[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.

[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.

[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.

[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.

Nucleic acid metabolism disturbance in progressive systemic sclerosis (systemic scleroderma).

The content of helical forms of RNA and DNA in plasma was determined in 28 patients with progressive systemic sclerosis (PSS). Various disturbances of nucleic acid (NA) metabolism were noted in those patients: the DNA level was increased in comparison with the standard, and the RNA level was decreased. During treatment a normalization of the given indices was observed. The DNA content in plasma of PSS patients correlated with activity of the process, RNA content with the course of the disease.

Interferon system in patients with rheumatoid arthritis and sclerodermia systematica.

In the blood of patients with rheumatoid arthritis and/or sclerodermia systematica usually acid-labile interferon-alpha (IFN-alpha) was found. Blood leukocytes cannot be considered the source of its production as they spontaneously produce IFN-gamma identified with specific antiserum. Blood leukocytes of tested patients generated in vitro a reduced amount of staphylococcus enterotoxin A-induced IFN-gamma and virus-induced acid-labile IFN-alpha. This findings support the assumption of impaired functioning of T- and B-blood cells in autoimmune diseases. The production of Newcastle diseases virus-induced IFN-alpha and influenza virus-induced acid-stable IFN-alpha by patients' leukocytes has not been altered. Acid-labile IFN-alpha obtained from the blood of tested patients, IFN-gamma spontaneously generated by leukocytes in vitro and acid-labile IFN-alpha produced by leukocytes in vitro following induction with influenza virus show similar sensitivity to pH 2.0 and time patterns of the antiviral state development in human diploid fibroblast culture.

[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.

[Immunocorrection in rheumatoid arthritis]. / Immunokorrektsiia pri revmatoidnom artrite.

The clinical and immunological parameters were compared over time in 125 patients with rheumatoid arthritis subjected to immunocorrection. As a result of the study the drugs and their combinations used are distributed in the following order as regards their efficacy: combined treatment with prospidin and tactivin; prospidin; immunoglobulin therapy with high doses; combined therapy with thymohexin and immunoglobulin (low doses); thymohexin; prodigiosan; immunoglobulin (low doses). The dynamics of cellular immunity did not always correlate with the clinical efficacy of the immunocorrection. No relationship was discovered between the functional activity of natural killers and peripheral macrophages and the dynamics of the clinico-laboratory characteristics. Stimulation of endogenous and con A-induced suppression provided a therapeutic effect only in cases of the induction of both suppression types whereas the combined use of prospidin and tactivin allowed the reduction of the intensity and rate of side effects and maintained functions of peripheral macrophages. Immunocorrection which enabled the decrease of the level of lymphocytes expressing HLA-DR antigens in blood turned out most effective.

[The use of interferon in treating systemic lupus erythematosus]. / Ispol'zovanie interferona v lechenii sistemnoi krasnoi volchanki.

We examined 55 SLE patients. By the treatment the patients entered 5 groups: groups I and II received gammaferon plus reaferon, groups III and IV received IFN plus cyclophosphamide and control group V received placvenil. Compared to controls, the best results were obtained in patients on gammaferon combined with cyclophosphamide. IFN preparations alone showed less pronounced effects. No changes were registered in the control group. We believe that IFN preparations demonstrated efficacy against SLE.

[New approaches to the therapy of rheumatoid arthritis]. / Novye podkhody k terapii revmatoidnogo artrita.

Design of highly selective biological substances made use of three basic components of a complex pathogenetic model of RA: the presence of antigen-presenting cells, genetic defects and autoimmune aggression. Efforts now are directed to development of monoclonal antibodies (MAB) to receptors of T-cells, B lymphocytes, MAB to CD 18 and CD54, cytokines, search for natural inhibitors of cytokines, introduction of cytokines. Many of such preparations including recombinant interferons proved clinically promising.

[Combined immunomodulating therapy in rheumatoid arthritis]. / Kombinirovannaia immunomoduliruiushchaia terapiia revmatoidnogo artrita.

Monotherapy with methotrexate (MT) was compared to combined therapy MT+tactivin (T) in a 2-year clinical trial including 127 patients with rheumatoid arthritis (RA). MT was given to 88 patients in a weekly dose 7.5 mg. In 39 patients this dose was given in combination with subcutaneous injections of T (100 micrograms two times a week for a months, then once a week). Both treatments induced a significant decline in severity of arthralgia, in the number of joints with inflammation, in the level of C-reactive protein and in ESR. Morning stiffness and pains in the joints at palpation were achieved after MT+T combination. Side effects were similar in both treatments.

[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.

[The significance of determining antibodies to viruses of the Herpesviridae family in rheumatic diseases]. / Znachenie opredeleniia antitel k virusam semeistva Herpesviridae pri revmaticheskikh zabolevaniiakh.

AIM: Assay of antibodies to cytomegalovirus (CMV), herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and Epstein-Barr virus (EBV) in rheumatic patients. Specification of their correlations with clinical symptoms. MATERIALS AND METHODS: 66 rheumatic patients were examined for the above antibodies. The admission diagnosis of rheumatic disease (RD) was confirmed in 42 of them. 24 were diagnosed to have active or chronic viral infection (A/CVI) simulating systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and other RD. RESULTS: IgG-antibodies to CMV and VCA-IgG to EBV were detected in 79 and 70.3% of the examinees, respectively. In SLE more frequent were IgM-antibodies to CMV (78.9%), in RA-IgM-antibodies to CMV (85.7%) and IgG-antibodies to EBV (85.7%) while in A/CVI--to CMV (IgM--86.4%), EBV (IgG--80%; IgM--73.7%), HSV-1 (IgM--57.1%). Analysis of clinical correlations indicated that high titers to CMV and to EBV are related in RD patients. CONCLUSION: It is necessary to examine rheumatic patients for antibodies to Herpesviridae viruses and prescribe antiviral drugs.

[Haptoglobin and ceruloplasmin in systemic scleroderma]. / Gaptoglobin i tseruloplazmin pri sistemnoi sklerodermii.

Content of haptoglobin and ceruloplasmin was estimated in blood serum of 23 patients with sclerodermia systematica. A statistically distinct decrease in ceruloplasmin concentration was observed in blood of the patients, whereas content of haptoglobin was markedly increased; this phenomenon reflects a level of the pathological process activity. The proteins are synthesized in various zones of liver lobes: haptoglobin--in the central zone, ceruloplasmin - in the peripheral one. Decrease in content of ceruloplasmin in blood of patients with sclerodermia systematica was due to impairment of hepatocytes, localized in peripheral parts of liver lobes.

[Significance of antibodies to herpesviridae viruses detectable in rheumatic diseases]. / Zhachenie vyiavliaemykh pri revmaticheskikh zabolevaniiakh antitel k virusam semeistva herpesviridae]

AIM: To assay antibodies to cytomegalovirus (CMV), herpes simplex virus type 1 and 2 (HSV-1, HSV-2) and Epstein-Barr virus (EBV) in rheumatic patients and to clarify clinical correlations. MATERIALS AND METHODS: A total of 66 patients were examined: 7, 19, 6, 3, 5, 2 and 24 with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), reactive arthritis (ReA), scleroderma systematica (SS), erythema nodosum (EN), hemorrhagic vasculitis (HV), active or chronic viral infection (A/CVI), respectively. Clinical, laboratory tests, tests for specific IgM- and IgG-antibodies to CMV, HSV-1, HSV-2, EBV, x-ray examinations were performed. RESULTS: IgG-antibodies to CMV were detected in 79%, VCA-IgG-antibodies to EBV in 70.3%, EA-IgG-antibodies to EBV in 56.6%, IgG-antibodies to HSV-1 in 42.1% of patients. Active CMV infection was diagnosed in 27.8%, active EBV infection in 56.6%, combination of CMV and EBV infection in 46.9% of cases. High titers of antibodies to CMV and EBV correlated with such symptoms as fever, arthritis, myalgia, carditis, hepatomegalia, migrating erythematous eruption. Acute-phase indices were related to high titers of antibodies to CMV and EBV. Elevated titers of antibodies to CMV and EBV were registered both in untreated patients and in patients treated with corticosteroids, nonsteroid antiinflammatory drugs and aminoquinoline drugs. CONCLUSION: In differential diagnosis of rheumatic diseases it is necessary to consider possibility of CMV and EBV infections. If these are detected, antiviral measures should be taken.

[Factors that determine the high blood viscosity syndrome in rheumatoid arthritis patients]. / Faktory, opredeliaiushchie sindrom povyshennoi viazkosti krovi u bol'nykh revmatoidnym artritom.

High blood viscosity is a syndrome that may be attributed to a group of the most important disorders of microcirculation under different pathological conditions of the body. The given syndrome manifests itself by disorders of red blood cell deformability (RBCD), high plasma and whole blood viscosity. 32 patients with a verified diagnosis of rheumatoid arthritis (RA) were examined, showing varying activity and systemic manifestations. There was a significant decrease of RBCD from 82.0 + 4.5% in patients with grade I activity to 33.0 + 15.0% in patients with grade III activity (p < 0.01). At the same time plasma viscosity remained practically unchanged. Whole blood viscosity rose with RA activity enhancement: in grade I, it was 1.87 + 0.60 relative units, in grade II, it was 2.80 + 0.80 relative units, in grade III, it constituted 5.30 + 3.70 relative units (p < 0.02). It is assumed that RBCD disturbance is one of the most leading signs in the development of high blood viscosity in RA patients.

[Treatment with megadoses of dexaven (dexamethasone) versus methypred (6-methylprednisolone) of patients with rheumatoid arthritis]. / Sravnitel'noe izuchenie éffektivnosti sverkhvysokikh doz deksavena (deksametazona) i metipreda (6-metilprednizolona) u bol'nykh revmatoidnym artritom.

AIM: To compare clinical effectiveness and tolerance of methylprednisolone (methypred) and dexamethasone (dexaven) in patients with rheumatoid arthritis (RA), to estimate side effects and complications rate. MATERIALS AND METHODS: The trial included 31 patients with seropositive RA (27 females, 4 males) stage II and III. Dexaven pulse-therapy was given to 16 patients in a dose 2 mg/kg for 3 days, 15 patients received methypred in a classic dose 1000 mg for 3 days. Clinical response was assessed on day 1, 7 and 30 after the treatment. RESULTS: Both drugs significantly reduced severity of arthralgia, morning joint stiffness, number of inflamed joints, the disease activity diminished 2-3-fold. Side effects were minimal. CONCLUSION: Dexaven (dexamethasone) is a drug of choice in pulse-therapy of RA. It is not inferior to routine treatment with methylprednisolone (methypred).

[Effects of low-intensity infrared impulse laser therapy on inflammation activity markers in patients with rheumatoid arthritis]. / Vliianie nizkointensivnoi infrakrasnoi impul'snoi lazernoi terapii na markery aktivnosti vospaleniia u bol'nykh revmatoidnym artritom.

AIM: To evaluate effects of low-intensity infrared impulse laser therapy (IRILT) on concentration of immunity activation [not readable: see text] (soluble receptors of TNF-alpha and neopterin) and indicator of the inflammation activity (concentration of C-reactive protein) in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: Enzyme immunoassay, radioimmunoassay, enzyme immunoassay and radial immunodiffusion were used to measure soluble receptors of TNF-alpha, neopterin and C-reactive protein in 38 females with verified RA receiving IRILT or sham procedures. RESULTS: IRILT induced lowering of neopterin, TNF-alpha soluble receptors (p < 0.01) and C-reactive protein (p < 0.01). CONCLUSION: The findings give pathogenetical grounds for IRILT use in RA as this treatment suppresses functional activity of macrophages which serve the main source of neopterin and the receptors synthesis.