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.

Eustrongylides (Nematoda:Dioctophymatidae): Epizootology and Special Characteristics of The Development Biology.

Eustrongylides spp. are the nematodes from the Dioctophymatidae family which are potentially dangerous for the mammal's heath. The first aim of the present research is to describe the biology, developmental characteristics and epizootology of the Eustrongylides spp. nematode. Eustrongylidosis is a parasitic disease commonly occurring in the countries with temperate continental, tropical and subtropical climate. The Eustrongylides spp. parasites are biohelmints with a complex life cycle. The development of the nematodes takes place in the aquatic environment and includes a vast range of intermediate, accidental and definitive hosts. It has also been reported in humans. The second aim of the research is to describe the clinical and pathomorphological changes in organs and tissues of the infected animals, and influence of biotic and abiotic factors on formation of the natural centers of spreading of eustrongylidosis; diagnostics of eustrongylidosis.

Dichotomy of Local Th1- and Systemic Th2/Th3-Dependent Types of Immune Response in Rheumatoid Arthritis.

Biomarkers of activity of rheumatoid arthritis were analyzed in the blood serum and synovial fluid of affected joints in 84 patients. Significant differences between the serum and synovial fluid levels were revealed for 10 of 17 analyzed biomarkers; the levels of IgM and proinflammatory cytokines TNFα, IL-1ß, IFNγ, and IL-6 were higher in the synovial fluid. The concentration of IL-10 in the synovial fluid was also elevated. In the peripheral blood, the content of antinuclear antibodies, circulating immune complexes, and cytokines IL-4 and TGF-ß was elevated. These findings attest to the development of local Th1 type immune response in affected joints paralleled by compensatory elevation of immunosuppressive cytokine IL-10 and systemic Th2/Th3 type immune response (judging from peripheral blood parameters) in patients with rheumatoid arthritis.

[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.

[Absorption of iodofolic acids by the cells of malignant tumors].

The uptake of 125-iodine labeled 3' iodofolic acid (I*F) and 3' iodo, 5 formyl tetrahydrofolic acid (I*FT) by the cells HeLa, ECV, L-41, human glioma, and rat glioma was studied. Human Embrionic Lung Fibroblasts (HELF) were taken for comparison as healthy cells. It was shown for *IF that its long-term uptake by cells L-41 and ECV is hundreds oftimes higher than those of HELF cells. The short-term uptake phase was studied for *IFT uptake. The dissociation constant was determined for a complex formed by *IFT and an acceptor in the HeLa cells, which is supposed to cause concentrative uptake of *IFT in cells. The dissociation constants of this acceptor complexes with folic acid, 3' iodofolic acid and 3',5'-diiodofolic acid were determined by competition with I*FT. The distribution ratio of *IF and *IFT in tissues of different organs of healthy mice and rats and rats with a sarcoma grafted on his thigh and glioma grafted into the brain was studied. As was shown there are large differences in the concentration of *IF and *IFT in the tumor and in the healthy tissue, *IF concentration in thigh muscle of healthy being 5 times lower than those in tumor grafted to the thigh, and *IFT concentration in healthy brain being 10 times lower than in brain tumor.

[Ultrasonic diagnostics of mediointimal hyperplasia as a predictor of atherosclerosis in old people].

The aim of the study was estimation of mediointimal hyperplasia of carotid artery for diagnosis of atherosclerosis in old people. 168 patients (94 male and 74 female) were in ultrasound investigation (Aloka 1100 in B-mode) of carotid, femoral arteries and abdominal aorta. Age 60-99 years old, mean 68.3. High level of blood cholesterin check in 41.46% patients. Low dencity lipoprotein mean 4.42 +/- 0.23 mmol/l, triglicerid 1.71 +/- 0.12 mmol/l, much more informative was mediointimal hyperplasia of posterior wall of carotid artery (regression rate r = 1.93). Ultrasound estimation of mediointimal hyperplasia of carotid artery is a safe, not expensive and informative method for diagnosis in screening of atherosclerosis in old people.

[Supportive antisecretory therapy in preventing duodenal ulcer recurrence].

Different points of view on the need to conduct supportive acid-suppressive therapy gave rise to this study. The study is aimed at evaluating the influence of the individual supportive therapy based on the results of intragastric pH-monitoring on the incidence of duodenal ulcers. The study is based on a two-year observation of 90 patients with duodenal ulcers. After the ulcers had scarred and the patients had been discharged from hospital, all the patients were divided into three groups for undergoing a follow-up supportive acid-suppressive therapy. As a result, it was revealed that the individually selected supportive antisecretory therapy controlled by intragastric pH-monitoring within two years of observation made it possible to reduce considerably the incidence of duodenal ulcer recurrence in comparison with traditional preventive treatment.

[Pharmacoeconomic evaluation of the efficacy of treating patients with duodenal ulcers].

High cost of medical care provided to the patients with duodenal ulcers requires improvement of treatment organization. This study is aimed at pharmacoeconomic evaluation of the efficacy of treating patients with duodenal ulcers. Two groups of patients were made up for the investigation. The first group was made up of patients who had undergone an individual antisecretory therapy based on intragastric pH-monitoring. The other group was made up of patients undergoing standard treatment without using intragastric pH-monitoring. Upon the comparison of the results in both groups, it was revealed that the "cost of illness" and "cost-efficacy" turned out to be lower in the group of patients where intragastric pH-monitoring for selecting individual antisecretory therapy was used.

Correction of anemia in patients with congestive heart failure increases resting energy expenditure.

BACKGROUND & AIM: Congestive heart failure (CHF) and anemia were reported to affect resting energy expenditure (REE). The aim of this study was to evaluate the effect of the correction of anemia on REE in subjects with CHF. PATIENTS AND METHODS: Nine anemic patients with compensated CHF and CRF were studied before and after correction of anemia. REE was studied by an open circuit indirect calorimeter, body composition by dual-energy-X-ray absorption and total body and extracellular water by multi-frequency bioelectrical impedence. Four anemic and 5 non-anemic CHF patients who did not receive any new treatment served as controls. RESULTS: After the correction of their anemia patients tended to increase weight (P<0.06), but no significant changes were observed in body composition. Daily caloric intake increased significantly (P<0.02). Ejection fraction increased (P<0.05) and pulse rate decreased significantly (P<0.001). REE and REEPP were in the normal range before correction but increased significantly afterwards (1402+/-256 vs. 1496+/-206 kcal/d, and 101+/-9 vs. 109+/-8, P<0.023 and P<0.006, respectively). CONCLUSION: Correction of anemia in patients with CHF increases their REE. This can be related either to improved tissue oxygenation and/or to increased caloric intake.

[The effect of enterosorption on the local immune processes in a toxic lesion of the large intestine]. / Vplyv enterosorbtsiï na mistsevi imunni protsesy pry toksychnomu urazhenni tovstoï kyshky.

The local immune homeostasis changed of the colon play a significant role in the pathogenesis of toxic colitis, induced by lead acetate. Chronic toxic colitis is accompanied by a considerable redistribution of plasmocytes-producers of the main immunoglobulins classes in the colon walls towards a primary IgA producers increase, a correlation between them and the local immune reactions tension and destabilization as well. Enterosorbent SCNP-2 influence on a pathological process in the colon under the chronic lead intoxication results in the local immune reactions improvement in the studied organ, its functional and structural elements impairment rate reduction as well as their adaptive properties increase.

Comparison of a vegetable-based (soya) and an animal-based low-protein diet in predialysis chronic renal failure patients.

There is some experimental evidence to suggest that progression of chronic renal failure (CRF) is slower on diets based on soya protein than on diets based on animal protein. We have compared the effect of a soya-based vegetarian low-protein diet (VPD) and an animal-based low-protein diet (APD) in 15 patients with CRF. 15 patients with CRF (51Cr-EDTA-measured glomerular filtration rate 15-50 ml/min/1.73 m2) were studied. In a randomized crossover trial, the patients were given each diet (each containing 0.75 g protein and 32 kcal per kilogram body weight) for a 6-month period. Nine patients completed the trial, 2 others dropped out because they could not tolerate the VPD, 3 because of unrelated medical complications, and 1 for technical reasons. The caloric intake was higher and the protein, phosphate and essential amino acid intake lower on the VPD than on the APD. The compliance with the suggested caloric intake was better with the VPD than with the APD (97 vs. 88% of recommended intake), as was the compliance with the suggested protein intake (94 vs. 112% of recommended intake) and with the suggested phosphate intake (102 vs. 116%). The mean glomerular filtration rate, as judged by 51Cr-EDTA, was similar after 6 months on each diet and remained unchanged throughout the entire year of the study. The rate of fall of glomerular filtration, as measured by the slope of 1/serum creatinine was slowed by 73% during the 1-year study period as compared with the prestudy period. Nutritional status (as measured by body mass index, midarm circumference, and lean body mass and percent body fat), serum transferrin, cholesterol and albumin, and total lymphocyte count were similar on the two diets. The serum albumin level on both diets, however, was significantly higher on the two diets than during the prediet period. Blood urea nitrogen, urine urea nitrogen, protein catabolic rate, and 24-hour urine creatinine and phosphate were lower on the VPD than on the APD. The 24-hour protein excretion was similar on the two diets. The two low-protein diets resulted in a slowing in the progression of CRF. A VPD is well tolerated in CRF and is associated with lower protein and phosphate intakes and a higher caloric intake than an APD and may, therefore, be used as a safe alternative or partial substitute for the usual APD in CRF.

[Treatment experience with rheumatoid arthritis patients during remission]. / Opyt lecheniia bol'nykh revmatoidnym artritom v period remissii.

94 rheumatoid arthritis (RA) patients were observed for 4-5 years to evaluate the effect of basic treatment and opportunities for prolonged remission. A regimen of combined treatment has been tested which allows for psychologic status of the patient, corrects weak points in the regulatory systems, affects mechanisms of nonspecific resistance. The combined treatment administered during RA remission has resulted in complete responses (remissions) more frequently, prolonged their duration. Destructive processes in the joints still present in remission were seen to slow down.

[The mechanism of the antioxidant action of D-penicillamine]. / Mekhanizm antioksidantnogo deistviia D-penitsillamina.

The mechanism of the antioxidative effect of D-penicillamine was studied under the conditions of NADPH- and CCl4-dependent lipid peroxidation in microsomes of rat liver and adrenalin autooxidation reaction. The antioxidative action of the drug was shown to be due to both its chelating properties and direct anti-radical influence. The chelating effect was more pronounced and depended on the concentration of ferric ions in the medium.

[The biochemical heterogeneity of rheumatoid arthritis]. / O biokhimicheskoi geterogennosti revmatoidnogo artrita.

The content of cyclic nucleotides (cAMP and cGMP) in plasma (or blood), synovial fluid and neutrophils was measured in 151 patients suffering from rheumatoid arthritis (RA) as was the content of prostaglandins (E2 and F2 alpha), ACTH, hydrocortisone, antioxidant system enzymes (superoxide dismutase and catalase). Part of the patients were examined over time. Relative stability of certain characteristics (the content of hydrocortisone, neuropeptides, superoxide dismutase, and so forth) was established throughout a long time, irrespective of the process activity or treatment provided. It is concluded that every RA patient has a "weak" biochemical component of his own, reflecting the activity or power of one or another regulatory system.

[The psychological personality characteristics of patients with rheumatoid arthritis]. / Psikhologicheskie osobennosti lichnosti bol'nykh revmatoidnym artritom.

A psychological examination of 135 patients with rheumatoid arthritis (RA) (Bechterew Institute questionnaire) was made. Harmonious, neurasthenic, hypochondriac, paranoiac, apathetic and anxious attitudes to the disease were most frequent. Psychological features of personality in patients with RA do not depend on the sex, degree of activity, course, stage and the disease duration. The psychological characteristics of the patients allow one to make a differentiated approach to psychotherapy and prescription of psychotropic drugs.

[Still's syndrome in adults as one of the causes of fever of unknown origin]. / Sindrom Stilla u vzroslykh kak odna iz prichin likhoradki neiasnogo geneza.

Based on their own investigations and reported data, the authors describe the clinical and laboratory signs of Still's syndrome in adults. Special attention is paid to an analysis of the feverish syndrome. The clinical cases of Still's syndrome running its course under the mask of fever of obscure genesis for a long time are provided. The possibilities of early diagnosis of the disease are under discussion.

[The electrophoresis with sinusoidal modulated currents of copper ions from a dimexide solution in the combined treatment of patients with rheumatoid arthritis]. / Elektroforez ionov medi sinusoidal'nymi modulirovannymi tokami iz rastvora dimeksida v kompleksnom lechenii bol'nykh revmatoidnym artritom.

Sinusoidal modulated current electrophoresis of Cu ions from dimexide solution was compared to hydrocortisone ultraphonophoresis in combined treatment of rheumatoid arthritis patients. High tolerance and therapeutic effect of combined action of sinusoidal modulated currents, Cu ions and dimexide permit advocation of this method as physical therapy for rheumatoid arthritis.

[Antioxidative activity of antiarthritic preparations]. / Antiokislitel'naia aktivnost' protivoartritnykh preparatov.

Antioxidative activity of acetyl salicylic acid, indometacin, ibuprophen, orthophen, delagil, D-penicillamine and levamysol was studied under conditions of NADPH- and CCl4-dependent lipid peroxidation both in rat liver microsomes and in adrenaline autioxidation. All the drugs studied exhibited only slight antioxidative activity being dissolved in mater, and especially towards lipid peroxidation, as compared with quercitrol and ionol; their activity was noted at concentrations exceeding distinctly the therapeutic doses. At the same time, D-penicillamine inhibited lipid peroxidation not only by means of free radicals neutralization but also via binding of iron ions. This property of the drug may be responsible for its effects, to some extent, in treatment of joint inflammations.