Digestive comorbidity is a serious problem that significantly aggravates the course of rheumatic diseases. Diseases of the gastrointestinal tract (GIT), liver, and pancreatobiliary system may present a threat to life and substantially worsen its quality. The incidence of many digestive diseases, such as gastric ulcer (including its complicated forms), cholelithiasis, and acute pancreatitis, in patients with rheumatic diseases (at least in those with rheumatoid arthritis) is considerably higher than in the population. The presence of this comorbidity poses substantial challenges during active anti-rheumatic therapy. Rheumatologists are very familiar with issues in the prevention of GIT complications due to the use of nonsteroidal anti-inflammatory drugs. However, new time presents new challenges. The widespread use of immunosuppressive agents and biologic agents requires careful monitoring of complications associated with liver and bowel diseases. This review considers a relationship of rheumatic diseases and anti-rheumatic therapy to comorbidities, such as cholelithiasis, acute pancreatitis, viral hepatitis B and C, and intestinal diverticula. 

New international guidelines for the diagnosis and treatment of systemic vasculitis involving large vessels, which had resulted from the systematic generalization of current scientific achievements and clinical experience, were published in 2015. The experts of the French Large Vessel Vasculitis Study Group have elaborated 15 recommendations covering a wide range of problems of giant cell arteritis; the European League Against Rheumatism and the American College of Rheumatology have presented 9 recommendations for the management of polymyalgia rheumatica. The purpose of this paper is to provide common characteristics of the main points of the new guidelines, by discussing some controversial issues. 

Diagnosis of acute rheumatic fever.

Objective: to determine the incidence and risk factors of venous thromboembolic events (VTEE) in patients with rheumatoid arthritis (RA).

Subjects and methods. The investigation enrolled 362 patients (302 women and 60 men) with RA fulfilling the 2010 American College of Rheumatology/European League Against Rheumatism criteria. The patients' mean age was 53.7±13.3 years; the disease duration was 12.4±10.9 years. All the patients were treated at the V.A. Nasonova Research Institute of Rheumatology in the period 2014 to 2015. Each patient underwent standard clinical examination of peripheral joints. RA activity was assessed with DAS28. There was a questionnaire survey that included traditional risk factors for VTEE and risk factors that might be due to RA and its therapy.

Results and discussion. 34 (9.9%) patients were found to have VTEE during their hospitalization or in their history. In 32 of them thromboses were located in the veins of the lower extremities, namely 18 and 14 patients had thromboses in the distal and proximal segments, respectively. One patient was recorded to have upper extremity vein thrombosis and another had central retinal vein thrombosis. Lower extremity deep vein thrombosis was complicated by pulmonary thromboembolism in one case. Multivariate analysis has shown that the risk factors of VTEE in RA patients are bed care, heart failure, varicose vein disease, and oral administration of glucocorticoids (GC) and intraarticular GC administration (>5 injections); the weighted coefficients of the risk factors are 1.0, 0.92, 3.13, 0.02, and 0.52, respectively. According to the model obtained (p < 0.0001), the risk of VTEE can be predicted using the following formula: Z = 1.0 × bed care (yes, 1 / no, 0) + 0.92 × heart failure (yes, 1 / no, 0) + 3.13 × varicose vein disease (yes, 1 / no, 0) + 0.02 × oral GC use (yes, 1 / no, 0) + 0.52 × intraarticular GC administration (>5 injections; yes, 1 / none, 0).

Conclusion. The risk of VTEE should be assessed to timely prescribe adequate prophylactic treatment and to prevent thrombotic events in RA. The classification function value Z = 1.65 identifies groups of patients at high and low risk for VTEE. Accordingly, the value Z >1.65 determines the high risk of thrombosis; in this case it has a sensitivity of 64%, a specificity of 82%, and a positive prognostic accuracy of 80%.

Objective: to reveal irreversible organ damages and to establish factors that influence their development in a RENAISSANCE cohort of patients with systemic lupus erythematosus (SLE) admitted to the clinic of the V.A. Nasonova Research Institute of Rheumatology in the period 2012 to 2014.

Subjects and methods. The investigation enrolled 231 young (mean age, 34.91±11.10 years) patients (209 women and 22 men) with a mean SLE duration of 107.65±97.36 months. On admission of the patients, the investigators collected history data (disease duration, the number of exacerbations and hospitalizations during the follow-up period), assessed current disease activity by SLEDAI-2K, irreversible organ damages by SLICC damage index (DI), and the therapy performed.

Results and discussion. Irreversible organ damages were absent in 95 (41%) patients; one or more damages associated with both disease itself and the therapy were observed in the other (59%) patients. There were low (1), mean (2–4), and high (>4) SLICC DI values in 64 (28%), 62 (27%), and 11 (5%) patients, respectively. Ocular lesions were most common (35%); a significant proportion of patients were found to have damages to the cardiovascular (22%), musculoskeletal (19%), and nervous (10%) systems. Lung disease, diabetes mellitus, and cancer were less prevalent (6.0, 3.4, and 1.3%, respectively). The patients with damages were significantly older (p = 0.02), had a longer disease duration (p = 0.0005) and more frequent SLE exacerbations and hospitalizations (p = 0.0003 and p = 0.001, respectively). The patients with DI ≥1 received glucocorticoids (GCs) longer (p = 0.001). At the onset of SLE they had significantly higher doses of GCs (mean 44.06±18.97 mg) than those without damages (35.91±20.12 mg; р = 0.002). DI correlated with GC doses at the onset of the disease, duration of GC use, number of hospitalizations and exacerbations. There was also a statistically significant correlation of overall SLICC DI with the duration of disease (r = 0.23) and the total dose of cyclophosphamide (CP) (r = 0.19).

Conclusion. Irreversible organ damages are present in 59 patients in the RENAISSANCE cohort. Older individuals develop a larger number of damages, with higher frequency of exacerbations and hospitalizations, longer use of GCs, and higher cumulative dose of CP. DI correlates with the dose of GC and does not depend on the activity and clinical manifestations of SLE at its onset. 

Many clinical observations show that patient’s genetic background is of great importance in determining the efficiency of treatment.

Subjects and methods. The instigation included 50 postmenopausal women with osteoporosis (OP), who were followed up at the Laboratory of osteoporosis, V.A. Nasonova Research Institute of Rheumatology. Body mineral density (BMD) in the lumbar spine (LI-IV), femoral neck (FN), and total hip was measured using dual-energy X-ray absorptiometry before and 12 months after treatment with bisphosphonates (BP). To estimate BMD changes, the investigators used ΔBMD in percent (Δ, %).

Results and discussion. The whole group showed a positive effect of BP therapy during a year, which was most pronounced in the lumbar spine (mean ΔBMD, about 4%), and a small increment in the proximal hip BMD (mean ΔBMD, about 2%). An analysis indicated a statistically significant correlation of MCP1 -2518A>G polymorphism with changes in LI-IV BMD after 12-month BP therapy. Thus, the female patients who were A allele carriers had a twice lower increase in LI-IV BMD due to BP therapy than those without this allele. The genetic variants of the CCR5 gene, which were related to Δ32 deletion, and IL1β -511C/T polymorphism were also associated with changes in FN BMD following 12-month BP therapy. The BMD increase due to BP therapy in the carriers of the CCR5 Δ32 mutation (wt/Δ32 genotype) was 3.5-fold than that in the carriers of the wild type gene (wt/wt genotype). Examination of IL1 -511C/T polymorphism demonstrated that the FN BMD increment in the carriers of the CC genotype was significantly higher than in those of the CT genotype (4.2±4.8 and 1.0±3.7%, respectively; р = 0.023). Our investigation revealed no significant relationship between VDR, LEPR, IL10, MHTFR, PPARG, SPP1, and CCR5(G/A) gene polymorphisms and 12-month BP therapy-induced BMD changes in the three study skeletal regions. The findings may suggest that genetic testing may be used to predict a response to BP. 

Objective: to estimate frequency of autoantibodies in a cohort of Russian patients with systemic sclerosis (SS) and to investigate clinical associations of these autoantibodies.

Subjects and methods. In 2012 to 2015, the investigation enrolled 300 patients (58 men and 242 women) who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) SS criteria. All patients underwent immunological examination including determination of antinuclear antibodies, anti-topoisomerase I (anti-Scl-70) antibodies, anti-centromere antibodies (ACA), anti-U1-ribonucleoprotein antibodies (anti-U1 RNP), and anti-RNP III antibodies.

Results and discussion. The vast majority of patients were middle-aged females with moderate disease duration. There was a preponderance of patients with limited cutaneous form (55.3%); 37.4% patients had diffuse SS; 5.9% had overlap syndrome; and <1% had visceral and juvenile SS. The vast majority (83.8%) of patients were found to have antinuclear factor. Among the SS-associated antibodies, anti-Scl-70 were most common and were revealed in approximately one-half of the patients. ACA was present in only 44 (14.6%) patients. There was a combination of positivity for ACA and anti-Scl-70 antibodies in 3 patients with limited cutaneous SS, including one with an early form of the disease. 26 patients had anti-U1 RNP antibodies. Among them, there was a preponderance of patients with limited cutaneous SS and overlap syndrome. Anti-RNP III antibodies were found in 5.5% of cases, mainly in those with limited cutaneous SS; these were observed in one patient with diffuse SS and interstitial lung disease. No kidney injury was seen in this patient group.

Conclusion. The characteristics of the Russian cohort are the preponderance of the limited cutaneous SS and the frequent detection of anti-Scl-70 antibodies in both diffuse and limited cutaneous SS; no correlation of anti-Scl-70 antibodies with rapid progression of the pathological process, with kidney disease.

Objective: to study the mechanisms determining the level of pain on the basis of an analysis of the expression profiles of the genes involved in joint destruction, inflammation, and metabolic regulation in the blood of patients with osteoarthritis (OA) with different expression levels of the Mammalian Target Of Rapamycin (mTOR) gene and at different disease stages.

Material and methods. Peripheral blood samples from 47 outpatients with OA, from 21 late-stage OA patients admitted to hospital for endoprosthetic knee joint replacement, and from 27 healthy individuals who formed a control group (mean age, 60.0±7.1, 56.6±8.9, and 58.6±8.3 years, respectively), as well as articular cartilage samples obtained intraoperatively from 21 patients with OA and at autopsy from previously healthy people (mean age, 38.2±4.3 years) who had died from trauma, were examined. Clinical, radiographic, ultrasound, and densitometric examination was performed. Total RNA was isolated from blood and after reverse transcription it was used to estimate gene expression levels in real-time polymerase chain reaction.

Results and discussion. In the low mTOR gene expression subgroup, the expression of all the study genes proved to be at the control level, except the matrix metalloproteinase 9 (MMP9) gene, the expression of which was significantly higher. In the patients with a high expression of the mTOR gene and in those with late-stage OA, the expression of all the study genes was much higher than in the control group. There was a positive correlation of the gene expression of the transforming growth factor β1 (TGF-β1) (r = 0.594; p = 0.005) and cathepsin K (r = 0.595; p = 0.003) in the blood and articular cartilage of patients with late-stage OA.

Conclusion. The different levels of pain in OA patients with different expression levels of the mTOR gene may be associated with the expression ratio of the genes MMP9 and tissue inhibitor of metalloproteinases 1 (TIMP1), the excessive or insufficient activity of the mTOR gene, and the expression of the growth factors TGF-І1 and vascular endothelial growth factor, which are involved in the processes of tissue regeneration. 

Objective: to investigate the clinical manifestations, courses, outcomes, and unfourable predictors of systemic lupus erythematosus (SLE) in the dwellers of Kyrgyzstan.

Subjects and methods. The investigators carried out a retrospective analysis of 107 patients with SLE, who fulfilled the respective 1982 American College of Rheumatology (ACR) criteria and had been examined and treated at the Clinic of the National Center for Cardiology and Therapy in 2001 to 2011, and a prospective follow-up of 75 of them until 2015. During the prospective follow-up study, 29 of the 75 patients died on average of 6.38±3.48 years after the first visit to the clinic and 46 were alive at the completion of the investigation. The patients’ baseline status was retrospectively analyzed. Disease activity was assessed using SLEDAI-2K. The outcome of SLE was determined as the number of exacerbations by the SLE flare index (SFI): moderate or severe, the occurrence of a complete or drug-induced remission, the development of irreversible organ damages by the Systemic Lupus International Collaborating Clinics/ACR damage index (SLICC/ACR DI) or death.

Results and discussion. The prospective follow-up study showed that among the 75 patients, only one achieved a complete clinical and immunological remission and 12 had drug-induced remission. All patients with significantly lower disease activity were observed to have a statistically significant DI increase by one or more scores (p < 0.05). Various irreversible organ damages were detected in 48 (64%) patients; these were found in the survivors 3.5 [2.0; 5.0] years after their first visit and in the deceased patients 1.5 [1.0; 3.0] years prior to death. The main causes of death were renal and pulmonary complications in 10 (34.5%) and 7 (24.1%) patients, respectively. Respiratory infections as severe pneumonias with progressive respiratory failure result in a fatal outcome in 5 (17.2%) cases. The independent risk factors for death were acute course (β = 0.18; p = 0.04), long disease duration out of remission (β = 0.51; p = 0.001), and SLICC/ACR DI progression (β = 0.32; p = 0.0004). High SLE activity failed to affect mortality rates (β = 0.09; p = 0.02) that showed no significant decrease over time (p = 0.14).

Conclusion. The poor predictors in patients with SLE were acute course, long disease duration out of remission, and progression of irreversible organ damages.

T regulatory cells (Tregs) play a key role in the immune system due to the suppression of a hyperimmune response to autoantigens and opportunistic enteric microorganisms. In recent years, there has been evidence that Tregs can suppress various immunoinflammatory responses to a wide range of physiological and pathological stimuli, including microorganisms, tumor cells, allogeneic grafts, and fetal cells.

Tregs express a broad spectrum of membrane molecules that determine their functional activity and make it possible to identify these cells; however, none has discovered a universal surface marker that would distinguish this cell subpopulation from a pool of T lymphocytes. The most specific intracellular marker for Tregs is the nuclear transcription factor Foxp3 that is of fundamental importance in the development of Tregs and their inhibitory function.

The results of the vast majority of studies indicate that there are increased numbers of Tregs in the synovial fluid of patients with rheumatoid arthritis (RA); however, the data on the level of this cell population in their peripheral blood are very contradictory. The majority of investigators have observed a decrease in the percentage of circulating Tregs while other studies have revealed its increase or no differences from the corresponding value of healthy donors or patients with osteoarthritis. It is believed that a quantitative defect in CD4+CD25+Foxp3+CD127 regulatory cells is especially characteristic of early RA and associated with the risk of the latter in asymptomatic patients positive for anti-cyclic citrullinated peptide antibodies. The use of disease-modifying antirheumatic drugs and biologic agents is accompanied by a certain change in the level and functional activity of Tregs, which is responsible for the therapeutic effect of the medicaments.

Thus, an important part is assigned to Tregs in the pathogenesis of autoimmune rheumatic diseases, RA in particular. The decrease in the level and functional activity of Tregs is likely to underlie the development of uncontrolled chronic inflammation leading to multiple organ damages. 

The literature review gives the data of recent investigations that have demonstrated that rheumatoid arthritis increases the incidence of venous thromboembolic events. It considers the pathogenesis of thrombosis in chronic inflammatory diseases and the relationship of an inflammatory process to thrombogenesis. Whether the drugs used in patients with rheumatoid arthritis have effects on the risk of thrombogenesis is discussed. 

The paper describes a clinical case of the typical variant of Cogan's syndrome (CS), a new nosological entity in the current classification of systemic vasculitides (SV), which belongs to a group of variable vasculitides. The literature review highlights in detail the problems of the diagnosis and treatment of this rare disease.

CS is characterized by inflammatory eye involvement (interstitial keratitis, uveitis, and episcleritis) and hearing problems (sensorineural hearing loss, vestibular disorders) with the possible development of vasculitis at other sites, aortitis, and aortic or mitral lesions. A systemic lesion involving the ears and eyes necessitates to rule out granulomatosis with polyangiitis (Wegener's) and to make a differential diagnosis with a wide range of diseases. The given data underline the need for the interdisciplinary collaboration of rheumatologists, otorhinolaryngologists, audiologists, oculists, and cardiologists in order to improve the diagnosis and treatment of this form of SV. 

In modern rheumatology, comorbid infections (CIs) have a significant impact on morbidity and mortality of patients with systemic lupus erythematosus (SLE). The increased susceptibility of SLE patients to infections is associated with various immune disorders. A number of risk factors for CIs in SLE, which are related to the disease and its treatment, have been identified. However, despite the fact that there are a sufficient number of these factors, the contribution of each of them varies considerably with the cohort of examined SLE patients. The paper considers the epidemiological, clinical, and laboratory characteristics of some bacterial and viral CIs in patients with SLE in current clinical practice. It underlines the importance of primarily influenza and pneumococcal vaccination in patients with SLE since among them the risk of deaths from lower respiratory tract infections is quite high. The ways of further investigations in the framework of the problem under consideration are outlined.

The paper reports the development of the adverse events of the skin and its appendages due to subcutaneous methotrexate, which serve as a manifestation of its toxicity in patients with rheumatoid arthritis. It discusses the possible mechanisms of their occurrence, although both clinical presentations and histological changes are not specific. 

The paper historically considers whether it is appropriate to use the term (concept) “drug-induced disease”. 

The expert meeting dedicated to the discussion of results of a local open-label multicenter observational study of the efficiency and safety of tofacitinib in patients with active rheumatoid arthritis with the inefficiency of disease-modifying antirheumatic drugs and to the elaboration of recommendations for the use for tofacitinib in the therapy of rheumatoid arthritis.

The results of the Third Eurasian Congress of Rheumatology (Minsk, 26–27 May, 2016).

All-Russian Conference on Spondyloarthritis in the 21st Century, dedicated to the occasion of the 75th birthday of I.G. Salikhov (Kazan, 21–23 April, 2016).