Objective: to study the efficacy and safety of rheumatoid arthritis (RA) treatment with monoclonal antibodies to interleukin 6 receptors (IL6R) – sarilumab (SAR) in combination with methotrexate (MT).Subjects and methods. The study included adult patients with moderate or severe RA and inadequate effect of MT monotherapy. Patients were randomized in a 1:1:1 ratio to subgroups receiving SAR (at doses of 150 or 200 mg) or placebo (PL) every 2 weeks in combination with a weekly intake of MT for 52 weeks. The primary endpoints of the study included the achievement of ACR20 after 24 weeks, the change of HAQ-DI after 16 weeks and assessment of radiological progression of joint destruction (modified total Sharp score mTSS) after 52 weeks.Results and discussion. In general, the initial characteristics of patients were similar in all groups. A statistically significant improvement of all three primary endpoints was found in the groups of patients treated with SAR 150 and 200 mg compared to the group of PL. ACR20 response after 24 weeks was achieved in 53.6% (p<0.0005), 65.9 and 19.6% of patients respectively (p<0.0001), the average change in HAQ-DI after 16 weeks was 20.53; 20.55 and 20.29 respectively (p<0.0001); the average change in mTSS after 52 weeks was 0.49; 0.11 and 2.30, respectively (p<0.0001).Conclusion. Both doses of SAR (150 and 200 mg every 2 weeks) in combination with MT demonstrated sustained clinical efficacy in patients with RA, which was confirmed by a significant improvement in symptomatic, functional and radiographic outcomes. SAR therapy was generally well tolerated. The adverse events observed in this study were consistent with the effects of the IL6 blockade.

Objective: to assess the long-term safety and efficiency of tocilizumab (TCZ) therapy in patients with early rheumatoid arthritis (RA) of moderate and high activity, who have completed the basic WA19926 study, as well as the rate of sustained drug-free remission.Subjects and methods. A long-term open-label multicenter Phase III extension study (ML28124) was conducted using a group of 49 patients (36 (73.5%) women and 13 (26.5%) men; mean age 53.3±10.8 years) with early RA of moderate and high activity. All the patients received an intravenous infusion of TCZ 8 mg/kg every 4 weeks for 104 weeks (a total of 27 infusions). The safety assessment criteria were the rate and severity of all adverse events (AE), serious AE (SAE), and AE of particular interest; the rate of AE causing drug dosage changes or withdrawal from the study; the frequency of clinically significant laboratory abnormalities. The analysis of efficiency (secondary end points) included changes of DAS8, which was calculated using erythrocyte sedimentation rate (ESR) (DAS28-ESR) and SDAI, the of tender joint count (TJC) and swollen joint count (SJC); the number of patients who had achieved drug-free remission; and the time to a RA exacerbation in patients who had achieved non-drug remission.Results and discussion. The total rate of AE was found to be 69.4%; that of SAE was 10.2%; SAE were 6.9% of the the total number of AE; AE of particular interest were 17.2% of the total number of AE. More than one-third (35.6%) of the AE caused drug dose changes or therapy discontinuation or complete cessation. The laboratory clinically significant abnormalities included those in complete blood cell counts (blood alanine aminotransferase, aspartate aminotransferase, total and direct bilirubin, creatinine, and glucose). The evaluation efficiency analysis showed that the main disease activity measures (DAS28-ESR, SDAI, SJC, and TJC) decreased at 104-week follow-up versus at baseline. The rate of drug-free remission was 71.4%; that of recurrence was 40.0% (the median time to recurrence was 23 weeks). The findings suggest that the safety profile of TCZ is acceptable in the long-term treatment of early RA and correspond to earlier results.

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.

The article summarizes the data of two randomized controlled trials (RCTs) Phase III MEASURE 1 and MEASURE 2 investigating the efficacy and safety of secukinumab (SEC) in treating ankylosing spondylitis (AS) and compares the data with the results obtained from Russian patients with active AS, who were enrolled in these RCTs.Subjects and methods. Among 590 patients included in the MEASURE 1 and MEASURE 2 trials, the Russian group totaled 107 patients: 44 and 29 patients took SEC in the MEASURE 1 and MEASURE 2 trials, respectively; 34 patients had placebo in the two trials.Results and discussion. A retrospective analysis of the results for the Russian patient group showed that the efficacy of SEC in treating AS was fully similar to that demonstrated in the entire MEASURE 1 and MEASURE 2 group cohort. At 1 to 16 weeks of SEC therapy, the MEASURE 1 trial Russian patients displayed a rapid clinical improvement in 52.6% (p = 0.043); and in the SEC 150- and 75-mg groups, ASAS20 improvement was achieved by 64% (p = 0.0015), respectively. The SEC 150-mg group in the MEASURE 2 trial exhibited an ASAS20 response in 66.7% of cases (p = 0.0063). The clinical response at 16 weeks in the patients randomized at baseline into SEC treatment groups was sustained for 52 weeks. The proportion of patients achieving ASAS20 response at 52 weeks was 63.2 and 68% in the MEASURE 1 trial (in the SEC 150- and 75-mg groups, respectively) and 73.3% in the MEASURE 2 trial (the SEC 150-mg group). At 52 weeks, ASAS40 reponse was achieved by 52.6% of the patients in the MEASURE 1 trial and by 60% of those in the MEASURE 2 trial (the SEC 150-mg group). In the MEASURE 1 trial, ASAS 5/6 response rates at 16 weeks were 42.1 and 52.0% in the SEC 150- and 75-mg groups (p = 0.0249 and p = 0.0013, respectively). In the MEASURE 2 trial, the proportion of the SEC 150-mg group patients achieving ASAS 5/6 response was 53.3% (p=0.0135). After 52 weeks, these rates were 57.9, 52, and 73.3%, respectively. The adverse reactions observed in both the placebo-controlled and later follow-up periods and in the Russian patient cohort suggest that SEC has an acceptable safety profile and good tolerability in patients with AC.

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.

As of now, there have been notable advances in treating immune inflammatory rheumatic diseases, which are associated with the interpretation of basic pathogenetic mechanisms of their development. The most well studied therapeutic targets are tumor necrosis factor-α, interleukin (IL)-6 and IL-1; inhibition of these cytokines with genetically engineered biological agents is not always clinically effective and rarely gives rise to remission. The new promising treatment of rheumatoid arthritis (RA) and other inflammatory arthritides is linked to the inhibition of IL-17A, a proinflammatory cytokine, involved in the development of inflammation and in the destruction of bone tissue. The paper summarizes new evidence for the prospects of using anti-interleukin-17 monoclonal antibodies to treat RA.

Certolizumab pegol (CZP) is a new drug from the group of tumor necrosis factor a inhibitors. The efficacy and safety CZP in the treatment of rheumatoid arthritis (RA) have been studied in the international 52-week RAPID-1 and 24-week RAPID-2 clinical trials that studied the use of CZP in combination with methotrexate (MTX) in patients with active RA unresponsive to MTX. The study populations of the RAPID 1 and RAPID 2 trials constituted the major portion of Russian patients (11.8 and 18.4%, respectively), including that in the prolonged open-labeled phases. The results of using CZP in Russian patients in the RAPID trials showed that they displayed a highly stable response to treatment and a rapidly developing clinical effect, that a therapy response could be predicted in the first 12 weeks, and that the incidence of local postinjection reactions was low.

Interleikin 1 (IL 1) vpervye byl opisan v 40-kh go- dakh XX v. kak vyzyvayushchii likhoradku faktor, vysvobozh- daemyi aktivirovannymi leikotsitami. V to vremya on na- zyvalsya «pireksin» ili «endogennyi pirogen» [1]. Kak pravilo, kletki organizma ne sposobny k spontannomu sintezu IL 1, a otvechayut ego produktsiei na infektsiyu, deistvie mikrobnykh toksinov, vospalitel'nykh agentov, drugikh tsitokinov, aktivirovannykh komponentov komple- menta ili sistemy svertyvaniya krovi [2, 3].

Interleikin 1 (IL 1) vpervye byl opisan v 40-kh go- dakh XX v. kak vyzyvayushchii likhoradku faktor, vysvobozh- daemyi aktivirovannymi leikotsitami. V to vremya on na- zyvalsya «pireksin» ili «endogennyi pirogen» [1]. Kak pravilo, kletki organizma ne sposobny k spontannomu sintezu IL 1, a otvechayut ego produktsiei na infektsiyu, deistvie mikrobnykh toksinov, vospalitel'nykh agentov, drugikh tsitokinov, aktivirovannykh komponentov komple- menta ili sistemy svertyvaniya krovi [2, 3].

AIM To study efficacy and tolerance of leflunomide (LF) in patients with polyarticular psoriatic arthritis (PsA). MATERIAL AND METHODS The analysis was made in 58 patients: 35 (60%) females, 23 (40%) males. Mean age of the patients was 44.9 +/- 10.8 years, PsA duration--9.7 +/- 7.5 years. LF was given by a standard scheme: 100 mg/day for 3 days then 20 mg/day for 6 months. PsA activity was assessed by the number of painful and inflamed joints, pain intensity, VAS, Likert quastionnaire data. Functional status of the patients was estimated according to Health Assessment Questionnaire. Skin syndrome was rated by pruritus scale, 5-score Likert scale and PASI (psoriasis Area and Severity Index). PASI was applied in patients with affected area 3% at least. Quality of life was assessed by Dermatology Life Quality Index. Basic criterion of the treatment efficacy was response by PsARC (Psoriatic Arthritis Response Criteria). The additional evaluation was made of the number of patients with improvement by criteria ACR 20, ACR 50 and ACR 75 as well as those with 50 and 75% response by PASI (PASI 50 and PASI 75). RESULTS To the end of the treatment the number of painful and inflamed joints decreased significantly (p < 0.001) as well as pain, VAS and Likert scores. To the treatment month 6 HAQ index diminished by 36%. According to PsARC, of 58 patients 36 (62%) patients responded. Improvement by ACR 20 was observed in 34 (59%) of 58 patients. PASI changes were not significant (p = 0. 144). DLQI diminished by 36% (p = 0.028). As shown by acute phase indices, LF had no effect on ESR (p = 0.45). CRP fell significantly to treatment month 3 (p < or = 0.001) and further changes were insignificant. LF tolerance was satisfactory. Ten patients (17%) withdrew because of side effects which were standard. Severe myelo- and hepatotoxicity were absent. CONCLUSION LF is highly effective in therapy of polyarticular PsA and has satisfactory tolerance. Perspectives of further use of LF in combined treatment of PsA are associated with its potential to inhibit the disease progression.

где g(u) – выбранная нами функция. Такая гипотеза звучит как «непредсказуемость g» или «условная независимость g». Например, если g(u) = u, мы говорим о «непредсказуемости среднего», а если g(u) = sign(u), то о «непредсказуемости знака». В принципе, понятие «непредсказуемость дисперсии» соответствует выбору g(u) = (u−E[u])2, но здесь, к сожалению, фигурирует неизвестный параметр E[u]. Зато легко говорить о совместной «условной независимости среднего и дисперсии», если g(u) = (u, u2)′. Еще раз подчеркнем, что выбор g(u) диктует то единственное (если функция g(u) скалярна) свойство непредсказуемости, которое будет проверяться обсуждаемыми тестами. При этом одно из таких свойств может быть не связано с другим. Например, возьмем чистую ARCH-модель yt = μ + εt, где εt|It−1 ∼ N ( 0, σt ) , а μ 6= 0. Здесь имеется условная независимость среднего, так как E [yt|It−1] = μ = const. Очевидно, что ряд, подчиняющийся такой модели, не обладает свойством условной независимости дисперсии, ибо σt 6= const. Менее очевидно (см. Christoffersen & Diebold, 2006), что он к тому же знакопредсказуем:

The results of the analysis of diagnostic significance of examination of natural antibodies (Nab) to agiotensin-converting enzyme (ACE) and its substrates in the serum of hypertensive patients indicate that concentration of Nab to ACE differ from this mean concentration in donors. An elevated level of Nab to ACE may be considered as a compensatory reaction to increased content of the enzyme in vascular endothelium and blood flow. The same patients were examined for antibodies to peptide angiotensin II (AT-II). Enzyme immunoassay has shown that a significantly elevated level of antibodies to AT-II was only in 5 examinees. The same patients had also high Nab to ACE. The study of a group of ischemic heart disease patients with adverse effects attributed to bronchial affection treated with enalapril and diroton (ACE inhibitors) demonstrates that deterioration of cough and external respiration function is not related to exacerbation of existing chronic pulmonary inflammation. None of the patients had elevated body temperature or inflammatory changes in the blood, other signs of inflammation. Enzyme immunoassay also proved that the initial level of Nab equaled mean value for donors or was insignificantly lower. Blood serum patients with side effects contained a significantly (p < 0.02) elevated quantities of Nab to bradikinin vs initial values. Thus, the proposed method of solid phase enzyme immunoassay quantifies Nab to ACE and its substrates in the patients.

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.