Christina Antoniadou

IL-1 antagonists have emerged as an effective treatment for refractory or GC-dependent recurrent pericarditis (RP). This study aims to describe long-term efficacy and safety of anakinra in anakinra-treated RP patients and retrospectively explore the effect of early anakinra initiation and the risk of recurrence upon tapering. This is a retrospective study, based on medical records. The main outcome was any recurrence (“flare”) after anakinra initiation. Twenty patients (14 males, 6 females) were included with a median (IQR) disease duration of 48 (24) months, and 4 (2) recurrences prior to anakinra initiation. The median (IQR) age at pericarditis onset was 50 (31) years. Sixteen were on GC (mean (SD) prednisolone dose 17.7 (12.3) mg). Anakinra was initiated after a median (IQR) time of 11.5 (11.5) months from the first episode of acute pericarditis. Nineteen achieved remission on anakinra. Twelve achieved GC withdrawal while 4 remained on low-dose prednisolone (mean [SD] dose 3 mg [1]). Nine patients proceeded to tapering of anakinra after a median (IQR) of 8 (16) months on standard dosage and 7 patients remained on extended-interval administration at the end of the follow-up period. Flares occurred in 3/9 patients with a history of ≤ 3 pericarditis recurrences before anakinra initiation versus 4/11 with > 3 recurrences [exploratory univariable OR 1.14, (CI 0.13–11.13)] and in 2/5 patients treated early (< 6 months following diagnosis) versus 5/15 in the late-treated group (≥ 6 months) [exploratory univariable OR 0.76 (CI 0.06–11.94)]. Annualized recurrence rates were lower after anakinra initiation [median (IQR) recurrences 0 (0.26) versus 5.33 (4.68)]. In exploratory logistic regression analyses, neither early/late anakinra initiation, number of pre-anakinra recurrences, nor tapering was significantly associated with the outcome. The analyses’ findings should be interpreted with caution, given the limited sample size, the wide confidence intervals and the potential lack of statistical power to detect existing associations. In this cohort of RP patients, anakinra was associated with favorable clinical outcomes, allowing for GC sparing and achieving lower recurrence rates after initiation compared with the pre-treatment period. The sustained disease control observed supports its long-term use, either at full dose or with careful tapering. Exploratory comparisons for potential existing associations with flares were limited by small sample size. To determine the ideal treatment duration and tapering strategies, larger prospective controlled studies are required.

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 ( n = 16) or placebo ( n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101–treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug’s inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Background and Aims: Several studies have suggested that mutations in MEFV, the gene responsible for familial Mediterranean fever (FMF), are frequently detected in inflammatory bowel disease (IBD) patients. We aimed to provide further evidence regarding a potential correlation between MEFV gene mutations and IBD by identifying all relevant studies and analyzing their results. Methods: EMBASE, PubMed/MEDLINE, and Google Scholar were used to identify all studies that published until January 2021 and reported MEFV mutation patterns in patients with ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis (IC) with or without a control group. The Newcastle-Ottawa quality assessment scale was used to appraise the quality of the included studies. Results: Thirteen observational studies, including 937 patients and 977 controls, were analyzed. MEFV mutation rate in IBD patients was 0.238 (95%CI: 0.209-0.270; I 2 =95%); MEFV mutated alleles were more frequent in IBD patients when compared with controls (p=0.03 for UC, p=0.01 for CD and IC). Subgroup analysis indicated that MEFV mutations were increased in patients with IC when compared with UC and CD (I 2 =91%, p<0.001). Patients with extra-intestinal manifestations and pancolitis had 2.57 (95%CI 1.07-6.14; p=0.03) and 2.02 (95%CI: 1.01-4.04, P=0.049) odds ratios to carry MEFV mutant genotypes, respectively. Exon 10 mutations had the most serious impact. No source of heterogeneity was detected. Conclusions: MEFV mutations are common in IBD and are linked with the presence of extra-intestinal manifestations and pancolitis. Further research to assess the clinical significance and evolutionary significance of MEFV mutations in IBD patients is warranted.

Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

Introduction: Electronic search filters on family medicine or general practice studies have been developed and validated in previous work. However, there has been no systematic effort to specifically identify and record protocols of randomized controlled trials (RCT) protocols in primary health care (PHC). The aim of the present study was to systematically identify published RCT protocols in PHC and capture information about specific protocol characteristics that may describe this field. Methods: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus from inception to December 2014 were systematically searched. Protocols of RCTs that were published in English and were relevant to PHC were considered as eligible. Protocols referred either to a mixed population, or to an intervention including a specialized part as well as pilot or feasibility trial protocols, were excluded. Specific protocol characteristics including publication year, country, prospective registration, funding, and publication sources were extracted. Results: The final database included 628 published RCT protocols (median publication year 2011; interquartile range 2009-2013). The majority of protocols were designed in the UK (n=141, 22.5%), the Netherlands (n=105, 16.7%), and USA (n=93, 14.8%). Research was mainly funded by the government (n=408, 65.0%) while 45 protocols (7.2%) included industry as the funding source. Two registries - International Standard Randomised Controlled Trials Number Registry (245 (42.9%)) and ClinicalTrials.gov (209 (36.6%)) - indexed most of the protocols. Journals from several scientific fields published the articles; the field of 'Primary Health Care Medicine, General and Internal' included 69 (11.0%) articles. Conclusion: A compilation of published RCT protocols on PHC was feasible. The majority of protocols on PHC were published over the past 10 years, funded by the government and designed in three main countries.