[Interferons and other cytokines in rheumatic diseases].

With the growth of rheumatic morbidity the spectrum of medicines for its management needs to be extended. Selected aspects of etiology and clinical course of rheumatic diseases are discussed with reference to prospects of their application for etiopathogenetic therapy.

[Pneumonia in patients with rheumatoid arthritis: the frequency of development, the specific features of its course and risk factors].

AIM: To study the frequency of development of pneumonia, the specific features of its course and risk factors (RF) in inpatients with rheumatoid arthritis (RA). MATERIALS AND METHODS: The archival records (a total of 9059 case histories) of patients with RA treated at the Institute of Rheumatology, Russian Academy of Medical Sciences, during 7 calendar years (1994-1996, 2003-2006) were retrospectively studied. Case histories containing evidence for pneumonia sustained during the patient's hospital stay were selected for analysis. During the analysis, the authors took into account the clinical characteristics of RA, laboratory and X-ray parameters, and comorbidity, including pneumonia. RESULTS: In the inpatients, the frequency of development of pneumonia was 0.8%. The risk factors of pneumonia were the high activity of RA, its systemic manifestations and no use of essential antirheumatic drugs. In 70% of RA patients developing pneumonia, the body temperature was normal or subfebrile; productive cough was absent in 50% of the patients; a third had no cough. Clear X-ray lung tissue infiltration was seen in 48% of cases. Clinical leukocytosis was absent in 50% of the patients; at the same time, there were statistically significant increases in the count of stab neutrophils and erythrocyte sedimentation rate. CONCLUSION: The inpatients with RA develop pneumonia in about 0.8% of cases, which is characterized by an obliterated course and usually develops with the high activity of RA, its systemic manifestations and no use of essential antirheumatic drugs.

[Herpesvirus infections in immunocompromised patients].

Testing of immunocompromised patients for markers of beta-herpesviruses--human herpesvirus type 6 (HHV-6) and cytomegalovirus (CMV), as well as gamma-herpesvirus--Epstein-Barr virus (EBV), revealed that all mentioned infections are frequently detected, mainlyas mixed infections. Chronic HHV-6 infection was diagnosed in more than half of the patients, whereas markers of acute phase of CMV and EBV infections were detected in 25% and 15% of patients respectively.

[An antidestructive effect of leflunomide in early rheumatoid arthritis].

AIM: To study effects of leflunomide on inflammatory and destructive processes in patients with early rheumatoid arthritis (RA). MATERIAL AND METHODS: The trial included 33 patients (27 females and 6 males) with a significant diagnosis of RA (A CR criteria) aged 19 to 60 years and duration of the disease from 6 months to 3 years (15.97 +/- 9.70 months). The activity of the inflammatory process and treatment efficacy were assessed by severity of the articular syndrome, duration of morning stiffness (DMS), pain and the disease activity (VAS), device examination, the disease activity by DAS28 indices, etc. The articular syndrome was assessed by the number of painful joints (NPJ), number of swollen joints (NSJ), etc. The functional status of the patient was evaluated by Keitel test, HAQ and hand grip. Calculations were made of erosive arthritis progression rate (EAPR) and joint fissure narrowing progression rate (FNPR). All the patients received leflunomide (100 mg/day for 3 days, then 20 mg/day). A 12-month course was finished by 14 patients, 4 patients were withdrawn because of side effects, the rest--by social causes. RESULTS: To the end of the trial leflunomide reduced NPJ by 84%, NSJ--by 95%, DMS--by 88%, articular pain by VAS--by 66%, the disease activity by VAS--by 70%. A positive trend in DAS28 criterium was observed (a significant suppression of RA activity after 1 month of therapy by 18%, after 4 months--by 39%, after 6 months--by 43%, by the end of the treatment--by 48%). For the initial 6 months EAPR was 0.50 +/- 0.67, for the following 6 months it lowered to 0.37 +/- 1.00, while FNPR decreased to 1.14 +/- 1.26 vs. 1.31 +/- 2 58 for initial 6 months. A positive change of the level of type 3 matrix metalloproteinase (a 20% and 16% by month 4 and to the end of the trial, respectively) was registered. CONCLUSION: A positive effect of leflunomide on RA inflammatory activity and progression rate of joint destruction was confirmed.

[Is antiviral therapy indicated in patients with rheumatological diseases?].

There is recently being observed increase of the specific weight of the opportunistic bacterial-and-viral infections, the initial onset or reactivation of which are associated with the immunity suppression, e.g. due to immunosuppressive therapy. Viral infection in cases with rheumatic diseases often leads to severe process of the main disease and development of serious complications, such as hepatitis, nephritis, pneumonia and others. This is especially actual at the early stages of the disease in cases with viral infection in the anamnesis, since in such cases it activates the main disease, that of course raises the question of the use of antiviral agents in the complex therapy.

[Evaluation of rheumatoid arthritis activity in clinical practice].

AIM: To develop inflammatory activity index (IAI) for assessment of rheumatoid arthritis (RA) activity in wide clinical practice. MATERIAL AND METHODS: Leflunomide was given to 414 patients for 18.4 +/- 5.7 weeks, on the average. The assessment of the drug efficacy was made by arthralgia severity according to visual analog scale (VAS), duration of morning stiffness, the number of painful joints at palpation, number of swollen joints (NSJ), general condition (GC) of the patient, ESR. DAS28 was used as a basic indicator of the disease activity and efficacy. IAI was formed on the basis of DAS28 and 3 baseline components--NSJ (28 joints), GC and ESR. RESULTS: DAS28 and IAI significantly correlated (r = 0.87, p < 0.01). Comparison of pairs of these indices can specify ranges of IAI corresponding to high, moderate and low RA activity in assessment by DAS28. CONCLUSION: IAI is a simple and reliable index of RA activity in clinical practice.

[Changes in indices of inflammatory activity in patients with rheumatoid arthritis during early stages of basic therapy with leflunomide]. / Dinamika pokazatelei vospalitel'noi aktivnosti u bol'nykh revmatoidnym artritom na rannikh étapakh bazisnoi terapii leflunomidom.

AIM: To assess leflunomide efficacy and tolerance in patients with rheumatoid arthritis (RA) during the first four months of the treatment. MATERIAL AND METHODS: The study included 200 RA patients treated in four Moscow clinical centers. Leflunomide was given in a dose of 100 mg/day for 3 days, then 20 mg/day for 16 weeks. The activity of the disease according to the criterion DAS 28 was assessed before the treatment and 4, 8, 12 and 16 weeks after the treatment start. RESULTS: RA activity diminished considerably after one month of leflunomide treatment. Later, the articular syndrome continued to improve. A significant improvement by DAS 28 was observed after 16 weeks of the treatment in 65% (129 of 200) patients, high RA activity persisted only in 17 of 90 patients. CONCLUSION: Leflunomide reduces articular inflammation and raises RA patients' quality of life at early stages of the treatment. This reduction continued for 4 months of the study. Therefore, adequate assessment of leflunomide efficacy should be made only after 4-6 months of therapy.

[Immunological features of rheumatoid arthritis in patients infected with viruses of hepatitis B, C and in patients with cryoglobulinemia]. / Immunologicheskie osobennosti revmatoidnogo artrita u bol'nykh, infitsirovannykh virusami gepatita B, C i s krioglobulinemiei.

AIM: To specify immunological features of rheumatoid arthritis (RA) associated with hepatitis B, C viruses (HBV, HCV) and cryoglobulinemia (CGE). MATERIAL AND METHODS: Four groups of patients with verified RA were examined immunologically: infected with HCV, infected with HBV, with CGE diagnosed by the capillary method, free of HBV, HCV, CGE. CGE was estimated by the spectrophotometric method, functional activity of the complement components--by hemolytic micromethod. Polymerase chain reaction, identification of serological markers of viral hepatitides B and C were conducted with application of commercial kits produced in Russia. RESULTS: In RA patients infected with HBV and HCV, functional activity of the complement was significantly reduced. RA patients with hepatitis C and CGE showed hypoactivity of all the complement components. A classic course of RA was associated with elevated levels of C1 and C3 components in normal values of C1q, C2, C4 and C5 components. CGE was highest in RA+HCV and RA+CGE groups. CONCLUSION: The study of immunological features of RA associated with HCV, HBV and CGE is important not only in scientific but also in practical aspect as it indicates the necessity of treating the above conditions with drugs which do not suppress complement system significantly.

[Current concepts of pharmacotherapy in rheumatoid arthritis]. / Sovremennye kontseptsii farmakoterapii revmatoidnogo artrita.

Although there were essential achievements in understanding the pathogenesis of rheumatoid arthritis (RA), the mentioned pathologies still remain one of the most complicated problems in practical medicine. Rheumatologists arrived, during the last decade, at a conclusion on a need in an early aggressive therapy, because the destructive changes develop in joints yet during the first 4 months starting from the onset of initial RA clinical signs. The approach towards treatment by non-steroid anti-inflammatory drugs changed with respect to the risk factors related with the onset of potential complications and to choosing the safest drugs, which became possible owing to the development of drugs, whose action is aimed at suppression of cyclo-oxygenase-2 (COG-2). The group of "disease-modifying antirheumatic drugs" (DMARD) was added two new cytotoxic drugs, i.e. cyclosporin A and leflunomid. A concept of combined therapy by 2 or 3 DMARD was elaborated to ensure an effect in case of tolerance to monotherapy. The feasibility and safety of therapy by glucocorticosteroids both with small daily doses and with pulse therapy in extra aggressive RA variations were proven. The use of biological agents, i.e. of monoclonal antibodies to TNF alpha and IL-4 or of their receptors antagonists, is an absolutely new trend in RA treatment. Treatment safety is in the focus of attention; monitoring methods were designed to ensure such safety.

[Use of monoclonal antibodies to tumor necrosis factor (remicade) in rheumatoid arthritis: preliminary results]. / Primenenie monoklonal'nykh antitel k faktoru nekroza opukholi (remikeid) pri revmatoidnom artrite: predvaritel'nye rezul'taty.

AIM: To study effectiveness and tolerance of monoclonal antibodies to tumor necrosis factor (the drug remicade) in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: Remicade treatment results are considered for 25 RA patients receiving methotrexate the activity of which was inadequate for these patients. Remicade was infused intravenously in a dose 200 mg 4 times for 22 weeks. RESULTS: Remicade produced positive clinical and laboratory effects as early as the first infusion. The response was observed during 22 weeks of the treatment in 17 of 25 patients. Remicade tolerance was good. One patient failed the treatment because of development of collapse. CONCLUSION: Pilot results of remicade trial point to its high therapeutic potential and perspectives in rheumatology.

[Dynamic changes in synovitis activity after intra-articular administration of xefocam in patients with rheumatoid arthritis (according to clinical and device examinations)]. / Dinamika aktivnosti sinovita posle vnutrisustavnogo vvedeniia ksefokama bol'nym revmatoidnym artritom (dannye klinicheskogo i instrumental'nykh metodov issledovaniia).

AIM: To assess efficacy of intraarticular administration of lornoxicam (xefocam) in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: Xefocam was injected into the knee joints of 58 patients with RA once a week for 3 weeks in a dose 8 mg. The treatment efficacy was evaluated by changes in the severity of arthralgias, pain in the joints at palpation, circumference of the knee joints at the level of the upper edge of the patella, ultrasound and thermography of the knee joints. RESULTS: Xefocam relieved arthralgia (in 44 patients at least by 30%), pain in the joints at palpation and joint circumference. Ultrasound investigation registered a significant thinning of the synovial membrane and amount of exudates. CONCLUSION: If local steroid therapy is not definitely indicated, intraarticular administration of xefocam can be effectively used for suppression of moderate inflammation in the joints in RA patients.

[Nimesil effectiveness in rheumatoid arthritis]. / Effektivnost' nimesila pri revmatoidnom artrite.

Clinical efficiency and safety of nimesil were studied in the multicenter open clinical trial of 52 patients with verified rheumatoid arthritis. Nimesil was given for 12 weeks in a daily dose 200-400 mg in addition to basic therapy. Clinical and laboratory parameters were assessed after 4 and 8 weeks of the treatment and after its end. The treatment produced a significant positive response of the articular syndrome. Marked improvement was registered in 11 (23.4%) patients, improvement--in 33 (79.2%) patients. Side effects were reversible and occurred in 8 (15.3%) patients. In 5 patients the drug was withdrawn. The conclusion is made on high efficiency and good tolerance of nimesil in rheumatoid arthritis patients.

[Alterations of rheological properties of blood in systemic sclerodermia]. / Narusheniia reologicheskikh svoistv krovi pri sistemnoi sklerodermii.

AIM: To study hemorheological status in systemic sclerosis (SS) patients. MATERIAL AND METHODS: Macro- and microrheology of blood were investigated in 70 SS patients. The rate of spontaneous aggregation of red blood cells [T1(s)], durability of the largest units [Ia2.5(%)], general hydrodynamic durability of units [beta(s-1)], limit of fluidity [tau 0 (mPa)], Casson viscosity K (mPa/s) were determined. RESULTS: The total severity of hemorheological disturbances was 1.90 +/- 0.07 with T1 = 4.98 +/- 1.52s, beta = 62.76 +/- 19.32s, Ia 2.5 = -0.78 +/- 12.83%, tau 0 = 7.00 +/- 0.45 mPa. The Casson viscosity did not differ from normal levels. Plasma viscosity was 1.71 +/- 0.18 rel units, viscosity of sera 1.55 +/- 0.14 rel.units. The severity of hemorheological disturbances did not differ in cute and chronic courses but the parameter beta (72.0 +/- 4.5) was significantly higher (p < 0.05) in the acute course. The severity of hemorheological disturbances was highest in SS patients with cardiac disease (p < 0.05) and in 10 year SS duration. CONCLUSION: The course of SS is complicated by progressive hyperaggregation syndrome promoting development of visceral pathology. Active correction of hemorheology is pathogenetically validated in SS.

Effect of bioresonance therapy on antioxidant system in lymphocytes in patients with rheumatoid arthritis.

We measured activities of superoxide dismutase, catalase, and glutathione peroxidase and content of nonprotein thiol groups (reduced glutathione) in blood lymphocytes from patients with rheumatoid arthritis before and during bioresonance therapy. The state of the antioxidant system in lymphocyte from patients receiving standard pharmacotherapy was characterized by activation of the key antioxidant enzymes and decreased content of thiol groups. Bioresonance therapy increased the content of thiol groups and normalized activities of superoxide dismutase and glutathione peroxidase. However, catalase activity remained above the control. Changes in the lymphocyte antioxidant system indicate that bioresonance therapy activates nonspecific protective mechanisms in patients with rheumatoid arthritis.

[Effects of alfacalcidol on mineral density of bone tissue in patients with rheumatoid arthritis]. / Vliianie al'fakal'tsidola na mineral'nuiu plotnost' kostnoi tkani u bol'nykh revmatoidnym artritom.

The analysis of antiosteoporotic efficacy of alphacalcidol was made in 50 patients with rheumatoid arthritis (RA). 30 RA patients received alphacalcidol in a dose 0.75-1.0 mcg/day for 12 months. 20 control RA patients did not receive the drug. Mineral density of the bone tissue (MD) of the proximal femur and low back spine was studied using double x-ray absorptiometry at the start of the treatment and 12 months after it. It was established that alphacalcidol stabilizes MD of the neck of the femur and low spine. A significant MD increase was observed in those areas of the proximal femur where cortical bone tissue prevails.

[Autoantibodies to vasoactive peptides and angiotensin converting enzyme in patients with systemic diseases of the connective tissue]. / Autoantitela k vazoaktivnym peptidam in angiotenzinprevrashchaiushchemu fermentu u bol'nykh s sistemnymi zabolevaniiami soedinitel'noi tkani.

AIM: To estimate the level of natural autoantibodies (NAAb) to angiotensin-converting enzyme (ACE) and endogenic mediators affecting vascular tone (bradykinin--BK, angiotensin II--AII, vasopressin--VP) as well as the activity of serum ACE in patients with systemic diseases of the connective tissue. MATERIAL AND METHODS: Levels of NAAb were measured by enzyme immunoassay in sera from 30 patients with SLE, 19 patients with rheumatoid arthritis (RA) and 36 patients with scleroderma systematica (SS). Serum from donors served control. IgM NAAb to ACE were measured by a new technique. Serum ACE activity was determined by the initial velocity of hydrolysis reaction using spectrofluometry. RESULTS: IgM NAAb were detected in the sera of both patients and donors. SS patients had the level of NAAb to ACE in diffuse form significantly higher than in limited (p < 0.05). In SLE and SS patients ACE activity was significantly lower (p < 0.05) than in healthy subjects and RA patients. Levels of NAAb to BK was significantly elevated (p < 0.01) in patients with SLE and RA vs donors while to AII in SS patients it was lowered (p < 0.001). Patients with diffuse SS had NAAb to BK higher than patients with SS limited form (p < 0.01). In SLE the lowest levels of NAAb to all the mediators studied were observed in patients with nephritis, for NAAb to VP the differences were significant (p < 0.05). In patients with urinary syndrome concentration of NAAb to BK was significantly higher (p < 0.01), differences between their levels in patients with nephritis and urinary syndrome were also significant (p < 0.05). CONCLUSION: Further studies are needed for specification of physiological or pathological role of NAAb to endogenic mediators.

[Bone mineral density in patients with rheumatoid arthritis]. / Mineral'naia plotnost' kostnoi tkani u bol'nykh revmatoidnym artritom.

AIM: To examine the prevalence of osteoporosis (OPO) and osteopenia (OPE) in female patients with rheumatic arthritis (RA). MATERIAL AND METHODS: 60 female patients with proved diagnosis of RA aged 34-64 years: 30 premenopausal women (median age 41.5 years, disease duration 9.5 years) and 30 postmenopausal women (median age 56.2 years, disease duration 10.2 years). Both groups have not undergone any glucocorticoid or antiosteoporotic therapy. Bone mineral density (BMD) was measured with a Dual Energy X-Ray Absorptiometry (DEXA) in the lumbar spine, proximal segments of the femur, forearm. RESULTS: In the group of premenopausal patients with RA the rate of OPE was 63% for forearm, 60% for femoral neck, 33% for lumbar spine. In postmenopausal women 53, 50 and 50%, respectively. CONCLUSION: Osteoporosis in RA is of a generalized character and can be encountered in peripheral skeleton more often than in the axial one. It is possible to estimate the BMD of one section by means of the BMD indicator of another section.

[In vivo and vitro effects of interferon-alpha 2b on functional activity of T-lymphocytes from patients with rheumatoid arthritis]. / Vliianie alpha2b-interferona in vivo i in vitro na funktsional'nuiu aktivnost' T-limfotsitov bol'nykh revmatoidnym artritom.

AIM: To investigate the effect of recombinant alpha 2b-interferon (r alpha 2b-IFN) on functional capacity of peripheral blood (PB) T cells in rheumatoid arthritis (RA) patients and the relationship between functional characteristics of T lymphocytes and the disease activity. MATERIALS AND METHODS: PB mononuclear cells (PBMC) were separated by Ficoll-Verografine++ gradient centrifugation from 24 healthy donors (HD) and 75 RA patients 19 of which were treated with r alpha 2b-IFN (realdiron, Biofa, Lithuania) in the dosage 1 million IU i.m. each other day for 20 days, 10 injections a course. Cell surface markers (CD3, CD4, CD8) and adhesion molecules (CD18, CD54, CD2) were analyzed using specific monoclonal antibodies (MoAbs) and flow cytometry on the PBMC, freshly isolated and treated for 72 hours with medium alone, PHA, r alpha 2b-IFN and their combination. The proliferative response of PBMC to MoAbs for CD3, PHA and r alpha 2b-IFN were assessed by 3H-thymidine incorporation. The percentage of spontaneous and inducing apoptosis was quantified by flow cytometry using propidium iodide staining. RESULTS: The expression of CD18 was lower on RA PB lymphocytes compared to HD PB lymphocytes (p < 0.05). After stimulation of PBMC in both RA patients and HD with PHA, percentages of CD2+, CD3+, CD4+, CD18+ cells significantly diminished (p < 0.05), whereas the percentages of CD54+ and CD18+ (p < 0.05) cells increased. We have found three types of RA PB lymphocytes response to complex factors in vitro: 1) the presence of the proliferative response to T-mitogens but not to r alpha 2b-IFN (56% of the patients); 2) the presence of the increased proliferative response to T-mitogens and r alpha 2b-IFN (17% of the patients); 3) the absence of the proliferative response to T-mitogens and r alpha 2b-IFN (27% of the patients). PBMC of HD demonstrate only the first type of the response. R2 alpha b-IFN demonstrated own mitogenic effect and increased mitogen-induced proliferation in PBMC cultures with a high proliferative response to T-mitogens. The levels of spontaneous and inducing apoptosis were increased in RA PB lymphocytes compared to HD. After stimulation with PHA, RA PB lymphocytes preferentially underwent apoptosis whereas cells of HD proliferated. High disease activity correlated positively with an increase of a proliferative response to mitogens and apoptosis and a decrease in the percentage of lymphocytes, expressed adhesion molecules. The treatment with r alpha 2b-IFN induces changes in T-cell response to mitogens similarly to those after incubation with r alpha 2b-IFN in vitro before treatment. CONCLUSION: Functional capacity of RA PB lymphocytes relates to the disease activity. Inhibitory or stimulatory effects of r alpha 2b-IFN depend on functional activity of RA lymphocytes. Using the test with alpha 2b-IFN incubation, we may predict changes of apoptosis and proliferation levels caused by different agents in RA lymphocytes after treatment with r alpha 2b-IFN.