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.

[Pleiotropic effects of atorvastatin in rheumatoid arthritis patients with no history of cardiovascular diseases].

AIM: To evaluate the effect of atorvastatin (liprimar) on the laboratory values of inflammation and blood lipid composition in rheumatoid arthritis (RA) patients with no history of cardiovascular diseases (CVD). Subjects and methods. Fifty women with grade II RA activity according to DAS28 and radiologic (erosive) Stages I-III were examined; the patients were not former or current smokers; all were seropositive; their mean age was 50.2±9.9 years. All the patients with RA were divided into 2 groups: Group 1 took no atorvastatin and continued to receive standard previously prescribed therapy; Group 2 used atorvastatin in a dose of 20 mg. Lipidogram readings and the levels of Apo-A and Apo-B, neopterin, tumor necrosis factor-α, C-reactive protein, sP-selectin, sE-selectin, interleukin (IL)-6, IL-10, IL-12, and matrix metalloproteinases 3 and 9 were assessed. RESULTS: The patients with RA show obvious blood lipid composition impairments. Incorporation of atorvastatin (liprimar) into combination therapy for RA not only causes a considerable reduction in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apo-B levels, but also positively affects the inflammatory activity of the disease, by lowering the level of proinflammatory cytokines and increasing that of the anti-inflammatory cytokine IL-10. CONCLUSION: The above changes may underlie the prevention of CVD complications in patients with RA.

[The role of subclinical inflammation in the formation of early signs of cardiac lesions in hypertensive disease].

Compromised diastolic relaxation of the left ventricle occurs in hypertensive disease with and without its hypertrophy. Classic ventricular hypertension takes some time to develop during which manifestations of myocardial diastolic dysfunction remain the sole criterion (marker) of the lesion. Patients with uncomplicated arterial hypertension display interrelated changes in inflammation, endothelial function, and disorders at the level of different organs. These relationships are believed to be underlain by common neurohumoral mechanisms.

[Determinants of the respiratory system status in hypertensive disease].

AIM: To analyze the respiratory system in hypertensive disease (HD). SUBJECTS AND METHODS: Forty-six hypertensive patients (mean age 43.2 +/- 4.0 years) were examined. Office blood pressure (BP) was measured. Electrocardiography, echocardiography, color Doppler ultrasonography of the brachial artery, 24-hour BP monitoring, spirography, body plethysmography, and study of the diffusion lung capacity for carbon monoxide were performed. The serum levels of interleukins 6, 8, and 10, tumor necrosis factor (TNF), and C-reactive protein (CRP) were measured. RESULTS: Inflammatory processes have been ascertained to contribute to the development and progression of HD. The increase in HD degree and stage is attended by a significant elevation of the plasma concentrations of proinflammatory cytokines, TNF, and CRP, which is due to the contribution of inflammatory processes in the vessel wall to the development of endothelial dysfunction, vascular remodeling, and organ lesions, including diminished lung function in HD. CONCLUSION: Arterial hypertension, inflammatory indicators, endothelial function, and the degree of lesions to organs, including those in the respiratory system, are related. The basis for this relation is the common neurohumoral mechanisms of progression of nonspecific inflammation, endothelial dysfunction, and target organ lesions.

[Pulmonary involvement in patients with hypertensive disease].

METHODS: Parameters of spirometry, body plethysmography, and pulmonary diffusion capacity were measured in 46 patients (age 35-60 years, 40 men, 6 women) with stage I-II hypertensive disease (HD) without bronchial and pulmonary diseases, systolic dysfunction of left ventricular myocardium, obesity, current or past smoking. RESULTS: Increase of severity of HD and elevation of average values of arterial pressure (AP) was associated with mixed type worsening of parameters of pulmonary ventilation capacity. Negative correlations existed between parameters of 24 hour arterial pressure monitoring and spirometry. Progression of microalbuminuria and endothelial dysfunction was associated with lowering of pulmonary vital capacity, alveolar volume, and diffusion capacity. CONCLUSION: The data presented allow to suggest that lungs can stand as target organ in hypertensive disease.

[Effect of perindopril on cognitive functions in young and middle aged patients with hypertensive disease].

We studied 40 men aged 26 - 59 years (mean age 49.0 +/- 1.9 years) with hypertensive disease (HD) and found that therapy based on the use of angiotensin converting enzyme inhibitor perindopril in young and middle aged patients with stage I and II HD appeared to be not only one of effective methods of correction of elevated arterial pressure (AP) but also of associated with it cognitive abnormalities. Effect of therapy was determined by achievement of target AP values and was more pronounced in patients older than 44 years. Favorable effects of perindopril in relation to parameters of cognitive functions in patients with HD allows to rate perindopril not only as effective and safe hypotensive preparation but as remedy exerting cerebroprotective effect.

[Ambulatory blood pressure monitoring in doctors of various specialties].

We compared parameters of 24-hour blood pressure (BP) monitoring during off duty free day and 24-hours on duty in male surgeons (n=76) and internists (n=53) aged 30 - 60 years. Arterial hypertension (AH) was diagnosed in 17.1 and 13.2% of surgeons and internists, respectively (p > 0.05). During on duty 24-hour BP monitoring surgeons without AH had higher nocturnal systolic and both nocturnal and diurnal diastolic BP than internists without AH. Moreover surgeons significantly more often had non-dipper type of systolic and diastolic BP (SBP and DBP) curve. In internists only mean nocturnal SBP differed between on and off duty days. Surgeons had higher levels of mean SBP and DBP, higher values of nocturnal indexes of time and SBP and DBP measurements. Percent of subjects with non-dipper 24-hour SBP and DBP rhythms during on duty day was higher among surgeons. Possibly high mortality and rate of vascular catastrophes in surgeons are to some extent related to the presence of stress induced cardiovascular phenomena described above.

[Clinical application of spirapril in patients with arterial hypertension combined with chronic obstructive pulmonary disease].

In this study quadropril (Spirapril, Pliva) was given for 2 months to patients with arterial hypertension combined with chronic obstructive pulmonary disease. The results show that quadropril (6 mg/day) is highly effective as monotherapy in patients with mild and moderate hypertensive disease. Its effects appear as significant lowering of mean 24 hour systolic and diastolic blood pressure (BP), lowering of diurnal and nocturnal BP. Therapy with quadropril for 8 weeks did not impair parameters of external respiration, produced no negative action on lipid and carbohydrate metabolism, was well tolerated, and caused no considerable side effects.

[Comparative characteristics of stress tests--bicycle ergometry test and psycho-emotional test--in patients with ischemic heart disease]. / Sravnitel'naia kharakteristika rezul'tatov nagruzochnykh prob -- veloérgometrii i psikhoémotsional'nogo testa u bol'nykh ishemicheskoi bolezn'iu serdtsa.

AIM: To compare efficacy bicycle exercise (BE) and psychoemotional tests (PET) in provoking myocardial ischemia and arrhythmia in patients with acute and chronic forms of ischemic heart disease (IHD). MATERIAL AND METHODS: BE and PET (mathematical count test) were performed in 108 IHD patients. 30 patients had stable effort angina (FC II-III), 48 patients had progressing effort angina and 30 patients were at the subacute stage of myocardial infarction. RESULTS: PET was less efficient in detection of myocardial ischemia but is more adequate in detecting episodes of painless ischemia and ventricular rhythm disorders compared to BE. The greatest differences in efficiency of the tests occurred in patients with acute forms of IHD. CONCLUSION: Application of different stress tests in IHD patients raises efficacy of detecting episodes of painful, painless myocardial ischemia and rhythm disorders, specifies mechanisms of coronary failure development.