[Efficacy and safety of magnet therapy using portable device for knee osteoarthritis. 55-week double-blind study results]. / Effektivnost' i bezopasnost' primeneniya magnitoterapii s pomoshch'yu portativnogo apparata pri lechenii osteoartrita kolennykh sustavov. Rezul'taty dvoinogo slepogo 55-nedel'nogo issledovaniya.

Instrumental physiotherapeutic treatment using portable devices is optimal for patients with rheumatic diseases due to the devices' greater accessibility. However, there are still issues concerning the efficacy of physical factors generated by portable equipment in osteoarthritis (OA), mostly due to the limited evidence. OBJECTIVE: To study the efficacy and safety of long-term use of the portable magnet therapy device ALMAG+ (Almag Active) in knee OA (KOA). MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled, prospective, 55-week clinical trial of the medical device was conducted. The study included patients with primary and secondary (associated with immunoinflammatory rheumatic diseases) KOA stages I-III according to Kellgren-Lawrence diagnosed using generally accepted criteria (R. Altman et al., 1986). Enrollment of patients with secondary KOA was allowed given that the remission or low disease activity was achieved. During the study patients had to receive steady drug therapy. No intra-articular injections of glucocorticosteroids, hyaluronic acid, PRP, and physiotherapy procedures for knees (electrotherapy, shockwave therapy, heat therapy, hydrotherapy, peloid therapy) were allowed three months or less before the enrollment and throughout the study. According to the approved protocol, 77 patients (mean age 52.73±12.97 years) from two research centers participated in the study: 32 (41.6%) were males, and 45 (58.4%) were females. Primary KOA occurred in 41 (52%) patients, 36 (46.8%) patients had secondary KOA (associated with rheumatoid arthritis, ankylosing spondylitis, Sjögren's disease, psoriatic arthritis, systemic lupus erythematosus, or diffuse scleroderma). All patients received NSAIDs as a concomitant therapy, 24.7% received diacerein, 28.6% received disease-modifying anti-rheumatic drugs, 2.6% received methylprednisolone up to 8 mg/day, and 9% received biologic therapy. After randomization, 40 (52%) patients received placebo treatments (Group 1) and 37 (48%) received active treatments (Group 2). Both groups were comparable in the main parameters. The proportion of smokers was higher in Group 2, but the difference was not statistically significant. During the 55-week follow-up, three courses of 18 daily home magnet therapy procedures each were performed. RESULTS: In both groups, starting from week 5 of the study, an improvement of pain on movement and at rest according to VAS compared to the baseline (p<0.01 at all assessment time points) was observed, which can be explained by a pronounced placebo effect, often observed in OA. The improvement of pain at rest was more prominent in Group 2 vs. Group 1 at Week 21 (p=0.038) and Week 55 (p=0.017) of the study, probably due to the anti-inflammatory effect. The overall WOMAC index score was also lower in Group 2 vs. Group 1 at Weeks 21 and 55 (p=0.03 at both time points). The mean articular cartilage thickness, determined by ultrasound, reduced in Group 1 and remained practically unchanged in Group 2 (p=0.011). No adverse events associated with the use of the ALMAG+ (Almag Active) device, according to the attending physician, and no exacerbations of immunoinflammatory rheumatic diseases during the study period were reported. CONCLUSION: The results of a double-blind, placebo-controlled study of magnet therapy using a portable device demonstrated analgesic, anti-inflammatory, and structure-modifying effects of this type of physiotherapeutic treatment. No adverse events and exacerbations of rheumatic diseases associated with the study treatment have been reported.

[Pathophysiological mechanisms of the therapeutic action of alternating electromagnetic fields in the treatment of osteoarticular pathology]. / Patofiziologicheskie mekhanizmy terapevticheskogo deistviya peremennykh elektromagnitnykh polei v lechenii kostno-sustavnoi patologii.

Treatment of osteoarticular pathology with an alternating electromagnetic field (AEMF) is used today as a promising, non-invasive and safe strategy of physiotherapy. It has been shown that the action of alternating electromagnetic fields on the musculoskeletal system triggers signaling cascades that effectively contribute to the restoration of bone and articular tissue. The pathophysiological mechanisms underlying the cellular and subcellular effects of stimulation by an alternating electromagnetic field during the restoration of bone and articular tissue are considered. It was pointed out the several key signaling pathways involved in the restoration of bone and articular tissue under the influence of electromagnetic fields with an analysis of the potential for therapeutic application of electromagnetic fields alone or in combination with other available therapies.

[Apparatus physiotherapy in the treatment of rheumatic diseases]. / Apparatnaya fizioterapiya v lechenii revmaticheskikh zabolevanii.

Rheumatic diseases are a major medical and social problem. The mechanisms' variety of these diseases' development requires different approaches: the strategies of drug and non-drug therapy in modern rheumatology are designed to be complemented to each other. The most relevant treatment of rheumatic conditions is the method of pulsed magnetic fields because the sensitivity of biological tissues to them is the highest one. OBJECTIVE: To evaluate the efficiency and safety of the ALMAG + magnetic therapy device in the treatment of osteoarthritis of the knee joints¼. MATERIAL AND METHODS: The article presents preliminary data of a double-blind, placebo-controlled study «Evaluation of the efficacy and safety of the ALMAG + magnetic therapy device in the treatment of osteoarthritis of the knee joints¼. The study includes 70 patients (25 men, 45 women) of which 34 (48.6%) are patients with primary osteoarthritis (OA) of the knee joints (OAKS) and 36 (51.4%) are with secondary knee OA (on the background of immunoinflammatory rheumatic diseases). The patients were randomely divided into 2 groups: the main group (active devices) with 34 (48.6%) patients and the control group (placebo devices) - 36 (51.4%) patients. Patients of the main and control groups were comparable in all main parameters. During the study, the patients underwent 3 courses of treatment with the ALMAG + apparatus or with a placebo apparatus during the year. The preliminary analysis includes data on 58 patients who underwent at least 2 courses of therapy (28 patients from the main group and 30 from the control group). RESULTS: Pain at rest decreased in the main group by 4.0±2.9 mm, in the control group - by 1.07±2.21 mm (p=0.420), after the second course - by 5.13±3.4 and 1.81±2.19 mm (p=0.406), respectively. In the main group, the total WOMAC index decreased after the 1st course of physiotherapy from 24.0±14.9 to 20.25±14.31 mm (p=0.038), after the 2nd course it slightly increased - to 22.96±14.8 mm (p=0.314), in the control group the WOMAC index did not change statistically significantly: it decreased after the 1st course from 26.3±21.9 to 24.6±20.83 mm (p=0.112), after the 2nd course it increased to 27.04±21.9 mm (p=0.088). CONCLUSION: Thus, the use of the ALMAG + apparatus at home contributed to a decrease in pain at rest and a significant decrease in the WOMAC index in patients with primary and secondary OA of the knee joints. Pulsed magnetotherapy did not cause adverse events or exacerbation of immunoinflammatory diseases.

[The role of rehabilitation and apparatus physiotherapy in rheumatic disease treatment strategies]. / Rol' reabilitatsii i apparatnoi fizioterapii v strategii lecheniya revmaticheskikh zabolevanii.

Rheumatic diseases are a serious medical and social problem. The variability of mechanisms for the development of this group of diseases requires different approaches: strategies of drug and non-medicament therapy in modern rheumatology are designed to complement each other. EULAR recommendations pay insufficient attention to the use of non-medical methods of joint disease treatment. According to modern research, multi-disciplinary rehabilitation strategies, including, in addition to drug therapy, educational programmes, physical training of various intensities, as well as the use of apparatus rehabilitation methods, have proven to be the most effective. Hardware physiotherapy seems to be optimal for the treatment of rheumatic patients due to its higher accessibility and lower cost in comparison with classical balneo- and peloidotherapy. With the use of magnetotherapy there is also greater safety and fewer contraindications to the procedures. The method of using pulsed magnetic fields is the most justified in the treatment of joint diseases, since the sensitivity of biological tissues to them is the highest. The clinical effectiveness of pulsed magnetotherapy has been demonstrated in several randomized placebo-controlled multi-centre studies. Against the background of carried out magnetic field therapy in patients were statistically significant reduction of pain and stiffness, improvement of joint function, which indicates the expediency of including the physical factor in the strategy of treatment of rheumatic diseases in combination with drug therapy.

Efficacy and tolerability of abatacept treatment: results of 12 months observation.

AIM: This article reports 1-year clinical outcomes of patients with rheumatoid arthritis (RA) receiving abatacept (ABA) therapy. MATERIALS AND METHODS: Patients (n=91) with high RA activity (DAS28 = 5.1 ± 1.0) and an inadequate response on synthetic DMARDs (mainly methotrexate, 70.3%) and biologics (mainly TNF-α inhibitors, 93%) were included in the study. The majority of patients were middle-aged (49 ± 13.5) womens, RF (72.5%) and ACPA (77%) positive, with moderate functional impairment - HAQ = 1.4 (0.9-2). ABA were administered IV, 10 mg/kg according to the standard scheme. The evaluation of the effectiveness of the therapy was carried out according to the EULAR / ACR 2011 criteria using SDAI, CDAI, HAQ and the intention to treat approach. RESULTS: ABA led to a significant (p <0.05) decrease activity of RA. Clinical improvement according to EULAR criteria after 6 months of treatment was registered in 70.9%, after 12 months 63%. Almost a third of patients (28.7%) achieved a good response after 3 months of therapy, 39,2% - after 6 months and 39% - after 12 months. The retention rate of ABA therapy after 6 months was 77%, after 12 months - 60%. There were no significant differences between "bio-naive", 1 Bio and ≥2 Bio groups in achieving EULAR response. A good response was achieved in 38%, 38% and 43%, respectively, but the lowest number of non-responders was registered in ≥2 Bio - 38%, 36% and 43%. ABA significantly improved functional status of patients, after 12 months a marked and moderate improvement in the HAQ was achieved in 39% and 21% of patients, respectively. Adverse events (AE) were registered in 22 patients. The most frequent AE were upper respiratory tract infections - 11 (12%) patients. CONCLUSION: Abatacept was effective in the overall population, and in all subgroups of patients. It has shown significant improvement of clinical and functional status in patients who had an inadequate response to previous therapy. ABA has a good safety profile. AE were registered only in a small number of patients.

Association of polymorphisms of HLA-DRB1 and TNF-308 G/A with radiographic joint damage in patients with early rheumatoid arthritis with high inflammatory activity, treated according to the principle of "Treat to target" (REMARKA study).

AIM: To clarify the association between HLA-DRB1 and TNFα (-308G>A) genes polymorphism and joint destruction/further progression during 12 months of the follow-up period (FUP) in patients with early (<6 months), active, predominantly antibodies to cyclic citrullinated peptide (ACCP) and rheumatoid factor (RF)-positive rheumatoid arthritis (RA) treated according to "Treat to target" strategy. MATERIALS AND METHODS: The study included 85 patients with early RA and duration of symptoms <6 months. All patients were initially assigned to subcutaneous methotrexate (MTX) with rapid dose escalation to 20-25 mg/week. Combination MTX + biological therapy, mainly adalimumab, was used when MTX was ineffective. Joint destruction was assessed by Sharp-Van der Heijde modification scoring method at baseline and after 12 months FUP. Real time polymerase chain reaction (PCR-RT) was used for TNFα gene polymorphism (-308G>A) genotyping. Low resolution PCR-RT with subsequent sequence-based typing of *04 were performed to study HLA-DRB1 gene polymorphism. The HLA-DRB1*01, *04:01, *04:04, *04:05, *04:08, *10 alleles were categorized as SE+ (Shared Epitope) alleles. RESULTS: As for TNFα gene polymorphism, it was demonstrated that the number of narrowings and total Sharp score values were almost twice as high at baseline in GG genotype carriers as compared to GA genotype carriers (р<0,005, and р<0,004 respectively). Similar association was found after 12mo FUP. The progression of joint destruction, assessed as the change (∆) in the number of erosions, joint space narrowings and the total score, was statistically significantly associated with HLA-DRB1*(SE) genotypes: the carriers of SE (SE+/SE+) double-dose had more advanced progression as compared to (SE+/SE-)/(SE-/SE-) carriers (р<0,028, р<0,019, р<0,035 respectively). CONCLUSION: Our data suggest that HLA-DRB1 (SE+) gene and TNFα (-308G>A) polymorphisms are associated with the progression of radiographic joint destruction in early, active RA patients managed according to "Treat to target" stratagy.

[Relationship between matrix metalloproteinase-3 levels and articular destructive changes in early and extended rheumatoid arthritis].

AIM: To estimate a relationship between matrix metalloproteinase-3 (MMP-3) levels and articular radiographic changes in early and extended rheumatoid arthritis (RA); to analyze the role of this biomarker in predicting the progression of joint destruction in RA. SUBJECTS AND METHODS: Forty-five patients with early RA and 42 with extended RA were examined. Radiography of the hands and distal feet was performed before and one year after therapy. Serum MMP-3 levels were measured by an enzyme immunoassay prior to and 12 and 24 weeks after treatment. RESULTS: After 52 weeks, in the early RA group, 16 patients continued monotherapy with methotrexate (MT); because of its inefficiency, 29 additionally received a biological agent in different follow-up periods. The extended RA group took tocilizumab for 24 weeks, then the drug was discontinued and the patients continued the former therapy with disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and glucocorticosteroids. One year later, radiographic progression was recorded in 20.5 and 22.5% of the patients with early and extended RA, respectively. ROC analysis indicated that in the early RA group the MMP-3 level of more than 34.3 ng/ml at 12 weeks of MT therapy was associated with the radiographic progression of articular destructive changes after 52 weeks of therapy (the area under the curve (AUC) was 0.7; 95% confidence interval (CI) 0.46 to 0.93). In the patients with extended RA, the baseline MMP-3 levels of ≤51.3 ng/ml was related to no radiographic progression following 52 weeks (AUC, 0.587; 95% CI 0.33 to 0.84). CONCLUSION: MMP-3 may be regarded as an early marker for joint destruction in RA. The determination of MMP-3 level with other immunological markers may be useful to identify a group of patients who have a potentially severer disease course and need more intensive therapy.

[N-terminal pro-brain natriuretic peptide levels and diastolic dysfunction in patients with early rheumatoid arthritis before the administration of disease-modifying antirheumatic drugs].

AIM: To determine N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with early rheumatoid arthritis (RA) before the use of disease-modifying antirheumatic drugs (DMARDs); to compare NT-proBNP values with traditional risk factors (TRF), cardiovascular diseases (CVD), inflammatory markers, and left ventricular (LV) diastolic dysfunction (DD). SUBJECTS AND METHODS: The investigation enrolled 74 patients with a valid RA diagnosis (the 2010 ACR/EULAR criteria), 56 (74%) women, median (Me) age, 54 years; disease duration, 7 months; seropositive for IgM rheumatoid factor (87%) and/or anti-cyclic citrullinated peptide antibodies (100%) with no history of the use of DMARDs and glucocorticosteroids. Duplex scanning and echographic findings were used to assess TRF for CVD and carotid artery atherosclerosis (CAA) in all the patients with early RA prior to therapy. An E/A ratio was used as a criterion for LVDD. RESULTS: NT-proBNP concentrations in patients with early RA proved to be higher than those in the control group (p<0.0001). Higher-than-normal NT-proBNP levels were seen in 36 (49%) patients. The patients with early RA and elevated NT-proBNP values were older and had a higher body mass index (BMI) than those with normal NT-proBNP levels. Those with elevated NT-proBNP concentrations were more frequently found to have CAA, coronary calcification, and coronary heart disease; their intima-media thickness was also larger and C-reactive protein (CRP) levels higher than in those with normal NT-proBNP values. There were correlations between NT-proBNP levels and erythrocyte sedimentation rate, CRP, simplified disease activity index, and clinical disease activity index. Multivariate analysis revealed that chronic heart failure (CHF), CAA, CRP and low-density lipoprotein (LDL) levels, and BMI correlated with NT-proBNP concentrations. LVDD was detected in 35 (48%) patients with early RA. The level of NT-proBNP in patients with DD was higher than in those without DD. Higher-than-normal NT-proBNP values were observed in 23 (65%) and 12 (32%) patients with and without LVDD, respectively. The optimal NT-proBNP level for CHF detection was equal to 237.4 pg/ml (86% sensitivity and 85% specificity); the area under the ROC curve was 0.879. CONCLUSION: Just at the early disease stage, the patients are noted to have a high NT-proBNP level that is influenced by higher BMI, low LDL levels, CAA, CHF, and high CRP values. In the patients with early RA, the diagnostically significant NT-proBNP concentration for CHF detection was higher (237 pg/ml) than in those without RA (125 pg/ml). The patients with early RA should undergo NT-proBNP determination, LVDD screening, correction of TRF for CVD, atherosclerosis treatment, and remission achievement.

[Left and right ventricular diastolic dysfunction in patients with early rheumatoid arthritis before prescribing disease-modifying antirheumatic therapy].

AIM: To estimate the rate of diastolic dysfunction (DD) of the left and right ventricles (LV and RV) in patients with early rheumatoid arthritis (RA) before using disease-modifying antirheumatic drugs (DMARDs) therapy and to investigate its association with traditional risk factors (TRFs) for cardiovascular diseases (CVD) and inflammatory markers. SUBJECTS AND METHODS: The investigation enrolled 74 patients with a valid diagnosis of RA, including 56 (74%) women (median age, 54 years; disease duration, 7 months); the patients who were seropositive for rheumatoid factor (RF) (87%) and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies (100%) who had not been on DMARDs or glucocorticosteroids. TRFs for CVD and carotid artery atherosclerosis were assessed from duplex scanning data and echocardiography was performed in all the patients with early RA before starting the therapy. The ratio of the maximum blood flow velocity during early diastolic filling (E) to that during atrial systole (A) was used as a criterion for LVDD and RVDD. There were 3 types of impaired ventricular filling: 1) E/A <1; 2) E/A = 1-2; 3) E/A > 2. RESULTS: LVDD and RVDD were detected in 35 (48%) and 17 (23%) patients, respectively. RVDD was recorded only in conjunction with LVDD. Among LVDD and RVDD, the former was prevalent. All the patients with early RA were divided into 3 groups: 1) patients with LVDD and RVDD; 2) those with LVDD; 3) those without ventricular DD. All the three groups were matched for the level of DAS28, anti-CCP antibodies, and RF. The incidence of arterial hypertension, dyslipidemia, and abdominal obesity was higher in the patients of Groups 1 and 2 than in those of Group 3. There was a progressive decrease in high-density lipoprotein (HDL) cholesterol concentrations and increases in triglyceride (TG) levels and atherogenic index from Group 3 to Group 1, with the concentrations of total cholesterol and low-density lipoprotein cholesterol being similar in the 3 groups. Coronary heart disease was recorded more frequently in Group 2 than in Group 3. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) proved to be also significantly higher in the patients with DD than in those without DD. Correlations were found between LV E/A and ESR, CRP, HDL cholesterol, TG, RV E/A and ESR, DAS28, TG. CONCLUSION: The patients with early-stage RA were found to have high incidence rates of LVDD and RVDD, which is related to the high prevalence of CVD, the high spread of TRF for CVD, and the high activity of an inflammatory process.

[The clinical informativeness of detection of antibodies to citrullinated proteins under rheumatoid arthritis].

The main diagnostic laboratory markers of rheumatoid arthritis are IgM rheumatoid factor and antibodies to citrullinated proteins. The IgM rheumatoid factor is a sensitive but insufficiently specific marker of rheumatoid arthritis. The antibodies to citrullinated proteins have a higher specificity for diagnostic of rheumatoid arthritis. The antibodies to cyclic citrullinated peptide and modified citrullinated vimentin are the main representatives of family of antibodies to citrullinated proteins applying in clinical diagnostic practice. The study was carried out to deternine the role of antibodies to citrullinated proteins and modified citrullinated vimentin in diagnostic, evaluation of activity and severity of destructive alterations under rheumatoid arthritis. The samplings of 993 patients with reliable diagnosis of rheumatoid arthritis. 179 patients with other rheumatoid diseases and 30 healthy donors were examined. The measurement of serum concentration of IgM rheumatoid factor and C-reactive protein was implemented by immune nephelometric analysis and antibodies to citrullinated proteins were analyzed by enzymoimmunoassay The erythrocyte sedimentation rate was established using the Westergreen technique. It was established that antibodies to modified citrullinated vimentin had the highest diagnostic specificity (83%), antibodies to cyclic citrullinated peptide had the highest diagnostic specificity (87%). The diagnostic specificity of joint detection of IgM rheumatoid factor, antibodies to citrullinated proteins and antibodies to modified citrullinated vimentin made up to 87%. In patients negative to rheumatoid factor the rate ofdetection of antibodies to citrullinated proteins made up to 34% and antibodies to modified citrullinated vimentin made up to 48%. The diagnostic effectiveness of detection of antibodies to citrullinitted proteins (ratio of likelihood of positive and negative results of test was correspondingly 5.5 and 0.3; area under ROC curve 0.8) and antibodies to modified citrullinated vimentin (ratio of likelihood of positive and negative results of test was correspondingly 4.4 and 0.2; area under ROC curve 0.9) surpassed the same in analysis of IgM rheumatoid factor (ratio of likelihood of positive results--3.2, ratio of likelihood of negative results--0.4, area under ROC curve--0.8). The weak positive correlation relationship was established between concentration of antibodies to cyclic citrillinatedpeptide/antibodies to modified citrullinated vimentin in blood serum and indicators of clinical laboratory activity of rheumatoid arthritis (ESR, CRP DAS 28, (r-0.2. p < 0.05). The high positive levels of antibodies to modified citrullinated vimentin associated with expressed destructive affection of joints (p < 0.02). The antibodies to cyclic citrullinated peptide are the most highly specific and clinically informative laboratory diagnostic marker of rheumatoid arthritis. The detection of antibodies to modified citrullinated vimentin is an important additional serological test to diagnose rheumatoid arthritis in IgM rheumatoid factor-negative and/or antibodies to cyclic citrullinated peptide-negative patients and to forecast severe destructive affection of joints under the given disease. The joint study of IgM rheumatoid factor, antibodies to cyclic citrullinated peptide and antibodies to modified citrullinated vimentin under rheumatoid arthritis has higher diagnostic sensitivity as compared with isolated antibodies to citrullinated proteins.

[Evaluation of methotrexate effect on the acute-phase response in rheumatoid arthritis after 12-week treatment].

UNLABELLED: DAS28 index calculated with regard for ESR, the number of swollen/painful joints and evaluation of the patient's condition by VAS is universally used to estimate activity of rheumatoid arthritis (RA). There is a variant of calculation using C-reactive protein (CRP) instead of ESR. Our experience indicates that ESR decreases more slowly than CRP during treatment and better reflects dynamics of patients' condition. From the practical standpoint it is important to estimate activity of RA because therapeutic modalities are chosen based on the DAS28 value. AIM: To study the influence of pharmaceutical form of methotrexate on the acute-phase response in rheumatoid arthritis. MATERIALS AND METHODS: The study included 32 patients (24 women, 8 men) aged 19-76 (mean 47.5 +/- 28.5) yr with active RA (DAS28 > 3.2) 4-30 months (11.5 +/- 7.4, median 8) in duration. Diagnosis was made using AXR criteria (1987), none of the patients previously received methotrexate injections. Inclusion criteria: initially high ESR (Westegren, mm/hr) and/or CRP (mg/l measured by a highly sensitive method). All patients were given methotrexate subcutaneously for 12 weeks as monotherapy (initial dose 10 mg, maximum one 25 mg/week). The cumulative dose was 211.36 +/- 17.2 mg. RESULTS: Side effects did not require withdrawal of methotrexate. CRP level decreased faster than ERS: a 70% decrease of CRP by week 12 was recorded more frequently than that of ESR. Slow dynamics of the number of swollen joints compared with CRP may be due to the low cumulative dose of methotrexate. Duration of the disease had no effect on dynamics of acute phase characteristics. CONCLUSION: Methotrexate injections resulted in markedly delayed development of clinical signs of improvement compared with laboratory values. CFP levels fell down much faster than ESR, Remission or low activity of RA (estimated from DAS28) occurred only in 38% of the cases after 3 month monotherapy by methotrexate injections. It is concluded that efficacy of this drug should be estimated no sooner than 4 months after the onset of the treatment.

[Management of patients with pulmonary fibrosis].

Rheumatoid arthritis (RA) is a chronic autoimmune systemic disease. Its systemic manifestations include interstitial lung lesions (ILL). According to morphological studies and X-ray computed tomography, the incidence of RA-associated ILL is 60-70% which gives reason to consider pulmonary fibrosis (PF) to be the main form of lung pathology in this disease. PF is a pathological process in the lungs characterized by high mortality rate and refractoriness to therapy. It is a heterogeneous group of disorders with progressive and irreversible destruction of lung architectonics due to scarification that in the end results in organ dysfunction, disturbed gaseous exchange and respiratory distress. Changes in the interstitial lung tissue resulting from local autoimmune rheumatoid inflammation develop by the same mechanisms that underlie idiopathic pulmonary fibrosis used as a model for classification, pathogenesis and treatment of RA-associated ILL. This review is focused on the therapeutic strategy for the management of PF in the context of consensus of the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT, 2010/2011).

[Pharmacotherapy for rheumatoid arthritis in the early 21st century: Russian and international experience].

The paper summarizes the data of international and Russian studies concerning current approaches to the pharmacotherapy of rheumatoid arthritis. Particular emphasis is placed on the substantiation of the treat-to-target concept, on the efficacy and safety of genetically engineered biological agents, including the inhibitors of tumor necrosis factor, interleukin-6 receptors, T-lymphocyte co-stimulation, and anti-B-cell therapy.

[Immunogenetic aspects of early rheumatoid arthritis].

The study is aimed to investigate the distribution of alleles of HLA-DRB1 gene in patients with early rheumatoid arthritis and healthy individuals in Russian population, and evaluate their significance as molecular genetic markers of rheumatoid arthritis predisposition and protection. The association between alleles of HLA-DRB1 genes, antibodies to cyclic citrullinated peptides and IgM rheumatoid factor was also studied. Low and high resolution HLA-DRB1 genotyping were compared. In the cohort of patients with early rheumatoid arthritis, the alleles of HLA-DRB1 gene were found to be markers of rheumatoid arthritis protection/risk, especially in the homozygous state. They determined production of antibodies to cyclic citrullinated peptides but were not associated with rheumatoid factor IgM levels. These findings support different autoimmune mechanisms of rheumatoid arthritis pathogenesis.

[Diagnosis and problems in therapy of interstitial lung disease associated with rheumatoid arthritis].

Rheumatoid arthritis (RA) is an inflammatory rheumatic disease of unknown etiology, which is characterized by symmetric, chronic, and erosive arthritis (synovitis) of the peripheral joints and systemic inflammatory involvement of the viscera. Lung pathology, including interstitial lung disease (ILD), is one of the common extra-articular manifestations in RA. ILD is considered to be present in almost 25% of the RA patients. To study a prognosis in RA patients with ILD was the objective of some investigations in the past decade, the majority of which concluded that the mean survival after the diagnosis was about 3 years. These indicators may reflect the predominance of usual interstitial pneumonia (UIP) in patients in specific trials as this type of lung disease is associated with a poorer prognosis. In addition, there are discrepant results on survival differences between RA patients with ILD and those with idiopathic ILD. However, the data were limited by a small number of cases in both medical centers and daily clinical practice. ILD is the only extra-articular manifestation of RA, the rate of which is increasing. ILD is considered to be a cause of death in nearly 6% of all the patients with RA. The pattern of ILD may be determined by high-resolution computed tomography and may be a major prognostic marker; the development of UIP is worst. The material is dedicated to the successes recently achieved in the diagnosis and therapy of RA-associated ILD. The state-of-the-art of investigations in this area is discussed.

[The comparative effectiveness of high-intensity dynamic training with the use of exercise machines and therapeutic gymnastics for the joints in the patients presenting with early rheumatoid arthritis].

The objective of the present work was to compare the effectiveness of two therapeutic exercise programs for the patients presenting with early rheumatoid arthritis (RA). The study included 51 patients. Fifteen of them (group 1) were given conventional medicamental therapy in combination with high-intensity dynamic physical exercises with the use of the Enraf-Nonius training devices (45-60 min). Eighteen patients of group 2 were offered 10 sessions of remedial gymnastics for the joints (45 min each) under the guidance of an instructor that were continued under the domestic conditions (45 min each session thrice weekly for 3 months). Eighteen patients of group 3 were given medicamental therapy alone (control). The parameters estimated in the study included the mean strength of knee joint extension and ankle joint flexion measured with the use of En-TreeM devices, articular pain (100 mm BAHI), DAS28, HAQ, and RAPID3 indices. It was shown that both programs of therapeutic exercises reduced the severity of the disease, improved the functional and motor activity of the patients and their quality of life. The majority of these characteristics were significantly different from those documented in the control group (p<0.05). The clinical effectiveness of high-intensity training with the use of exercise machines was higher than without them (articular pain was reduced by 57.9% (p<0.01), DAS28 by 24.7% (p<0.05), HAQ by 60.7% (p<0.01). RAPID3 by 47.5% (p<0.01), mean strength of extension of the weak and strong knee joints increased by 87.9% (p<0.01) and 70.5% (p<0.01) respectively, the strength of flexion of the severely and less severely affected ankle joints increased by 84.6 (p<0.01) and 68.8% (p<0.01) respectively. Compliance with regular performance of therapeutic joint exercises during 3 months was higher (83.3%) than with high-intensity dynamic training with the use of exercise machines (60%). It is concluded that the latter modality should be recommended to the younger patients with RA (below 40 years), a short history of the disease, and its low activity.

[Combined step-by-step rehabilitation of the patients presenting with early-onset rheumatoid arthritis].

The objective of the present study was to develop the program for combined step-by-step rehabilitation of the patients presenting with early-onset rheumatoid arthritis (RA); the secondary objective was to estimate the effectiveness of this program. A total of 34 patients were recruited for the participation in the study. They received medicamental therapy in combination with the rehabilitative treatment during 6 months. The hospital-based treatment included therapeutic exercises for large joints under the supervision of a specialist (45 min), occupational therapy (45 min), local aerial cryotherapy of wrist, knee, and ankle joints (10 sessions 15 min each at a temperature of -60 degrees C), ortheses, and the educational program (4 daily studies 90 min each). The outpatient and home-based treatment included therapeutic exercises for large joints (45 min), wrist exercises (45 min) three times every week, ortheses. 26 patients received only medicamental therapy (control group). The following characteristics were measured: the average power of extension of knee joints and of flexion of ankle joints (by means of En-TreeM analysis of movements), wrist grip strength, articular pain (100 mm VAS, DAS28, HAQ, RAPID3 indices). The rehabilitative program ensured excellent compliance with basal therapy, reduced requirements for symptomatic medicines, and improved adherence to the methods for the formation of the correct movement patterns, orthesis wearing, and regular therapeutic exercises. The rehabilitative treatment resulted in the relief of articular pain by 70.4% (p < 0.01), decrease of DAS28 by 31.9% (p < 0.05), HAQ by 75.8% (p < 0.01), and RAPID3 by 60.1% (p < 0.01). The grip strength of the more seriously injured wrist increased by 44.9% (p < 0.05) and that of the less damaged one by 31.3% (p < 0.05). The average extension power of the weaker knee joint increased by 88.7% (p < 0.01) and that of the stronger joint by 67.7% (p < 0.01). The average flexion power of the more seriously injured ankle joint increased by 81.6% (p < 0.01) and that of the less damaged one by 70.2% (p < 0.01). The two groups were significantly different in terms of the majority of characteristics evaluated. It is concluded that the combined rehabilitative treatment helps to control the activity of the disease, enhances the functional abilities, improves the locomotor activity and quality of life of the patients with early-onset rheumatoid arthritis.

[The efficiency and safety of adalimumab treatment in patients with active rheumatoid arthritis unresponsive to standard therapy: Russian national study results].

AIM: To confirm the efficacy and safety of adalimumab (ADA) added to the standard antirheumatic therapy performed in patients with rheumatoid arthritis (RA) of moderate and high activities. SUBJECTS AND METHODS: The open-labeled multicenter study enrolled 100 adult patients (11 men, 89 women; mean age 50.9 +/- 11.1 years) with active RA according to the ACR criteria (1987) despite their treatment with disease-modifying antirheumatic drugs, the average number of which in the history was 2.1 per man. At baseline, DAS28 CRP was as many as 6.2 +/- 0.84 scores; C-reactive protein (CRP) was 37.1 +/- 34.7 mg/l. In accordance with the indications officially registered in the European Union and the Russian Federation, ADA was given in a dose of 40 mg 2 weeks. Before administration of the drug, every patient underwent screening examination for tuberculosis, which used a tuberculin test and chest X-ray. The screening covered a period of the treatment up to 24 weeks and its subsequent period within 70 days after administration of the last dose of ADA in order to study its safety. RESULTS: DAS28-CRP scores decreased from 6.14 +/- 0.86 (at baseline) to 3.39 +/- 1.1 (by the end of the study). At 12 weeks, 22% of the patients achieved a low RA activity (DAS28-CRP < or = 3.2 scores); 14% achieved clinical remission (DAS28-CRP < or = 2.6 scores); at 24 weeks, these were 37 and 25% of the patients, respectively. There were differences in effectiveness in terms of the baseline disease activity. At 24 weeks, ACR20, ACR50, and ACR 70 responses were achieved in 88, 67, and 26% of the patients, respectively. The HAQ functional index reduced from 1.9 +/- 0.6 (at baseline) to 1.081 +/- 0.64 (at 12 weeks) and 1.04 +/- 0.68 (at 24 weeks) scores. Twenty-four patients were recorded as having 40 adverse reactions (AR), including only one severe AR (septic arthritis). There were no cases of tuberculosis. CONCLUSION: The Russian multicenter study demonstrated the high clinical efficacy of ADA in patients with the moderate and high activity of RA unresponsive to standard therapy, as well as its satisfactory safety.

[Magnetic resonance imaging of the hand as an early diagnostic method for rheumatoid arthritis].

AIM: To provide the qualitative and quantitative characteristics of changes revealed by the data of magnetic resonance imaging (MRI) of the hand and by those of X-ray study of the hand and foot in patients with early rheumatoid arthritis (ERA). SUBJECTS AND METHODS: The study enrolled 110 patients (90 females, 20 males; age 49.6 +/- 12.2 years) examined in the framework of the RADICAL program at the Research Institute of Rheumatology, Russian Academy of Medical Sciences. The mean duration of the disease was 5.61 +/- 3.17 months. The diagnosis of rheumatoid arthritis was established by the 1987 ARA criteria in all the patients on primary standard examination comprising X-ray study of the hand and feet and evaluation by the modified Sharp method. MRI of the hand was performed in all the patients, by assessing the result by the OMERACT-RAMRIS procedure. RESULTS: Destructive changes (cysts and erosions) evidenced by X-ray study were found in the wrists, metacarpophalangeal articulations (MPA), and foot in 7.27, 8.2, and 13.64%, respectively. MRI revealed destructions in the wrist, MPA, and metacarpal bone base in 50, 60, and 16.36%, respectively. Overall, erosions could be seen on X-ray films and MRI scans in 20.91 and 67.27%, respectively (p < 0.0001). MRI revealed bone edema (osteitis) in 46.4% of the patients; there was no difference in the detection rate between the extremities. MRI synovitis was found in 99% of the patients, the right hand being significantly more commonly affected. Detailed characterization of the changes revealed by MRI and Xray was obtained in patients with ERA. CONCLUSION: MRI detected erosions significantly more frequently than did X-ray (p < 0.001), which confirms the high value of low-field MRI diagnosis on primary examination of patients with ERA and supports the opinion that the results of this study should be included into the diagnostic criteria of ERA.

[Clinical and immunological aspects of early-stage rheumatoid arthritis].

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by a systemic inflammatory and destructive joint lesion that is manifested by the involvement of various organs and systems into the pathological process. Whether the variants of the course and outcomes of RA may be predicted early is the most important inadequately studied problem. HLA-DRB1* genotypes affect disease severity; however, different alleles encoding the identical amino acid sequence have a varying association with the disease and their combinations can differently increase the risk of RA. Total epitope (SE) is associated not only with the risk of RA as a whole, but also with the development of the severe course of the disease to a greater extent. A number of studies have demonstrated that if a patient has concurrently antibodies to cyclic citrullinated peptide (CCP) and rheumatoid factor, as well as HLA-DRB1 alleles, the likelihood of rapid X-ray progression is 10 times greater than that in a patient without these markers. The paper considers the course of early RA depending on the combined determination of immunological and immunogenetic markers (SE and CCP antibodies). Each of them makes a substantial contribution to the development of a destructive process in early RA, which necessitates the assessment of a combination of the factors.