[Experience of anticipatory therapy with IL-6 receptor inhibitors and perspectives for its use in the evolution of COVID-19].

The Advisory Board chaired by the chief specialist in infectious diseases of the Ministry of Health of Russian Federation, Professor V.P. Chulanov was held on June 18, 2022 in Saint Petersburg. Aim. The main purpose of the Board was following discussion: the analysis of the real-world data of levilimab as an anticipatory therapy for COVID-19 in hospitalized patients; the review of the experience and perspectives of levilimab as an anticipatory anti-inflammatory option for outpatient patients who meet defined clinical and laboratory criteria. Results. The analyzed data on clinical efficacy and safety formed the basis of recommendations proposed by experts for the use of levilimab in the inpatient and outpatient medical care for COVID-19.

[Clinical value of antibodies in inflammatory bowel diseases].

Inflammatory bowel disease IBD (Crohns disease CD, ulcerative colitis UC) immune-mediated diseases of the digestive tract of unknown etiology. The basis of the pathogenesis of IBD is a violation of the protective mechanisms of the intestinal barrier as a result of a complex interaction of environmental factors, a genetic predisposition and defects in the activation of the immune response in the lymphoid tissue of the intestinal mucosa. Three groups of antibodies are detected in the sera of IBD patients: autoantibodies, antimicrobial antibodies and antibodies to peptide antigens. In CD, the most useful diagnostic markers are ASCA; in UC patients pANCA. Antibodies are not among the diagnostic criteria for CD and UC, the diagnosis of which is traditionally made on the basis of a complex of clinical, radiological, endoscopic and histological signs, but can be used as useful additional non-invasive markers for early diagnosis, assessment of clinical phenotypes, prognosis and effectiveness of treatment of these diseases.

[Survival of bDMARDs in bionaive patients with rheumatoid arthritis: data from a retrospective 12-month follow-up].

AIM: Analysis of survival on biological therapy in previously bionaive patients with rheumatoid arthritis (RA) during the first year of therapy in real clinical practice. MATERIALS AND METHODS: The retrospective study included 204 adult patients with RA. In the hospital, patients were first prescribed therapy with various biological disease-modifying antirheumatic drugs (bDMARDs): infliximab, adalimumab, etanercept, certolizumab pegol, tocilizumab, abatacept (ABA), rituximab (RTM). Patients were divided by age in accordance with the classification adopted by WHO. Clinical forms of RA were presented: RA, seropositive for rheumatoid factor, RA, seronegative for rheumatoid factor, RA with extra-articular manifestations, adult-oneset Stills disease, juvenile RA. The reasons for the cancellation of bDMARD during the first year of treatment were: insufficient effectiveness (including primary inefficiency), adverse events, administrative reasons, clinical and laboratory remission, death. RESULTS: A year after being included in the study, treatment was continued in 92 (45%) patients and was discontinued in 112 patients. The average time of treatment amounted to 0.750.33 years. The longest duration of treatment was in the RTM and ABA groups (0.920.22 and 0.830.29 years, respectively). In 56 (50%) patients, bDMARD was canceled due to insufficient effectiveness (including primary inefficiency), 28 patients (25%) due to the development of adverse reactions, 19 (17%) patients for administrative reasons, 7 (6.25%) patients due to drug remission. During the first year of therapy, there were 2 (1.75%) deaths due to severe comorbid conditions in patients, one of whom received RTM, the other tocilizumab. CONCLUSION: Study showed that 45% of patients with RA continue treatment with first-time bDMARD for more than 12 months. The most common reason for discontinuation of therapy was its lack of effectiveness. The best survival rate of bDMARDs was observed in RTM and ABA. When selecting bDMARD in each case, it is necessary to take into account the continuity at all stages of treatment.

Efficacy and tolerability of abatacept treatment: results of 12 months observation.

AIM: This article reports 1-year clinical outcomes of patients with rheumatoid arthritis (RA) receiving abatacept (ABA) therapy. MATERIALS AND METHODS: Patients (n=91) with high RA activity (DAS28 = 5.1 ± 1.0) and an inadequate response on synthetic DMARDs (mainly methotrexate, 70.3%) and biologics (mainly TNF-α inhibitors, 93%) were included in the study. The majority of patients were middle-aged (49 ± 13.5) womens, RF (72.5%) and ACPA (77%) positive, with moderate functional impairment - HAQ = 1.4 (0.9-2). ABA were administered IV, 10 mg/kg according to the standard scheme. The evaluation of the effectiveness of the therapy was carried out according to the EULAR / ACR 2011 criteria using SDAI, CDAI, HAQ and the intention to treat approach. RESULTS: ABA led to a significant (p <0.05) decrease activity of RA. Clinical improvement according to EULAR criteria after 6 months of treatment was registered in 70.9%, after 12 months 63%. Almost a third of patients (28.7%) achieved a good response after 3 months of therapy, 39,2% - after 6 months and 39% - after 12 months. The retention rate of ABA therapy after 6 months was 77%, after 12 months - 60%. There were no significant differences between "bio-naive", 1 Bio and ≥2 Bio groups in achieving EULAR response. A good response was achieved in 38%, 38% and 43%, respectively, but the lowest number of non-responders was registered in ≥2 Bio - 38%, 36% and 43%. ABA significantly improved functional status of patients, after 12 months a marked and moderate improvement in the HAQ was achieved in 39% and 21% of patients, respectively. Adverse events (AE) were registered in 22 patients. The most frequent AE were upper respiratory tract infections - 11 (12%) patients. CONCLUSION: Abatacept was effective in the overall population, and in all subgroups of patients. It has shown significant improvement of clinical and functional status in patients who had an inadequate response to previous therapy. ABA has a good safety profile. AE were registered only in a small number of patients.

[Modern look at the problems of investigation of antinuclear antibodies in systemic lupus erythematosus (literature review).]

In the review, topical aspects of the study of antinuclear antibodies (ANA) in systemic lupus erythematosus (SLE) are considered. ANA is the main serological marker of SLE. In the sera of patients with SLE, antibodies to DNA, histones, nucleosomes, extractable nuclear antigens (Sm, U1 ribonucleoprotein, Ro / SSA, La / SSB, ribosomal protein P), nucleolar antigens and other cellular structures are detected. The ANA study using indirect immunofluorescence on HEp-2 cells (IIF-HEp-2) is recommended as a standard screening test for the diagnosis of SLE. The use of automated systems for the interpretation of cellular fluorescent tests contributes to the standardization and improvement of the reproducibility of the IIF. A new international nomenclature of types of nuclear, nucleolar (nucleolar), cytoplasmic and mitotic luminescence of ANA in IIF-HEp-2, including 28 variants of anticell ("Anti-cell" - AC) patterns was developed. In the practice of clinical diagnostic laboratories, high-performance automated methods for the determination of ANA based on ELISA, immunoblot, fluorescent, chemiluminescent and multiplex immunoassay are widely used. New mono- and multiplex methods of solid-phase analysis are expediently used as confirmatory reflex tests for the detection of varieties of antigen-specific ANA in patients with SLE with positive results of IIF-HEp-2. Identification of ANA profiles using multiplex technologies is a useful tool for implementing a personalized approach to diagnosis, evaluation of activity, prognosis, clinical and immunological subtypes, and the effectiveness of SLE therapy. The need for an ANA study not only to confirm the diagnosis of SLE, but also to identify the disease in the early and preclinical stages with the intention to prevent the development of the pathological process is discussed. Detection of monospecific anti-DFS70 antibodies allows to exclude the diagnosis of SLE inANA IIF-HEp-2 positive subjects. Presented is a modern algorithm for testing ANA with SLE.

[Clinical value of multiplex immune assay of antinuclear antibodies in systemic lupus erythematosus.]

A promising trend in the diagnosis of systemic autoimmune diseases is the multiplex immune assay (MIA) of autoantibodies and other laboratory biomarkers using microchips. The aim of the work was to study the diagnostic and prognostic significance of MIA antinuclear antibody (ANA) profiles in systemic lupus erythematosus (SLE). 94 patients with SLE, 70 patients with other rheumatic diseases and 30 healthy donors were examined. ANA (antibodies to doublestranded - dsDNA, Sm, SS-A/Ro, SS-B/La antigens, nucleosomes, ribosomal protein P-RibP and ribonucleoprotein - RNP-70) were determined in the serum by MIA using the xMAP technology. In MIA, antibodies to dsDNA, Sm and RibP have a high diagnostic specificity (Sp) (95.0-99.0%) and a likelihood ratio of positive results (LR+) (9.67-15.0), i.e. are the most "useful" diagnostic tests, and antibodies to RNP-70, SS-A/Ro and nucleosomes are classified as "useful" tests for the diagnosis of SLE (Sp: 84.0-95.0%, LR+> 2.0). Determination of profiles from 3 or more antigen-specific ANA by MIA increases the Sp method to 98.0-100%, and the LR+ - to the maximum values. Profiles from 7 subpopulations of ANA (antibodies to dsDNA, Sm, RibP, SS-A/Ro,SS-B/La, nucleosomes and RNP-70, 57.9%, 71.9%, 82.5%, 61.4 %, 84.2%, 50.9%, 84.2%) were found in the chronic variant of SLE. In the acute course of the disease, 4 subpopulations of ANA are simultaneously detected (antibodies to dsDNA, Sm, SS-A/Ro and nucleosomes, 77.3%, 45.5%, 40.9% and 72.7%); in subacute course there are 2 subpopulations of ANA (antibodies to dsDNA and nucleosomes, 53.3% and 46.7%). The activity index of SLEDAI-2K positively correlates with the concentration of antibodies to dsDNA (r = 0.55, p < 0.05), nucleosomes (r = 0.65, p < 0.05), RibP (r = 0.32; p < 0.05) and Sm (r = 0.36, p < 0.05) in the blood. There was no reliable relationship between the production of varieties of ANA and the index of organ damage. Mucocutaneous disorders, lupus-nephritis and neurolupus were most often associated with the detection of antibodies to dsDNA (53.2-64.0%), nucleosomes (55.3-66.0%), SS-A/Ro (38.0-40.4%) and Sm (27.8-36.2%). MIA of ANA profiles is an important tool for implementing a personalized approach to diagnosis, evaluation of activity, course and clinical and immunologic subtypes of SLE.

[Pharmacotherapy for rheumatoid arthritis in the early 21st century: Russian and international experience].

The paper summarizes the data of international and Russian studies concerning current approaches to the pharmacotherapy of rheumatoid arthritis. Particular emphasis is placed on the substantiation of the treat-to-target concept, on the efficacy and safety of genetically engineered biological agents, including the inhibitors of tumor necrosis factor, interleukin-6 receptors, T-lymphocyte co-stimulation, and anti-B-cell therapy.

[Immunogenetic aspects of early rheumatoid arthritis].

The study is aimed to investigate the distribution of alleles of HLA-DRB1 gene in patients with early rheumatoid arthritis and healthy individuals in Russian population, and evaluate their significance as molecular genetic markers of rheumatoid arthritis predisposition and protection. The association between alleles of HLA-DRB1 genes, antibodies to cyclic citrullinated peptides and IgM rheumatoid factor was also studied. Low and high resolution HLA-DRB1 genotyping were compared. In the cohort of patients with early rheumatoid arthritis, the alleles of HLA-DRB1 gene were found to be markers of rheumatoid arthritis protection/risk, especially in the homozygous state. They determined production of antibodies to cyclic citrullinated peptides but were not associated with rheumatoid factor IgM levels. These findings support different autoimmune mechanisms of rheumatoid arthritis pathogenesis.

[Clinical experience with infliximab administration in patients with rheumatoid arthritis (according to Russian register data)].

AIM: To analyse the data on infliximab administration (efficacy, tolerance, toxicity) in patients with rheumatoid arthritis (RA) in Russia by clinical evidence provided by the multicenter observation trial. MATERIAL AND METHODS: The register included 297 patients with a documented diagnosis of RA who had for the first time treated with infliximab. The efficacy of the drug was evaluated by EULAR criteria based on the dynamics of DAS28 index. RESULTS: The results of infliximab treatment show good response of RA patients to standard courses of infliximab. A good/satisfactory effect by EULAR criteria was achieved in 80% patients to week 22 of therapy and in 85% to week 46. After 6-month (22 week) infliximab treatment a good effect was achieved in 15.7% patients, satisfactory--in 64.7%; 19.6% patients did not respond. Remission (DAS28 < 2.6 units) was achieved in 7% patients. Infliximab tolerance was satisfactory. Non-severe infusion reactions were most frequent unwanted effects. To treatment week 22, ten patients developed serious side effects causing the drug discontinuation. CONCLUSION: The results of the Russian register confirm a high therapeutic potential and satisfactory tolerance of infliximab observed in real rheumatological practice of the treatment of severe RA. These results agree with those of European registers of infliximab.

[Administration of monoclonal antibodies to B-lymphocytes (rituximab) in rheumatoid arthritis in Russia].

AIM: To assess efficacy and tolerance to anti-B-cell drug rituximab in therapy of rheumatoid arthritis (RA) by the data of RF register of this drug. MATERIAL AND METHODS: Rituximab was studied in 42 patients with high RA activity. 37 patients received rituximab according to a conventional scheme: 2 intravenous 1000 mg infusions with a 2-week interval. The rest patients received 2 intravenous 500 mg infusions. The response was evaluated by DAS28 index. RESULTS: Rituximab administration resulted in almost complete elimination of B-cells from peripheral blood. This produced a significant positive effect manifesting with reduction in the number of inflamed and painful joints. This trend was evident to observation week 8 reaching maximum to week 24. Clinical response correlated with decline of inflammation as shown by ESR and CRP. According to DAS28 index, good and satisfactory results were registered in 8 weeks in 62% patients, in 16 weeks--in 86%, in 24 weeks--in 100%. Rituximab tolerance was good. CONCLUSION: Effective treatment with rituximab for rheumatoid arthritis opened a new perspective in antirheumatic biological therapy and demonstrated an important role of B-cells in the disease development. This drug is recommended for wide use in the treatment of severe rheumatoid arthritis resistant to prior therapy including TNF-alpha blockers.

[Early diagnosis of rheumatoid arthritis in modern clinical practice (results of a follow-up of a Moscow cohort of early arthritis patients participating in the program RADICAL)].

AIM: To estimate potentialities of early diagnosis of rheumatoid arthritis (RA) diagnosis in clinical practice in the course of the RADICAL program. MATERIAL AND METHODS: Of 366 patients participating in the trial 61 (16.7%) were males and 305 (83.3%) were females at the age of 47.76 +/- 14.1 years. The longest duration of the symptoms before consulting a doctor was 51 weeks, mean duration--5.7 weeks, 55% patients had the symptoms for 3 weeks. All the patients have undergone laboratory examination including leukocyte count, platelet count, estimation of ESR, concentration of C-reactive protein (CRP), rheumatoid factor (RF) and antibodies to a cyclic citrullated peptide (ACCP); roentgenography of the wrists and feet. On demand, antinuclear factor (ANF) and HLA-B27 were investigated. RA was diagnosed on the basis of ACR classification criteria. If the criteria were not complete at the moment of the study, the patient was referred to the group of "undifferentiated arthritis" (UA). The patients were examined before the treatment, 6 and 12 months later. The treatment was made according to Russian clinical recommendations. RESULTS: Prior to admission to hospital, 58% patients were suspected for RA, 18.3%--osteoarthrosis (OA), 14%--reactive arthritis. 18.9% were not diagnosed, other diagnoses were considered in 12.6% patients. At primary examination RA was diagnosed in 212 (57.9%) patients, UA was in 133 (36.3%) patients, 21 (5.7%) patients had other diagnoses. Twelve months later RA, UA and other diseases were diagnosed in 256 (69.9%), 70 (19.1%) and 40 (10.9%) patients, respectively. CONCLUSION: A 3-stage algorithm of early RA diagnosis is proposed. At the stage of the first contact with the patient in an outpatient clinic a valid RA suspition with consideration of modified EULAR criteria must be formulated. At the second stage a district rheumatologist must examine the patient outpatiently with determination of ACR classification criteria. In diagnosis verification the treatment must be started according to APP and EULAR clinical recommendations. If RA diagnosis can not be verified or rejected, the patient must be refered to hospital (stage 3). If verification of RA diagnosis is impossible, the diagnosis should be formulated as UA.

[Neutralisation of interferon gamma--a new trend in therapy of rheumatoid arthritis].

AIM: To evaluate objectively therapeutic potentialities of a novel method of biological therapy--blocking interferon gamma (IF-gamma)--by means of a comparative analysis of using antibodies to IF-g (anti-IF-gamma) and tumor necrosis factor alpha (anti-TNF-alpha) in resistant rheumatoid arthritis (RA). MATERIAL AND METHODS: A double blind trial included 55 patients with resistant RA. They received 5 intramuscular injections of anti-IF-gamma (n = 20), anti-TNF-alpha (n = 20) and placebo (15 patients). The results were assessed on the treatment day 7 and 28. RESULTS: 16 patients withdrew because of the treatment uneffectiveness (2 from the group on anti-IF-g, 3--on anti-TNF-alpha, 11--on placebo). To the treatment day 28 the patients given anticytokines achieved significant improvement of all clinical indices while placebo group had no improvement. The highest response was observed in the group on anti-IF-gamma (ACR 70). As shown by ultrasound investigation, a significant reduction of the synovial membrane thickness took place also in administration of anti-IF-gamma. Most frequent side effect of the anticytokine therapy was mild dermatitis at injection site on treatment day 8-11. CONCLUSION: Therapeutic efficacy of anti-IF-gamma was comparable with efficacy of anti- TNF-alpha and even was superior in some aspects. The block of IF-gamma holds much promise in the treatment of RA.

[State-of-the-art biological therapy of rheumatoid arthritis].

State-of-the-art state of biological therapy of rheumatoid arthritis is analyzed. Its pathogenetic reasons are represented. Main direction of this therapy, such as blocking of tumor necrosis factor alpha and interleukin-1, inhibition of interaction between T-lymphocytes and antigen representing cells, elimination of B-cells, are considered. Special attention is devoted to new perspective methods of biological treatment, among which the special interest has first applied in RAMS Institute of Rheumatology method of interferon-gamma neutralization. Combination of anti-inflammatory, immune depressive and significant destructive actions leads to significant curative effect of biological therapy, exceeding results of the use of classic basic drugs including methotrexate. The achievement of clinical remission of rheumatoid arthritis first became the real aim of its treatment, and methods of biological therapy in contrast to former "disease-modifying" remedies could be considered as real "disease-controlling" drugs. Biological therapy revolutionized modern rheumatology and in the nearest years would demonstrated new fundamental accesses.

[Prospects of the anti-cytokine therapy in rheumatoid arthritis]. / Perspektivy antitsitokinovoi terapii revmatoidnogo artrita.

The development and introduction of the anti-cytokine therapy applicable to rheumatoid arthritis (RA) is a most significant achievement in RA therapy. A high degree of purpose-orientation and selectivity of the mentioned method ensuring a high therapeutic effect and providing, simultaneously, for defining a number of important chains in RA pathogenesis is an essential advantage of the discussed approach. The clinical use of neutralization of key cytokines TNF-alpha, IL-1 and IF-gamma is a serious progress within this trend. Possibilities of developing new directions of the cytokines therapy are preconditioned, to a great extent, by the role of new, including little-studied cytokines, in the evolution of immune inflammation. A search for more simple low-molecular inhibitors of cytokines, which do not cause any tolerance-related problems, is another important trend. Hopefully, a further study of anti-cytokines and of their application in combination with other antirheumatic drugs will improve the general treatment results and outline new opportunities in antirheumatic therapy.

[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.

[Double-blind trial of the effectiveness of antibodies to interferon-gamma and tumor necrosis factor-alpha in rheumatoid arthritis (preliminary results)]. / Dvoinoe slepoe issledovanie éffektivnosti antitel k interferonu-gamma i faktoru nekroza opukholi-alpha pri revmatoidnom artrite (promezhutochnye rezul'taty).

AIM: Objective evaluation of the effectiveness and tolerance of antibodies to interferon-gamma (TNF-gamma) vs those to tumor necrosis factor-alpha (TNF-a) and placebo in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: A double blind randomised controlled trial of effectiveness and tolerance of anticytokine antibodies was conducted in 30 patients with active RA. The drugs were given i.m. for 5 consecutive days. The results were assessed on day 7 and 28. RESULTS: Antibodies to both cytokines produced a marked therapeutic effect in RA, much greater than placebo effect. Improvement by day 7 was achieved in 9, 7 and 2 patients on anti-TNF-a, anti-INF-g and placebo, respectively. By day 28 in 8, 8 and 0 patients, respectively. Tolerance of anticytokines was good. Significant differences between the results of treatment with anti-INF-g and anti-TNF-a were not found. CONCLUSION: Administration of antibodies to INF-a proved ineffective and well tolerated method in the treatment of severe RA resistant for a number of standard basic drugs. Anti-IFN-a holds great promise when used in combination with classic antirheumatoid drugs, primarily with methotrexate.

[New approaches to biological immunomodulation therapy of rheumatoid arthritis: neutralization of basic cytokines]. / Novye podkhody k biologicheskoi immunomoduliruiushchei terapii revmatoidnogo artrita: neitralizatsiia osnovnykh tsitokinov.

AIM: Investigation of efficacy of antibodies ot interferons in rheumatoid arthritis (RA) versus relevant efficacy of the tumor necrosis factor (TNF), comparison of the above cytokines in monotherapy and combined treatment. MATERIALS AND METHODS: An open controlled randomized trial of clinical benefit and tolerance of anticytokine antibodies was performed in a group of RA patients at stage II, III and IV (1, 20 and 4 patients, respectively). The activity degree II and III was in 10 and 15 patients, respectively. All the patients had articular functional insufficiency of the second degree. 21 patients failed previous therapy with basic drugs including immunodepressants. RESULTS: The anticytokine antibodies proved to be highly effective in RA. Positive changes in teh disease activity were achieved early after the end of the 5-day course in 88% of patients. The most definite immediate therapeutic effect was noted in usage of TNF antibodies both in monotherapy and in combination with other anticytokines. Long-term effect was the best in patients given antibodies to interferon gamma. Interferon-alpha antibodies produced weaker effect. The combined treatment had no advantages over the monotherapy. CONCLUSION: A significant therapeutic effect of antibodies to interferon-gamma is indicative of an important role of this cytokine in RA pathogenesis. Anticytokine antibodies are promising as a component of combined therapy of patients with resistant RA.