Familial aggregation (repeated cases of the disease in the families of probands) is considered as an argument in favor of the genetic nature of Behсet's disease (BD). The results of a survey of 180 patients with BD in three ethnic groups indicated that there were repeated cases of recurrent aphthous stomatitis (RAS) in 54 (30%) families: more commonly among Dagestanis (n =32), less commonly in Chechens (n = 12) and Russians (10). Thus, the relatives of the RAS proband should be included in a group at risk for BD.

The main manifestation of joint and spine diseases, such as osteoarthritis, nonspecific back pain, and soft tissue rheumatic disorders, is musculoskeletal pain (MSP). It leads to considerable morbidity as well as temporary and permanent disability in millions of people of our country. These people need adequate medical care and most significantly a prompt and maximally complete analgesia. Unfortunately, serious problems are being faced in this field of medicine. The lack of a unified approach or continuity in the therapeutic process, inadequate knowledge of the pathogenesis of MSP and of the possibilities of its therapy may substantially hamper the work of practitioners.

The meeting of Russian experts who were represented in different medical specialties and discussed the optimization of MSP treatment policy was held in Moscow on 20 June 2015. According to the results of the meeting, the authors identified the main points regarding the theoretical and practical aspects of MSP and also proposed an algorithm for the treatment of this pathology. It seems that the use of this algorithm will be able to facilitate the work of practitioners and to enhance the efficiency and safety of analgesic therapy.

The analysis covering the five-year period (2010–2014) showed that the adult population of the Russian Federation showed increases in the incidence of rheumatoid arthritis (RA), estimated per 100,000 population, by 5%, in that of spondylopathies (SP), osteoarthritis (OA), and osteoporosis (OP) by 32.2, 12.1, 7.3%, respectively, and an 8.6% decrease in that of only reactive arthropathies (ReA); the incidence of psoriatic arthritis (PsA) and systemic connective tissue diseases was virtually unchanged with increment of 1.3 and 0.3%, respectively. Our attention is engaged by the high incidence of RA (300.7) in the North Caucasian (NC) Federal District (FD) with a considerable increment (+30%) over the 5 years and by that in the Volga (V) FD throughout the analyzed period (342.4 in 2014). The incidence of SP higher than Russia's average was noted in the NCFD (124.5) with a 48.4% increment by 2014 and in the Far Eastern FD (136.1 with a 47.5% increment); and that was especially high in the Crimean (C) FD (380.0). The incidence of ReA remained constantly high in the NCFD (as high as 129.0 in 2014); on the contrary, it turned out to be very low in the CFD (7.8%). Only the NCFD showed a higher than average incidence of PsA (59.0) throughout the analyzed period in Russia. In 2014 the incidence of OA below Russia's average was seen in the NCFD (1893.3) and CFD (1875.8). The high incidence of OP was observed in the Ural (148.9) and Siberian (228.2) FDs. At the same time it was low in a number of FDs: the Southern FD (54.1), NCFD (68.7), and VFD (89.9) and very low in CFD (36.7).

Autoinflammatory diseases (AIDs) are characterized by periodic, sometimes self-limiting attacks that appear as fever and clinical symptoms resembling rheumatic ones, in the absence of autoimmune or infectious diseases. The group of AIDs encompasses a broad spectrum of nosological entities; some of them have been recently dealt with by rheumatologists.

Objective: to define the spectrum of AIDs in the practice of a pediatric rheumatologist from the results of visits to the Russian Federal Rheumatology Center.

Subjects and methods. The investigation enrolled patients who had visited the V.A. Nasonova Research Institute of Rheumatology in 2007 to 2015 for fever and other signs of a systemic inflammatory process in order to specify their diagnosis and to rule out infections, blood cancer, and other diseases. All underwent conventional rheumatologic examination, HLA Class A typing, and molecular genetic testing.

Results and discussion. 101 patients aged 6.5 months to 60 years with AIDs were identified over 9 years and diagnosed as having the following diseases. Familial Mediterranean fever (FMF) was detected in 17 patients (the female to male (M/F) ratio was 6:11); Behсet's disease (BD) in 25 children (M/F, 14:11), cryopyrin-associated periodic syndromes (CAPS) in 17 patients, including Muckle–Wells syndrome in 13 (M/F, 4:9); chronic infantile neurologic cutaneous articular and neonatal onset multisystem inflammatory disease (CINCA/NOMID) syndrome in 4 (M/F, 3:1), periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome in 17 (M/F, 10:7), hyper-IgD syndrome/mevalonate kinase deficiency syndrome in 3 (M/F, 0:3), tumor necrosis factor receptor periodic syndrome (TRAPS) in 7 (M/F, 4:3), undifferentiated AID in 14, and Blau syndrome in one patient. The patients with BD were rather ethnically diverse: among them, there were representatives of North Caucasian peoples, Tatars, Uzbeks, Moldavians, and others; there were 7 ethnic Russians. There was a preponderance of Armenians among FMF patients (15/17). Ethnic Russians were predominant among the patients with other nosological entities. HLA-B5 antigen was found in 9 (36%) patients with BD. Molecular genetic analysis confirmed the diagnosis in virtually all the patients with monogenic AIDs.

Conclusion. The most common AIDs in our practice were BD, FMF, CAPS, and PFAPA. The patients with CAPS were closest in clinical and laboratory presentations to those with rheumatic disease, particular to those diagnosed with systemic juvenile arthritis and this disease should be kept in mind in differential diagnosis. Our practical experience indicated that targeted therapy with interleukin 1 inhibitors was effective in CAPS patients. This treatment is able to substantially improve an initial poor prognosis.

Objective: to determine the efficiency of dual anti-B cell therapy in patients with active systemic lupus erythematosus (SLE).

Subjects and methods. The clinic of the V.A. Nasonova Research Institute of Rheumatology followed up three patients with significant SLE, who took rituximab (RTM) at a dose of 500–1000 mg, three months after completion of RTM infusions they received belimumab (BLM) calculated with reference to 10 mg/kg once monthly, a total of 8 infusions. The follow-up lasted 1 year. The efficiency and tolerability of the therapy and the concentrations of autoantibodies, complement, and B-lymphocyte subpopulations were estimated at baseline and then every 3 months.

Results and discussion. During dual anti-B cell therapy, there was considerable clinical improvement, no signs of recurrent SLE throughout the follow-up period, as well as normalization of laboratory markers for disease activity (the concentrations of antibodies against native DNA and complement components C3 and CD4) and persistent depletion of autoreactive B lymphocytes, plasma cells in particular. In all patients, the dose of glucocorticoids (GC) could be decreased to 7.5 mg/day calculated with reference to prednisolone at 2 months after the therapy was completed.

Conclusion. Dual anti-B cell therapy is a novel promising treatment for active SLE. This treatment regimen contributes to rapid suppression of disease activity, to long-term persistence of the obtained effect, and to reduced risk of severe irreversible organ damages, by minimizing the dose of GCs.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired systemic diseases mainly involving skeletal muscles. The main representatives of IIM are polymyositis (PM) and dermatomyositis (DM). Epidemiological surveys demonstrate that there is a relationship between PM/DM and malignant neoplasms (MNs), the detection risk of which is higher than that in the population of respective age groups. The rate of MNs in PM/DM ranges from 9 to 50%. The relationship to MNs is described in each subtype of IIM; however, these are most common in DM. The patients suffering from PM/DM associated with MNs have a worse prognosis than those without MNs. The early detection of MNs could improve the prognosis in these patients. The investigations published identify demographic, clinical, and laboratory factors increasing MN detection risks in patients with PM/DM. Just the same, they all cover small patient groups; the findings are heterogeneous and not well convincing, which calls for a further larger-scale study of this problem.

Objective: to reveal and identify the specific features of paraneoplastic myositis (PnM).

Subjects and methods. The investigation included 320 patients with a valid diagnosis of IIM, who had been followed up in the period of 1996 to 2016. The patients underwent laboratory tests, manual proximal muscle strength testing using a 10-point scale and electromyographic examination with needle electrodes.

Results and discussion. PnM was detected in 32 (10%) of the 320 patients with IIM. Among the patients with PnM, there were 6 (19%) men and 26 (81%) women. The mean age at the onset of PnM was 55.4 years. PnM manifested with characteristic musculocutaneous syndrome in 19 (59%) patients; 18 (41%) of them were found to have MNs within the first year after disease onset. The manifestation of MNs was preliminary to the picture of PM/DM in 13 (41%) patients. The most commonly detected conditions were ovarian cancer (37.5%), MNs of the lung and breast (15%); next were MNs of the intestine (12.5%), blood (6.3%), uterus (6%), and stomach (3.1%). The median survival was 5 years in patients with PnM.

Many patients with rheumatoid arthritis (RA) develop myocardial damage that is frequently latent and usually manifests itself as congestive heart failure and arrhythmias in the late period of the disease.

Objective: to comparatively study the time course of clinical, structural, and functional changes in the myocardium in RA patients taking methotrexate (MTX) and a combination of MTX and hydroxychloroquine (HC) during a 4-year follow-up period.

Subjects and methods. Clinical data and echocardiographic, carotid artery ultrasonographic, and Holter electrocardiogram (ECG) monitoring readings were analyzed in 83 patients with RA with disease duration of < 10 years, who had received MTX (n = 44) or a combination of MTX and HC (n = 39) for 4 years. RA activity remained low (DAS28 ≤ 3.1) during the follow-up period.

Results and discussion. Over 4 years, the RA patients showed significant increases in left ventricular mass index (from 106.20 [98.14; 112.44] to 114.23 [109.12; 131.19]), in the rate of eccentric left ventricular hypertrophy (from 22.9 to 40.9%), frequent supraventricular extrasystoles (from 13.3 to 22.8%), different types of premature ventricular contractions (from 14.2 to 26.2%), paroxysmal ventricular tachycardia (from 1.2 to 3.6%), intraventricular conduction disturbances (from 3.6 to 14.4%), and first-degree atrioventricular block (from 2.4 to 4.8%), as well as atherosclerotic plaques in the carotid arteries (from 6.0 to 10.8%) (p < 0.05). During combined therapy with MTX and HC, the increase in the rate of eccentric left ventricular hypertrophy, high-grade premature ventricular contractions, and right bundle-branch block was not so great as that during MTX monotherapy (5.1 and 29.6%; 5.1 and 18.2%; 2.6 and 11.4%, respectively).

Conclusion. There is evidence that HC intake has a positive impact on myocardial structural and functional parameters in RA patients.

Rheumatoid arthritis (RA) is a chronic inflammatory disease causing joint destructive changes and disability.

Objective: to investigate the association between the ultrasound signs of active inflammation and destruction of the joints, as evidenced by radiography, in RA patients treated with a treat-to-target strategy and to study whether ultrasound study (USS) of the joints can be used to predict the occurrence of their destructive changes.

Subjects and methods. The investigation included 81 patients (medium age 56 [46; 62] years) with RA, who had been followed up at the V.A. Nasonova Research Institute of Rheumatology within the first Russian strategic study of pharmacotherapy for RA – REMARCA (Russian invEstigation of MethotrexAte and biologicals for eaRly aCtive Arthritis). In all the patients, methotrexate (Metoject, MEDAS, Germany) as the first disease-modifying anti-rheumatic drug was subcutaneously injected at an initial dose of 10 mg/week with its rapid escalation up to 20–25 mg/week. Then the therapy was added by biologicals as the need arose. Clinical and laboratory parameters were analyzed immediately before and then after 12, 24, 36, and 48 weeks. Efficacy was assessed using the European League Against Rheumatism (EULAR) criteria, CDAI, and SDAI. USS of eight articular areas (the wrist, second and third metacarpophalangeal, second and third proximal interphalangeal, second and fifth metatarsophalangeal joints) in the hand and foot of the clinically dominant side was carried out in all the patients before treatment and then after 12, 24, 36, and 48 weeks. Semiquantitative gray-scale (GS) assessment and power Doppler (PD) were performed. Radiographic examination was done before and after 48 weeks of therapy. The Sharp method modified by van der Heijde was employed to estimate X-ray changes.

Results and discussion. In the group of patients with radiographic progression, the activity of inflammation, as evidenced by PD USS, was significantly higher at 48 weeks of the follow-up; at the same time, the median PD score was 0 in the absence of progression. At 48 weeks, radiographic progression was significantly more common in the group of patients with persistently active synovitis than in the group without inflammation (odds ratio (OR) 4.76; 95% confidence interval (CI) 1.2–18.9; р = 0.018). At 48 weeks of therapy, the PD score of 0 (complete lack of vascularization in the study joints) had satisfactory sensitivity (77%) and satisfactory specificity (59%) (the area under the curve was 0.698; p < 0.024; 95% CI 0.544–0.852). Multivariate analysis showed that GS USS scores after 24 weeks of therapy proved to be significant predictors of progressive erosive joint changes at 48 weeks of therapy (OR = 0.15; 95% CI, 0.023–0.207; p = 0.015). At the same time, the PD score following 24 weeks of therapy could not predict joint destruction (OR = 0.104; 95% CI, -0.043 to 0.251; р = 0.16). Clinical disease activity indices and baseline PD and GS scores were of no significant prognostic value.

Conclusion. We found a significant association of radiographic progression with active synovitis, as evidenced by PD USS at 48 weeks of therapy; however, we did not obtain any convincing evidence for the prognostic value of the baseline ultrasound signs of inflammation.

Systemic sclerosis (SS) is a systemic disease, the basis for which is microcirculatory disorders, inflammation, and generalized fibrosis. Interstitial lung disease (ILD) is one of the primary manifestations of SS. Assessment of SS activity and severity is hindered as it is very difficult to differentiate fibrous and inflammatory changes that are mostly interrelated and have a similar picture.

Objective: to estimate activity index (AI) and total severity index (TSI) for the follow-up of SS patients with different variants of ILD. Subjects and methods. The investigation enrolled 77 patients with SS and ILD, who were followed up at the V.A. Nasonova Research Institute of Rheumatology; their mean age at inclusion was 46±13 years. All the patients underwent high-resolution computed tomography (HRCT) of the chest and determination of TSI and AI scores at baseline and after an average of 59±12 months. According to the time course of HRCT revealed pulmonary changes over a 5-year follow-up, the patients were divided into 3 groups: 1) patients with improvement (n=16); 2) those without changes (n=39); 3) those with deterioration (n=22). The disease was regarded as active with AI scores of ≥3.

Results and discussion. The mean AI scores for the entire patient cohort were low and substantially unchanged during the follow-up period, amounting to 2.1±1.55 and 2.37±1.55 (p > 0.05) at the start and at the end of the investigation, respectively. Following 5 years, only Group 3 showed AI scores of > 3. At inclusion, the groups did not differ in AI scores; however, 5 years later AI became significantly higher in Group 3 than that in Groups 1 and 2 (p = 0.004 and p=0.03, respectively). During the follow-up, TSI remained substantially unchanged and averaged 6.5±2.5 and 6.9±2.3 at inclusion and at the end of the investigation, respectively. Moreover, TSI tended to decline in Groups 1 and 2; but it significantly increased in Group 3 (p = 0.006) and at the end of the investigation it was significantly higher than that in Group 1 (p = 0.002). There was a direct correlation between AI and TSI in the total cohort of patients both at baseline and 5 years later (R = 0.57 and R = 0.53; p < 0.05). Direct correlations were found between the indices within Groups 2 (R = 0.51 and R = 0.37) and 3 (R = 0.67 and R = 0.71) at baseline and at the end of the follow-up, respectively; p < 0.05).

Conclusion. In our investigation, AI and TSI reflected the course of ILD in patients with SS. ILD progression, as evidenced by HRCT, was followed by a significant increase in AI and TSI scores; they directly correlated between. Thus, AI and TSI may be used for monitoring progression of the disease.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is a serious problem that substantially hinders the treatment of patients with rheumatic diseases (RD) particular when there is a need for using cytotoxic and biological agents (BAs).

Objective: to estimate the rate of HBV and HCV infection in RD patients followed up at the V.A. Nasonova Research Institute of Rheumatology Clinic in 2011 to 2014.

Subjects and methods. All case histories of the RD patients hospitalized in the given period were analyzed. Infection with HBV and HCV was assessed from the presence of HBsAg and anti-HCV, respectively.

Results and discussion. There were a total of 16,553 admissions to the V.A. Nasonova Research Institute of Rheumatology Clinic over 4 years. HBV and HCV were detected in 0.33 and 0.74%, respectively; their combination was found in 0.03% (a total of 1.1%) of the patients. About half of the patients took cytotoxic agents and glucocorticoids; 29.8% received BAs, mainly rituximab. Moderate and high chronic hepatitis activity was noted in 4.9% of the patients; liver cirrhosis was observed in 2.7%. Over the follow-up period, alanine aminotransferase and aspartate aminotransferase levels were not elevated in the vast majority of patients.

Conclusion. HBV and HCV infection is often detected in patients with RD. The infected patients and persons with chronic viral hepatitis require careful follow-up and the decision whether to perform prophylactic antiviral therapy when using cytotoxic agents and BAs.

Laboratory medicine in the early 21st century has achieved advances due to the development and prompt practical introduction of innovative molecular cell technologies, which have assisted in increasing the diagnostic sensitivity and specificity of laboratory tests and in substantially expanding the spectrum of study biomarkers in rheumatology. High-technology automated analytical systems using both classical uniplex methods for immunochemical analysis (indirect immunofluorescence test, enzyme immunoassay, immunoblotting, immunodot assay, immunonephelometry, chemiluminescence immunoassay, and radioimmunoassay) and multiplex diagnostic platforms based on DNA, RNA, protein and cellular microchips, polymerase chain reaction, flow cytometry, and mass spectrometry have been used in the past decade to determine biomarkers of rheumatic diseases (RD) in blood, synovial fluid, urine, biopsy specimens of the synovial membrane, kidney, and other affected tissues.

Present-day generation of molecular and cellular biomarkers (autoantibodies, acute-phase inflammatory proteins, cytokines, chemokines, vascular endothelial activation markers, immunoglobulins, complement components, lymphocyte subpopulations, osseous and cartilaginous tissue metabolic products, intracellular signaling molecules, proteases, and genetic, epigenetic, and transcriptomic markers) is an important tool for prevention, early diagnosis, assessment of disease activity, progression rate, clinical laboratory subtypes of RD, prediction of the efficiency of therapy and the risk of adverse events during treatment. Deciphering of the key pathogenetic mechanisms of RD could identify the molecular and cellular biomarkers that might be used as therapeutic targets. Biologicals (monoclonal antibodies and hybrid protein molecules) that selectively inhibit proinflammatory cytokines and membrane molecules mediating the pathological activation of immunocompetent cells are successfully used to treat RD today.

The alternative therapies of RD include the use of low-molecular-weight chemically synthesized agents that suppress the activity of tyrosine kinases. The important area of this therapy is to restore immunological tolerance and to correct autoimmune disorders by means of autologous hematopoietic stem cells, mesenchymal stromal cells, autologous tolerogenic dendritic cells, regulatory T and B cells, gene therapy, and peptide antigens. The prospects for the laboratory diagnosis of RD are associated with the necessity of harmonizing and standardizing the current methods to determine autoantibodies and with the search for and clinical validation of novel proteomic, transcriptomic, and genomic biomarkers.

The review of Russian and foreign literature provides a detailed analysis of topical issues associated with the impact of comorbid anxiety and depressive disorders and cognitive impairments on the efficiency of anti-inflammatory and disease-modifying therapy in patients with rheumatoid arthritis.

The paradigm of therapy for psoriatic arthritis (PsA) has recently undergone considerable changes due to development and clinical introduction of highly effective targeted drugs based on monoclonal antibodies – inhibitors of different cytokines. The data available in the literature on the possibilities of using interleukin 17 (IL-17) inhibitors as a promising PsA therapy were analyzed. The IL-17-mediated signaling pathway was shown to play an important role in both the chronization of synovial inflammation and in the occurrence and development of bone erosions, bone proliferation, and enthesitis in this disease. The combination of the high efficiency and acceptable safety of IL-17 and IL-23 inhibitors could suggest that they might be used as first-line agents for the treatment of PsA or as second-line therapy if tumor necrosis factor-α inhibitors were ineffective or intolerable. The active design of three novel drugs aimed at suppressing IL-17 was noted to only confirm the key role of this cytokine in developing psoriatic disease.

The paper gives the data of clinical trials supporting the high efficacy of secukinumab against the key clinical manifestations of PsA. The most important advantage of the drug is the lack of immunogenicity. It is pointed out that the latest edition of the EULAR Guidelines (2015) proposes to include this class of drugs in an algorithm for the treatment of PsA patients.

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by the occurrence of tumor-like foci in different organs with a unique histological pattern (moirо-like fibrosis, obvious lymphoplasmacytic infiltration with large numbers of IgG4+ plasma cells, and obliterating phlebitis) and elevated serum IgG4 levels in the majority of patients. Its first-line therapy is glucocorticoids at a starting dose of 0.6 mg/kg/day (equivalent to prednisolone); however, this treatment entails a great number of adverse events and high recurrence rates. The paper provides a review of today's literature on the treatment of IgG4-RD; particular emphasis is laid on the description of therapy with glucocorticoids and rituximab.

The past two decades have been marked by the design of a great variety of innovative biological agents, the clinical introduction of which could substantially improve the results of treatment for rheumatic diseases. At the same time, there are a larger number of reports on their administration-associated adverse events, often paradoxical ones (these drugs indicated in many autoimmune processes may induce similar autoimmune processes).

COMMENTARY ON THE PAPER «USE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS FOR THE TREATMENT OF AXIAL SPONDYLOARTHRITITIDES, INCLUDING ANKYLOSING SPONDYLITIS, MONITORING THEIR EFFICACY AND SAFETY (DRAFT GUIDELINES OF THE EXPERT SPONDYLOARTHRITIS DIAGNOSIS AND TREATMENT GROUP)» BY I.Z. GAIDUKOVA ET AL.

The clear definition of the concept of «flare in axial spondyloarthritis» is of paramount importance for clinical trials and routine practice in particular. It will be able to unify the characteristics of outcomes over a particular period of time on the one hand and to standardize therapeutic approaches on the other. On 4 February 2016, the journal Annals of Rheumatic Diseases published the on-line paper «Preliminary definitions of 'flare' in axial spondyloarthritis, based on pain, BASDAI and ASDAS-CRP: an ASAS initiative» by L. Gossec et al., which was devoted to this topic.

March 26, 2016 Minutes No. 16 of the Rheumatology Task Force Meeting, Expert Council, Ministry of Health of the Russian Federation.