The clinical analysis of the results of genetically engineered biological therapy identifies a number of patterns of the mechanism of action of this therapy and the pathogenetic features of rheumatic diseases. The results of using genetically engineered biological agents (GEBA) having different mechanisms of action allow one to identify categories of rheumatoid arthritis patients with different pathogenetic features. Various cytokines can play a major pathogenic role in a clinically similar inflammatory process. The therapeutic effect of tumor necrosis factor-α (TNF-α) inhibitors exhibits the predominance of their nonspecific anti-inflammatory activity over the immunosuppressive one. Contrary to the previous ideas of cytokine hierarchy, TNF-α neutralization does not block the effects of interleukin 6 (IL-6). Anti-B-cell therapy is most effective in patients with significant autoimmune disorders; a contrary pattern is observed when TNF-α inhibitors are used. TNF-α is very important in the development of an inflammatory process in ankylosing spondylitis (AS) while the role of IL6 is insignificant. Autoimmune disorders in AS are not marked; whereby predominantly immunotropic GEBAs (rituximab and abatacept) are ineffective in this disease. The blocking of a biological reaction to inflammation cannot coincide with the suppression of the inflammatory process proper.

Objective: The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials
report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe
the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis.

Research design, methods, and results: This double-blind, placebo-controlled trial (98 centres, 18 countries) includes ambulatory Caucasian men and women aged ≥50 years with primary knee osteoarthritis of the medial tibiofemoral
compartment (Kellgren and Lawrence grade 2 or 3), joint space width (JSW) 2.5 to 5 mm, and knee pain on most days in the previous month (intensity ≥40 mm on a visual analogue scale). Patients are randomly allocated to three groups (strontium ranelate 1 or 2g/day, or placebo). Follow-up is expected to last 3 years. The primary endpoint is radiographic change in JSW from baseline in each group versus placebo. The main clinical secondary endpoint is WOMAC score at the knee. Safety is assessed at every visit. It is estimated that 1600 patients are required to establish statistical significance with power >90% (0.2 mm ±10% between-group difference in change in JSW over 3 years). Recruitment started in April 2006. The results are expected in spring 2012.

Clinical trial registration: The trial is registered on www.controlled-trials.com (number ISRCTN41323372).

Conclusions: This randomised, double blind, placebo-controlled study will establish the potential of strontium ranelate in improving structure and symptoms in patients with knee osteoarthritis.

The diagnosis of enthesitis can help in differentiating early psoriatic arthritis (ePsA) from early rheumatoid arthritis (eRA).

Objective. To estimate the diagnostic value of detecting enthesitis during clinical examination and ultrasound in ePsA and eRA.

Subjects and methods. The trial included 36 patients with ePsA and 33 with eRA. Entheses were evaluated using the Leeds Enthesitis Index (LEI): lateral humeral epicondyle and medial femoral condyle (MFC), Achilles tendon insertion site (ATAP), and plantar fascia (PF) point on the right and on the left. Enthesitis (on ultrasound) presented with thickening, reduced echo density, and vascularization at Doppler energy imaging. DAS, DAS28, SDAI, CDAI, M±SD, Me [25th, 75th percentile], t-test, Fisher's exact test, χ2test, U test, and Spearman correlation coefficients (R) were calculated; the value p < 0.05 was considered statistically significant.

Results. Clinical examination revealed enthesitis in 41.6% of the patients with ePsA and in 39.4% of those with eRA (p >0.05). No significant differences were found between ePsA and eRA according to LEI (0.5 [0; 2] and 1 [0; 2] and to LEI+PF (1 [0; 2] and 1 [0; 2], respectively). Enthesitis of MFC and PF was significantly more frequently detected in ePsA than in eRA – 12 (33.3%)/2 (6.1%) and 10 (27.8%)/2 (6.1%) patients, respectively. In eRA versus ePsA, enthesitis of MFC was more frequently found (16 (48.4%) and 8 (22.2%) patients), respectively. Ultrasound revealed no significant differences between the groups in enthesitis. In ePsA, there was a significant correlation between DAS, DAS28, SDAI, CDAI, LEI, and LEI+PF.

Conclusion. Enthesis ultrasound cannot differentiate ePsA from eRA. Clinical examination more frequently detects enthesitis in the knee joints in eRA and in the calcaneal region in ePsA.

Objective: to study the association of ultrasound (US) remission criteria with the clinical and laboratory indicators of inflammatory activity, functional status, and X-ray changes in patients with rheumatoid arthritis (RA) during tocilizumab (TCZ) therapy.

Subjects and methods. The trial included 36 patients with RA (meeting the 1987 American College of Rheumatology (ACR) criteria) who had received TCZ for 6 months. The authors made a clinical and laboratory assessment of RA activity (DAS28-CRP, and SDAI), functional impairments (HAQ index) and US verification of wrist joint synovitis (a Voluson-i device, GE, 4-13-MHz linear transducer) at baseline and 6 months after therapy. No signs of grey-scale (B-mode) and power Doppler (PD) synovitis (B = 0; PD = 0) or minimal B-mode synovitis, and not more one PD hypervascular signal (В ≤1; PD ≤1) were arbitrarily taken as US remission criteria. Destruction changes were evaluated by hand and foot X-ray using the Sharp method modified by van der Heijde (SHS).

Results. After 6 months of therapy, about 80% of the patients in clinical remission retained moderate or significant synovitis, as evidenced by US studies. There were no clinical differences in clinical activity indices and functional impairments between the patients who were and were not in US remission (p > 0.05). The 12-month follow-up SHS score was significantly higher with the preservation of 6-month therapy signs of B-mode synovitis and PD hypervascularization (of not more than one signal) than that in US remission (p < 0.05). There was no relationship of X-ray progression to the clinical and functional statuses (p > 0.05).

Conclusion. Subclinical synovitis is observed even in clinical remission of RA. Destruction progression is significantly
related to synovitis persistence, as shown by ultrasonography.

Objective: to investigate the levels of cytokines in patients with systemic lupus erythematous (SLE) and to determine their correlation with SLE activity and organ damage, as well as their changes during rituximab (RTM) therapy.

Subjects and methods. The trial enrolled 26 patients (5 men and 21 women) with a median (Me) age of 27 [range 23-40] years and a SLE duration of 9 to 300 months (Me 72 [range 36-108] months and 30 healthy donors marched with
the examinees for gender and age. Disease activity was assessed using the SLEDAI-2K index. The serum levels of 27 cytokines were measured utilizing X-MAP technologies on a BioPlex 200 device (Bio-Rad, USA). The patients were divided into 2 groups of 13 persons in each: lupus nephritis (LN) and no renal injury. All the patients included in the trial received RTM therapy.

Results. A statistically significant elevation in the concentrations of interleukin 13 (IL-13) and G-CSF was found in the patients with SLE versus the healthy control group (p = 0.03 and p = 0.03, respectively). The LN group displayed a statistically significant increase in the concentrations of IL-4, IL-6, IL-7, IL-13, and G-CSF as compared with the non-LN group (р = 0.039, р = 0.03, р = 0.037, р = 0.03, and р = 0.028, respectively). ROC analysis established the sensitivity and specificity of all indices in the LN group. The area under the ROC curve was equal for all indicators. The highest specificity of IL-13 (85%) was observed in the LN group. These cytokines other than that of IL13 (62%) showed the same sensitivity (70%).

Conclusion. The patients with LN had statistically significantly elevated concentrations of IL4, IL6, IL7, IL13, and G-CSF. The findings suggest that these cytokines are associated with VN.

Objective: to study the efficiency and tolerance of rituximab (RTM) treatment in patients with scleroderma systematica (SDS) with interstitial lung injury (ILI).

Subjects and methods. The trial included 27 patients (26 women and 1 man) (mean age 45.7±13.0 years), with diffuse (n=13) and circumscribed (n = 14) forms and a disease duration of > 5 years in 63%. All the patients underwent chest
computed tomography; examination of external respiratory function, including forced vital capacity (FVC) and diffusing capacity of the lung (DCL), as well as echocardiographic study. The efficiency of the treatment was evaluated from changes in FVC, skin score, and disease activity index. The indicators were compared prior to the treatment and one year after the first administration of RTM. The latter was injected with premedication (125–500 mg of methylprednisolone intravenously) 500–1000 mg per administration. The mean dose of RTM was low and amounted to 1.3 g per year.

Results. As estimated by the physician, good, satisfactory, no effects were seen in 81.5, 14.8, and 3.7% of the patients, respectively. There was a significant increase in mean FVC one year after the first administration of RTM and a reduction in the total activity of the disease, including skin syndrome. DCL was substantially unchanged in the entire group. In the diffuse and circumscribed forms of the disease, FVC increased significantly and to the same extent. A clinically significant increase in FVC (by 11%) was achieved in patients with a disease duration of ≤5 years and mild lung injury. In people with a more than 5-year disease duration, FVC was initially decreased to a greater extent and the treatment-induced increase was only 3.7%. A significant and permanent decline in peripheral blood B lymphocytes was noted when both the standard dose (2 g) of RTM and its lower doses (0.5–1 g) were administered. RTM treatment was well tolerated, but complicated by mild intercurrent infections in 11% of cases within the first 2 months after RTM administration.

Conclusion. The findings substantiate the indications for RTM use primarily in the early stage of the disease. The admittedly low doses of RTM have an inadequate effect if the disease is long-lasting. Further study of dosage regimens
for RTM is required within the framework of controlled trials.

Osteoarthrosis is the most common rheumatic disease and occurs in more than 50% of all rheumatic patients. These patients are diagnosed and treated by rheumatologists, orthopedists, and neurologists in the primary health care of
Bulgaria. The problems in these patients are primarily encountered by general practitioners (family physicians) who estimate the need for specialized medical care. The paper considers the organizational aspects of primary medical care
for patients with ostheoarthosis. Six-year data are analyzed.

Osteoarthrosis (OA) is one of the most common causes of hand pains, leading to lower quality of life (QL). In addition to pain and functional impairment, the patients' aesthetic dissatisfaction that cannot be now determined or measured
is of prime importance

Objective: to assess a number of QL aspects and to measure the level of aesthetic discomfort in patients with hand OA.

Subjects and methods. Sixty women aged 45–75 years with hand OA were included. The number of painful and deformed joints was determined and functional impairments were evaluated using the AUSCAN questionnaire. The patients filled out the questionnaire to determine the level of dissatisfaction with the appearance of their hands; the Ellis stress test for irrational beliefs was carried out.

Results. The patients with hand OA were found to have significant aesthetic discomfort comparable with level of joint pain. Deformity phobia in the future and external discomfort because of hand deformity were most pronounced; a wish for surgical correction was less pronounced. Comparison of the results obtained in different age groups determined the highest levels of anxiety and wish for surgical correction in younger women. The patients' aesthetic dissatisfaction was also influenced by employment and internet usage.

Conclusion. Aesthetic discomfort is an important component of lower QL in patients with hand OA. Further investigation of this factor and elaboration of criteria for its estimation are needed.

Objective: to evaluate the symptom- and structure-modifying effect of alflutop versus placebo (PL) in patients with knee osteoarthrosis (OA).

Subjects and methods. The trial enrolled 90 patients with knee OA (ACR criteria and Kellgren–Lawrence Stages II–III) and pain on walking ≥ 40 mm on a visual analogue scale (VAS) who signed their informed consent. The patients were randomly assigned to two groups: 1) 45 patients who received alflutop as 1-ml intramuscular injections for a 20-day cycle at a 6-month interval for 2 years (a total of 4 cycles during 2 years); 2) 45 patients who were given PL (isotonic sodium chloride) injections following the same pattern. As concomitant therapy ibuprofen was used in a dose of 600–1200 mg/day. The efficiency of treatment was evaluated using the OMERACT-OARSI criteria, changes in the three scales WOMAC, EQ-5D, pain and general health status (GHS) on VAS; 15-m walking time, and therapeutic efficiency assessment by the physician and patient. At the beginning and at the end of the investigation, knee joint X-ray and magnetic resonance imaging were performed and the time course of changes in the level of biochemical markers (CTX-II and COMP) was determined to evaluate the structure-modifying effect of alflutop. Adverse reactions were recorded at each visit. A Statistica 10.0 data package was used for statistical analysis.

Results. At the end of the trial, the use of aflutop versus PL showed a significant pain reduction in an intent-to-treat population (p=0.003). Analysis of a per protocol population indicated that the pain reduction was more marked in the aflutop group. WOMAC showed that the differences between the groups in the absolute value of pain intensity reduction were significant. A significance stiffness reduction was seen in the alflutop group at Visit 3; no significant decrease was found in the PL group (p < 0.001). Improvements in joint function and reduction in joint WOMAC index were noted in the alflutop group after the first cycle of therapy and these remained throughout the follow-up (p = 0.001). At Visit 6, significantly better quality of life was observed only in the alflutop group (p = 0.0045). Analysis of the GHS scale revealed that the differences between the groups were significant (p = 0.03). In the alflutop and PL groups, the therapy respondents were 73 and 40%, (p = 0.001). Among the alflutop-treated patients, 79% reduced the daily dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and 21% completely discontinued using them. In the PL group, only 23% needed daily lower intake of NSAIDs.

Conclusion. The double-blind randomized placebo-controlled trial established the symptom-modifying effect of alflutop in patients with knee OA.

In 1980, the American College of Rheumatology proposed the first criteria as tentative for the diagnosis of scleroderma systematica (SDS). These criteria were aimed at revealing the comprehensive picture of mainly the diffuse form of the disease. They could not timely make a diagnosis in the low manifestive forms of the disease or virtually reveal its early stages that were most therapeutically promising. The review traces the evolution of approaches to diagnosing SDS and considers the novel classification criteria elaborated to select patients for epidemiological surveys and clinical trials. They include 8 parameters, each having scores. Skin thickening on both hands above the metacarpophalangeal articulations was highest (9 scores). The clinical variants of skin thickening on the fingers as its swelling (2 scores) or sclerodactyly (4 scores) are estimated from the maximum scores, as digital ischemia (sores, 2 scores; cicatricles, 3 scores). Teleangiectasias and characteristic capillaroscopic changes, as well as leading lung injury (pulmonary hypertension and/or interstitial lung disease) are rated as 2 scores each. Three scores are added to the total amount when Raynaud's syndrome is present and SDS-specific (anti-Scl-70, anti-centromere, and anti- RNA polymerase III) autoantibodies are detected. The patients gaining a total of 9 scores or more are classified as having definite SDS. Testing the novel criteria on a validation sample of 405 people showed that their sensitivity and specificity were 91 and 92%, respectively.

As of now, there have been notable advances in treating immune inflammatory rheumatic diseases, which are associated with the interpretation of basic pathogenetic mechanisms of their development. The most well studied therapeutic targets are tumor necrosis factor-α, interleukin (IL)-6 and IL-1; inhibition of these cytokines with genetically engineered biological agents is not always clinically effective and rarely gives rise to remission. The new promising treatment of rheumatoid arthritis (RA) and other inflammatory arthritides is linked to the inhibition of IL-17A, a proinflammatory cytokine, involved in the development of inflammation and in the destruction of bone tissue. The paper summarizes new evidence for the prospects of using anti-interleukin-17 monoclonal antibodies to treat RA.

Osteoporosis (OP) is a frequent complication of ankylosing spondylitis (AS). The risk factors of OP in AS are permanent inflammatory activity, disease duration, patient immobilization, and vitamin D deficiency. Proinflammatory cytokines that favor osteoclustogenesis play a fundamental role in the pathogenesis of bone resorption in AS. The problem of OP in AS cannot be viewed in isolation from bone metabolism as a whole and from the processes of pathological osteogenesis. Ankylosis-induced spine rigidity concurrent with vertebral body OP increases the risk of spinal fractures in patients with AS. Osteogenesis in AS leads to overestimation of the results obtained by dual-energy X-ray absorptiometry (DXA) when determining lumbar bone mineral density (BMD). Lateral DXA scanning of the spine is a more sensitive technique for BMD estimation. The early use of tumor necrosis factor-α inhibitors is able to prevent OP in patients with AS.

The paper analyzes the results of an investigation into the relationship between Behcet's disease (BB) and mental disorders. It establishes the importance of an emotional stress factor for developing the clinical symptoms and disease. In its turn, the systemic immune inflammatory disease and its complications become a source of mental disorders. The literature describes different variants of BB, but anxiety-depressive spectrum disorders and moderate cognitive impairments are most common. The presence of depression contributes significantly to lower quality of life in patients with BB.

The paper gives data on the epidemiology and risk factors of gout. It considers remission and transition of the disease to its chronic form as possible outcomes of the disease and presents data on its progression and the impact of drug
therapy on the course of the disease.

Acetylsalicylic acid that has long widely used in rheumatoid arthritis and condemned by rheumatologists to oblivion since the late 20th century and it may take its rightful place in the treatment of both rheumatoid arthritis and other rheumatic diseases.

IgG4-related diseases are a new nosological entity that encompasses a few previously known diseases. IgG4-related systemic disease is diagnosed if two or more affected organs are detected. This group of diseases has two similar signs: serological (elevated serum IgG4 subclass concentrations) and histological (organ and tissue infiltration from plasmo-cytes secreting IgG4, and eosinophils, and the development of fibrosclerosis and phlebitis obliterans). The paper describes two cases. In one case, a multisystemic disease was observed virtually at its onset whereas in the other this lesion was diagnosed several years after the natural course of the disease.

Spinal injury in gout occurs rarely at a young age. In the past 5 years, the Pubmed has published only 44 papers on this site of tophi mainly in gouty patients over 40 years of age. We report two such cases in patients with chronic tophaceous gout in a 28-year-old man with a 3-year history of gout and in a 30-year-old man with its 7-year history. In both cases, spinal injury with tophus masses gave rise to neurological symptomatology. Computed tomography and magnetic resonance imaging were of informative value in identifying the causes of pain. In one case, the patient underwent laminectomy; histological evidence confirmed the gouty genesis of spinal injury.

An annual European Congress of Rheumatology took place from 12–15 June 2013 in Madrid. The Congress program was extremely diverse; it included discussion of new evidence on the diagnosis and treatment of the most common
rheumatic diseases, their etiology and pathogenesis, personified therapy and more. The optimization of pharmacotherapy for rheumatoid arthritis (RA) and the choice of therapy strategy in different groups of patents occupied a
central place at the Congress. New guidelines for the management of patients with RA were given. A number of reports concerned the efficiency and safety of using tocilizumab in RA, the possibility of discontinuing therapy with genetically engineered biological agents (GEBAs) when achieving a remission, and the maintenance of drug-free remission in RA. The Congress discussed the new results of the AMPLE trial, one of the first direct comparative studies of the efficacy of two GEBAs (subcutaneous formulations of abatacept and adalimumab). A large number of reports dealt with the use of tumor necrosis factor-α inhibitors, the evaluation of their immunogenicity, the analysis of reasons for therapy discontinuation, as well as adverse reactions occurring during treatment. Some aspects of therapy with conventional disease-modifying anti-rheumatic drugs were discussed. Thus, a lot of new data that can optimize therapy for a common rheumatic disease, such as RA, were presented at the Congress.