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.

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.

[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.

[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.

[The possibilities of an individual approach to intra-articular drug administration in rheumatoid arthritis patients]. / Vozmozhnosti individual'nogo podkhoda k vnutrisustavnomu vvedeniiu medikamentov bol'nym revmatoidnym artritom.

A study was made of the possibilities of an individual approach to intraarticular administration of protease inhibitors, cytostatics and orgoteine in patients with rheumatoid arthritis (RA). The activity of hyaluronidase, superoxide dismutase, the level of rheumatoid factor and the phagocyte count in synovial fluid were examined. With regard to the results of synovial fluid analysis in 67 RA patients, contrykal, orgoteine or cyclophosphamide were administered intra-articularly (based on an individual approach) in addition to corticosteroid hormones. It has been shown that with the individual approach to intraarticular drug administration the number of repeated punctures of the joints decreased by 18.8% while the amount of glucocorticosteroid hormones administered was twice as reduced.

[The laser therapy of rheumatoid arthritis]. / Lazernaia terapiia revmatoidnogo artrita.

About 300 patients with rheumatoid arthritis (RA) underwent multimodality treatment including laser radiation of varying wavelengths. Use was made of helium-neon, infrared, argon and helium-cadmium lasers. A new method of combined laser therapy by radiation of helium-cadmium and helium-neon lasers is described. A scheme of optimal parameters and types of laser radiation recommended for the treatment of different clinical varieties of RA is provided.

[Treatment of Sjögren's syndrome with protease inhibitors]. / Lechenie sindroma Shegrena ingibitorami proteaz.

The authors reported the results of therapy of 28 patients with primary and secondary Sjogren's syndrome by iv injections of protease inhibitors (contrykal and trasylol). Findings of clinical and laboratory tests showed a significant increase in salivation and lacrimation. The elimination of concomitant oral candidosis raised the efficacy of treatment of xerostomia in many patients.