Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART)

Abstract Background Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. Methods Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. Discussion The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

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AB0108 IRAK4 INHIBITION SUPPRESSES PROINFLAMMATORY CYTOKINE PRODUCTION FROM HUMAN MACROPHAGES STIMULATED WITH SYNOVIAL FLUID FROM RHEUMATOID ARTHRITIS PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3793 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1353.2-1353

Author(s):

A. Yadon ◽

D. Ruelas ◽

G. Min-Oo ◽

J. Taylor ◽

M. R. Warr

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Fluid ◽

Signaling Pathways ◽

Proinflammatory Cytokines ◽

Proinflammatory Cytokine ◽

Cytokine Production ◽

Interleukin 1 ◽

Proinflammatory Cytokine Production ◽

Human Macrophages ◽

Percent Suppression

Background:Rheumatoid arthritis (RA) is characterized by chronic, uncontrolled joint inflammation and tissue destruction. Macrophages are thought to be key mediators in both the initiation and perpetuation of this pathology.1,2The RA synovium contains a complex inflammatory milieu that can stimulate macrophage-dependent production of proinflammatory cytokines through multiple signaling pathways.1,2Existing evidence indicates that toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) along with their agonists, damage-associated molecular patterns (DAMPs) and IL-1β, are highly expressed in RA joints and are important mediators of synovial macrophage activation and proinflammatory cytokine production.1-9IRAK4 (interleukin-1 receptor-associated kinase 4) is a serine/threonine kinase that facilitates TLR and IL-1R signaling in many cell types, including macrophages.10IRAK4 inhibition represents an opportunity to reduce proinflammatory cytokine production in the joints of patients with RA.Objectives:To investigate the effect of a highly selective IRAK4 inhibitor on proinflammatory cytokine production from human macrophages stimulated with synovial fluid from patients with RA.Methods:Primary human monocytes from 2 independent donors were differentiated for 6 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) to generate human monocyte-derived macrophages (hMDMs). hMDMs were then pretreated with an IRAK4 inhibitor for 1 hour and subsequently stimulated for 24 hours with RA synovial fluid from 5 patients. Culture supernatants were then assessed for secretion of proinflammatory cytokines by MesoScale Discovery.Results:RA synovial fluid stimulation of hMDMs resulted in the production of several proinflammatory cytokines, including IL-6, IL-8, and TNFα. Pretreatment of hMDMs with an IRAK4 inhibitor resulted in the dose-dependent inhibition of IL-6, IL-8, and TNFα production, with an average EC50± SD of 27 ± 31, 26 ± 41, and 28 ± 22 nM, respectively. Maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 76 ± 8.8, 73 ± 15, and 77 ± 13, respectively. To evaluate the specific IRAK4-dependent signaling pathways mediating this response, hMDMs were pretreated with inhibitors of TLR4 (TAK242) and IL-1R (IL-1RA) prior to stimulation with RA synovial fluid. Both TAK242 and IL-1RA inhibited proinflammatory cytokine production. For TAK242, maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 39 ± 25, 48 ± 24, and 50 ± 21, respectively. For IL-1RA maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 18 ± 18, 20 ± 23, and 16 ± 18, respectively. The broad range of inhibition across each stimulation highlights the complexity and variability in the signaling pathways mediating proinflammatory cytokine production from hMDMs stimulated with RA synovial fluid, but demonstrates that RA synovial fluid can stimulate proinflammatory cytokine production in hMDMs, at least partly, through IRAK4-dependent pathways.Conclusion:This work demonstrates that IRAK4 inhibition can suppress proinflammatory cytokine production from macrophages stimulated with synovial fluid from patients with RA and supports a potential pathophysiological role for IRAK4 in perpetuating chronic inflammation in RA.References:[1]Smolen JS, et al.Nat Rev Dis Primers.2018;4:18001.[2]Udalova IA, et al.Nat Rev Rheumatol.2016;12(8):472-485.[3]Joosten LAB, et al.Nat Rev Rheumatol.2016;12(6):344-357.[4]Huang QQ, Pope RM.Curr Rheumatol Rep.2009;11(5):357-364.[5]Roh JS, Sohn DH.Immune Netw.2018;18(4):e27.[6]Sacre SM, et al.Am J Pathol.2007;170(2):518-525.[7]Ultaigh SNA, et al.Arthritis Res Ther.2011;13(1):R33.[8]Bottini N, Firestein GS.Nat Rev Rheumatol.2013;9(1):24-33.[9]Firestein GS, McInnes IB.Immunity.2017;46(2):183-196.[10]Janssens S, Beyaert R.Mol Cell.2003;11(2):293-302.Disclosure of Interests:Adam Yadon Employee of: Gilead, Debbie Ruelas Employee of: Gilead, Gundula Min-Oo Employee of: Gilead, James Taylor Employee of: Gilead, Matthew R. Warr Employee of: Gilead

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Cardiac sarcoidosis: systematic review of literature on corticosteroid and immunosuppressive therapies

European Respiratory Journal ◽

10.1183/13993003.00449-2021 ◽

2021 ◽

pp. 2100449

Author(s):

Julien Stievenart ◽

Guillaume Le Guenno ◽

Marc Ruivard ◽

Virginie Rieu ◽

Marc André ◽

...

Keyword(s):

Adverse Events ◽

Cardiac Sarcoidosis ◽

Positive Impact ◽

Immunosuppressive Agents ◽

Left Ventricular ◽

Randomised Control Trial ◽

Cochrane Library ◽

Prisma Statement ◽

Threatening Condition ◽

Life Threatening

BackgroundCardiac sarcoidosis (CS) is a life-threatening condition in which clear recommendations are lacking. We aimed to review systematically the literature on cardiac sarcoidosis treated by corticosteroids and/or immunosuppressive agents in order to update the management of CS.MethodsUsing Pubmed, Embase and Cochrane Library databases, we found original articles on corticosteroid and/or standard immunosuppressive therapies for CS which provided at least fair SIGN overall assessment of quality and analyse the relapse rate, major cardiac adverse events (MACEs) and adverse events. We base our methods on Prisma statement and checklist.ResultsWe retrieved 21 studies. Mean quality provided by SIGN assessment was 6.8/14 (range 5–9). Corticosteroids appeared to have a positive impact on left ventricular function, atrioventricular block, and ventricular arrhythmias. For corticosteroids alone, nine (45%) studies (n=351) provided data on relapses, representing an incidence of 34% (n=119). Three studies (14%, n=73) provided data on MACEs (n=33), representing 45% of MACEs in patients treated by corticosteroid alone. Nine studies provided data on adjunctive immunosuppressive therapy in which four studies (n=78) provided data on CS relapse, representing an incidence of 33% (n=26). Limitations consisted in no randomised control trial retrieved and unclear data on MACEs in patients treated by combined immunosuppressive agents and corticosteroids.ConclusionsCorticosteroids should be started early after diagnosis but the exact scheme is still unclear. Studies concerning adjunctive conventional immunosuppressive therapies are lacking and benefits of adjunctive immunosuppressive therapies are unclear. Homogenous data on CS long-term outcomes under corticosteroids, immunosuppressive therapies and other adjunctive therapies are lacking.

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Magnetic Resonance Imaging as a Predictor of Survival Free of Life‐Threatening Arrhythmias and Transplantation in Cardiac Sarcoidosis

Journal of the American Heart Association ◽

10.1161/jaha.115.003040 ◽

2016 ◽

Vol 5 (5) ◽

Cited By ~ 14

Author(s):

Kaj Ekström ◽

Jukka Lehtonen ◽

Helena Hänninen ◽

Riina Kandolin ◽

Sari Kivistö ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Cardiac Sarcoidosis ◽

Resonance Imaging ◽

Life Threatening

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Three-dimensional Printing of Customized Bioresorbable Airway Stents

10.1101/2020.09.12.294751 ◽

2020 ◽

Author(s):

Nevena Paunović ◽

Yinyin Bao ◽

Fergal Brian Coulter ◽

Kunal Masania ◽

Anna Karoline Geks ◽

...

Keyword(s):

Three Dimensional ◽

Standard Of Care ◽

Time Frame ◽

Psychological Burden ◽

Three Dimensional Printing ◽

Life Threatening ◽

Reasonable Time Frame ◽

Printed Materials ◽

Airway Stents

AbstractCentral airway obstruction is a life-threatening disorder causing a high physical and psychological burden to patients due to severe breathlessness and impaired quality of life. Standard-of-care airway stents are silicone tubes, which cause immediate relief, but are prone to migration, especially in growing patients, and require additional surgeries to be removed, which may cause further tissue damage. Customized airway stents with tailorable bioresorbability that can be produced in a reasonable time frame would be highly needed in the management of this disorder. Here, we report poly(D,L-lactide-co-ε-caprolactone) methacrylate blends-based biomedical inks and their use for the rapid fabrication of customized and bioresorbable airway stents. The 3D printed materials are cytocompatible and exhibit silicone-like mechanical properties with suitable biodegradability. In vivo studies in healthy rabbits confirmed biocompatibility and showed that the stents stayed in place for 7 weeks after which they became radiographically invisible. The developed biomedical inks open promising perspectives for the rapid manufacturing of the customized medical devices for which high precision, tuneable elasticity and predictable degradation are sought-after.

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Successful Outpatient Management of Severe Ionized Hypercalcemia Secondary to Cholecalciferol Ingestion in a Puppy

Journal of the American Animal Hospital Association ◽

10.5326/jaaha-ms-7078 ◽

2022 ◽

Vol 58 (1) ◽

pp. 37-41

Author(s):

Adrienne M. Felix ◽

Rebecca K. Davies

Keyword(s):

Body Weight ◽

Medical Management ◽

Biochemical Parameters ◽

Reference Range ◽

Oral Prednisone ◽

Standard Of Care ◽

Outpatient Management ◽

Published Report ◽

Life Threatening

ABSTRACT A 4 mo old female intact boxer was presented because of polyuria, lethargy, and vomiting after ingestion of cholecalciferol rodenticide roughly 3 days prior. Blood work revealed an ionized hypercalcemia 2.23 mmol/L (reference range 1.04–1.33 mmol/L) on presentation. Because of financial limitations, the patient was unable to be hospitalized for standard of care. She was treated with a pamidronate infusion and discharged with medical management to include oral prednisone, furosemide, and subcutaneous fluids. The dog’s signs, body weight, and biochemical parameters were serially monitored over 3 wk as the ionized hypercalcemia resolved. To the authors’ knowledge, this is the first published report documenting a successful outpatient medical protocol for potentially life-threatening hypercalcemia secondary to cholecalciferol toxicosis in a puppy.

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Management of pulmonary toxicity associated with immune checkpoint inhibitors

European Respiratory Review ◽

10.1183/16000617.0012-2019 ◽

2019 ◽

Vol 28 (154) ◽

pp. 190012 ◽

Cited By ~ 14

Author(s):

Myriam Delaunay ◽

Grégoire Prévot ◽

Samia Collot ◽

Laurent Guilleminault ◽

Alain Didier ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Pulmonary Toxicity ◽

Immune Checkpoint Inhibitors ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Serious Adverse Events ◽

Programmed Cell Death 1 ◽

Life Threatening

Immunotherapy has become a standard of care in oncology, following the recent approvals of cytotoxic T-lymphocyte-associated protein-4 and programmed cell death-1 inhibitors in lung cancer, melanoma, renal cell carcinoma, Hodgkin's lymphoma, bladder, head and neck cancers. Besides their efficacy, these agents also generate specific immune-related adverse events. Due to the increasing prescription of immune-checkpoint inhibitors, the incidence of immune toxicity will continue to rise. The awareness of immune-related adverse events is key to ensuring both diagnosis and management of the possible serious adverse events. Although severe immune-related adverse events remain rare, they can lead to discontinued treatment or to death if they are not forecasted and managed properly. Even if lung toxicity is not the most frequent adverse event, it remains critical as it can be life-threatening. Herein, the main aspects of pulmonary toxicity are reviewed and guidelines are also proposed in order to manage the possible side-effects.

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Anakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases

International Journal of STD & AIDS ◽

10.1177/0956462420915394 ◽

2020 ◽

Vol 31 (8) ◽

pp. 808-812 ◽

Cited By ~ 3

Author(s):

Alexander J Keeley ◽

Vivak Parkash ◽

Anne Tunbridge ◽

Julia Greig ◽

Paul Collini ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Therapeutic Option ◽

Interleukin 1 ◽

High Dose ◽

Inflammatory Reactions ◽

Amyloid A ◽

The United Kingdom ◽

First Case ◽

Life Threatening ◽

Dose Corticosteroid

Paradoxical reactions, including immune reconstitution inflammatory syndrome (IRIS), are common in patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Paradoxical reactions may confer substantial morbidity and mortality, especially in cases of central nervous system (CNS) TB, or through protracted usage of corticosteroids. No high-quality evidence is available to guide management in this scenario. Interleukin-1-mediated inflammation has been implicated in the pathophysiology of TB–IRIS. We describe two cases where anakinra (human recombinant interleukin-1 receptor antagonist) was used as steroid-sparing therapy for life-threatening protracted paradoxical inflammation in HIV-associated TB. In the first case of disseminated TB with lymphadenitis, protracted TB–IRIS led to amyloid A amyloidosis and nephrotic syndrome. In the second case of disseminated TB with cerebral tuberculomata, paradoxical inflammation caused unstable tuberculomata leading to profound neuro-disability. In both cases, paradoxical inflammation persisted for over a year. Protracted high-dose corticosteroid use led to adverse events yet failed to control inflammatory pathology. In both patients, anakinra successfully controlled paradoxical inflammation and facilitated withdrawal of corticosteroid therapy. Following anakinra therapy, nephrotic syndrome and neuro-disability resolved, respectively. Anakinra therapy for protracted paradoxical inflammation in HIV-associated TB may be a viable therapeutic option and warrants further research.

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Rituximab Twice Weekly for Refractory Thrombotic Thrombocytopenic Purpura in a Critically Ill Patient with Acute Respiratory Distress Syndrome

Case Reports in Oncology ◽

10.1159/000505236 ◽

2020 ◽

Vol 13 (1) ◽

pp. 153-157

Author(s):

Bahjat Azrieh ◽

Arwa Alsaud ◽

Khaldun Obeidat ◽

Amr Ashour ◽

Seham Elebbi ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Thrombotic Thrombocytopenic Purpura ◽

Distress Syndrome ◽

Standard Of Care ◽

Critically Ill Patient ◽

Microangiopathic Hemolytic Anemia ◽

Thrombocytopenic Purpura ◽

Life Threatening

Thrombotic thrombocytopenic purpura (TTP) is a rare, serious, life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and hypercoagulability. The etiology is a deficiency of ADAMTS13 which is usually caused by acquired antibodies. Plasma exchange and steroids is the standard of care in the treatment of TTP. However, there are refractory cases of TTP which require further management. Rituximab appears to be a safe and effective therapy for refractory and relapsing TTP. Here we report a challenging case of TTP that responded to treatment with rituximab twice weekly. According to our knowledge, rituximab twice weekly has never been used for TTP before.

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