The paper presents achievements associated with the study of antiphospholipid syndrome from its description to the present time, i.e. over the last 30 years, worldwide and at the V.A. Nasonova Research Institute of Rheumatology.

One of the most striking achievements in the pharmacotherapy of rheumatoid arthritis (RA) and other human immunoinflammatory diseases (IIDs) late in the 20th century is associated with the design of a fundamentally new group of medications that received the name biological agents (BAs). However, the introduction of innovative BAs into clinical practice not only could enhance the efficiency of therapy and improve prognosis in patients with the most severe forms of IIDs, but has also led to a dramatic increase in the cost of treatment. Progress in the design of biosimilars is related to many factors, including expiry of the term of patents for many brand-name BAs, such as infliximab, adalimumab, etanercept, and rituximab. Over the last 5 years, a large number of biosimilars have been designed and their design is being continued. The European Medicines Agency, the World Health Organization, and the U.S. Food and Drug Administration have developed a regulatory framework and general requirements for the manufacture and characteristics of biosimilars. Federal Law No. 429-FZ «On Amendments to the Federal Law "On Circulation of Medicines"» dated December 22, 2014 defines a biosimilar drug as a biological medicine product that is similar to the parameters of quality, efficiency, and safety with the reference biologic drug in the same formulation, and the same route of administration. The review presents an update on the requirements for biosimilars used to treat IIDs, their interchangeability and promises in further clinical application. Particular emphasis is laid on the chimeric monoclonal antibodies to tumor necrosis factor-α infliximab biosimilar Flammegis (Egis Pharmaceuticals, Hungary), that has been registered in Russia for the treatment of RA, ankylosing spondylitis and other IIDs, as well as the chimeric monoclonal antibodies to B-lymphocytes rituximab biosimilar Acellbia in a phase III clinical trial that is in the closing stage. Preliminary provisions and recommendations of the All-Russian public organization «Association of Rheumatologists of Russia» concerning the place of biosimilars in rheumatology are formulated.

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for the management of knee osteoarthritis (OA), published in December 2014, provides practical guidance for the prioritization of interventions. This current paper represents an assessment and endorsement of the algorithm by Russian experts in OA for use in Russian clinical practice, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA, in support of the clinicians’ individualized assessment of the patient. Medications recommended by the ESCEO algorithm are available in Russia. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOA) is advised, for which high-quality evidence is provided only for the formulations of patented crystalline glucosamine sulphate (pCGS) (Rottapharm/Meda) and prescription chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs but without the systemic safety concerns. To be effective, topical NSAIDs must have high bioavailability, and among NSAIDs molecules like etofenamate have high absorption and bioavailability alongside evidence for accumulation in synovial tissues. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk: benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability.

Objective: to investigate the efficacy and tolerability of amtolmetin guacil (AMG; Niselat®, Dr. Reddy's Laboratories Ltd, India) versus previous therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA) and signs of dyspepsia.

Subjects and methods. The open-label observational study included 220 patients aged 30–65 years who suffered from knee OA and intense pain during NSAID intake and had symptoms of dyspepsia in the absence of contraindications to the use of AMG. Among the comorbidities that generally occurred in 68% of the patients, there was a preponderance of hypertension (42%), lower extremity varicose veins (6.4%), and diabetes mellitus (6%). Treatment efficacy was evaluated using three domains of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), by also taking into account pain intensity and general health assessment on the visual analogue scale. A Severity of Dyspepsia Assessment (SODA) scale was used to rate dyspepsia.

Results and discussion. AMG had a marked analgesic effect confirmed by 40% or more pain reduction that occurred in 72.5% of the patients. The high analgesic effect of AMG was confirmed by a statistically significant (p <0.001) reduction in the WOMAC index (pain and stiffness) and by an increase in functional activity. There was a significant decrease in painless and painful signs of dyspepsia, as well as positive changes in the measures “overall assessment of dyspepsia severity” (p < 0.001) and “satisfaction with treatment”. Overall assessment of AMG tolerability was only positive: excellent (33%), good (56%), and satisfactory (11%). There were no serious adverse events (AE). AE were graded as moderate and mild in 8 and 82% of cases, respectively. AE were recorded in 7.7% of the patients.

Conclusion. The findings suggest that AMG offers good prospects for knee OA treatment.

Objective: to investigate the count and characteristics of the phenotype of T regulatory cells (Treg) in the peripheral blood of healthy donors and patients with early rheumatoid arthritis (RA), by using multicolor flow cytometry.

Subjects and methods. The investigation enrolled 39 patients with early RA. The percentage and absolute count of Treg (FoxP3+CD25+, surface CD152+, intracellular CD152+, FoxP3+CD127, CD25+CD127, FoxP3+ICOS+, FoxP3+CD154+; and FoxP3+CD274+) was determined by multicolor flow-cytometry. A control group consisted of 20 healthy donors matched for sex and age with the examined patients.

Results and discussion. In the patients included in the study, the median [25th; 75th percentiles] DAS28 was 5.01 [4.2; 5.8]; high, moderate, and low activity showed 22 (48.9%), 20 (44.4%), and 3 (6.7%) patients, respectively. The patients with early RA had a lower percentage of FoxP3+CD25+ cells and a lower percentage and absolute count of FoxP3+ICOS+, FoxP3+CD154+, and FoxP3+CD274+ T cells than the healthy donors (p<0.05 in all cases). There was a negative correlation of the percentage of FoxP3+CD25+ cells with C-reactive protein (CRP) (r = -0.4), that of intracellular CD152+ with DAS28 (r = -0.35), erythrocyte sedimentation rate (ESR) (r = -0.46), and CRP (r=-0.54); that of FoxP3+CD127 with CRP (r = -0.42); that of CD25+CD127 with DAS28 (r = -0.38), Simplified Disease Activity Index (r = -0.41), Clinical Disease Activity Index (r = -0.36), ESR (r = -0.39), and CRP (r = -0.47) (p < 0.05 in all cases).

Conclusion. The findings suggest that the functional activity of Treg is impaired in early RA, which has an impact on the activity of the inflammatory process.

Objective: to compare the efficacy and safety of abatacept (ABC) in patients with different duration of rheumatoid arthritis (RA).

Subjects and methods. The investigation enrolled 86 patients with previous inefficiency or intolerability of therapy with synthetic disease-modifying antirheumatic drugs (DMARDs), mainly with methotrexate, and/or biological agents (BAs), such as adalimumab, etanercept, rituximab, infliximab, certolizumab pegol, and tocilizumab. The patients were divided into 2 groups. Group 1 included 29 (34%) patients with early RA (< 2 years' disease duration); Group 2 consisted of 57 (66%) patients with long-term RA (> 2 years' disease duration). The patients' mean age was 49±13.4 years; most of them were women who had a high RA activity (the mean DAS28 value was 5.2±1.15), were seropositive for rheumatoid factor and anti-cyclic citrullinated peptide antibodies. All the patients underwent standard clinical and laboratory examinations. ABC was injected intravenously at a dose of 10 mg/kg according to the standard regimen. Every 3 months, disease activity was assessed with DAS28; functional status was evaluated with the Health Assessment Questionnaire (HAQ).

Results and discussion. In the early and advanced RA patients, the mean DAS28 at baseline was 5.2±0.9 and 5.2±1.3, respectively. After 3 months of ABC treatment, it significantly decreased in both groups (p < 0.05). An improvement according to the criteria of the European League Against Rheumatism (EULAR) occurred in 76% of the early RA patients and in 74.5% of the advanced RA ones. Following 3 and 6 months of therapy, there were no significant differences between the two groups in the rate of a good response: the latter was obtained in 31 and 42% of early RA cases and in 25.5 and 40% of advanced RA cases, respectively. After 3 and 6 months, both groups showed a comparable number of those who did not respond to treatment (24 and 12.5% in the early RA group and 25.5 and 25% in the advanced RA group, respectively). During ABC therapy, both groups also displayed a significant decrease of HAQ disability index (DI) (p < 0.05). A total of 14 adverse events (AE) were recorded in 13 (15%) patients. The most common AE proved to be acute respiratory viral infections that were observed in 6 (7%) patients. Serious AE were seen in 3 (3.4%) patients.

Conclusion. ABC therapy leads to decrease of RA activity in the majority of patients who have previously received ineffective therapy with DMARDs and BAs. There were no significant differences in good response rates according to the EULAR criteria between the advanced and early RA groups. Following 3 months of treatment, the decrease of HAQ DI was significantly more pronounced in the early RA group. AE were registered only in 15% of the patients. ABC has established itself as an effective drug that has a good safety profile and is able to occupy a niche in the therapy of both late and early RA.

Objective: to investigate the immunogenicity, safety, and clinical efficacy of 23-valent polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) during a two-year follow-up study.

Subjects and methods. The prospective open-label comparative study enrolled 110 people, of them there were 81 (73.6%) women and 29 (26.4%) men at the age of 23 to 76 years, including 79 patients with RA, as well as 31 subjects without systemic inflammatory rheumatic diseases (RD) (a control group). The group of RA patients exhibited a predominance of middle-aged women who had > 3 years’ disease duration and a moderate inflammatory activity (the mean value of DAS28, 4.32). 52 patients received methotrexate (MTX), 14 had Leflunomide (LEF), and 13 were treated with tumor necrosis factor-α (TNF-α) inhibitors + MTX.
The 23-valent polysaccharide pneumococcal vaccine Pneumo-23 (Sanofi Pasteur, France) was administered in a single dose of 0.5 ml subcutaneously during continuous MTX or LEF therapy for the underlying disease or 3–4 weeks before the use of TNF-α inhibitors. Clinical examinations of the patient and conventional clinical and laboratory studies were performed during control visits (1, 3, 12, and 24 months after vaccination). Clinical effectiveness and safety were evaluated in all the patients included in the study. The serum levels of anti-pneumococcal capsular polysaccharide antibodies (Ab) were measured in 72 patients with RA and in 30 individuals in the control group during a 12-month follow-up study, including in 25 patients with RA for a 24-month follow-up study by enzyme immunoassay using commercial VaccZymeTM Anti-PCP IgG Enzyme Immunoassay kits (The Binding Site Group Ltd, Birmingham, United Kingdom). Along with this, the post-immunization response coefficient was calculated for each patient as the ratio of postvaccination Ab levels during Visits 2, 3, 4, and 5 to the baseline Ab level.

Results and discussion. No clinical and radiological symptoms of pneumonia were recorded in any case during the follow-up period. The patients with RA and the control group showed a more than double significant increase of anti-pneumococcal Ab level during 3 months following vaccination. Despite the decrease in their concentration by month 12, the latter remained at the appropriate level and significantly increased at 24-month follow-up. Vaccination was well tolerated. A favorable course of the postvaccinal period was noted in all cases. There were no adverse reactions to vaccination in 72 (65%) patients; 38 (35%) patients were noted to have pain, skin swelling and hyperemia up to 2 cm in diameter at the site of injection, as well as low-grade fever. There were no episodes of a RD exacerbation or any new autoimmune disorders during the follow-up period.

Conclusion. The findings were suggestive of the sufficient immunogenicity and good tolerability of 23-valent pneumococcal vaccine in patients with RD during the two-year follow-up period.

Objective: to estimate changes of uveitis activity using BOS24 (Behсet's disease Ocular attack Score 24) during antiinflammatory and immunosuppressive therapy in patients with Behcet's disease (BD).

Subjects and methods. 103 (75.6%) of the 138 patients with BD fulfilled the 1990 International Study Group for Behсet's Disease (ISGBD) criteria had eye lesions; 55 (53.4%) of the 103 patients had an exacerbation of uveitis. 55 patients with an exacerbation of uveitis were found to have active inflammation in 94 eyes. The activity of uveitis was monitored during anti-inflammatory and immunosuppressive therapy, by using BOS24 that consists of 6 parameters with maximal possible value 24.

Results and discussion. The mean BOS24 for 94 eyes with active uveitis at baseline was 9.33±0.91. The most pronounced inflammatory changes were found in the posterior chamber of the eye, mainly in the area of the peripheral retina, rarely in the area of the fovea and in the optic disc. All the patients with an exacerbation of uveitis received systemic therapy with glucocorticoids, cyclosporine and/or azathioprine. After 8.92±3.47 months of treatment, the mean BOS2 decreased significantly (p < 0.001) to 2.20±1.02. The most substantial positive changes were noted in the anterior chamber of the eye (p = 0.03), vitreous humor (p < 0.01), and peripheral retina (p < 0.001).

Conclusion. BOS24 is a reliable tool to quantify uveitis activity in patients with BD and its dynamics during antiinflammatory and immunosuppressive therapy.

Objective: to determine the frequency of traditional risk factors (TRFs) for cardiovascular diseases (CVD) in patients with systemic sclerosis (SS) and to analyze their relationship to the clinical manifestations of SS, as well as to structural changes, as evidenced by echocardiography (EchoCG).

Subjects and methods. The investigation enrolled 125 patients with SS and 50 sex- and age-matched, apparently healthy individuals included in a control group. Standard electrocardiography was performed in all and EchoCG – in 121 patients. The Systematic Coronary Risk Evaluation (SCORE) scale was used to assess the risk of fatal CVD in 100 patients with SS and in 47 control individuals within 10 years.

Results and discussion. The frequency of TFRs in patients with SS was not significantly different from that in the control group, except for the occurrence of hypercholesterolemia and increased body mass index (BMI). In SS, BMI >25 kg/m2 was observed significantly more often and the frequency of hypercholesterolemia was lower than in the controls (p <0.018). Hypertension and diabetes mellitus were slightly more frequently encountered in SS patients than in the controls, but this difference was insignificant. Taking into account the Russian Society of Cardiology (RSC) guidelines, the cardiovascular risk (CVR) was assessed with the SCORE scale. A very high CVR was much more common in SS and a moderate CVR was much more frequently seen in the control group. There were no substantial differences in the frequency of low and high CVRs. SS is characterized by the increased frequency of high total CVD risk as compared to the controls. Hypertension, overweight, and over 50 years of age were associated with more obvious structural heart disease.

Conclusion. TRFs make a substantial contribution to the formation of a high CVR in patients with SS, promoting the development of atherosclerosis and its complications. Assessment of TGFs in SS patients will facilitate identifying patients at high risk for cardiovascular death and timely prescribing therapy. Hypertension is an important TGF that in SS is associated with considerable structural changes in the heart; therefore adequate blood pressure control is of importance in improving SS prognosis especially in patients older than 50 years.

The relief of suffering, which is associated with a rapid and complete elimination of painful sensations, is the most important challenge facing physicians of many specialties. It is obvious that it can be solved only when you understand clearly the processes governing the development and chronization of pain. Inflammation, a universal adaptive mechanism that always accompanies damage to living tissues, plays a key role. Part 1 of this review considers the main stages of development of an inflammatory response, beginning with primary damage accompanied by the release of molecules acting as an alarm and ending with the deployment of a complete picture of the inflammatory response with the involvement of many cell elements and the overexpression of cytokines and proinflammatory mediators. The biological basis of the peripheral and central nociceptive sensitization phenomenon that is rigidly associated with inflammation is presented. Particular emphasis is placed on the possible natural completion of the inflammatory response, on the adaptive mechanisms regulating this process and on the reasons that prevent this and determines inflammation chronization.

The paper discusses the materials of investigations dealing with falls as an independent risk factor for fractures in patients with rheumatoid arthritis (RA). It gives data on the incidence and possible risk factors of falls in this category of patients. According to the data obtained, the prevalence of falls in different countries varies from 10 to 50%, which may be related to differences in the methods of collecting information, and the relationship of the investigated factors with the risk of falls in patients with RA is uniquely unproven and calls for further investigations.

Behсet's disease (BD) is systemic vasculitis with multiorgan failure. According to the 1990 International Study Group for Behсet's disease (ISGBD) criteria, the main manifestations of the disease include recurrent mouth and genital ulcers; skin and eye lesions. Inflammatory diseases of the eye are diagnosed in 50–70% of patients with BD. Our described case illustrates the late diagnosis of BD in a 13-year-old girl, which led to severe eye disease (significantly decreased visual acuity of the left eye) 2 years after disease onset. The lesion of ocular posterior segments is the pathognomonic sign of BD. This symptom concurrent with other major manifestations of BD (skin and genital lesions) and the ethnicity of the patient (a resident of Dagestan, the region through which there was the Great Silk Road) should have promoted the earlier diagnosis of the disease.