Efficacy and Safety of Levilimab in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: 56-Week Results of Phase III Randomized Double-Blind Placebo-Controlled Trial SOLAR.

. Previously, 24-week results of phase III double-blind, placebo-controlled randomized clinical study (SOLAR) of levilimab in subjects with active rheumatoid arthritis (RA) proved a superiority of levilimab over placebo. Here, we present 1-year efficacy and safety data of the SOLAR study. OBJECTIVES: . To evaluate the efficacy and safety of levilimab in combination with methotrexate (MTX) in subjects with MTX resistant active RA. MATERIALS AND METHODS: : The study was conducted at 21 clinical sites in Russia and Belarus. All randomized subjects have completed the study between November 2019 and October 2021. Adult subjects (154) aged ≥18 years with confirmed diagnosis of RA1 were randomly assigned (2 : 1) to receive either levilimab (162 mg, SC, QW) + MTX (n = 102) or placebo + MTX (n = 52). After W24 of the study all subjects continued to  receive open label levilimab. Subjects who have achieved DAS28-CRP ≤ 2.6 at W24 were switched to maintenance (Q2W) regimen of levilimab at W28 (LVL QW/Q2W and PBO/LVL Q2W arms). Those with DAS28-CRP > 2.6 at W28 continued with QW regimen (LVL QW and PBO/LVL QW arm). The PBO/LVL Q2W arm contained only one subject, thus not included in the analysis. The efficacy analysis was performed in a population of all randomized subjects. Those with missing data due to study discontinuation or rescue therapy prescription were considered non-responders. Otherwise, the analysis was performed on complete cases. Safety was assessed through monitoring of adverse events (AEs) in a population of those, who received at least on dose of LVL (n = 152). RESULTS: : Better response to treatment was observed in LVL QW/Q2W as it composed of those who reach DAS28-CRP ≤ 2.6 at W24. At this time point 15/27 (55.6%) of them achieved ACR70; 23/27 (85.2%) achieved DAS28-CRP remission (<2.6) and 7/27 (25.9%) achieved ACR/EULAR2011 remission of RA. After switching to LVL Q2W, rates of ACR70 and DAS28-CRP<2.6 did not significantly changed until W52: 17/27 (63.0%) and 21/27 (77.8%), respectively, yet the proportion of subject with ACR/EULAR 2011 remission further increased and reached 12/27 (44.4%). LVL QW arm was diminished by subjects who achieved high response to treatment at W24 and composed LVL QW/Q2W arm. Thus, ACR70, and remissions rate in this arm was close to zero at W24. However, continuation of LVL QW in those who not achieved DAS28-CRP ≤ 2.6 at W24 induced ACR70 response in 37/75 (36.0%), DAS28-CRP remission in 35/75 (46.7%) and ACR/EULAR 2011 remission in 8/75 (10.7%) at W52. The most common adverse events (reported in ≥5% of subjects) were blood cholesterol increase (30.3%), ALT increase (23.0%), lymphocyte count decrease (17.1%), ANC decrease (16.4%), blood triglycerides increase (13.8%), bilirubin increase (11.2%), AST increase (9.9%), WBC decrease (9.9%), IGRA with Mycobacterium tuberculosis antigen positive (7.2%), and injection site reactions (5.9%). No deaths occurred. CONCLUSIONS: : Open label period confirmed the lasting efficacy and safety of levilimab in combination with MTX in subjects with MTX resistant active RA and suggested the possibility of switching to levilimab maintenance regimen (once every 2 weeks) (Q2W) in those who achieved remission of RA at week 24.

[Aerobic exercise and fatigue indices in rheumatoid arthritis patients in the health resort care setting]. / Aerobnye uprazhneniya i pokazateli ustalosti u bol'nykh revmatoidnym artritom v usloviyakh sanatorno-kurortnogo lecheniya.

Fatigue is one of the most common symptoms of rheumatoid arthritis (RA). There is strong evidence that physical activity is an effective way to reduce fatigue. OBJECTIVE: To evaluate the effectiveness of aerobic exercise (walking) to reduce fatigue in RA patients in the health resort setting. MATERIAL AND METHODS: The study involved 102 female patients with RA (age 54.38±11.3 years, body mass index 20-29 kg/m2, DAS28-ESR ≤3.2, with severe fatigue of VAS ≥50) who received 21 days of health resort treatment. The health-improving and therapeutic complex includes dosed physical activity, aerobic exercises (walking). Visual analog scale (VAS0-100) and Bristol Rheumatoid Arthritis Fatigue Scale-Numerical Rating Scale (BRAF-NRS V2) were used to assess fatigue, and the 50-meter walking test was used to evaluate the functional status of patients. RESULTS: A correlation between walking duration and the number of steps at a distance of 50 m (p<0.001) as well as between these indices and fatigue (p<0.001) was shown. A positive effect of a standard three-week medical rehabilitation program for patients with RA on fatigue NRS severity (p=0.003) and NRS effect (p=0.037), as well as on patients' functional status (reduced time spent on the 50-meter test, p=0.01) was demonstrated. When comparing groups of RA patients with low (group 1, <5000-6000 steps per day) and optimal (group 2, ≥7000-8000 steps per day) aerobic exercise, positive results were noted in the short term (at 3 weeks) (p<0.001). CONCLUSION: Aerobic exercise is a promising intervention for treating fatigue in rheumatoid arthritis patients. Medical rehabilitation in a resort setting is the best starting point to encourage performing regular physical activity, as well as the best way to develop exercise programs tailored to rheumatoid arthritis patients.

Emulsive polymerization as a method of enzyme modification preserving biological properties of nanostructures.

The proposed method of emulsive polymerization provides the possibility of modifying and obtaining insoluble forms of superoxide dismutase (SOD), glutathione reductase, and streptolysin-O preserving nanoobjects (conformationally active centers and antigenic determinants) in their native states. Apart from enzymatic and immunological properties, the samples acquired some new features: resistance to high temperature, resistance to 3 M KCNS solution and buffer solutions with high concentration of hydrogen ions, and resistance to preserving solutions. Magnetic properties provide the possibility of simplifying enzyme-linked immunosorbent and immunofluorescence assays. In addition, sensitivity of these assays was by an order of magnitude higher and the specificity fully preserved. Taking all the facts into account, we prepared agents for long-term and repeated use. Due to preserved enzymatic properties, insoluble forms of SOD and glutathione reductase can be considered as a tool for correction of peroxide-antioxidant balance and associated immunological abnormalities.

[Interrelationship between antibodies to enzymes of antioxidant system and cardiac involvement in patients with systemic scleroderma].

In blood of patients with systemic scleroderma we detected antibodies to the antioxidant system enzymes. Level of specific immunoglobulins rose with increase of the disease activity. Antioxidant system of the body is represented by a number of enzymes called to negate pathogenic effect of active forms of oxygen. In pathological states balance between factors of aggression and defense is disturbed. This leads to even more deep damage of tissues. Taking into consideration important role of immunological shifts in development of atherosclerosis one can suggest that autoantibodies to enzymes represent one of mechanisms of derangement of the work of enzymatic systems. Significantly higher levels of antibodies were detected in patients with symptoms of involvement of the cardiovascular system. We measured blood serum antibodies according to elaborated by us method of indirect immuno enzyme analysis with the use of immobilized antigenic forms of enzymes.

[Clinical and pathogenetic significance of antibodies to antioxidative enzymes in patients with Raynaud's syndrome].

Patients presenting with systemic scleroderma were found to have antibodies to antioxidative enzymes the levels of which increased with activity of the disease. Taking into account the important role of immune disorders in the development of systemic sclerosis, it can be conjectured that antienzyme antibodies may cause dysregulation of enzymatic systems. Serum antibodies were detected by the original modification of indirect enzyme immunoassay using immobilized antigenic forms of enzymes. All patients with high antibody titers presented with class II-IV Raynaud"s syndrome (RS). Pathogenetic mechanisms of RS are complicated and poorly known, it is supposed to be a multifactor pathology associated with disturbances in neural, vascular, mediator, and immune systems. Reperfusion and free oxygen radicals may also contribute to the development of ischemia in RS. The antioxidative system is known to involve a number of enzymes that neutralize pathogenic effects of free oxygen species. Disturbance of equilibrium between aggressive and protective factors under pathological conditions leads to further aggravation of tissue lesions. The presence of antienzyme antibodies in the blood of patients with primary RS may be regarded as an unfavourable prognostic factor preceding a systemic disease of connective tissue.

[Antibodies to enzymes of purine metabolism as a factor of gastrointestinal tract lesions in systemic scleroderma].

Antibodies to Adenosine Deaminase (AD) and Guanin Deaminase (GDA) were founded in sera of systemic sclerosis (SS) patients, their concentration positive correlated with activity of disease. Increased levels of antibodies to AD and GDA correlated with the severity of gastrointestinal tract injury (especially pancreatitis and hepatitis). It is shown that level of antibodies to AD and GDA differs reliable from contents of these antibodies, in sera of healthy persons. It is shown that AD enzymatic activity was decreased, while activity of GDA was increased. The antibodies to enzymes may be one of the possible causes of change of enzymes activity in sera of SS patients. The method of immunoenzyme determination of level of antibodies to AD, G on the basis of immobilized form of magnet sorbent was developed for immune diagnostics of SS.