BackgroundIdiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disease [1,2] that has similar pathogenesis with adult-onset Still’s disease and monogenic autoinflammatory diseases [3,4]. IL-1α and IL-1β are the pivotal cytokines in the pathophysiology of acute pericarditis and its recurrence [5]. This report presents the interim analysis of clinical trial with goflkicept (original, fusion protein, heterodimer, binding IL-1α and IL-1β) in patients with IRP. Trial registration: ClinicalTrials.gov, NCT04692766.ObjectivesTo evaluate the efficacy and safety of goflikicept treatment in patients with IRP.MethodsSubjects with recurrence (n=9) or in inter-recurrence period (n=13) were enrolled in the run-in period of 12 weeks for treatment with NSAIDs and/or colchicine or 24 weeks for treatment with corticosteroids (CS).Dose finding approach was applied, where subjects from the first cohort (n=10) received subcutaneous goflikicept 80 mg every 2 weeks, subjects from the second cohort (n=12) - 240 mg load within the first week, 80 mg within the seсond week, thereafter 80 mg every 2 weeks on top of background NSAIDs, colchicine and/or CS. Treatment response is considered as an achievement or maintenance of the following criteria: chest pain NRS≤3, CRP≤5 mg/L, absent or mild (<10 mm) pericardial effusion on Day 14. In responders NSAIDs/colchicine were stopped immediately, CS therapy was reduced and terminated within 12 weeks and for the next 12 weeks patients were on goflikicept monotherapy. At the end of the run-in responders proceeded into the double-blind, placebo-controlled randomized-withdrawal (RW) period, where received goflikicept 80 mg every 2 weeks or placebo. Primary endpoint was the time to the first pericarditis recurrence. In case of recurrence, the patients were unblinded, patients from placebo group retreated with goflikicept. According to interim analysis plan efficacy/safety analysis included only unblinded data during the RW period.ResultsTreatment response was achieved in 8 of 9 patients, enrolled with recurrence and all patients enrolled without recurrence remained in remission at Day 4. There were no new recurrence events on goflikicept therapy, despite NSAIDs/colchicine/CS discontinuation during the run-in period. In the run-in period mean NRS, CRP and pericardial effusion decreased from baseline (Figure 1). Decrease of concentrations of IL-1RA, IL-6, calprotectin was reported during the run-in period, which confirms anti-inflammatory effect of goflikicept. A total of 20 patients were randomized. Recurrent pericarditis occurred in 8 of 10 patients in placebo group, there were no recurrence events in goflikicept group to the moment of this interim analysis. After retreatment with goflikicept and recurrence resolution there were no new recurrence events. Adverse events (AEs) occurred in 15 of 22 patients (68,2%) during the run in period. During the run- in period, 6 of 22 patients (27%) experienced infections, 4 (18,2%) cholesterol elevation, 3 (13,6%) lymphopenia, 2 (9,1%) lipase elevation, 2 (9,1%) injection site reactions. AEs occurred in 4 of 8 patients (50%) during placebo treatment in the RW period. AEs occurred in 6 of 8 patients (75%) after retreatment with goflikicept. There were no deaths, no new safety signals. Overall safety profile was similar to those described for other IL-1 blockers.ConclusionThe first data show ability to achieve and maintain IRP remission on goflikicept monotherapy with favorable risk-benefit ratio. Final data will be provided.References[1]www.orpha.net. Assessed January 14, 2022[2]Blank N, Lorenz HM. Current Rheumatology Reports (2018)21:18[3]Imazio M. Heart. 2011 Nov;97(22)1882-92[4]Calabuig IJ, Sanches Soriano RM, Marco Domingo TF et al. Rev Esp Cardiol. 2017;70(3):208–219[5]Imazio M, Lazaros G, Gattorno M. European Heart Journal 2021 Epub ahead of print. PMID: 34528670AcknowledgementsThis study is sponsored by R-Pharm JSC.Disclosure of InterestsAlexey Maslyanskiy Consultant of: R-Pharm, Valentina Myachikova Speakers bureau: Novartis, Sobi, Olga Moiseeva Speakers bureau: Bayer, Janssen, Pfizer, Oksana Vinogradova Speakers bureau: AstraZeneca, Ekaterina Gleykina Speakers bureau: Bayer,Johnson & Johnson, AstraZeneca, Pfizer, Yan Lavrovsky Employee of: R-Pharm Overseas Inc, Sergey Grishin Employee of: R-Pharm JSC, Dmitry Salazanov Employee of: R-Pharm JSC, DARIA BUKHANOVA Employee of: R-Pharm JSC, Alina Egorova Employee of: R-Pharm JSC, Margarita Shchedrova Employee of: Employee of R-Pharm JSC, Mikhail Samsonov Employee of: R-Pharm JSC.
Aim To analyze cases of idiopathic recurrent pericarditis (IRP) in the structure of pericardial diseases of various origins from patient visits to the Multidisciplinary Federal Center.Material and methods A retrospective analysis of case records was performed for patients admitted to the V.A. Almazov National Medical Research Center from January 1, 2015 through January 1, 2020 for pericardial effusion of different etiologies.Results For the study period, 4 981 new cases of pericardial damage of different etiologies were found. Among these cases, postpericardiotomy syndrome accounted for 4 360 cases and pericarditis for 621 cases. IRP was detected in 34 cases, which amounted to 5.4 %. Based on the study data, the estimated IRP prevalence in the Russian Federation can be 1.1 cases per 100 thousand population.Conclusion IRP should be regarded as a new autoinflammatory disease, the prevalence of which borders on that of adult Still disease and should be addressed within the concept of orphan diseases. Current knowledge of the pathogenesis and data from recent studies demonstrated a great importance of interleukin-1 blockade as a leading mechanism for achieving remission. This has justified conduction of a randomized clinical study at the Center.
To reveal the clinical significance of criteria and non-criteria antiphospholipid antibodies detected by line immunoassay in comparison with ELISA, systemic lupus erythematosus patients with and without thrombotic events were investigated. Thus, 107 systemic lupus erythematosus patients (48% with deep vein thrombosis or/and arterial thrombosis) and 120 healthy donors were enrolled. Serum antiphospholipid antibodies were detected by ELISA (Orgentec Diagnostika, Germany) and line immunoassay (GA Generic Assays, Germany). Lupus anticoagulant and IgG to cardiolipin and β2GPI but not IgM as well as triple positivity by ELISA and line immunoassay were linked with thrombosis in systemic lupus erythematosus. IgG to phosphatidylinositol and phosphatidylserine by line immunoassay showed significantly higher levels in systemic lupus erythematosus with deep vein thrombosis/arterial thrombosis than without and were independent risk factors for deep vein thrombosis (odds ratio 3.9, 95% confidence interval 1.1, 13.2) and arterial thrombosis (odds ratio 5.1, 95% confidence interval 1.3, 19.8) as well as thrombosis (odds ratio 3.6, 95% confidence interval 1.1, 11.3) and recurrence thereof (odds ratio 6.9, 95% confidence interval 2.1, 22.6), respectively. The occurrence of >4 IgG antiphospholipid antibodies by line immunoassay was an independent risk factor for thrombosis (odds ratio 10.9, 95% confidence interval 1.2, 101.5), arterial thrombosis (odds ratio 14.6, 95% confidence interval 2.5, 86.3), deep vein thrombosis (odds ratio 5.8, 95% confidence interval 1.0, 32.4) and recurrence of thrombosis (odds ratio 35.9, 95% confidence interval 3.8, 342.8). Line immunoassay is a promising multiplex test for the simultaneous detection of criteria and non-criteria antiphospholipid antibodies. Profiling of antiphospholipid antibodies by line immunoassay can differentiate systemic lupus erythematosus patients with thrombosis from systemic lupus erythematosus patients without and assess the risk for thrombosis and recurrence thereof.
BackgroundAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder with unknown etiology. The main problem for rheumatologists is a lack of generally accepted methods for assessing AOSD activity.ObjectivesTo compare the usefulness of traditional and novel biomarkers for assessing the AOSD activityMethodsThe cross-sectional study included 27 patients over the age of 18 with a relapse of AOSD who were examined at the Almazov National Medical Research Centre from 2018 to 2021.All patients fulfilled the AOSD classification criteria by Yamaguchi. Clinical manifestations were scored in a Pouchot AOSD activity score. The serum concentrations of IL-1, IL-6, IL-18, ferritin, calgranulin, procalcitonin and the level of glycosylated ferritin (GF) were examined. Standard commercial reagents were used for detection clinical analysis of blood, C-reactive protein (CRP) and aminotransferases. Statistical analysis was performed using the licensed statistical applications Statistica 10.0 for Windows (StatSoft Inc., USA), and Prisma GraphPad 8.0 (GraphPad Software, USA). Results were expressed as median (25th–75th percentile) and analysed for statistical significance using nonparametric tests. For quantitative features comparison, the Mann–Whitney U test was used. The correlation coefficient was obtained by nonparametric Spearman’s rank correlation test. P values < 0.05 were considered statistically significant. Data from commercial test systems are taken as the basis for normal biomarker indicators.ResultsClinical data were available from 27 patients with AOSD (6 male and 21 female). The median age was 41.3 [26;50]. The median Pouchot activity score was 6 [4.5;7]. The course of AOSD was monocyclic in 1 patient, polycyclic in 23, and chronic in 3. Elevated leukocyte count > 10,000/μl was detected in 17 patients (63%), 9 patients (33%) had an elevated leukocyte count > 15,000/μl.An increase in biomarkers was detected in most patients: calgranulin was increased in 24 out of 26 patients (92.3%), ferritin was increased and GF was decreased in 21 out of 25 patients (84%). Among those 25 patients, the decrease in GF was less than 20% in 13 patients (52%). IL-18 increased in 17 patients (63%), IL-6 increased in 22 patients (81.5%), and procalcitonin increased in 16 out of 26 patients (61.6%). The median of procalcitonin concentration was 0.08 [0.01; 30.1]. No increase in IL-1 beta was detected.A correlation analysis revealed a direct relationship between the concentration of IL-18, ferritin and the Pouchot system score. An inverse relationship existed between these indicators and the level of GF (rs=0.803, p=0.001) and between calgranulin and IL-6 (rs=0.46, p=0.02). It was noted that the younger the age of the patients, the higher the concentration of IL-18 (rs=-0.449, p=0.019).ConclusionThe most promising additional laboratory biomarkers for assessing AOSD activity are calprotectin, IL-18, and ferritin. Despite a slight increase in procalcitonin as one of the indicators of the acute phase of inflammation, it remains an effective biomarker of sepsis; however, it is recommended to focus on threshold concentrations above 0.5.References[1]Ruscitti P, Cipriani P, Masedu F, Iacono D, Ciccia F, Liakouli V, Guggino G, Carubbi F, Berardicurti O, Di Benedetto P, Valenti M, Triolo G, Valentini G, Giacomelli R. Adult-onset Still’s disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers. BMC Med. 2016 Dec 1;14(1):194. doi: 10.1186/s12916-016-0738-8.[2]Feist E, Mitrovic S, Fautrel B. Mechanisms, biomarkers and targets for adult-onset Still’s disease. Nat Rev Rheumatol. 2018 Oct;14(10):603-618. doi: 10.1038/s41584-018-0081-x.[3]Lapin S, Maslyansky A., Lazareva N., Vasilyeva E., Totolyan A. The significance of the quantitative determination of procalcitonin for the diagnosis of septic complications in patients with autoimmune rheumatic diseases. Clinical laboratory diagnostics. 2013. No. 1.Disclosure of InterestsValentina Myachikova Speakers bureau: Novartis, Sobi, Evgenii Kuvardin: None declared, Kira Zotkina Speakers bureau: Novartis Amgen, Olga Tkachenko: None declared, Sergey Lapin: None declared, Alexey Maslyanskiy Speakers bureau: Boehringer Ingelheim Pharmaceuticals, Novartis, R-PHARM. Eli Lilly
Treatment algorithms for systemic sclerosis have not been completely developed. Effectivity of medications are usually used in clinical practice has a low level of evidence. Therefore, it is necessary to find a new treatment approaches for this nosological form. In the paper described clinical case of olokizumab treatment in a patient with diffuse systemic sclerosis with interstitial lung disease, polyserositis, severe microcirculatory alterations.
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