The paper presents the main milestones of a long-term study of the time course of acute rheumatic fever (ARF) in a Russian contingent of patients from different age groups, the results of studying of the clinical types of the disease, developing, and introducing methods for its diagnosis, treatment, rehabilitation and prevention programs. It highlights a path of successes and disappointments in the control of ARF, the way in which every answer is followed by a new question.

 

Early arthritis, which is frequently defined as undifferentiated arthritis, can be an early stage of rheumatoid arthritis (RA), the first manifestation of a wide spectrum of rheumatic diseases and remain undifferentiated for a long time or end spontaneously. The article discusses new European League Against Rheumatism (EULAR) guidelines for the management of patients with early arthritis, which reflect the past decade's advances in new methods for the diagnosis and treatment of early arthritis primarily as a cardinal RA symptom complex. The guidelines include three general principles and 12 recommendations for the diagnosis and treatment of early arthritis. Special attention is given to the need for early use of methotrexate, monotherapy with the latter is the gold standard for the pharmacotherapy of RA. In conclusion, the paper discusses new evidence for the possibilities of preventing RA in a group of anti-cyclic citrullinated peptide antibodies positive patients with arthralgias.

 

The investigators carried out an analysis of the efficacy and safety of secukinumab (SEC) in the randomized placebocontrolled trials (RPCTs) FUTURE 1 and FUTURE 2, as well as a subanalysis of the data obtained in the Russian population of patients with active psoriatic arthritis (PsA). The FUTURE 1 and FUTURE 2 trials enrolled a total of 1003 patients with active PsA. They received SEC (n = 703) or placebo (PL) (n = 300). The use of SEC 300 or 150 mg without previous intravenous (IV) loading dose or either 150 or 75 mg with the IV loading dose led to a significant improvement in patients with PsA. The positive changes in the main clinical manifestations of PsA at 24 weeks persisted until 52 weeks of therapy. SEC was effective in both the patients who had not previously received tumor necrosis factor-α inhibitors and those who had previously taken these drugs, and the result of therapy did not depend on concomitant methotrexate use.

The incidence of cancer was low and comparable in the SEC and PL groups. Analysis of the combined data on the safety of the two RPCTs showed that the treatment duration-adjusted incidence of malignant neoplasms was 0.5 per 100 patient-years in the SEC groups and 0.9 in the PL groups. The safety profile of SEC in these RPCTs corresponds to that in the previous studies of the drug.

The data from the pooled analysis of the Russian subpopulation of patients with PsA fully agree with the results obtained in the evaluation of all the patients included in FUTURE 1 and FUTURE 2 and confirm the most important role of IL-17А in the pathogenesis of PsA.

Anti-heterogeneous nuclear ribonucleoprotein (RNP) autoantibodies (AAbs) are encountered in many autoimmune rheumatic diseases (ARDs). The potential diagnostic value of the RA33 AAb complex consisting of RNP A2 and alternative domains of the splicing proteins RNP B1 and RNP B2 is now of interest to rheumatologists. Subjects and methods. The authors studied the frequency of anti-RNP B1 AAbs in 300 patients with systemic ARDs, including those with rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjö gren's syndrome (SS) and in 53 people without ARDs, who constituted a control group. Serum anti-RNP B1 AAbs were assessed by enzyme immunoassay. Results and discussion. The frequency of anti-RNP B1 AAbs in patients with ARDs was much higher than that in the control group: 170/300 (56.6%) and 8/53 (13%) patients, respectively. Anti-RNP B1 AAbs were detected in 78.5% (113/144) of the patients with RA; 40.3% (23/57) of those with AS, in 67.5% (27/40) of those with SSc, in 36.4% (16/44) of those with SLE, and in 13.3% (2/15) of those with SS. The diagnostic sensitivity of the marker for RA was 78.5%, its diagnostic specificity was 84.9%; the likelihood ratio of positive and negative results was 5.24 and 0.24, respectively. In the patients with RA, the level of anti-RNP B1 AAbs significantly correlated with that of C-reactive protein and erythrocyte sedimentation rate, while in those with SSc the detection of anti-RNP B1 AAbs was related to the rigidity of the vascular wall and the presence of hypertension. The frequency of anti-RNP B1 AAbs among the RA patients seronegative for rheumatoid factor and anti-cyclic citrullinated peptide antibodies was 15.4%. Conclusion. Anti-RNP B1 AAs are a useful laboratory marker (with the upper limit of the normal range being 3.3 U/ml), but are of limited value in the diagnosis of RA. Anti-RNP B1 AAbs may be regarded as an additional diagnostic marker for RA.

α1-Antitrypsin (α1-AT) deficiency is a common genetic disorder characterized by low serum α1-AT levels and a clinical manifestation of pulmonary emphysema and liver disease. In addition to its classical manifestations, α1-AT deficiency frequently accompanies granulomatosis with polyangiitis (GPA); in this case the role of α1-AT deficiency in the clinical course of GPA has not been defined. Objective: to estimate the prevalence of pathological α1-AT phenotypes in GPA and other systemic vasculitides (SV) and to determinate their impact on the clinical course of GPA. Subjects and methods. The investigation enrolled 86 patients with SV, including GPA (n=47), microscopic polyangiitis (MPA) (n=16), eosinophilic granulomatosis with polyangiitis (EGPA) (n=12), and polyarteritis nodosa (PAN) (n=11). A control group included 46 healthy donors. Isoelectric focusing was used to phenotype α1-AT in blood samples and its concentrations were determined. The phenotypes of α1-AT were compared with the overall SV activity index using the Birmingham Vasculitis Activity Score (BVAS), the vasculitis damage index (VDI), the nature of an organ lesion, and the markers of immune inflammation (proteinase 3-antineutrophil cytoplasmic antibodies, total IgG, and C3 and C4 fractions of the complement system). Results and discussion. Pathological α1-AT phenotypes were detected in 17% (8/47) of the patients with GPA, 6.25% (1/16) of those with MPA and absent in EGPA and PAN. Patients with GPA had PiZZ (n=1), PiMZ (n=4), PiMF (n=2), and PiMS (n=1) phenotypes; those with MPA had a PiMS-phenotype. The detection of a pathological α1-AT phenotype in patients with GPA was characterized by the high values of BVAS and VDI (p<0.05) and the elevated levels of serum creatinine (p><0.01), anti-proteinase 3 antibodies, IgG, C3 and C4 fractions of the complement system (p><0.05). Conclusion. Pathological α1-AT phenotypes are more frequently detected in patients with GPA, which is accompanied by an enhanced immunological activity of the disease and high activity and damage indices. Key words: α1-antitrypsin; α1-antitrypsin deficiency; phenotyping; granulomatosis with polyangiitis; systemic vasculitis.><0.05) and the elevated levels of serum creatinine (p<0.01), anti-proteinase 3 antibodies, IgG, C3 and C4 fractions of the complement system (p<0.05). Conclusion. Pathological α1-AT phenotypes are more frequently detected in patients with GPA, which is accompanied by an enhanced immunological activity of the disease and high activity and damage indices.

 

Ankylosing spondylitis (AS) is a systemic inflammatory disease involving not only the skeleton, but also other organs. The data on the frequency and clinical significance of extraskeletal manifestations are contradictory. Objective: to assess the frequency and severity of extraskeletal manifestations (ESMs) of AS in the authors' own clinical practice. Subjects and methods. 452 patients (363 men and 89 women) with AS fulfilling the 1984 relevant New York criteria were examined at the V.A. Nasonova Research Institute of Rheumatology in 2005 and 2014. The patients' median age was 31.5 [24; 41] years; median disease onset age, 19 [15; 23] years; disease duration, 11 [7; 18] years; HLA B27 was identified in 442 (97.7%) patients. In addition to standard laboratory and instrumental examinations, transthoracic echocardiography was performed in 172 patients. Rehberg's test, IgA test, histological examination of subcutaneous fat tissue or duodenal mucosa for amyloid, and renal ultrasound were made if there were urinary abnormalities and elevated creatinine levels. If indicated, there were consultations by an ophthalmologist with an appropriate instrumental examination (with evidence of uveitis in the history), a dermatologist, a nephrologist, an urologist, a gastroenterologist, and a endoscopist. Uveitis, cardiac involvement (conduction disturbance, aortic and valvular changes), inflammatory bowel disease (IBD), glomerulonephritis, and psoriasis were borne in mind as ESMs. The absolute number and percentage of patients having any ESM over the follow-up period were estimated. The number of exacerbations per year and that of complications were taken into account when evaluating uveitis; the magnitude of valvular regurgitation and the presence of prosthetic valves and a pacemaker were considered when assessing cardiac damage; the total body surface area (BSA) and the psoriasis areas and severity index (PASI) were estimated in psoriasis; the presence and stage of chronic kidney disease (CKD) and/or macrohematuria were kept in mind in nephropathy; when evaluating IBD, the Harvey–Bradshaw index (HBI) was determined on the basis of a stool frequency, the presence of blood in the stool, abdominal pain, and general well-being. Results and discussion. ESMs were detected in 218 (48%) of the 452 patients. Uveitis was present in 140 (30%) patients; in one-fourth of them, it relapsed frequently: three or more exacerbations per year and more than 10 during the disease; 41 (29%) patients had uveitis complications accompanied by visual impairment. Cardiac conduction disturbance was revealed in 61 (13%) patients. Five of them underwent pacemaker implantation. 71 (41.2%) patients were found to have aortic and valvular changes, including aortic root dilatation/thickening in 60 (34.8%) patients and aortic/mitral valve leaflet thickening in 63 (36.6%). Grades 3 and 4 valvular regurgitation was noted in 10 (5.8%) patients; valve replacement was carried out in 9 (5.2%) cases. Nephritis was diagnosed in 16 (3.5%) patients, 4 of them had Stage 2 or above of CKD. Psoriasis was present in 17 (3.7%) patients; 2 of them had severe psoriasis (BSA >10%). IBD (ulcerative colitis or Crohn's disease) was diagnosed in 16 (3.5%) patients, including 4 who showed a severe course. 79 (36%) patients were observed to have a concurrence of two or more ESMs; that of uveitis and heart disease was most commonly seen. Conclusion. ESMs are observed in nearly half (48%) of the patients with AS and can be concurrent; the most common ESMs of AS are uveitis, aortic root and heart valve lesions, and cardiac conduction disturbance. ESMs worsen the course and prognosis of AS.

 

Objective: to assess the psychometric properties of EQ-5D and RAPID-3 indices in patients with panniculitis (PN). Subjects and methods. A total of 83 patients (80 women, 3 men) diagnosed with PN, followed up at the V.A. Nasonova Research Institute of Rheumatology in 2013–2015 were examined. The patients’ mean age was 43.4±13.9 years; median disease duration was 5 [2; 24] months. All the patients filled out the EQ-5D and RAPID-3 questionnaires during the first visit and 12 months later. The sensitivity of the questionnaires was assessed by comparing the index scores with the treatment response that was estimated by the achievement of nodular regression at the time of a follow-up examination. The construct validity was determined using a correlation analysis with external criteria. Results and discussion. Positive clinical changes (achievement of nodular regression) were correlated with improvement in EQ-5D and RAPID-3 scores. The median posttreatment change in EQ-5D index scores was 0.27 [0.12; 0.45] (p=0.005), and after treatment the RAPID-3 scores decreased by an average of 9.2±5.2 (p=0.0011). Assessing the validity of EQ-5D index scores in patients with PN revealed moderate correlations not only with clinical (nodular tenderness on palpation, as evaluated by a visual analogue scale, but also with laboratory (erythrocyte sedimentation rate, C-reactive protein levels) parameters. The RAPID-3 function assessment index correlated with the clinical signs of PN. Conclusion. The EQ-5D and RAPID-3 questionnaires are valid and sensitive common instruments for assessing quality of life and functional status in patients with PN.

 

Objective: to assess the real practice of prescribing drugs for osteoarthritis (OA) by physicians in the Republic of Tajikistan. Subjects and methods. The paper presents the results of a questionnaire survey of 274 physicians of different specialties (therapists, rheumatologists, traumatologists, surgeons, neurologists, and family medicine specialists) in order to identify common prescribing practice in the treatment of patients with OA in the Republic of Tajikistan. It shows changes in the doctors' therapeutic tactics (in 2013 and 2015) in terms of the introduction of the national management protocol for patients with OA. The results were compared with the data of evidence-based medicine; ways for the optimal introduction of efficient techniques into the practical activity of doctors were sought for. Results and discussion. The analysis of the survey showed that in clinical practice the majority (97.8%) of physicians considered it necessary to use nonsteroidal anti-inflammatory drugs (NSAIDs) in OA. It was ascertained that the physicians commonly prescribed diclofenac (64% in 2013 and 48.6% in 2015), ibuprofen (38.2 and 37.3%), nimesulide (33.7 and 36.2%), and indomethacin (14.6 and 18.9%). They more rarely used lornoxicam or meloxicam (15.7% in 2013 and 18.4% in 2015) and coxibs (14.6 and 8.6%). In 2013, structure-modifying drugs were prescribed only in 7.8% of cases; this figure was 50.3% in 2015. The analysis of local (intra-articular) therapy indicated that glucocorticoids (hydrocortisone (6%), triamcinolone (11%), and betamethasone (14%)) were used in 31% of cases. In their practice, only 7% of the respondents prescribed intra-articular hyaluronic acid injections. NSAIDs were established to be the drugs of choice by physicians in treating patients with OA; in this case, non-selective NSAIDs were more commonly prescribed due to their availability, whereas chondroprotectors were administered less frequently, although there was an increase in the frequency of their use after introducing the national protocols for treating rheumatic diseases.

 

Objective: to establish the specific features of changes in the levels of heat shock proteins (HSP), chemokines, and a marker for collagen degradation in the blood of patients with osteoarthritis (OA) depending on the stage of the disease. Subjects and methods. 99 patients with knee OA were examined in the rheumatology room, Vladivostok Polyclinic Three. The diagnosis was verified in accordance with the 2010 European League Against Rheumatism (EULAR) criteria. This group comprised 87 (88%) women and 12 (12%) men; the patients’ mean age was 66.7±7.9 years; the disease duration was 5.9±4.0 years. A control group included 21 apparently healthy women and 9 men; their mean age was 59.6±8.3 years. Enzyme immunoassay was carried out to determine the concentrations of query molecules in the blood of the patients included in the investigation. The investigators used ELISA kits for HSP70, HSP27 (SunLong Biotech Co. Ltd, China), CRTAP (cartilage-associated protein, CAP), TNF-α (tumor necrosis factor-α), and CXCL17 (chemokine (C-X-C motif) ligand 17) (Cloud-Clone Corp., USA). Results and discussion. The levels of HSP27 and HSP70, their ratio, and CAP in OA were significantly lower than those in the control group. Those of TNF-α and CXCL17 were, on the contrary, considerably higher than those in the control group. In the patients with OA, HSP70 demonstrated an inverse correlation with the levels of CAP and TNF- α. CAP was statistically significantly correlated with TNF-α. The latter was directly related to CXCL17. When the duration of the disease was 10 or more years, the level of CAP was significantly higher than that in patients with a 5–9-year history of OA (p < 0.05) and did not differ from that in those with OA of 1–4-year duration (p > 0.05). The level of CXCL17 reduced statistically significantly with longer disease duration (p < 0.05). In a group of patients with a 1–4-year history of OA, the disease duration had a direct significant correlation with the levels of CAP and TNF-α. When the history of the disease was 5–9 years, there was a significant direct relationship of the duration of OA to CAP and CXCL17. In the patients who fell ill 10 or more years ago, the duration of the disease was directly correlated with the levels of CAP, TNF-α, and CXCL17.

 

Bacterial arthritis (BA) and prosthetic joint infection (PJI) are very relevant problems under current conditions. BA and PJI are responsible for 0.2–0.7% of all hospital admissions per year. The increase in the number of endoprosthesis replacements is accompanied by the rising number of patients with periprosthetic infection. The frequency of fatal outcomes in patients with BA and PJI has not changed significantly over the past 25 years and amounts to 5–15%. The lecture gives an update on the etiology, pathogenesis, clinical presentations, diagnosis, and treatment of the above nosological entities. Emphasis is placed on the importance of a comprehensive approach to treating PJI, which involves a combination of surgery and etiotropic antibacterial therapy.

 

The paper analyzes the key biological effects of cytokines that play a central role in the pathogenesis of immunoinflammatory rheumatic diseases. Special attention is drawn to major proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-17. There are data from a preclinical study of the innovative original biological agents (BAs) designed by the JSC «BIOCAD»: BCD-085, a humanized anti-IL-17 monoclonal antibody, BCD-089, a humanized anti-IL-6 receptor monoclonal antibody, and BCD-121, a humanized bispecific antiTNF-α and anti-IL-17 monoclonal antibody. The preclinical findings prove the specific activity of the drugs in suppressing the inflammatory process, as well as the low toxicity and good tolerance in animals, which could justify investigation of the the drugs during human clinical trials and open up prospects for effective and affordable treatment in Russian patients.

 

The literature review deals with various aspects of the concurrence of rheumatoid arthritis (RA) and autoimmune thyroid diseases (Hashimoto's thyroiditis and Graves' disease). It discusses the prevalence, genetic predisposition, similarity of pathogenesis and clinical symptoms, as well as the ability of organ-specific autoantibodies (anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies) and hypothyroidism to affect the course of RA and the risk of cardiovascular complications.

 

The results of the PRECISION trial were published in late 2016. During this trial, a total of 24,081 patients at high cardiovascular risk took celecoxib 200-400 mg/day, naproxen 750–1000 mg/day or ibuprofen 1800–2400 mg/day for more than 1.5 years (20.3±16.0 months). The findings show that the frequency of vascular catastrophes (death, nonfatal myocardial infarction, and stroke) in patients receiving celecoxib was not higher than that of the similar complications in those taking the control drugs. At the same time, celecoxib demonstrated a statistically significant advantage in reducing the risk of serious gastrointestinal complications. New evidence refutes the concept of high cardiovascular risk that is common to all coxibs and confirms the provisions of national guidelines for the rational use of nonsteroidal anti-inflammatory drugs (NSAIDs), which were published in 2015. This review presents recent data on the risk of NSAID-related complications, including a brief description of the design and results of the PRECISION trial.

 

The discussion provides evidence for the long-felt need to standardize the terms reflecting the harm of drugs.