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BackgroundThe cytokine interleukin (IL)-1 plays a pivotal role in immune-mediated disorders, particularly in autoinflammatory diseases. Targeting this cytokine proved to be efficacious in treating numerous IL-1-mediated pathologies. Currently, three IL-1 blockers are approved, namely anakinra, canakinumab and rilonacept, and two additional ones are expected to receive approval, namely gevokizumab and bermekimab. However, there is no systematic review on the safety and efficacy of these biologics in treating immune-mediated diseases.ObjectiveTo evaluate safety and efficacy of anakinra, canakinumab, rilonacept, gevokizumab, and bermekimab for the treatment of immune-mediated disorders compared to placebo, standard-of-care treatment or other biologics.MethodsThe PRISMA checklist guided the reporting of the data. We searched the PubMed database between 1 January 1984 and 31 December 2020 focusing on immune-mediated disorders. Our PubMed literature search identified 7363 articles. After screening titles and abstracts for the inclusion and exclusion criteria and assessing full texts, 75 articles were included in a narrative synthesis.ResultsAnakinra was both efficacious and safe in treating cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), gout, macrophage activation syndrome, recurrent pericarditis, rheumatoid arthritis (RA), and systemic juvenile idiopathic arthritis (sJIA). Conversely, anakinra failed to show efficacy in graft-versus-host disease, Sjögren’s syndrome, and type 1 diabetes mellitus (T1DM). Canakinumab showed efficacy in treating CAPS, FMF, gout, hyper-IgD syndrome, RA, Schnitzler’s syndrome, sJIA, and TNF receptor-associated periodic syndrome. However, use of canakinumab in the treatment of adult-onset Still’s disease and T1DM revealed negative results. Rilonacept was efficacious and safe for the treatment of CAPS, FMF, recurrent pericarditis, and sJIA. Contrarily, Rilonacept did not reach superiority compared to placebo in the treatment of T1DM. Gevokizumab showed mixed results in treating Behçet’s disease-associated uveitis and no benefit when assessed in T1DM. Bermekimab achieved promising results in the treatment of hidradenitis suppurativa.ConclusionsThis systematic review of IL-1-targeting biologics summarizes the current state of research, safety, and clinical efficacy of anakinra, bermekimab, canakinumab, gevokizumab, and rilonacept in treating immune-mediated disorders.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021228547.

Objectives The objective of this systematic review was to assess the effects of interleukin-1β (IL-1β) inhibitors on gout flares. Methods Studies published between 2011 and 2022 that evaluated the effects of IL-1β inhibitors in adult patients experiencing gout flares were eligible for inclusion. Outcomes including pain, frequency and intensity of gout flares, inflammation, and safety were assessed. Five electronic databases (Pubmed/Medline, Embase, Biosis/Ovid, Web of Science and Cochrane Library) were searched. Two independent reviewers performed study screening, data extraction and risk of bias assessments (Cochrane Risk of Bias Tool 2 for randomised controlled trials [RCTs] and Downs and Black for non-RCTs). Data are reported as a narrative synthesis. Results Fourteen studies (10 RCTs) met the inclusion criteria, with canakinumab, anakinra, and rilonacept being the three included IL-1β inhibitors. A total of 4367 patients with a history of gout were included from the 14 studies ( N  = 3446, RCTs; N  = 159, retrospective studies [with a history of gout]; N  = 762, post hoc analysis [with a history of gout]). In the RCTs, canakinumab and rilonacept were reported to have a better response compared to an active comparator for resolving pain, while anakinra appeared to be not inferior to an active comparator for resolving pain. Furthermore, canakinumab and rilonacept reduced the frequency of gout flares compared to the comparators. All three medications were mostly well-tolerated compared to their comparators. Conclusion IL-1β inhibitors may be a beneficial and safe medication for patients experiencing gout flares for whom current standard therapies are unsuitable. Review protocol registration PROSPERO ID: CRD42021267670.

Inhibitors of the innate immune system’s NLRP3 inflammasome promise potential in Parkinson disease, Alzheimer disease, non-alcoholic steatohepatitis, gout and much more, catching the eye of Novartis, Genentech and others.Inhibitors of the innate immune system’s NLRP3 inflammasome promise potential in Parkinson disease, Alzheimer disease, non-alcoholic steatohepatitis, gout and much more, catching the eye of Novartis, Genentech and others.

SARS-CoV-2 is a betacoronavirus causing severe inflammatory pneumonia, so that excessive inflammation is considered a risk factor for the disease. According to reports, cytokine storm is strongly responsible for death in such patients. Some of the consequences of severe inflammation and cytokine storms include acute respiratory distress syndrome, acute lung injury, and multiple organ dysfunction syndromes. Phylogenetic findings show more similarity of the SARS-CoV-2 virus with bat coronaviruses, and less with SARS-CoV. Quercetin is a carbohydrate-free flavonoid that is the most abundant flavonoid in vegetables and fruits and has been the most studied to determine the biological effects of flavonoids. Inflammasomes are cytosolic multi-protein complexes assembling in response to cytosolic PAMP and DAMPs, whose function is to generate active forms of cytokines IL-1β and IL-18. Activation or inhibition of the NLRP3 inflammasome is affected by regulators such as TXNIP, SIRT1 and NRF2. Quercetin suppresses the NLRP3 inflammasome by affecting these regulators. Quercetin, as an anti-inflammatory, antioxidant, analgesic and inflammatory compound, is probably a potential treatment for severe inflammation and one of the main life-threatening conditions in patients with COVID-19.

Stroke is a major cause of death and disability worldwide. Endovascular thrombectomy has been impactful in decreasing mortality. However, many clinical results continue to show suboptimal functional outcomes despite high recanalization rates. This gap in recanalization and symptomatic improvement suggests a need for adjunctive therapies in post-thrombectomy care. With greater insight into ischemia-reperfusion injury, recent preclinical testing of neuroprotective agents has shifted towards preventing oxidative stress through upregulation of antioxidants and downstream effectors, with positive results. Advances in multiple neuroprotective therapies, including uric acid, activated protein C, nerinetide, otaplimastat, imatinib, verapamil, butylphthalide, edaravone, nelonemdaz, ApTOLL, regional hypothermia, remote ischemic conditioning, normobaric oxygen, and especially nuclear factor erythroid 2-related factor 2, have promising evidence for improving stroke care. Sedation and blood pressure management in endovascular thrombectomy also play crucial roles in improved stroke outcomes. A hand-in-hand approach with both endovascular therapy and neuroprotection may be the key to targeting disability due to stroke.

Key Points A 'cytokine storm' is the final pathophysiological pathway in macrophage activation syndrome (MAS), and blocking various cytokines could be an attractive therapeutic strategy Standard doses of anti-IL-1 and anti-IL-6 biologic therapies do not have a major effect on MAS rates even if the underlying disease responds well to the treatment Several case reports suggest that anakinra might be effective at least in some patients with systemic juvenile idiophatic arthritis (sJIA)-associated MAS, particularly when used in high doses Findings from several studies support IFN-γ blockade as a novel therapy for haemophagocytic lymphohistiocytosis (HLH); increasing evidence suggests the same approach could be beneficial in MAS presenting as a complication of rheumatic diseases The exact mechanism of predisposition to MAS in sIJA is yet to be defined, but might be independent of underlying sJIA activity and similar to infection-associated secondary HLH Whole-exome/genome sequencing approaches exploring hypomorphic mutations that affect the cytolytic pathway to support this theory might reveal promising therapeutic alternatives Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic disease, most notably systemic juvenile idiopathic arthritis. Findings from studies in animal models and from clinical observations, particularly in relation to the effects of anticytokine biologic therapies, have led to new concepts of the pathophysiology of this phenomenon. Macrophage activation syndrome (MAS) refers to acute overwhelming inflammation caused by a 'cytokine storm'. Although increasingly recognized as a life-threatening complication of various rheumatic diseases, clinically, MAS is strikingly similar to primary and secondary forms of haemophagocytic lymphohistiocytosis (HLH). Not surprisingly, many rheumatologists prefer the term secondary HLH rather than MAS to describe this condition, and efforts to change the nomenclature are in progress. The pathophysiology of MAS remains elusive, but observations in animal models, as well as data on the effects of new anticytokine therapies on rates and clinical presentations of MAS in patients with systemic juvenile idiopathic arthritis (sJIA), provide clues to the understanding of this perplexing clinical phenomenon. In this Review, we explore the latest available evidence and discuss potential diagnostic challenges in the era of increasing use of biologic therapies.

Objective To compare the long-term disease state, in terms of activity and damage, of children with juvenile idiopathic arthritis (JIA) who had their disease onset in methotrexate (MTX) or biologic eras. Methods Patients were included in MTX or biologic era cohort depending on whether their disease presentation occurred before or after January 2000. All patients had disease duration ≥ 5 years and underwent a prospective cross-sectional assessment, which included measurement of disease activity and damage. Inactive disease (ID) and low disease activity (LDA) states were defined according to Wallace, JADAS10, and cJADAS10 criteria. Articular and extraarticular damage was assessed with the Juvenile Arthritis Damage Index (JADI). Results MTX and biologic era cohorts included 239 and 269 patients, respectively. Patients were divided in the “functional phenotypes” of oligoarthritis and polyarthritis. At cross-sectional visit, patients in the biologic era cohort with either oligoarthritis or polyarthritis had consistently higher frequencies of ID and LDA by all criteria. The measurement of disease damage at cross-sectional visit revealed that the frequency of impairment of > 1 JADI-Articular items was higher in MTX than in biologic era cohort (17.6% versus 11% in oligoarthritis and 52.6% versus 21.8% in polyarthritis). Likewise, frequency of involvement of > 1 JADI-Extraarticular items was higher in the MTX than in the biologic era cohort (26.5% versus 16.2% in oligoarthritis and 31.4% versus 13.5% in polyarthritis). Conclusion Our study provides evidence of the remarkable outcome improvement obtained with the recent therapeutic advance in JIA.

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.

Chronic kidney disease (CKD) is a condition caused by the gradual decline of renal function that approximatively affects 10–12% of the world population, thus representing a public health priority. In CKD patients, chronic and systemic low-grade inflammation is observed, and it significantly contributes to disease development and progression, especially for patients with advanced disease. It also results in CKD-associated complications and increased mortality. The low-grade inflammation is due to different factors, such as the decline of glomerular filtration rate, increased immune system activation, reactive oxygen species release, and intestinal homeostasis. Therefore, the possibility to control chronic low-grade inflammation in CKD deserves great attention. In this review, we will examine the current possible pharmacological approaches to counteract the inflammatory state in CKD, focusing our attention both on the pro-inflammatory factors and the pro-resolving mediators involved in CKD inflammatory state.

Familial Mediterranean fever (FMF) is the most common monogenic periodic fever syndrome and characterized by recurrent episodes of fever, serositis, arthritis, dermal manifestations, and long-term renal complications. The MEFV gene was described in 1997 as the gene responsible for FMF and is inherited in autosomal recessive manner. It encodes mutated protein pyrin, an important player in the innate immune system and the component of inflammasome which leads to exaggerated inflammatory response through uncontrolled production of interleukin-1. The recent progress in molecular genetics and understanding of pathogenesis showed a more complicated picture of FMF inheritance, penetrance, and pathogenesis. The pathogenesis is not completely understood although the gene responsible for FMF has been identified. Whether the pyrin mutation effect in FMF is due to a loss of function or a gain of function is still controversial. The diagnosis is mainly clinical and the genetic testing is indicated to support it. Colchicine remains the mainstay of treatment of FMF since 1972. It decreases the attacks, improves quality of life, and prevents amyloidosis. The recent advances in genetic testing and molecular studies has led to the development of new therapies of interleukin-1 inhibitors; anakinra, canakinumab, and rilonacept.