scholarly journals Development of the doctrine of auto-inflammatory diseases in the XXI century

2019 ◽  
Vol 56 ◽  
pp. 5-18 ◽  
Author(s):  
E. S. Fedorov ◽  
S. O. Salugina ◽  
N. N. Kuzmina
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Autoinflammatory Diseases ◽  
Clinical Rheumatology ◽  
Course Assessment ◽  
New Class ◽  
Hereditary Autoinflammatory Diseases ◽  
Relationship Of

The article presents the development of the doctrine of autoinflammatory diseases (AID) in the last decade. Data on interleukin 1, inflammasomes and their role in the development of AID are presented. The paper also contains the data about interferonopathies and, in particular, proteasomal illnesses as a new class of hereditary autoinflammatory diseases. Variety of AID variants, including diseases with the dominance of one system damage (skin, intestines, bones) is shown. Advances in the AID diagnosis and course assessment of are discussed. Relationship of the AID with the problems of fundamental and clinical rheumatology is demonstrated.

scholarly journals Interleukin-1 in the pathogenesis and treatment of inflammatory diseases

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3720-3732 ◽  
Author(s):  
Charles A. Dinarello
Keyword(s):  
Disease Severity ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Immunosuppressive Drugs ◽  
Autoinflammatory Diseases ◽  
Inflammatory Conditions ◽  
Sustained Reduction ◽  
Anti Inflammatory ◽  
Smoldering Myeloma ◽  
Acute And Chronic Inflammation

Abstract More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1β is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1β neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1β activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.

scholarly journals The off-label use of anakinra in pediatric systemic autoinflammatory diseases

2020 ◽  
Vol 12 ◽  
pp. 1759720X2095957
Author(s):  
Valerio Maniscalco ◽  
Sarah Abu-Rumeileh ◽  
Maria Vincenza Mastrolia ◽  
Edoardo Marrani ◽  
Ilaria Maccora ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
Case Series ◽  
Autoinflammatory Diseases ◽  
Off Label Use ◽  
Off Label ◽  
Rheumatologic Diseases ◽  
Valuable Treatment ◽  
Label Use

Interleukin 1 (IL-1), a central mediator of innate immunity, is considered a master cytokine of local and systemic inflammation. IL-1 has emerged as pivotal in the pathogenesis of autoinflammatory diseases (AIDs), and blockade of its pathway has become a crucial target for therapy. Anakinra (ANA), a recombinant IL-1β receptor antagonist, was the first anti-IL-1 agent employed in clinical practice. ANA is currently approved for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, and cryopyrin-associated autoinflammatory syndrome. It has also been successfully used for off-label treatment of various monogenic, polygenic, or undefined etiology systemic AIDs. This review describes currently available evidence for the off-label use of ANA in pediatric rheumatologic diseases. Specifically, the use of ANA in Kawasaki disease, idiopathic recurrent pericarditis, Behçet disease, monogenic AIDs, undifferentiated AIDs, chronic non-bacterial osteomyelitis, macrophage activation syndrome, and febrile infection-related epilepsy, in terms of its safety and efficacy. In selected pediatric rheumatic disorders, the off-label administration of ANA appears to be effective and safe. In order to control severe and/or relapsing disease, ANA should be considered as a valuable treatment option in children suffering from rare inflammatory diseases. However, currently available data consist of retrospective studies and short case series; thus, randomized controlled trials and larger series with long-term follow up are mandatory to better assess the efficacy and cost effectiveness of ANA in these challenging patients.

scholarly journals POS0672 FIRST-IN-HUMAN STUDY OF GS-5718, AN ORAL IRAK-4 INHIBITOR, IN HEALTHY SUBJECTS: PHARMACOKINETICS, SAFETY, TOLERABILITY, AND ASSESSMENT OF EFFECT OF FOOD AND ACID REDUCING AGENTS ON EXPOSURE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 581.1-581
Author(s):  
K. Anderson ◽  
C. H. Hsueh ◽  
O. Gurtovaya ◽  
A. Mathur ◽  
J. Taylor ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Dose Range ◽  
Human Study ◽  
Reducing Agents ◽  
Pharmacokinetic Parameters ◽  
Once Daily ◽  
Effect Of Food

Background:GS-5718 is a potent and selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in clinical development for treatment of inflammatory diseases.Objectives:The aim of this first-in-human study was to evaluate the pharmacokinetics, safety, and tolerability of GS-5718; and the effect of food and acid-reducing agents (ARA) on GS-5718 pharmacokinetics in healthy subjects.Methods:This was a blinded, randomized, placebo-controlled, single and multiple (once daily for 10 days) oral dose study. Healthy male and female subjects were enrolled in ascending dose cohorts and randomized to receive GS-5718 (15, 50 or 150 mg) or placebo. GS-5718 was administered fasted in the single ascending dose cohorts, and under fed conditions (standard meal) in the multiple dose cohorts. The effects of a high-fat meal and omeprazole (a representative ARA) on GS-5718 50 mg dose pharmacokinetics were also evaluated. Serial blood samples were collected and GS-5718 pharmacokinetic parameters were characterized. Safety was assessed by review of adverse events (AEs), clinical laboratory tests, and vital signs.Results:A total of 74 subjects (n = 62 GS-5718; n = 12 placebo) enrolled and completed study drug treatments in this study. GS-5718 was generally well tolerated at all evaluated dose levels; AEs were mild in severity and no dose-limiting toxicities, serious AEs, nor clinically relevant electrocardiogram or vital sign abnormalities were observed in subjects administered GS-5718. GS-5718 exposure was approximately dose proportional across the evaluated multiple ascending dose range. GS-5718 showed low-to-moderate pharmacokinetic variability with median half-life of 25 to 33 hours and 1.6 to 2.4- fold accumulation at steady-state, which was achieved by Day 5-7 of dosing. Food had no clinically meaningful impact on GS-5718 exposure (AUC and Cmax) at the 50 mg dose. Co-administration of omeprazole with GS-5718 reduced GS-5718 exposure (AUC and Cmax) by 23% and 43%, respectively, at the 50 mg dose.Conclusion:GS-5718, administered once daily, was well tolerated following single or multiple dosing up to 150 mg. The pharmacokinetic and safety profile of GS-5718 support the further development in inflammatory diseases with once-daily administrations.Disclosure of Interests:Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Chia-Hsiang Hsueh Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Oksana Gurtovaya Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Anubhav Mathur Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, James Taylor Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Adrian Serone Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences

ChemInform Abstract: 10H-Phenothiazines: A New Class of Enzyme Inhibitors for Inflammatory Diseases.

ChemInform ◽  
2009 ◽  
Vol 40 (20) ◽  
Author(s):  
Y. S. Sadanandam ◽  
Meera M. Shetty ◽  
A. Bhaskar Rao ◽  
Y. Rambabu
Keyword(s):  
Enzyme Inhibitors ◽  
Inflammatory Diseases ◽  
New Class

Biologic disease-modifying antirheumatic drugs in the treatment of major monogenic autoinflammatory diseases: literature review and clinical observation

2021 ◽  
Vol 15 (6) ◽  
pp. 95-100
Author(s):  
S. O. Salugina ◽  
E. S. Fedorov
Keyword(s):  
High Efficiency ◽  
Interleukin 1 ◽  
Autoinflammatory Diseases ◽  
Disease Modifying Antirheumatic Drugs ◽  
Antirheumatic Drugs ◽  
Disease Modifying ◽  
Factor Α ◽  
Genetically Determined ◽  
Late Stages

Autoinflammatory diseases (AIDs) are a heterogeneous group of rare genetically determined conditions, the main manifestations of which are episodes of fever in combination with other signs of systemic inflammation: skin rashes, musculoskeletal and neurological disorders, damage to the organs of vision, hearing, etc., as well as acute phase markers and the absence of autoantibodies. The use of biological therapy, especially inhibitors of interleukin 1 (iIL1), in most common monogenic AIDs (mAID) – FMF, TRAPS, HIDS/MKD, CAPS – has shown its high efficiency and led to significant progress in the treatment of these patients. Currently, iIL1 are the first-line drugs for mAIDs therapy, primarily CAPS. In the case of their ineffectiveness or intolerance in certain situations, other biologic disease-modifying antirheumatic drugs can also be used – inhibitors of tumor necrosis factor α and iIL6, but this issue needs further investigation. The article describes a patient with mAID, in whom the diagnosis was made more than 40 years after the onset; administration of targeted therapy even in the late stages of the disease led to a significant improvement in many symptoms and quality of life. 

Biologics in Microangiopathic Wounds

2018 ◽  
Vol 17 (4) ◽  
pp. 205-213
Author(s):  
Massimo Papi ◽  
Claudia Papi
Keyword(s):  
Inflammatory Diseases ◽  
Platelet Rich Plasma ◽  
Connective Tissue Diseases ◽  
Local Therapy ◽  
Biologic Agents ◽  
Biologic Drugs ◽  
New Class ◽  
Skin Ulcers ◽  
Inflammatory Processes ◽  
Inflammatory Molecules

In the last decades the possibility to diagnose a skin ulcer has greatly improved. We learnt that a consistent percentage of nonhealing ulcers may be caused by a microangiopathic disorder that has not been properly investigated and cured. Pathogenetically, we can distinguish 2 main groups: (1) ulcers due to inflammatory microangiopathy, mainly including cutaneous small and medium vessel vasculitis, pyoderma gangrenosum, and connective tissue diseases, and (2) ulcers due to occlusive microangiopathy. The group of microangiopathic occlusive ulcers is more heterogeneous and includes different disorders ranging from livedo vasculopathy to calciphylaxis, hydroxyurea-induced ulcers, antiphospholipid antibodies ulcers, and various other types. These conditions can induce thromboses or anatomo-functional occlusion of cutaneous microvessels. Despite different physiopathologic mechanisms, the ulcer resulting from a primitive microangiopathy may receive basic treatments that are in the complex similar to other pathogenetically different wounds, including MOIST-based local therapy and elastic compression when it is not contraindicated. Persistent inflammatory processes are increasingly demonstrated as responsible for the chronicity of many skin ulcers. New data concerning the biological phases of wound healing and the molecules that play crucial roles in this process suggested the use of new specific therapies. Some of them such as growth factors and platelet-rich plasma are prevalently used as topical biologic agents with variable benefits. In recent years, a new class of systemic anti-inflammatory molecules, better known as biologic drugs, have been introduced in the cure of chronic inflammatory diseases that can induce microangiopathic injuries and ulcerative complication. They enlarged the therapeutic options in case of nonresponder microangiopathic ulcers and could represent a future model of “pathogenetically based” therapy of skin ulcers.

scholarly journals Cold-induced urticarial autoinflammatory syndrome related to factor XII activation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jörg Scheffel ◽  
Niklas A. Mahnke ◽  
Zonne L. M. Hofman ◽  
Steven de Maat ◽  
Jim Wu ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Gene Mutations ◽  
Coagulation Factor ◽  
Hek293 Cells ◽  
Receptor Protein ◽  
Local Source ◽  
Factor Xii ◽  
Mutant Proteins ◽  
Hereditary Autoinflammatory Diseases ◽  
Immune Pathway

AbstractHereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.

scholarly journals Development of an ultra-sensitive human IL-33 biomarker assay for age-related macular degeneration and asthma drug development

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Elaine Mai ◽  
Joyce Chan ◽  
Levina Goon ◽  
Braeden K. Ego ◽  
Jack Bevers ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Age Related Macular Degeneration ◽  
Reduced Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 33 ◽  
Age Related ◽  
Significant Difference ◽  
High Concentrations

Abstract Background Over the past decade, human Interleukin 33 (hIL-33) has emerged as a key contributor to the pathogenesis of numerous inflammatory diseases. Despite the existence of several commercial hIL-33 assays spanning multiple platform technologies, their ability to provide accurate hIL-33 concentration measurements and to differentiate between active (reduced) and inactive (oxidized) hIL-33 in various matrices remains uncertain. This is especially true for lower sample volumes, matrices with low hIL-33 concentrations, and matrices with elevated levels of soluble Interleukin 1 Receptor-Like 1 (sST2), an inactive form of ST2 that competes with membrane bound ST2 for hIL-33 binding. Results We tested the performance of several commercially available hIL-33 detection assays in various human matrices and found that most of these assays lacked the sensitivity to accurately detect reduced hIL-33 at biologically relevant levels (sub-to-low pg/mL), especially in the presence of human sST2 (hsST2), and/or lacked sufficient target specificity. To address this, we developed and validated a sensitive and specific enzyme-linked immunosorbent assay (ELISA) capable of detecting reduced and total hIL-33 levels even in the presence of high concentrations of sST2. By incorporating the immuno-polymerase chain reaction (iPCR) platform, we further increased the sensitivity of this assay for the reduced form of hIL-33 by ~ 52-fold. Using this hIL-33 iPCR assay, we detected hIL-33 in postmortem human vitreous humor (VH) samples from donors with age-related macular degeneration (AMD) and found significantly increased hIL-33 levels when compared to control individuals. No statistically significant difference was observed in aqueous humor (AH) from AMD donors nor in plasma and nasosorption fluid (NF) from asthma patients compared to control individuals. Conclusions Unlike existing commercial hIL-33 assays, our hIL-33 bioassays are highly sensitive and specific and can accurately quantify hIL-33 in various human clinical matrices, including those with high levels of hsST2. Our results provide a proof of concept of the utility of these assays in clinical trials targeting the hIL-33/hST2 pathway.

scholarly journals Interleukin-1, Tumour Necrosis Factor and Treatment of the Septic Shock Syndrome

1992 ◽  
Vol 3 (suppl b) ◽  
pp. 11-19
Author(s):  
Charles A Dinarello
Keyword(s):  
Septic Shock ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Neutralizing Antibodies ◽  
Inflammatory Diseases ◽  
Leukocyte Adhesion ◽  
Interleukin 1 ◽  
Platelet Activating Factor ◽  
Surface Receptors ◽  
Necrosis Factor

Treating the septic shock syndrome with antibodies that block only endotoxin has its limitations. Other targets for treating septic shock include neutralizing antibodies to the complement fragment C5a, platelet activating factor antagonists and blockade of endothelial cell leukocyte adhesion molecules. Specific blockade of the pro-inflammatory cytokines interleukin-1 (IL-1) or tumour necrosis factor (TNF) reduces the morbidity and mortality associated with septic shock. Moreover, blocking IL-1 and TNF likely has uses in treating diseases other than septic shock. Use of neutralizing antibodies to TNF or IL-1 receptors has reduced the consequences of infection and inflammation, including lethal outcomes in animal models. The IL-1 receptor antagonist, a naturally occurring cytokine, blocks shock and death due to Escherichia coli as well as ameliorates a variety of inflammatory diseases. Soluble TNF and IL-1 surface receptors, which bind their respective cytokines. also ameliorate disease processes. Clinical trials are presently evaluating the safety and efficacy of anticytokine therapies either alone or in combination.

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