The project of working classification of ankylosing spondylitis is described. New concepts for this disease [e.g., stages of disease (rather than stages of sacroiliitis), extra-axial and extraskeletal manifestations] are proposed and comprehensively interpreted. The main complications of the disease are described. Recommendations for diagnostic formulation are presented.

There has been significant progress in research focused on rheumatoid arthritis (RA) over the past decade. Nine innovative biologics agents – monoclonal antibodies and recombinant proteins inhibiting activity of the key proinflammatory cytokines and pathological activation of T and B cells involved in the development of the immune-inflammatory process – have been designed to treat RA. However, the radical improvement of prognosis in RA patients depends both on launching innovative drugs and refining the treatment strategy. This strategy is based on early diagnosis, which makes it possible to initiate the very early («window of opportunity drug») active and tightly controlled anti-inflammatory therapy aimed at achieving remission as soon as possible (the «Treat to Target» conception). The «Treat to Target» conception formulated by EULAR in 2010 has been widely incorporated in national guidelines on management of RA elaborated in many countries, including Russia. A new edition of EULAR recommendations was prepared in 2013; it has accumulated the scientific progress and clinical experience over the past three years. The publication is aimed at providing the general characteristics of the key provisions in the new recommendations and discussing some disputable problems that have not been solved yet and require further research.

Objective. Background Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis.
Methods. Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372).
Results. The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo:
-0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with
strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated.
Conclusions. Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.
Additional supplementary data are published online only. To view these files please visit the journal online (http://dx.doi. org/10.1136/annrheumdis-2012-202231)

Objective. To evaluate the effectiveness and tolerance of Etanercept (ETN) therapy in patients with rheumatoid arthritis (RA).
Material and Methods. 188 adult patients with severe and moderate RA (average DAS28 score of 6.26±0.89) subcutaneously received 50 mg/wk ETC during 24 wk along with therapy using disease-modifying antirheumatic drugs (DMARDs). The effectiveness was assessed using the EULAR and ACR20/50/70 criteria, dynamics of HAQ, SDAI, CDAI, ESR, and the C-reactive protein level.
Results. By the end of the study, low activity of the disease according to EULAR (DAS28 score ≤ 3.2) was achieved in 31.9% of patients; remission (DAS28 score ≤ 2.6) was achieved in 17% of patients. ACR20/50/70 response was achieved in 72.3; 47.8 and 20.2% of patients, respectively. A decrease in the HAQ index by at least 0.25 points was achieved in 67.5% of patients. The overall EULAR response (moderate and good) was observed in 79.3% of patients; SDAI and CDAI remission/low activity was observed in 52.3 and 52.7% of patients, respectively. Some patients achieved clinical response only by the 25th week of treatment. The originally moderate RA activity and administration of methotrexate are the factors determining higher ETN effectivity in RA patients. The general tolerance of ETN was satisfactory; no uncommon adverse effects were observed.
Conclusions. Analysis of the results of ETN therapy for 6 months attests to high effectiveness of this drug. Its advantages include the rapid clinical effect in most patients and good tolerance. ETN can be recommended for treatment of patients with moderate and severe RA when the conventional DMARDs therapy turns out to be insufficiently effective.

Cardiovascular events caused by early development and rapid progression of atherosclerotic vascular disease are the main reason behind early lethality among patients with systemic lupus erythematosus (SLE). The rapid development of atherosclerosis in patients with this disease is related to the inflammatory nature of SLE and associated with different inflammatory mediators.
Objective. To specify the role of markers and inflammatory mediators (soluble CD40L (sCD40L), soluble tumor necrosis factor α receptors (sTNFα), and neopterin) in the development of atherosclerosis in SLE patients. Materials and Methods. 227 patients (156 females and 71 males) with SLE were examined; median age was 35.6±0.7 years; mean duration of disease was 132.9±7.7 months. The presence of the conventional risk factors (RF) of cardiovascular diseases was determined in SLE patients and control group individuals. Thickening of the intima-media complex and presence of atherosclerotic plaques are signs of atherosclerotic lesion of vessels. The control group consisted of 116 individuals having no rheumatic diseases. Serum concentrations of sCD40L, sTNFα, and neopterin were determined in 187, 193, and 155 SLE patients, respectively, and in 20 control group individuals.
Results. sCD40L, sTNFα, and neopterin levels in SLE patients were higher than those in the control group (p<0.05). sCD40L concentration was associated with age, presence of conventional RFs, cholesterol (CS) level, low-density lipoprotein CS, SLE-related factors (SLEDAI-2K score, duration of disease, subclinical manifestations of atherosclerosis, and presence of ischemic heart disease (p>0.05 in all cases)). A relationship was found between sTNFα concentration and arterial hypertension, systolic and diastolic arterial blood pressure levels, concentrations of triglycerides (TG), high-density lipoprotein CS (HDL CS), apolipoprotein A1, factors associated with SLE (duration of disease, chronic kidney disease, SLEDAI-2K score, and lesion index (p<0.05 in all cases)). No reliable association was detected between the sTNFα and manifestations (clinical and subclinical) of atherosclerosis. A reliable difference was revealed between the sTNFα levels depending on gender: the average sTNFα level in males and females was 5.2±1.1 and 4.2±0.3 ng/ml, respectively (p=0.027). The neopterin level correlated with concentrations of TG, LDL CS, atherogenity index, clinical manifestations of atherosclerosis, and SLE-related factors: SLEDAI-2K score and presence of chronic kidney disease (p<0.05 in all cases).
Conclusions: sCD40L is the key biological marker of atherosclerotic lesions in blood vessels; the increase in its concentration can be used to predict the risk of cardiovascular complications in SLE patients. The results allow one to consider neopterin both as an immunological indicator of autoimmune pathology and as a predictor of atherosclerotic lesions in blood vessels and related cardiovascular catastrophes. The increase in sTNFα can be used as a laboratory marker of the activity of SLE and atherosclerotic vascular disease.

Objective. To assess the changes in clinical, immunological, X-ray indicators and expression of the mTOR (mammalian target of rapamycin) genes, the key regulator of cell growth and proliferation; ULK1 (autophagy marker); р21 (cyclindependent kinase inhibitor); caspase 3 (indicator of apoptotic activity); MMP9 (matrix metalloproteinase 9) and cathepsin K, which participate in joint destruction, and proinflammatory cytokine TNFα (tumor necrosis factor α) in blood of patients with rheumatoid arthritis (RA) receiving methotrexate (MT) therapy.
Materials and Methods. Thirty-three RA patients (21 with positive and 12 with negative rheumatoid factor (RF), respectively; median age, 47.1 years) and 28 healthy volunteers (median age, 45.1 years) were examined. All patients have been receiving MT for 2 years. The clinical response was assessed according to the DAS28 score. ESR and the serum levels of anti-cyclic citrullinated peptide antibodies (ACPA), C-reactive protein (CRP), and RF were also determined. Degenerative changes in the joints were evaluated by X-ray examination. Gene expression was measured in peripheral blood cells using reverse transcriptase reaction and real-time polymerase chain reaction.
Results. MT therapy considerably reduced the disease severity according to DAS28 score, as well as the number of swollen and painful joints both in seropositive (RF+) and seronegative (RF-) RA patients. Ten patients reached remission by the end of the study. In (RF-) RA patients, the absence of progression of joint destruction was accompanied by the absence of any significant changes in expression of MMP9 and cathepsin K, as well as a stronger suppression of TGFα (its expression became comparable to that in the control group). Patients who achieved remission showed a significant decrease in the expression level of the cathepsin K gene as compared to that at the start of the study. In (RF+) RA patients, MT therapy significantly reduced the clinical and immunological indicators; however, the increased number of erosion sites and further joint space narrowing was observed. It was accompanied by a considerable increase in the expression levels of the MMP9, cathepsin K, and TGFα genes as compared to those in healthy individuals.
Conclusions. The changes in expression of the genes responsible for destruction of the hyaline cartilage and bone matrix (MMP9 and cathepsin K) and the TGFα level in blood of RA patients due to MT therapy correlate with the changes in clinical, immunological, and X-ray parameters used to evaluate patient's condition in clinical practice.

Methotrexate (MTX) is the first-line medication to treat rheumatoid arthritis (RA). However, it may have serious adverse effects (AE) on liver, kidneys, hematopoietic system, etc., thus requiring meticulous control over patient’s condition and the dynamics of laboratory indicators. A number of drugs may affect MT pharmacokinetics and increase its toxicity. In theory, proton pump inhibitors (PPIs) may have this effect. Objective. To assess the relationship between the coadministration of MT and PPIs and the risk for developing drug-induced complications.
Material and Methods. A retrospective analysis of clinical symptoms and laboratory indicators in 539 RA patients (median age, 52.5±14.6 years; 86.8% females and 13.2% males) who received MTX in 2009–2011 was carried out. Fifty-two patients who received PPIs on a regular basis were included in the study. The control group consisted of 104 PPI-naive patients comparable in terms of gender, age, and therapy. The numbers of patients with increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), alkaline phosphatase (ALP); anemia (hemoglobin level < 110 g/l in females and <120 g/l in males), leukopenia (<4.0•109/l), elevated creatinine level, and proteinurea (qualitative and quantitative values) were compared.
Results. No significant intergroup differences were revealed. MTX showed no clinically manifested AE. The odds ratio (OR) and 95% confidence interval (CI) for changes in laboratory indicators were as follows: ALT 1.35 (95% CI 0.22–8.32), AST 0.66 (95% CI 0.13–3.38), ALP 0.98 (95% CI 0.955–1.01), anemia 1.19 (95% CI 0.517–2.71), and proteinurea 1.95 (95% CI 0.83–4.59; р=0.17). A small increase in the creatinine level was observed in one case for each group.
Conclusions. The results showed no significant increase in toxicity when low doses of MTX and PPIs were coadministered in RA patients. There was a trend towards more frequent proteinurea in patients who received both drugs. This fact requires further research.

Objective. To study the effect of infliximab (INF) on serum levels of RANKL and osteoprotegerin (OPG), as well as on structural and functional properties of the vascular wall in patients with rheumatoid arthritis (RA).
Material and Methods. A total of 79 RA patients who corresponded to the classification criteria ACR (1987) or ACR/EULAR (2010) and were seronegative for IgM rheumatoid factor (RF) were examined. The mean age of patients was 43.6±8.5 years. The serum levels of OPG and RANKL were determined by ELISA (Biomedica, Austria); the common carotid arteries (CCAs) were visualized using an Acuson X/10 ultrasonic complex equipped with a 7 MHz linear sensor in the β-mode prior to therapy and after 12-month therapy with INF.
Results and Discussion. An increased OPG level was observed mostly in patients with RA duration up to 1 year; an increase in RANKL level was pronounced stronger in patients with PA duration over 2 years. The disturbance of structural and functional properties of the arterial bloodstream was revealed, manifesting itself as an increase in the intimamedia complex thickness, diameter and rigidity index of CCA that were stronger pronounced in patients with late onset RA. A correlation analysis showed the presence of reliable relationship between the RANKL and OPG levels and CCA remodeling parameters. INF therapy showed high clinical effectiveness and correction effect on the RANKL/OPG system. In addition, it was accompanied by a reduction of signs of CCA remodeling, which was stronger pronounced in patients with early RA.
Conclusion. The results prove the reasonability of using INF at early stages of RA in order to optimize the therapy and achieve more efficient control of cardiovascular complications.

Objective. To study the association between the clinical manifestations and work ability in patients with rheumatoid arthritis (RA) and to elaborate mathematical methods for predicting work productivity indicators according to the evaluation of the functional status of patients and disease activity.
Material and Methods. A total of 185 RA patients were examined; 105 of them were employed. The mean age was 48.2±11.3 years; RA duration was 77.9±70.7 months; DAS28 4.68±1.53; visual analogue scale (VAS) score was 40.6±22.2; HAQ was 1.3±0.7. The employed patients in the test group had a longer duration but weaker activity of RA according to DAS28 as compared to those in the control group (p<0.05). The WPAI indicators in the test and control groups, respectively, were as follows: presenteeism – 39.0±26.3 vs. 57.9±16.8%; total productivity decrease (TPD) – 54.6±34.1 vs. 65.2±23.3%; daily activity (DA) – 52.3±26.3 vs. 55.3±14.8%. The multiple regression method was used to create prognostic equations. A significant divergence of the distribution of absenteeism rates from the normal distribution prevented selection of regression equations.
Results. HAQ, VAS pain, and DAS28 turned out to be optimal for selecting equations. The Spearman correlation coefficients with WPAI indicators were higher than 0.4 in all the cases. The following prognostic equations were obtained:
Presenteeism (%) = 0.66 + 11.31 • HAQ + 0.44 • VAS pain + 2.17 • DAS28 (R2 = 0.46),
TPD (%) = 8.53 + 3.90 • HAQ + 0.47 • VAS pain + 4.73 • DAS28 (R2 = 0.28),
DA (%) = 11.27 + 11.87 • HAQ + 0.36 • VAS pain + 1.96 • DAS28 (R2 = 0.44).
Verification of the predicted WPAI values using the data of an additional group has demonstrated the coincidence of the predicted and actual values for presenteeism and TPD. However, the correlation coefficient between the predicted and actual presenteeism indicators was considerably higher (0.68 vs. 0.51). The predicated DA differed considerably from the actual ones.
Conclusion. Multiple regression analysis was used to obtain and verify the prognostic equations for presenteeism, TPD, and DA. The resulting regression equation for calculating presenteeism is characterized by sufficient significance for predicting this indicator in RA patients. HAQ and RA duration (months) are the most significant variables for predicting work ability.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease causing joint dysfunction; reduction of quality of life (QoL); loss of work ability, self-care ability, and executing daily routines in most patients 5–10 years after the disease onset.
Objective. To study QoL and the functional status (FS) of Russian RA patients receiving tocilizumab (TCZ).
Material and Methods. The study involved 42 patients with verified RA diagnosis (moderate or high activity) who had earlier undergone inefficient therapy with basic anti-inflammatory medications. The limitation of the FS of the RA patients was determined quantitatively using the Russian-language version of the HAQ questionnaire. QoL was evaluated using the EuroQol-5D (EQ-5D) Quality of Life questionnaire prior to treatment and after 4, 8, 12, 16, 20, and 24 weeks.
Results. TCZ therapy demonstrated a rapid improvement of the FS of RA patients with a 64% decrease in the HAQ index (ΔHAQ=1.12), which corresponded to a 50% improvement of the health status of patients according to the ACR criteria.
The median value [25th; 75th percentile] of the EQ-5D index was 0.52 [-0.02; 0.52]; 27.7% patients assessed their QoL as “worse than death”. The index reliably increased by week 8 of therapy; there were no patients with the negative EQ-5D index by week 24. Depending on QoL, all the patients were subdivided into two groups. Group 1 (n=12) comprised the patients with the EQ-5D no higher than 0; in group 2 patients (n=30), it was higher than 0. The groups were comparable in terms of disease duration, age, disease activity indices, and the previous treatment. The low QoL index in all 12 patients in group 1 was attributed to the infeasibility of performing daily activities and the reliably higher pain level (75.0 [61.0; 86.0] and 66.0 [48.0; 71.0] in groups 1 and 2, respectively; p=0.02). Improved QoL and reduced pain level were observed in both groups as early as after the first TCZ infusion. By week 24, the pain level decreased to 26.5 [11.0; 24.0] and 10.0 [2.0; 31.0] in groups 1 and 2, respectively. The EQ-5D index in group 1 became positive by week 8 of therapy.
Conclusion. TCZ therapy quickly improves the FS and QoL of RA patients, including those with the most severe condition.

The history of treatment of ankylosing spondylitis (AS) and the reasons behind the development of modern approaches to its therapy are briefly described. The main tasks and principles of non-pharmacological and drug therapies for AS
are briefly reported. The need for therapeutic physical training is emphasized, since its role in maintaining the functional status in this group of patients has been proved. The lecture casts doubt on effectiveness of physiotherapy and
other physical techniques because of the poor evidence base. The lecture emphasizes the disease-modifying role of nonsteroidal anti-inflammatory drugs and requirement to receive them constantly for patients with Bechterew's disease. Meanwhile, the basic anti-inflammatory drugs in patients with this disease are reported to play an auxiliary role and to have no effect on disease progression. The pronounced clinical effectiveness of all tumor necrosis factor α inhibitors is emphasized; certain differences in their therapeutical effect are described. The problems of surgical treatment, which deal with correction of disease complications or undesirable effects, are discussed.

Osteoarthritis (OA) is one of the most common diseases, pain and joint dysfunction being its main symptoms. Although OA is a progressive disease causing disability, rapid progression is observed only in some patients. According to the data obtained by different authors, the progressive course of gonarthrosis is typical of 34–55% patients, which is likely to be attributed to variability of the risk factors of disease progression that every single patient has. As the reasons behind OA progression have been studied more thoroughly, the notion of the disease pathogenesis has recently changed. While articular cartilage lesion was considered to be the main reason and the joint space narrowing and concomitant changes in the subchondral bone (SCB) were regarded as a secondary process SCB is now believed to play the initiating role in disease evolution. It was found that acceleration of metabolic processes in SCB in OA patients causes incomplete mineralization of bone and reduces its biomechanical properties. These data initiated the search for new approaches to therapy for OA. A large number of medications that are potentially able to inhibit disease progression are being actively studied. Special attention is paid to the agents affecting the processes of bone tissue remodeling. In addition to bisphosphonates and calcitonin (whose effectiveness in treating OA has been studied over the past decades), much attention has recently been paid to strontium derivatives, in particular, to strontium ranelate (SR). It has been proved that SR stimulates preosteoblast replication, osteoblast differentiation, type 1 collagen synthesis, and mineralization of bone matrix. Meanwhile, SR inhibits osteoclast differentiation and activity, resulting in the reduction of SCB resorption, which is a potentially significant effect in OA therapy. In addition to its effect on SCB, SR can influence the bone tissue. It was
found during the studies that SR reliably enhances the formation of bone matrix (namely, synthesis of high molecular weight proteoglycans) both in the normal articular cartilage and in patients with OA. The symptomatic effect of SR has been demonstrated in clinical trials. A reliable deceleration of joint space narrowing in patients who received SR therapy (compared to those who received placebo) has also been proved.

The data showing an association between gout and hyperuricemia with renal failure, arterial hypertension, metabolic syndrome, type 2 diabetes mellitus, and ischemic heart disease are reported. The data on the role of gout and comorbid conditions as independent risk factors of developing atherosclerosis and cardiovascular catastrophes are presented. Furthermore, the effect of drug therapy for gout on the risk of developing comorbid conditions and cardiovascular
catastrophes is discussed.

Periprosthetic infection (PI) in patients with rheumatoid diseases (RD) after total hip joint endoprosthesis (THJE) is a relevant problem of rheumoorphopedics that has not been solved yet. The relative assessment of PI incidence rate after THJE and treatment outcomes in patients with this complication is expected to be carried out. A total of 1201 THJE performed in 1069 patients with RD are considered. The female : male ratio was 3.6 : 1; the mean age was 49.6 years (range: 16 to 83 years). 323 patients had rheumatoid arthritis (RA); 124 patients had juvenile rheumatoid arthritis (JRA); 80 patients had ankylosing spondylitis (AS); 79 patients had systemic lupus erythematosus (SLE); 11 patients had systemic sclerodermatitis (SSD); 18 patients had psoriatic arthropathy (PsA); and 353 patients had osteoarthritis (OA). Other RD were revealed in 81 patients. PI were detected in 9 (0.84%) of 1069 patients with RD, including 7 (2.17%) of 323 patients with RA; 1 (0.8%) of 124 patients with JRA; and 1 (0.28%) of 353 patients with OA. No PI were detected in 81 patients who had other RD. An eightfold (in patients with RA) and a threefold (in patients with JRA) increase in PI compared to that in patients with OA attests to the high risk of this complication in patients with inflammatory as compared to the patients with degenerative RD. After integrated treatment (revision surgery, sanation, continuous irrigation with antibiotics/lavasept), the graft was preserved in OA patients; the complication was prevented in RA patients. Six patients will be subjected to repeated revision surgery; one patient died of diabetes complications after the graft had been removed. A significant increase in PI incidence rate after THJE in patients with RA and JRA as compared to that in OA patients allows one to regard inflammatory RD as risk factors of this complication. The low effectiveness of the procedure for integrated therapy for PI in RD patients indicates that it needs to be modernized.

Radiosynoviorthesis (RSO), also known as radiosynovectomy, is an approved method of treatment for inflammatory joint disorders that is commonly used both in the industrialized American and European countries as well as in the developing Asian and African countries. In terms of frequency of its use, this method ranks second among all the methods for radionuclide therapy in Germany. The treatment includes intra-articular administration of radiopharmaceuticals as microparticles (colloidal forms, macroaggregates, or microspheres) containing radioactive isotopes, which are rapidly phagocytized by the synovial membrane cells. Indications for therapy include inflammatory joint disorders of different genesis: rheumatoid arthritis, psoriatic arthritis, osteoarthritis and intra-articular effusion after joint endoprosthetics. RSO is the optimal method for local therapy for arthritis in patients with hemophilic arthropathy, since it both heals the inflammation and reduces the frequency of bleeding relapses. This aspect is of particular significance for the developing countries where the disease is often complicated by arthropathies due to the lack of coagulation factor. The main advantages include the low frequency of undesired reactions and low radiation burden to a patient. Depending on the degree to which a joint is affected, the frequency of responses to therapy is 50–80%, reaching 90% in patients with hemophilic arthropathy.

Weber-Christian disease (WCD), also known as idiopathic lobular panniculitis, is a rare disease belonging to the group of diffuse connective tissue diseases. No therapy for WCD has been developed; empirical treatment is typically used. The first description of the use of tumor necrosis factor α inhibitors in a female patient with infiltrative WCD is presented. The tactics of managing this patient category are analyzed.

The article focuses on the problem of secondary ineffectiveness of tumor necrosis factor α infliximab (INF) and describes an attempt of using plasmapheresis (PF) to eliminate this problem in a patient with ankylosing spondylitis who had received INF treatment at a dose of 5 mg/kg for a long time (over 4 years). After PF, the IFF therapy ensured a long-term clinical and laboratory improvement of patient's condition. One can assume that PF made it possible to overcome secondary ineffectiveness of INF and can be used in some patients in cases when INF cannot be replaced with another TNFα inhibitor.