Высокотехнологичные хирургические методы в комплексном восстановительном лечении суставной патологии верхних и нижних конечностей у больных с ревматическими заболеваниями

A large clinical material (1693 patients with rheumatic diseases — RD, 2066 operations) was used to develop a three-level medical rehabilitation system using differentiated, including high-technology surgical methods depending on the nosology, RD stage, localization of joint diseases of the upper and lower extremities during adequate drug therapy. A positive result persisting for 1 to 20 years was achieved in 60—92% of cases.На большом клиническом материале (1693 пациента с ревматическими заболеваниями — РЗ, 2066 операций) разработана трехуровневая система восстановительного лечения с использованием дифференцированных, в том числе высокотехнологичных, хирургических методов в зависимости от нозологии, стадии РЗ, локализации суставной патологии верхних и нижних конечностей на фоне медикаментозной терапии. В 60—92 % случаев достигнут положительный результат, сохранявшийся от 1 года до 20 лет

SHOULD DISEASE-MODIFYING THERAPY BE STOPPED IN PATIENTS WITH RHEUMATOID ARTHRITIS BEFORE ENDOPROSTHETIC JOINT REPLACEMENT?

Objective: to analyze disease activity, functional state, quality of life (QL), and the frequency of infectious complications in methotrexate (MT) – or leflunomide (LF)-treated patients with rheumatoid arthritis (RA) who had undergone endoprosthetic replacement of the large joints of the lower limbs. Subjects and methods. One hundred and fourteen patients with RA who had undergone endoprosthetic replacement of the knee and hip joints were divided into 3 groups: 1) 36 patients who continuously received MT or LF in the perioperative period; 2) 42 patients who dis- continued MT or LF 2 and 4 weeks, respectively, prior to surgery; 3) 36 patients who took no disease-modifying anti-rheumatic drugs (DMARDs) within 12 months before surgery. Disease activity was estimated by the DAS28 index. QL was determined using the EQ-5D questionnaire and functional capacity was estimated by the HAQ index. Results and discussion. In all the groups, there was a preponderance of patients with moderate RA activity (more than 60%). In Groups 1 and 2, the mean dose of MT was about 10 mg weekly and that of LF was 20 mg daily. The use duration of glucocorticoids (GC) and their doses were comparable in all the groups. Twelve months after surgery, DAS28 significantly reduced from 4.22±1.08 to 3.58±1.07 months in Group 1 (p = 0.01); in Group 2, the decrease was insignificant: from 4.17±1.17 to 3.80±1.15 (p > 005); in Group 3, RA activity remained as before. All the groups achieved 50% functional improvement; better results were obtained in the group of patients who continued to use DMARDs in the perioperative period (∆HAQ=-0.67). The difference in the Eq-5D index corresponded to a moderate QL improvement: ∆EQ-5D = 0.28, 0.29, and 0.31 in Groups 1, 2, and 3, respectively (p < 0.05). There were no significant group differences. Deep infection in the endoprosthetic replacement area was detected in 2.8, 2.4, and 8.3% of cases, respectively (p > 005). Conclusion. Continuous use of MT and LF leads to a reduction in total disease activity and to functional improvement in patients with RA after endoprosthetic joint replacement, without increasing the frequency of infectious complications

Enhanced regulatory gene expressions in the blood and articular cartilage of patients with rheumatoid arthritis

Objective: to study the expression ratio of the non-tissue specific regulatory genes mTOR, р21, ATG1, caspase 3, tumor necrosis factor-а (TNF-а), and interleukin-6 (IL-6), as well as matrix metalloproteinase 13 (MMP-13) and X type collagen (COL10A1), cartilage resorption-associated MMP13 and COL10A1 in the blood and knee articular cartilage in patients with rheumatoid arthritis (RA). Subjects and methods. Twenty-five specimens of the distal femoral articular cartilage condyles were studied in 15 RA patients (mean age 52.4+9.1 years) after endoprosthetic knee joint replacement and in 10 healthy individuals (mean age 36.0+9.1 years) included into the control group. Twenty-eight blood samples taken from 28 RA patients (aged 52+7.6 years) prior to endoprosthetic knee joint replacement and 27 blood samples from healthy individuals (mean age 53.6+8.3 years; a control group) were also analyzed. Real-time quantitative polymerase chain reaction was applied to estimate the expression of the mTOR, p21, ATG1, caspase 3, TNF-а, IL- 6, COL0A1, and MMP-13 genes. The levels of a protein equivalent in the p70-S6K(activated by mTOR), p21, and caspase 3 genes concerned was measured in the isolated lymphocyte lysates, by applying the commercially available ELISA kits. Total protein in the cell extracts was determined using the Bradford assay procedure. Results. The cartilage samples from patients with end-stage RA exhibited a significantly higher mTOR, ATG1, p21, TNFа, MMP-13, and COL10A1 gene expressions than did those from the healthy individuals. At the same time, IL6 gene expression was much lower than that in the control group. The expressions of the mTOR, ATG1, p21, TNFа, and IL 6 genes in the blood of RA patients were much greater than those in the donors. Caspase 3 expression did not differ essentially in the bloods of the patients with RA and healthy individuals. The bloods failed to show MMP-13 and COL10A1 expressions. High mTOR and p21 gene expressions were accompanied by the elevated concentrations of the corresponding proteins in the cell lysates of the patients with RA compared to the controls. Conclusion. The findings suggest for the first time that regulatory mTOR, ATG1, p21, and TNFа gene expressions are enhanced in the blood and articular cartilage of RA patients. These changes are accompanied by the increased expression of MMP 13 gene that is responsible for articular cartilage resorption. Therefore, the higher expression of the examined regulatory genes in the blood of RA patients may be indicative of articular cartilage degradation

High-technology surgical methods in the comprehensive medical rehabilitation of patients with rheumatic diseases and joint pathology of the upper and lower extremities

A large clinical material (1693 patients with rheumatic diseases — RD, 2066 operations) was used to develop a three-level medical rehabilitation system using differentiated, including high-technology surgical methods depending on the nosology, RD stage, localization of joint diseases of the upper and lower extremities during adequate drug therapy. A positive result persisting for 1 to 20 years was achieved in 60—92% of cases

ASSOCIATION OF BLOOD GENE EXPRESSIONS IN RHEUMATOID ARTHRITIS PATIENTS WITH CLINICAL AND LABORATORY PARAMETERS BEFORE AND AFTER METHOTREXATE THERAPY

The genes, the high basic expression of which indicates the efficiency of methotrexate (MTX) therapy in relieving joint inflammation and destruction in patients with rheumatoid arthritis (RA), have been defined.Objective: to find an association between the initial expression of the genes: mTOR (mammalian target of rapamycin), a major regulator of cell growth and proliferation; ULK1 (an autophagy marker 1); p21 (a cyclin-dependent kinase inhibitor); kaspase-3 (an apoptosis activity indicator); MMP-9 (matrix metalloproteinase 9), and cathepsin K, which are involved in joint destruction, and the cytokines: TNF-α (tumor necrosis factor-α), TGFβ1 (transforming growth factor β1) and Runx2 (Runt-related transcription factor 2) in the blood of RA patients with disease activity and joint destruction before and after MTX therapy during 24 months.Subjects and methods. Forty patients (mean age, 47.5 years) with RA lasting < 2 years) and 26 healthy donors (mean age, 45.1 years) were examined. All the patients took MTX for 2 years. A clinical response was assessed with disease activity score (DAS28); erythrocyte sedimentation rate and the serum levels of anti-cyclic citrullinated peptide antibodies (ACCPA), C-reactive protein (CRP), and rheumatoid factor (RF) were also estimated. Joint destructive changes were assessed by radiography. Furthermore, blood and knee articular cartilage samples from 21 patients (mean age, 50.4 years) with late-stage RA and cartilage samples from 25 healthy individuals were investigated. Gene expression in the cells of peripheral blood and cartilage was determined by real-time reverse transcriptase polymerase chain reaction.Results and discussion. MTX therapy considerably reduced disease activity assessed by DAS28, CRP levels, stiffness, tender and swollen joint counts (TJC and SJC); however, joint space (JS) narrowing (JSN) substantially increased compared with the baseline values. The expression of the ULK1, p21, MMP-9, cathepsin K genes, and TGFβ1 was increased both at the beginning of the investigation and 24 months later whereas the initially higher expression of mTOR, TNF-α, caspase 3, and Runx2 was decreased by the end of therapy to the level of the healthy individuals. The initial expression of the TGFβ1, Runx2, caspase 3, and р21 genes correlated negatively with the RF level measured both at the beginning of the investigation and 24 months later. There was a positive correlation of the initial expression of ULK1 and MMP-9 with CRP levels prior to therapy and that of the initial expression of MMP-9 with baseline DAS28 scores and NSJ. Moreover, the initial expression of the TNF-α gene positively correlated with JSN at the end of therapy and that of the p21, caspase 3, and Runx2 genes with a change in DAS28. There was also a negative correlation of the initial expression of the mTOR gene with the SJC and the number of erosions; the p21 and TNF-α genes correlated negatively with SJC and TJC; and the TNF-α, TGFβ1, Runx2, and cathepsin K genes also negatively correlated to the duration of stiffness at the end of therapy. A positive correlation was found between the expression of the cathepsin K and TGFβ1 genes in the blood and articular cartilage of patients with late-stage RA.Conclusion. The expression of the MMP-9 and ULK1 genes is associated with disease activity. The high initial blood expression of the other examined genes is associated with the more effective action of MTX on stiffness (TNF-α, Runx2, cathepsin K, and TGFβ1), TJC and SJC (mTOR, p21, and TNF-α), and the progression of joint destruction (mTOR) and may play a protective role. The positive correlation of the blood and articular cartilage expression of the TGFβ1 and cathepsin K genes may point to their co-regulation in these tissues in RA

Molecular mechanisms of pain regulation in patients with osteoarthritis

<p><strong>Objective:</strong> 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.</p><p><strong>Material and methods.</strong> 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.</p><p><strong>Results and discussion.</strong> 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.</p><p><strong>Conclusion.</strong> 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. </p

Does endoprosthetic replacement of large joints improve quality of life in patients with rheumatoid arthritis?

Objective: to analyze the course of rheumatoid arthritis (RA), to assess its previous therapy, and to evaluate the efficiency of endoprosthetic replacement of knee or hip joints (EKJ or EHJ). Subjects and methods. The study enrolled 50 patients with RA who had undergone EKJ (Group 1; n = 32) or EKJ (Group 2; n = 18); their mean age was 51.8±11.6 and 48.7±8.5 years and the disease duration was 16.5±7.8 and 15.5±7.5 years, respectively. Their quality of life (QL) was estimated by the EQ-5D and SF-36 questionnaires; joint functional capacity was assessed by the HAQ index and the Harris and Insall scales. Results and discussion. Before surgical treatment, the majority of patients took methotrexate (MT) in a weekly dose of 7.5-10 mg, which was prescribed 7-10 years after the disease onset. Oral glucocorticoids (GC) were given to 65.4 and 84.6% of the patients of Groups 1 and 2, respectively. Six months after endoprosthetic replacement, there was functional improvement: the HAQ index decreased from 1.64±0.7 to 1.40±0.6 after EKJ (p = 0.003) and from 2.07±0.6 to 1.72-0.7 after EHJ (p = 0.04). The EQ-5D QL index increased from 0.52 [0.0- 0.61] to 0.59 [0.52-0.69] scores after EKJ (p = 004) and from -0.02 [-0.02-0.52] to 0.52 [-0.02-0.62] scores after EHJ (p = 0.096). There was a significant improvement in the SF-36 physical component summary (PCS): APCS = 4.3 (p = 0.04) after EKJ and APCS = 5.7 (p = 0.02) after EHJ and a trend towards stabilization of the patients' mental status. Conclusion. The majority of patients had not initially received adequate disease-modifying anti-inflammatory therapy for many years. Endoprosthetic replacement of the lower limb joints in the first 6 months after surgery improved the functional capacity of the operated joint, by increasing QL in the patients as a whole. There was no substantial decrease in global disease activity 6 months following surgery

PREDICTION OF THE COURSE OF OSTEOARTHROSIS FROM mTOR (MAMMALIAN TARGET OF RAPAMYCIN) GENE EXPRESSION

Objective: To study whether the course of the disease can be predicted in patients with osteoarthrosis (OA), by monitoring mTOR (Mammalian Target Of Rapamycin) gene expression in their blood. Material and methods. The investigation was conducted on the peripheral blood samples from 33 outpatients (58.4±7.4 years) with OA; 10 patients (56.5±8.9 years) before endoprosthetic knee joint replacement, и 27 healthy individuals (55.6+8.3 years) who formed a control group. Total RNA was isolated from the blood and used to estimate the gene expression of mTOR, autophagy-related protein 1 (ATG1), the cyclin-dependent kinase inhibitor p21, caspase 3, and tumor necrosis factor-а (TNF-а) by real-time polymerase chain reaction. Results. Analysis of gene expression in the outpatients with OA identified two subgroups: in one subgroup (n = 13) mTOR expression was considerably much less than that in the control group; the expression of ATG1 and p21 did not differ greatly from the control and that of caspase 3 and TNF-α was significantly higher. The other outpatients (n = 20) and all the examined patients needing endoprosthetic replacement were ascertained to have a higher gene expression of mTOR, ATG1, p21, caspase 3, and TNF-α than in the control group. Before endoprosthetic replacement, severe joint destruction in patients with OA was associated with enhanced gene expression of mTOR, ATG1, p21, and caspase 3. Conclusion. In early-stage disease, increased mTOR gene expression may serve as a prognostic marker of the severity of the disease and articular cartilage destruction