Immunoinflammatory (autoimmune) diseases are among the most severe chronic diseases in humans. These include autoimmune rheumatic diseases that affect children and adults: rheumatoid arthritis, juvenile arthritides, spondy- loarthritides, psoriatic arthritis, as well as systemic lupus erythematosus and other systemic connective tissue diseases. The article examines the Russian experience of diagnosis and pharmacotherapy of rheumatic diseases and the main trends in research. They include the development of prevention strategy, the introduction of innovative methods for early diagnosis, treatment, and prognosis of outcomes of the most severe forms of autoimmune rheumatic diseases under the concept of personalized medicine. 

The article is devoted to the discussion of the new recommendations for the diagnosis and treatment of gout, which were developed within the international program «3e Initiative».

In 2013, Russia registered officially the indications for the use of monoclonal antibodies to B-lymphocytes (rituximab, RTM) in systemic vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA-SV). This communication presents the preliminary results of the Russian register of the RTM application in autoimmune diseases (NORMA) that has included 50 patients with ANCA-SV treated in 14 cities of the Russian Federation. Twenty-five of 50 (50%) patients received repeated courses of RTM.

RTM has demonstrated a high efficacy and a good profile of treatment safety in patients with ANCA-SV in real-life national clinical practice. Among 25 patients who had been followed up for over 12 months, the remission was achieved in 92% of cases, a decrease in the ANCA-SV activity was observed in 8%. The efficacy of RTM increased when performing repeated courses, while it has been noted that the positive results can be obtained by prescribing a repeated course of RTM at a reduced dose (500–1000 mg). Prescription of the repeated courses was primarily required in patients with granulomatosis and polyangiitis affecting the lungs.

Care should be taken when combining RTM treatment with cytostatics (primarily with cyclophosphamide) because of the risk of secondary immunodeficiency and infectious adverse events (AE), which have been the most frequent serious AE (12%) in patients with ANCA-SV.

Objective. To evaluate the efficacy and safety of rituximab (RTM) treatment in the long-term follow-up of patients with systemic lupus erythematosus (SLE) refractory to standard therapy.
Material and methods. RTM therapy was prescribed to 97 SLE patients with high disease activity and insufficient effica- cy of using high doses of glucocorticoids (GC) and cytostatics. The median follow-up time (25th; 75th percentiles) was 18 [12; 36] months. The most common clinical manifestations of SLE included nephritis (62%), skin lesion (33%), and lesion of the nervous system (22.7%). The clinical assessment of the SLE activity was carried out using the SLEDAI-2K activity index. In assessing the therapy efficacy, the following concepts were used: the partial response (PR), complete response (CR), and flare. Flare was classified as moderate (MF) and severe (SF) using the SLE flare index (SFI). Results. Immediately after RTM therapy, depletion of B-cells was determined in 78% of the patients with SLE. During the 6-year follow-up, the effect of RTM therapy was achieved in 84% of the patients after repeated courses of RTM (CR – 56%, PR – 28%). In total, flares were observed in 24 (24.7%) patients; the median interval from RTM administration to flare was 12 [12; 24] months. In the long-term follow-up, the decline in the SLEDAI-2K index, normalization of laboratory test values, and the decrease in the daily GC dose were noted. Most patients tolerated well both the first and repeated courses of RTM therapy.

Conclusion. According to the results of the long-term follow-up, RTM therapy is a highly effective method to treat SLE patients with the ineffectiveness of previously conducted standard therapy with GC and cytostatics. Good tolerance of RTM treatment has been noted; no increase in risk of infectious complications or adverse reactions has been found. 

Objective. To study the content of the suppressor population of regulatory T cells (Treg) according to the expression of CD4, CD25, CD127 molecules, as well as the expression of two functional molecules (CTLA-4 and CD39) in patients with rheumatoid arthritis (RA).
Material and methods. 16 samples of peripheral blood of RA patients and 10 blood samples of healthy donors were analyzed. All patients received disease-modifying anti-rheumatic drugs. The expression level of all studied molecules was assessed by flow cytofluorometry.

Results. The content of T-helpers in peripheral blood of RA patients was 36.3 ± 7.1% of the total number of lympho- cytes and was lower than that in the control (43.8 ± 6.2%, p<0.05). The number of activated CD4+CD25+ T cells in these patients increased twofold (RA 23.7 ± 9.8%, control 11.1 ± 2.0% of the number of CD4+ T cells, p<0.05). The relative amount of CD4+CD25high (RA 2.7 ± 1.0%, control 1.5 ± 0.8%) and CD4+CD25highCD127low/- (RA 2.5 ± 1.0%, control 1.6 ± 0.9% of CD4+ T cells) Treg cells in RA patients was significantly higher than that in healthy individuals (p<0.05). The expression of the CTLA-4 negative regulatory molecule and CD39 ectonucleotidase by Treg cells of RA patients did not differ from the control.

Conclusion. The study demonstrated that RA is characterized by an increased content of Treg cells of CD4+CD25high and CD4+CD25highCD127low phenotypes rather than CD4+CD25+CD127low, as well as by the control-like expression of CTLA-4 and CD39 functional molecules by Treg cells.

Objective. To evaluate the symptom- and structure-modifying effect of Alflutop compared to placebo (PL) in patients with knee osteoarthritis (OA).
Material and methods. The study included 90 patients with knee OA (according to the criteria of the Russian Association of Rheumatologists) at the stage 2–3 (according to the Kellgren-Lawrence scale); pain score when walk- ing ≥ 40 mm (assessed using the visual analog scale). All the patients provided an informed consent. The patients were randomly divided into two groups: group 1 (n=45) received an intramuscular injection of 1 mL Alflutop for 20 days with 6-month intervals for 2 years (a total of 4 courses for 2 years); group 2 (n=45) received an injection of PL (iso- tonic sodium chloride solution) in the same way. Ibuprofen at a dose of 600–1200 mg/day was administered as concomitant therapy. To evaluate the structure-modifying effect of Alflutop, X-ray of the knee joint was performed at the beginning and end of the study; the level of biochemical markers (CTX-II and COMP) was determined at the beginning, after 3 months, and at the end of the study. A statistical analysis was performed using the Statistica 10 software package.

Results. After the 2-year follow-up, a statistically significant negative trend was detected less frequently in the group of patients treated with Alflutop compared to the PL group (6.1 and 38.4%, respectively). The statistically significant delay in joint space narrowing was observed in patients who received Alflutop in contrast to patients who received PL (the numerical score of the joint space, the Wilcoxon test; p=0.0003). An increase in osteo- phyte size was observed in 72% of the patients receiving PL, and only in 27% of the patients receiving Alflutop (medial and lateral osteophytes of the femoral bone, the Wilcoxon test; p=0.0078; medial and lateral osteophytes of the shin bone, the Wilcoxon test; p=0.0001 and p=0.0039, respective- ly). Augmentation of subchondral osteosclerosis was determined more often in the PL group (the McNemar's test; p=0.0313). The level of the marker of cartilage degradation CTX-II tended to decrease after 3 months of Alflutop therapy, which has persisted until the end of the study. This indicates a decrease in the articular cartilage degradation. In the PL group, the CTX-II level remained unchanged. A tendency to an increase in the level of the marker of cartilage degradation COMP was found in the PL group.

Conclusion. Based on double-blind, placebo-controlled, randomized study, the structure-modifying effect of Alflutop in knee OA has been proved. Alflutop delays the radiographic progression of knee OA, joint space narrowing and osteophyte growth, and reduces the degradation of the articular cartilage matrix.

Objective. To identify the clinical features of gout in women.
Material and methods. A cross-sectional, comparative, multicenter study included 340 patients with gout (289 males and 51 females) who had been examined at V.A. Nasonova Research Institute of Rheumatology of the Russian Academy of Medical Sciences and at the Main Clinical Hospital of the Russian Interior Ministry Troops from 2002 to 2009. The main group was comprised of females; the comparison group consisted of males. The mean age of females was 52.3 ± 11.4 years; the mean age of males was 52.3 ± 10.4 years; the median duration of disease [25th; 75th per- centiles] was 4.8 [2.0; 7.6] years in females and 5.9 [3.3; 11,5] years in males (p=0.0053).
Results. In the group of females, the median duration of the first arthritis attack was 14 [10; 20] days; in the compari- son group, it was 10 [7; 14] days (p=0.0014). Chronic arthritis was observed in 66.7% of females and in 31.8% of males (p<0.0001); it progressed faster in females. The median number of the joints affected during the disease was 12 [7; 17] in females, and 7 [4; 12] in males (p=0.00025). Tophi developed earlier in females than in males (the median duration of disease, before they occurred, was 3 [2; 7] and 6 [4; 10], respectively; p=0.00036). The number of tophi was greater (the median 5 [3; 8] and 2 [1; 6], respectively; p=0.0066). Females were diagnosed with type 2 diabetes mellitus (DM) (p=0.021) and chronic kidney disease (p<0.0001) more often than males; a higher serum cholesterol level (p=0.022) was observed. Females received diuretics (57% vs. 20%; p<0.0001) more often than males; however, they consumed alcoholic beverages less frequently (57 and 20%; p<0.0001; 28 and 4%; p<0.0001; respectively).
Conclusion. In females, gout progression is more severe; females were diagnosed with type 2 diabetes mellitus and chronic kidney disease more frequently than males; they also had a higher cholesterol level. Females were more likely to administer diuretics and consume less alcohol.

The diagnosis of ankylosing spondylitis (AS) in the real-life practice is delayed for 7–8 years on average. Educational programs for primary care physicians may promote the disease diagnosis.
Objective. To analyze the effectiveness of the educational programs for the early diagnosis of AS for primary contact physicians in the real-life clinical practice in Kazan.

Material and methods. The development of the educational programs and determination of their effectiveness com- prised three stages: 1) determination of the level of knowledge and problems in the diagnosis and treatment of AS among primary care physicians and neurologists; 2) development of educational programs suitable to be used in the real-life clinical practice; 3) analysis of the effectiveness of implementing the programs according to the reports on work of the City Rheumatology Center in 2009–2011.

Results. After running the courses, the number of patients with AS at the Kazan City Rheumatology Center increased almost twofold, from 378 in 2009 to 683 in 2011; the period from the onset of the disease to diagnosis was simultane- ously reduced from 8.4 to 3.5 years.
Conclusion. The educational programs for primary care physicians and neurologists in Kazan have promoted shorten- ing of the AS diagnosis time. 

Objective. To study how the patients with ankylosing spondylitis (AS) follow recommendations for performing physi- cal exercises.
Material and methods. To clarify the compliance of patients with AC to physical exercise, a special questionnaire was designed. The Exercise Benefits/Barriers Scale (EBBS) was used to assess the perception of physical exercises. The study included 79 patients (the mean age of 34.5 ± 9.4 years) with AS (diagnosed according to the New York criteria) who have been treated at the clinic of V.A. Nasonova Research Institute of Rheumatology of the Russian Academy of Medical Sciences.

Results. Of the 79 patients included in the study, 77.2% were doing therapeutic exercises; 41.0% of patients were doing them every day. 41.0% of the patients have received sets of exercises from the attending doctor, 41.0 % from the Internet, and 18.0% from other sources (brochures for patients or courses for patients with AS). The average total EEBS score was 114.2 ± 17.8 points; the benefits score was 87.1 ± 12.8; and the barriers score was 27.1 ± 5.0. The most frequent responses to question about the benefits of physical exercises were as follows: «They reduce the feeling of stress and tension» (90.6%) and «They increase the muscle strength» (93.7%). «I am tired physically from doing exercises» (96.6%) was the most common barrier to execution of physical exercises.

Conclusion. Despite the positive perception of physical exercises, only 41.0% of the patients with AS have done them every day. The lack of information about exercises recommended for AS patients, the frequency of their use, the effect on the disease activity and functionality significantly limits the use of exercises by patients with AS. It remains unclear exactly, which sets of exercises are most effective and what regularity of exercises should be used to prevent impair- ment of the functions of the spine and joints. 

Pulmonary pathology is diagnosed in patients with rheumatoid arthritis (RA). The external respiratory function (ERF) examination is widely used to assess the functional capacity of the lungs.
Objective. To evaluate ERF in patients with RA.
Material and methods. The study included 155 patients with RA. A MasterScreen Body plethysmograph (Erich Jaeger) was used to determine the ERF parameters (diffusing lung capacity, DLC; forced inspiratory vital capacity, FIVC; forced expiratory volume in 1 second, FEV1; total lung capacity, TLC; the FEV1/FIVC ratio, and the modified Tiffeneau index). DLC was measured by the single-breath method. ERF parameters were represented as a percentage of the appropriate value for a given gender, age, and height of the patient.

Results. Of the 155 examined patients with RA, a decrease in the DLC parameter was detected in 107 (69%), while in 87 (81%) patients, the decrease was less than 10% of the proper values. An analysis of the state of the ERF parameters revealed a decrease in FEV1 in 48 (31%) patients, FIVC in 41 (27%) patients, and TLC in 36 (23%) patients. The restrictive type of lung ventilation was determined in 27% of patients, bronchial obstruction in 31% of patients, an iso- lated decrease in DLC in 12% of patients with RA. In 31% of cases, no deviations of the ERF parameters from normal values were found. A statistically significant negative correlation between the clinical activity of RA and the DLC level (r = -0.59; p<0.05) was found.

Conclusion. The study revealed a high frequency of variation in the ERF parameters in patients with RA. In most cases, the variation was demonstrated by DLC. The obstructive changes were prevalent among RA patients. The high percentage of smokers among RA patients with the obstructive type of ventilation may indicate the influence of smok- ing on the development of bronchial obstruction. Our work revealed the significant relationship between the degree of RA activity and the DLC value.

The results of multicenter, open-label trial aimed at assessing the effectiveness, safety, and compliance of medication Ketonal Duo in 602 patients with osteoarthritis (OA) are presented. The trial duration was 28 days. The medication demonstrated a reliable analgesic effect and good tolerance; adverse events were observed in 4.7% of patients. The effect was observed in 97.9% of patients with OA according to the physician's opinion and in 99.1% as reported by the patients. Most patients and physicians consider the medication to have maximal convenience. 

Macrophage activation syndrome (MAS) is one of the histiocytic diseases developing from cells of a macrophage series, hemophagocytic lymphohis- tiocytosis (HLH). Rheumatic diseases have been demonstrated to be often associated with the development of SAM, most often upon systemic juve- nile arthritis (SJA). Certain issues have been discussed concerning pathogenesis with the concept of the defect of mechanisms of T-cell cytotoxicity and a reduction of the activity level of natural killer (NK) cells, which are associated with a mutation in the PRF1 gene encoding perforin, as well as the overproduction, by T-lymphocytes and histiocytes, of the number of cytokines (interleukin 1β – IL1β, interferon γ, the tumor necrosis factor α, the soluble IL2-receptor), which indirectly lead to activation of tissue macrophages and production of proinflammatory cytokines. The diagnosis problems associated with the low sensitivity and specificity of the HLH 2010 diagnostic criteria for hemophagocytic syndrome, which are based on the molecular genetics and pathomorphological diagnosis of HLH, are discussed. The diagnostic criteria for macrophage activation syndrome (2012) developed for SJA are presented. Thrombocytopenia, hyperferritinemia, and pathohistological signs of hemophagocytosis are of greatest significance. Attention is paid to the need for the diagnosis of subclinical and mild forms of SAM, to identification of the potential risk groups, and prevention of SAM development. The problems of differential diagnosis are considered with allowance for the similarity of clinical manifestations with SJA, treat- ment tactics using the HLH 2004 protocol, and biological therapy. 

One of the breakthroughs in pharmacology of the XXI century is the development of a new class of drugs, which are low molecular weight (<1 kDa), chemically synthesized substances (small molecules) intended for oral administration. Their point of application is tyrosine kinases, the enzymes involved in regulation of intracellular signaling that deter- mines the biological activity of cytokines. Tofacitinib (TOFA, Tofacitinib, Yakvinus; Pfizer), the first oral reversible inhibitor of JAK approved for treatment of rheumatoid arthritis (RA), is of special interest. The clinical efficacy and low toxicity of TOFA have been proved in a series of phase III randomized placebo-controlled studies, combined under the acronym ORAL, which has included more than 5000 patients with RA. Further research is needed, aimed at assessing the efficacy and safety of TOFA during prolonged use in real-life clinical practice (including through national registers) in patients with various forms of RA and comorbid diseases. It is reasonable to conduct «strategic» research of TOFA, designed in accordance with the concept of goal-directed treatment.

The nervous system is often involved in the pathological process in systemic lupus erythematosus (SLE). Neuropsychic SLE includes a combination of syndromes. Headache, seizures, cognitive disorders, cerebrovascular diseases are the most common ones. Pathogenetic mechanisms for the development of neuropsychic syndromes are different. Individual diagnostic and therapeutic strategies for the disease and the patient should be used. This article presents the literature and our own data on the most common neuropsychic syndromes associated with SLE. 

Zara Vladimirovna Khetagurova 

The article presents an overview of the lectures and workshops of the VI scientific educational course by the European League against Rheumatism (EULAR) dedicated to systemic lupus erythematosus (SLE), which was held in Pisa, Italy, in early September 2013. The course aims were to train young practicing rheumatologists to make early diagnosis and provide timely and adequate treatment with allowance for the current concepts of SLE etiopathogenesis; the use of the EULAR recommendations and classification criteria; and analysis of complex clinical cases. The main issues of this course included lesion of the nervous system in SLE, lupus nephritis, therapy with traditional and biological response modifiers, management of pregnancy in SLE patients, the need for standardization of the methods for the diagnosis and treatment of these conditions. 

Minutes No10 of the Meeting of the Rheumatology Task Force, Expert Council, Ministry of Health of the Russian Federation on March 29, 2014.