0.01) and TG — from 0.8 [0.7; 1.4] to 1.1 [0.9; 1.4] mmol/L (p=0.03). There were no significant changes in the level of LDL-C and HDL-C, and CA, their medians at the beginning and end of therapy were 3.3 [2.8; 4.1] and 3.6 [3.3; 4.1]; 3.0 [1.2; 1.  5] and 1.3 [1.2; 1.6]; 2.6 [2.3; 3.6] and 3.2 [2.4; 3.6] mmol/L, respectively. There was a tendency to increase the frequency of non-target TC values from 44 to 75%, LDL-C from 69 to 81%, TG from 12.5 to 19%, and AC from 37.5 to 62.5% (p>0.05).

Conclusion. Lipid profile changes were found in 69% of patients with ePSA and correlated with disease activity. The lower inflammatory activity during ADA therapy was accompanied by elevated TC and TG levels.

Objective: to investigate the impact of therapy with the interleukin-6 receptor inhibitor tocilizumab (TCZ) on the time course of changes in N-terminal pro-brain  natriuretic  peptide (NT-proBNP) levels in patients with rheumatoid arthritis (RA) during a 12-month follow-up period.

Subjects and methods. 31 RA patients (26 women and 5 men) with an inadequate  response and/or intolerance  to disease-modifying antirheumatic drugs (DMARDs) were included. Their median age was 54 [45; 61] years; the disease duration – 110 [62; 168] months; DAS28 – 6.2 [5.1; 7.1]; SDAI – 35.0 [23.9; 51.0], and CDAI – 30.0 [21.0; 42.0]. All the patients were seropositive for rheumatoid  factor (RF),  84% – for anti-cyclic citrulinated  peptide (anti-CCP) antibodies. Extra-articular manifestations were found in 54% of patients. Patients with chronic heart failure were notincluded. The RA patients were found to have a high frequency of traditional  risk factors for cardiovascular diseases (CVD): hypertension  (75%), dyslipidemia (61%), smoking (17%), overweight (61%), a family history of CVD (36%), and hypodynamia (68%). Coronary heart disease was diagnosed in 11% of patients. The inefficacy of three or more NSAIDs was noted in 45% of cases; intolerance  to previous therapy with NSAIDs was observed in 55%. The patients received TCZ at a dose of 8 mg/kg every 4 weeks: 39% received TCZ alone; 61% – in combination  with methotrexate (MTX), the MTX median dose was 20 [18; 25] mg/week. The level of NT-proBNP was measured before and 12 months after TCZ therapy.

Results and discussion. After 12 months of treatment with TCZ 54% of patients had disease remission (DAS28 <2.6), 46% – low disease activity (DAS28 <3.2). Median DAS28 value decreased from 6.2 [5.1; 7.1] to 2.7 [1.5; 3.3] (p<0.01), erythrocyte sedimentation rate (ESR) – from 38 [24; 54] to 8 [4; 16] mm/h (p<0.01), C-reactive  protein (CRP)  – from 27 [10; 49] to 0.5 [0.2; 0.7] mg/L (p<0.01) and NT-proBNP – from 75.8 [43.0; 100.7] to 37.8 [25.1; 78.5] pg/l (p=0.01), although the frequency of its increased values (≥100 pg/ml)  remained unchanged  (13%). There was a correlation of ΔNT-proBNP with ΔESR (r=0.43;  p<0.05) and with ΔCRP (r=0.46;  p<0.05). No association was found between ΔNT-proBNP, RA activity measures, RF, and anti-CCP. The level of NT-proBNP in patients treated with TCZ alone and in combination  with MTX did not differ considerably.

Conclusion. After 12 months of treatment to suppress RA activity, there was a decrease in NT-proBNP levels when TCZ was used alone and in combination with MTX. The lower concentration of NT-proBNP was associated with a reduction  in acute phase measures (CRP and ESR). Control  of RA activity results in the reduced damaging effect of inflammation on the myocardium.

Remission duration and minimal disease activity (MDA) during treatment with biological agents (BA) and after their discontinuation in patients with early psoriatic arthritis (PsA) have been insufficiently studied.

Objective: to study the timing of the onset and duration of remission and MDA after BA initiation and discontinuation in patients with early PsA, followed up according to the Treat-to-Target (T2T) principles.

Subjects and methods. The investigation enrolled 34 patients (18 men, 16 women) with early PsA who met the CASPAR criteria, had participated  in the All-Russian Registry and followed up according to the T2T principles.The patients' mean age was 38±11 years; the duration of PsA and psoriasis was 12.0±10.0 and 89.8±91.1 months, respectively. At the beginning of the follow-up, the median DAS and DAPSA scores were 4.05 [3.72; 5.10] and 33.55[28.34; 41.77], respectively. All the patients were prescribed BAs (adalimumab  (n=21), ustekinumab  (n=8), certolizumab  pegol (n=3)  or etanercept (n=2)) in combination  with methotrexate. The median therapy duration was 9 [6.5; 15] months. The activity of the disease and efficiency of PsA therapy were evaluated using DAS, DAPSA and the criteria for MDA (tender joint count of ≤1, swollen joint count of ≤1, PASI score ≤1 or BSA ≤3, pain intensity on visual analogue scale (VAS) ≤15 mm, patient's assessment of disease activity on VAS ≤20 mm; HAQ score ≤0.5; enthesitis index ≤1) at the beginning of the investigation and then every 3 months. The number of patients who had achieved remission (DAS <1.6; DAPSA ≤4) or MDA (5 of 7 criteria) during BA therapy at least once during the 24-month follow-up was determined.  The absence of remission or MDA at the time of examination  was considered to be an exacerbation. The duration of remission and MDA was estimated after BA discontinuation according to the activity indices at the time of examination  by a physician every 3 months.

Results and discussion. During the 24-month follow-up, DAS/DAPSA  remissions were achieved at least once by 28 (82%)/27 (79%) patients, respectively; and MDA was seen in 28 (82%). The first DAS/DAPSA  remission occurred after an average of 4.8±2.2/5.8±3.2 months; MDA – after 4.0±1.9 months. The average DAS/DAPSA  remission duration was 9.1±5.0/8.3±5.0 months,  respectively, and MDA – 11.0±5.5 months. Seven (21%) patients responded to therapy, but did not achieve neither DAPSA, nor DAS remission and 6 (18%) patients did not have MDA. 8 patients in remission continued  to receive BAs until the end of the follow-up. Nineteen  patients discontinued therapy for various reasons. After discontinuation of BAs, the physician recorded DAS exacerbation in 11 (55%) patients after an average of 6.5±2.3 months and DAPSA exacerbation in 12 (60%)after 5.8±2.3 months. According to the patient assessment, an exacerbation developed in an average of 3.5±3.4 months after BA discontinuation. A DAS/DAPSA  exacerbation was observed in 5 (15%) patients during BA therapy after an average of 11.5±4.7/12.0±4.7 months.

Conclusion. During BA therapy, the majority of patients with early PsA achieved remission and MDA following an average of 5 months after the start of treatment using the T2T strategy. After BA discontinuation, an exacerbation occurs in more than half of patients. Following BA discontinuation, the remission duration recorded by the physician according to the activity indices averages 6 months; the duration of subjective improvement  according to the patient assessment was 3 months. With continued  BA treatment, 15% were observed to have lost its efficiency after an average of 12 months.

Objective: to present cases of Behcet's disease (BD) concurrent  with axial spondyloarthritis  (axSpA).

Subjects and methods. A total of 470 patients with BD who met the International Standard Bibliographic Description (ISBD) criteria were examined at the V.A. Nasonova Research Institute of Rheumatology in the period from 1990 to

2018. In 9 of them, BD was concurrent  with axSpA; 7 out of the 9 patients met the 1984 modified New York criteria for ankylosing spondylitis (AS) and two patients fulfilled the 2009 ASAS non-radiographic axSpA criteria.

Results and discussion. Most (55.6%) patients were men. BD was preceded by axSpA in 6 patients. The symptoms of AS joined an average of 8.4 [2; 10] years after the onset of the clinical manifestations of BD. Three patients developed BB 9–15 years after the onset of the first symptoms of axSpA. The mean duration  of BD was 14.0±7.8 years and that of axSpA was 10.9±6.2  years. All the patients were HLA-B27-positive; three were found to have B5 antigen.All the 9 patients had mucocutaneous manifestations  that were characteristic  of BD. Four patients were diagnosedas having eye injuries: generalized uveitis with retinal vasculitis, posterior uveitis with or without retinal vasculitis. Gastrointestinal tract lesions were detected in 44.4% of cases. Peripheral  arthritis was present in all the patients. Entheseal involvement was observed in 66.7% of patients. The radiographic signs of bilateral sacroiliitis according to the modified New York criteria were found in 7 (77.8%) patients; MRI revealed active inflammatory changes in the area of the sacroiliac joint in 3 (33.3%) patients.

Conclusion. The fact that there may be an overlap between BD and axSpA should be taken into account in everyday clinical practice, which will assist in choosing the optimal treatment strategy.

Objective: to investigate the clinical and laboratory manifestations of systemic lupus erythematosus (SLE) with nervous system lesions in a Kyrgyz cohort.

Subjects and methods. The prospective study enrolled 460 patients with SLE who fulfilled American College of Rheumatology (ACR) 1987 and SLICC 2012 criteria, and had been followed up at Academician M. Mirrahimov National  Center for Cardiology and Therapy, from January 2012 to December  2017 according to the Eurasian RENAISSANCE Register program. The 1999 ACR classification criteria were used to evaluate the neuropsychiatric manifestations of SLE (NPSLE). A psychiatrist diagnosed neuropsychiatric disorders according to the ICD-10. A psychologist identified cognitive impairment, by using the specific Mini-Mental State Examination (MMSE)  (a minischeme for examining a patient's mental status).

Results and discussion. Various NPSLEs  were detected  in 103 (22.39%) of the 460 patients.  According to the 1999 ACR criteria, 103 patients were diagnosed as having 155 different NPSLEs,  including 123 (79.35%) patients who had central nervous system (CNS)  disorders and 32 (20.65%) with peripheral  nervous system (PNS) damages. There were 76 (61.79%) focal 47 (38.21%) diffuse CNS disorders. Most patients with diffuse NPSLEs  were observed to have psychosis, the main manifestations  of which were visual and auditory hallucinations (72.34%). The patients with focal NPSLEs  had cerebrovascular disease (43.42%) with increase of level of antinuclear  antibodies,  antibodies against double-stranded DNA and hypocomplementemia (95.56, 86.52, and 73.85%, respectively). Patients  with CNS lesions were significantly more likely than those with PNS to have lupus nephritis and hematological  disorders (leukopenia,  lymphopenia, and thrombocytopenia), as well as high immunological  activity.

Conclusion. Most patients with diffuse NPSLEs were observed to have psychosis with visual and auditory hallucinations  (72.34%), and those with focal NPSLEs had cerebrovascular disease (43.42%) with a high frequency of immunological disorders. Lupus nephritis and hematological disorders with high immunological activity were significantly more common  in patients with CNS lesions than in those with PNS ones.

Among the patients fulfilling the criteria for systemic sclerosis (SS), there is a subgroup without SS-specific antinuclear antibodies, but positive for anti-ribonucleoprotein (anti-U1 RNP)  antibodies. The clinical significance of this type of antinuclear  antibodies in SS is not clear. The presence of anti-U1  RNP antibodies is of great interest, since they are not only present in other rheumatic diseases, but are also considered as a marker for mixed connective tissue disease. Objective: to reveal the frequency of anti-U1RNP antibodies in patients with SS and to provide the clinical and laboratory characteristics of patients positive for these antibodies.

Subjects and methods. 330 patients who fulfilled the 2013 ACR/EULAR criteria for SS and had been followed at the V.A. Nasonova Research Institute of Rheumatology from 2012 to 2017 were included. Anti-U1 RNP were determined by enzyme immunoassay (reference values: 0–25 U/ml).

Results and discussion. Anti-U1RNP were detected in 65 (19.7%) patients with SS (85% of patients were highly positive; 15% were low-positive). The group included 8 men and 57 women; their mean age was 46±14 years. The disease duration was 11±7.9 years. Skin lesions were minimal; 59 (91%) patients had a limited form of the disease with swelling in the hands (scleredema)  in 40% of cases and sclerodactyly in 60%. Raynaud's phenomenon was present in all the patients. One-half of the cases were observed to have peripheral ischemic disorders: digital scars and/or sores (43%), as well as necroses and ulcers of other sites, which were relatively rare (8%). Interstitial lung disease (ILD)  was identified in 63% of cases. Elevated pulmonary artery systolic pressure (PASP) ≥40 mm Hg, as shown by echocardiography, was detected in 26% of cases and was associated mainly with the presence of ILD; pulmonary arterial hypertension  was  confirmed in three patients. Esophageal lesions were found in 61% of patients. One-third of patients had signs of scleroderma cardiopathy.  The feature of the group was the common  involvement of the locomotor system: joints with arthralgia and/or synovitis in 65% and muscles with mild and moderate myopathy in 43%. Erythrocyte sedimentation rate (ESR) and C-reactive protein levels were frequently elevated. The concurrence with Sjö gren's syndrome was common  (in one-third of patients). None case of scleroderma renal disease was recorded; the mean values of kidney function were within the normal range; however, the glomerular filtration rate was lower than 80 ml/min/m2 in 17% of patients. All the patients were positive for antinuclear  factor (HEp-2); in addition, there was rheumatoid  factor (22%), antibodies against Ro/SS-A  (41%), La/SS-B (18%), double-stranded DNA (42%), Scl70 (7%), and anticentromere antibodies (9%); 39 out of the 55 (71%) patients who were highly anti-U1  RNP-positive fulfilled the mixed connective tissue disease criteria proposed by R. Kasukawa et al. (1987).

Conclusion. The investigation allows one to discuss of the presence of a special phenotype  of SS, which is characterized  by peculiar clinical manifestations in the presence of anti-U1  RNP overproduction.

Calcium pyrophosphate  crystal deposition disease (CPCDD) is among the most common  inflammatory rheumatic diseases; however, studies of cardiovascular risks in CPCDD have not been conducted.

Objective: to stratify a cardiovascular risk in patients with CPCDD according to the systematic coronary risk evaluation (SCORE)  algorithm that allows determination of an individual 10-year risk of cardiovascular death.

Subjects and methods. The one-stage,  single-center  study of a cardiovascular risk enrolled 118 patients (43 men and 75 women) with CPCDD. Laboratory studies included determination of fasting serum glucose, total cholesterol, uric acid, magnesium,  phosphorus,  and total calcium. The level of C-reactive  protein (CRP)  was measured by a highly sensitive method;  CRP >5 mg/L was taken as a high level; parathyroid  hormone  was determined  by chemiluminescence immunoassay.  The SCORE  table was used to assess the total cardiovascular risk in all the patients.

Results and discussion. The patients' mean age was 60.7±12.4 years. According to the SCORE scale, very high and high risks of cardiovascular death were found in 59 (50%) and 6 (5%) patients, respectively; only in 10% of cases this risk was associated exclusively with age (> 65 years); 60 (50.8%) of the 118 patients did not have previous cardiovascular events or atherosclerosis risk factors. Coronary heart disease was detected in 28.8% of the 118 patients; hypertension was identified in 64%; diabetes mellitus (DM)  was found in almost 15%. The mean SCORE values did not significantly differ in men and women. The level of CRP was higher in men than that in women (8.6±4.6 and 7.3±3.5 mg/dL,  respectively; p = 0.04). Glomerular  filtration rate (GFR) <60 ml/min was detected in 11 patients at a very high cardiovascular risk due to the presence of chronic kidney disease; two of them were also diagnosed with DM; two had chronic heart failure, one patient had a history of stroke and another  had that of myocardial infarction.  The patients with GFR  <100 ml/min were more frequently found to be at high risk by the SCORE scale than those with GFR >100 ml/min: 61% (60/98) and 25% (5/20) of patients, respectively (p = 0.003). Hyperparathyroidism (HPT)  was detected in 12 (10%) patients, and 7 of them were at a very high risk by the SCORE scale; however, hypercalcemia was diagnosed in only three cases. The results of the SCORE stratification of the whole group showed that 64 (54.2%) of the 118 patients with CPCDD were at a very high or high risk, the latter was very high in exactly half of the cases (n = 59.

Conclusion. One-half of patients with CPCDD have a very high cardiovascular risk. In addition to the high detection  rate of traditional  cardiovascular risk factors (hypertension, smoking, hypercholesterolemia, and DM),  the presence of chronic microcrystalline  inflammation, concomitant metabolic disorders and diseases (hyperuricemia, HPT,  decreased renal function)  should be taken into account when determining the cardiovascular risk in patients with CPCDD.

The lecture considers in detail modern ideas about the epidemiology, pathogenesis, and clinical manifestations of Behcet's disease/syndrome, as well as the principles of diagnosis, assessment of the activity and severity of the disease, and approaches to therapy.

Rheumatoid arthritis (RA) is an immune-mediated inflammatory (autoimmune) rheumatic disease of unknown etiology, which is characterized  by chronic erosive arthritis (synovitis) and systemic damage of internal organs and leads to early disability and shorter life expectancy in patients. Much attention  is paid to studying the role of interleukin 6 (IL6) in the spectrum of proinflammatory cytokines involved in the pathogenesis of RA. The clinical introduction of anti-IL  receptor monoclonal  antibodies, such as tocilizumab and sarilumab, that inhibit the activity of this cytokine, is an important  step in the improvement  of RA treatment. The review considers the data from the main randomized controlled trials of the efficacy and safety of sarilumab in RA and discusses the prospects for using the drug to treat this disease.

Juvenile-onset  systemic lupus erythematosus (SLE) is a significant and urgent problem in the practice of pediatricians and rheumatologists  in both verifying its diagnosis and choosing treatment policies, by taking into account the features of the onset, the types of the disease course, and the high probability of an unfavorable prognosis. Despite the tremendous progress made in rheumatology at the beginning of the 21st century, the results of SLE therapy in children and adolescents cannot be considered to be satisfactory: only 13% of patients who fell ill in childhood have drug-free remission in adulthood with a lower quality of life and a higher index of damage. The purpose of this review is to analyze the efficacy and safety of rituximab that, despite the absence of its officially recorded indications,  has relatively widely entered the actual clinical practice of pediatric rheumatologists  as the drug of choice in the highly active, prognostically unfavorable course of SLE.

Medical rehabilitation is a set of non-drug methods aimed at reducing pain and functional disorders, restoring working ability, social activity, and mental stability in patients. This is a necessary part of treatment in patients with rheumatic diseases, which is as important as pharmacotherapy in many cases (for example, osteoarthritis, chronic nonspecific back pain, and spondyloarthritis). Unfortunately, many Russian physicians underestimate the possibilities of nondrug approaches, referring to the fact that the effectiveness of medical rehabilitation and physiotherapy methods have not been evaluated during clinical trials and their therapeutic significance has passed no serious test in the context of evidence-based medicine. This is not entirely true. This review presents data from a large number of clinical trials and related meta-analyses of studies evaluating the efficiency of the most commonly used medical rehabilitation techniques: cryotherapy, laser therapy, magnetotherapy, ultrasound therapy, percutaneous electroneuromyostimulation, acupuncture, manual therapy, massage, and therapeutic exercises.

The retrospective study enrolled 8 patients with ANCA-associated  systemic vasculitis (AASV) and hip joint (HJ) injury with indications for total hip arthroplasty (HA); a total of 11 HJs were operated on. The patients’ median age at the time of the first HA was 54 [31; 76] years. The median duration of follow-up after HA was 3 [0.5 to 12.5] years. Wegener’s granulomatosis was diagnosed in 5 patients; microscopic polyangiitis in 2 patients, and eosinophilic granulomatosis polyangiitis (or Churg-Strauss  syndrome) in one case. At the onset of AASV, the median Birmingham Vasculitis Activity Score (BVAS) was 12 [6; 26]; four patients had a 5-year mortality rate of 21% (Five-Factor Score (FFS)  = 1). AASV remission was induced by anti-B cell therapy with rituximab (RTM) in 6 patients. A total of 10 total HAs were performed for aseptic necrosis of the femoral head and another HA was carried out for a femoral neck fracture. At the time of HA, complete remission (BVAS = 0) was observed in 7 cases of AASV; incomplete remission (BVAS = 3) was seen in one patient. All endoprosthesis  components  were stable; there were no signs of osteolysis. In all cases, HA was successful in increasing HJ functional activity and in reducing pain (the Harris hip score averaged 54 before HA and 87 at 6 months after surgery). None of the patients had AASV recurrence  or developed postoperative complications  (except for the need for blood transfusion).

The authors’ own experience suggests that total HA is a potentially highly effective and relatively safe treatment in patients with AASV, including those with severe AASV and unfavorable prognostic factors. To reduce the risk of postoperative complications  (primarily thromboembolism, infections, and RTM-induced late-onset  neutropenia), total HA should be performed in the period of AASV remission under the control of comorbid conditions  and in the close cooperation  of rheumatologists  and orthopedic  surgeons. The following recommendations for the management of patients with rheumatic diseases should include patients with AASV for elective total HA.