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European Journal of Preventive... Jun 2020Novel therapies are needed for recurrent pericarditis, particularly when corticosteroid dependent and colchicine resistant. Based on limited data, interleukin-1 blockade... (Observational Study)
Observational Study
AIMS
Novel therapies are needed for recurrent pericarditis, particularly when corticosteroid dependent and colchicine resistant. Based on limited data, interleukin-1 blockade with anakinra may be beneficial. The aim of this multicentre registry was to evaluate the broader effectiveness and safety of anakinra in a 'real world' population.
METHODS AND RESULTS
This registry enrolled consecutive patients with recurrent pericarditis who were corticosteroid dependent and colchicine resistant and treated with anakinra. The primary outcome was the pericarditis recurrence rate after treatment. Secondary outcomes included emergency department visits, hospitalisations, corticosteroid use and adverse events. Among 224 patients (46 ± 14 years old, 63% women, 75% idiopathic), the median duration of disease was 17 months (interquartile range 9-33). Most patients had elevated C-reactive protein (91%) and pericardial effusion (88%). After a median treatment of 6 months (3-12), pericarditis recurrences were reduced six-fold (2.33-0.39 per patient per year), emergency department admissions were reduced 11-fold (1.08-0.10 per patient per year), hospitalisations were reduced seven-fold (0.99-0.13 per patient per year). Corticosteroid use was decreased by anakinra (respectively from 80% to 27%; < 0.001). No serious adverse events occurred; adverse events consisted mostly of transient skin reactions (38%) at the injection site. Adverse events led to discontinuation in 3%. A full-dose treatment duration of over 3 months followed by a tapering period of over 3 months were the therapeutic schemes associated with a lower risk of recurrence.
CONCLUSION
In patients with recurrent pericarditis, anakinra appears efficacious and safe in reducing recurrences, emergency department admissions and hospitalisations.
Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Colchicine; Drug Administration Schedule; Drug Resistance; Drug Tapering; Female; Humans; Immunologic Factors; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Pericarditis; Recurrence; Registries; Time Factors; Treatment Outcome; Young Adult
PubMed: 31610707
DOI: 10.1177/2047487319879534 -
Frontiers in Immunology 2022The cytokine interleukin (IL)-1 plays a pivotal role in immune-mediated disorders, particularly in autoinflammatory diseases. Targeting this cytokine proved to be...
BACKGROUND
The 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.
OBJECTIVE
To 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.
METHODS
The 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.
RESULTS
Anakinra 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.
CONCLUSIONS
This 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 REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021228547.
Topics: Arthritis, Juvenile; Arthritis, Rheumatoid; Biological Products; Cryopyrin-Associated Periodic Syndromes; Diabetes Mellitus, Type 1; Familial Mediterranean Fever; Gout; Humans; Immune System Diseases; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Pericarditis
PubMed: 35874710
DOI: 10.3389/fimmu.2022.888392 -
Journal For Immunotherapy of Cancer Jan 2022In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS)...
In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.
Topics: Adult; Aged; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Neurotoxicity Syndromes; Receptors, Chimeric Antigen
PubMed: 34996813
DOI: 10.1136/jitc-2021-003847 -
Autoimmunity Reviews Mar 2021The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell... (Review)
Review
The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet's syndrome, Sjogren Syndrome, and cancer. This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL-1 soluble receptor rilonacept, and the IL-1 receptor antagonist anakinra. These advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine in a broad spectrum of diseases.
Topics: COVID-19; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Receptors, Interleukin-1; SARS-CoV-2
PubMed: 33482337
DOI: 10.1016/j.autrev.2021.102763 -
La Revue Du Praticien Jan 2021"Pericarditis Acute pericarditis is a common disease, most often idiopathic or viral. This is usually a mild condition but recurrences are frequent. The predominant... (Review)
Review
"Pericarditis Acute pericarditis is a common disease, most often idiopathic or viral. This is usually a mild condition but recurrences are frequent. The predominant pathophysiological hypothesis is that of underlying dysimmune disorders, involving an inflammatory response of the innate immune system typical of "autoinflammatory diseases", mainly mediated by interleukin-1 [IL-1] with activation of inflammasome; and an adaptive immune system response, typical of «autoimmune diseases», primarily mediated by autoantibodies and autoreactive T cells. The clinical picture associates fever, chest pain, changes in the electrocardiogram and possible pericardial effusion. Treatment is based on the combination of aspirin/nonsteroidal anti-inflammatory drugs and colchicine for several weeks. In refractory pericarditis, low dose corticosteroid therapy and / or immunosuppressive agents have been proposed with limited efficacy. Growing evidency suggest a place for IL-1 receptor antagonists in the treatment of recurrent pericarditis. Many studies have shown the effectiveness of anakinra with a good safety profile. Other IL-1 receptor antagonists have shown promising results (canakinumab, rilonacept). Further evaluation in larger prospective clinical trials is needed to confirm the long-term efficacy and safety of anti-IL1."
Topics: Aspirin; Colchicine; Humans; Interleukin 1 Receptor Antagonist Protein; Pericarditis; Prospective Studies; Recurrence
PubMed: 34160952
DOI: No ID Found -
Rheumatology (Oxford, England) Nov 2019Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these... (Review)
Review
Systemic juvenile idiopathic arthritis and adult-onset Still's disease are rare autoinflammatory disorders with common features, supporting the recognition of these being one disease-Still's disease-with different ages of onset. Anakinra was recently approved by the European Medicines Agency for Still's disease. In this review we discuss the reasoning for considering Still's disease as one disease and present anakinra efficacy and safety based on the available literature. The analysis of 27 studies showed that response to anakinra in Still's disease was remarkable, with clinically inactive disease or the equivalent reported for 23-100% of patients. Glucocorticoid reduction and/or stoppage was reported universally across the studies. In studies on paediatric patients where anakinra was used early or as first-line treatment, clinically inactive disease and successful anakinra tapering/stopping occurred in >50% of patients. Overall, current data support targeted therapy with anakinra in Still's disease since it improves clinical outcome, especially if initiated early in the disease course.
Topics: Adult; Antirheumatic Agents; Arthritis, Juvenile; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Patient Safety; Severity of Illness Index; Still's Disease, Adult-Onset; Treatment Outcome
PubMed: 31769856
DOI: 10.1093/rheumatology/kez350 -
Seizure Aug 2022There is scarce evidence of effective treatments for the chronic phase of Febrile infection-related epilepsy syndrome (FIRES). This study aimed to analyze the outcomes...
PURPOSE
There is scarce evidence of effective treatments for the chronic phase of Febrile infection-related epilepsy syndrome (FIRES). This study aimed to analyze the outcomes of treatment with anakinra and tocilizumab.
METHODS
Retrospective study including patients receiving either anti-interleukin-1 (anti-IL-1, anakinra) or anti-IL-6 (tocilizumab) during the chronic phase of FIRES. We evaluated seizure outcomes, non-seizure comorbidities, and adverse events. Additionally, an indirect control group including patients during the chronic phase of FIRES non-treated with-IL therapies was evaluated.
RESULTS
Five patients were included; three females. Median age at FIRES: 8 years (IQR: 6-10). Five patients received anakinra; one patient switched to tocilizumab after ineffectiveness. Median treatment duration was 9months (IQR: 7-20). While no patients became seizure-free, 20-50% reduction in seizure frequency was reported in 3/5 patients after 6 months with anakinra. Retention rate was 100% at 6 months and 40% at 12months. Three patients reported reduced seizure intensity and rescue medication needed, and better behavior/communication. Similar improvement was reported for the patient switching to tocilizumab. Patients with the best response received anti-IL a median of 9 years after acute phase. All discontinuations were due to ineffectiveness. There were none relevant adverse events apart from one patient presenting transient seizure aggravation. Nine patients were included in the control group; none of them showed relevant improvement in seizure outcomes or cognitive/behavioral comorbidities. Only one presented mild improvement in seizure frequency during the 6-months follow-up.
CONCLUSION
This study provides promising data on effectiveness/safety of anakinra and tocilizumab in the chronic phase of FIRES. These findings warrant prospective/larger studies.
Topics: Antibodies, Monoclonal, Humanized; Drug Resistant Epilepsy; Encephalitis; Epileptic Syndromes; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Prospective Studies; Retrospective Studies; Seizures
PubMed: 35759951
DOI: 10.1016/j.seizure.2022.06.012 -
The Israel Medical Association Journal... 2016Behçet's disease (BD) is a systemic inflammatory disorder characterized by a protean clinical spectrum and an enigmatic pathogenesis. After being classified as an... (Review)
Review
Behçet's disease (BD) is a systemic inflammatory disorder characterized by a protean clinical spectrum and an enigmatic pathogenesis. After being classified as an autoimmune disorder, spondyloarthritis and vasculitis, today BD is considered at the crossroad between autoimmune and auto-inflammatory syndromes. Many pathogenetic, clinical and therapeutic clues support this recent interpretation, enabling novel treatment choices such as interleukin (IL)-1 inhibition. Thus, in the last decade the IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibody canakinumab were increasingly administered in BD patients resistant to standard therapies, leading to interesting results and intriguing new pathogenetic implications. However, further studies are essential to both establish how the innate and acquired immune systems interact in BD patients and identify the best way of administering anti-IL-1 agents with regard to dosage, interval of administration, and organ response.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Autoimmunity; Behcet Syndrome; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Treatment Outcome
PubMed: 27228638
DOI: No ID Found -
Revue Medicale de Liege Jul 2020This is the case report of a 57-year-old women with a 10-year long history of urticarial-like exanthema and monoclonal immunoglobulin M Kappa gammopathy, associated to...
This is the case report of a 57-year-old women with a 10-year long history of urticarial-like exanthema and monoclonal immunoglobulin M Kappa gammopathy, associated to arthralgia with pain of the lower limbs. A cutaneous biopsy and an inflammatory syndrome on laboratory testing helped to diagnose an urticarial vasculitis. A treatment with colchicine was set up but the response to therapy was not satisfactory. The diagnosis of Schnitzler syndrome was eventually suggested based on the combination of monoclonal gammopathy, urticarial and pain. A therapy with anakinra, an interleukin-1-receptor antagonist (IL-1), was started accordingly. The response was remarkable on skin rash, bone pain and laboratory testing including inflammatory syndrome.
Topics: Biopsy; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Middle Aged; Schnitzler Syndrome; Skin; Urticaria
PubMed: 32779911
DOI: No ID Found -
International Immunopharmacology Oct 2022Despite the progressing knowledge in COVID-19 management, remdesivir is the only agent that got approval to inhibit viral replication. However, there are limited data... (Review)
Review
Despite the progressing knowledge in COVID-19 management, remdesivir is the only agent that got approval to inhibit viral replication. However, there are limited data about effective immunomodulatory agents to prevent cytokine release in COVID-19. Cytokine release syndrome in COVID-19 resembles secondary hemophagocytic lymphohistiocytosis, in which interleukin-1 (IL-1) plays a key role. Anakinra is the first recombinant IL-1 receptor antagonist studied for off-label use in COVID-19 treatment. This study reviews the current clinical evidence on the role of interleukin-1 in COVID-19-related cytokine storm, therapeutic effects, significant clinical concerns, and pros and cons of anakinra administration in the management of COVID-19 patients. In this review, four items are shown to be important for achieving the optimal therapeutic effects of anakinra in COVID-19 patients. These items include duration of treatment ≥ 10 days, doses ≥ 100 mg, intravenous administration, and early initiation of therapy. Also, anakinra might be more beneficial in the early stages of the disease when higher levels of cytokines are yet to be observed, which could prevent progression to severe illness and mechanical ventilation. Further studies are required to address the SARS-CoV-2 induced cytokine release syndrome and the role of anakinra in identifying ideal treatment approaches for COVID-19 patients based on their clinical status.
Topics: Cytokine Release Syndrome; Cytokines; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35905562
DOI: 10.1016/j.intimp.2022.109075