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CNS Drugs Sep 2022Autoimmune encephalitis represents a potentially treatable immune-mediated condition that is being more frequently recognized. Prompt immunotherapy is a key factor for... (Review)
Review
Autoimmune encephalitis represents a potentially treatable immune-mediated condition that is being more frequently recognized. Prompt immunotherapy is a key factor for the management of autoimmune encephalitis. First-line treatments include intravenous steroids, plasma exchange, and intravenous immunoglobulins, which can be combined in most severe cases. Rituximab and cyclophosphamide are administered as second-line agents in unresponsive cases. A minority of patients may still remain refractory, thus representing a major clinical challenge. In these cases, treatment strategies are controversial, and no guidelines exist. Treatments proposed for refractory autoimmune encephalitis include (1) cytokine-based drugs (such as tocilizumab, interleukin-2/basiliximab, anakinra, and tofacitinib); (2) plasma cell-depleting agents (such as bortezomib and daratumumab); and (3) treatments targeting intrathecal immune cells or their trafficking through the blood-brain barrier (such as intrathecal methotrexate and natalizumab). The efficacy evidence of these drugs is mostly based on case reports or small case series, with few reported controlled studies or systematic reviews. The aim of the present review is to summarize the current evidence and related methodological issues in the use of these drugs for the treatment of refractory autoimmune encephalitis.
Topics: Basiliximab; Bortezomib; Cyclophosphamide; Encephalitis; Hashimoto Disease; Humans; Immunoglobulins, Intravenous; Interleukin 1 Receptor Antagonist Protein; Interleukin-2; Methotrexate; Natalizumab; Rituximab; Steroids
PubMed: 35917105
DOI: 10.1007/s40263-022-00943-z -
The Lancet. Oncology Jun 2023T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events... (Review)
Review
Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European Myeloma Network.
T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.
Topics: Humans; Multiple Myeloma; Antibodies, Bispecific; Cytokine Release Syndrome; Interleukin 1 Receptor Antagonist Protein; Consensus; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 37269857
DOI: 10.1016/S1470-2045(23)00159-6 -
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 -
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 -
Expert Opinion on Biological Therapy Jul 2020The management of a child with juvenile idiopathic arthritis (JIA) requires a combination of pharmacological, physical, and psychosocial therapies in order to induce... (Review)
Review
INTRODUCTION
The management of a child with juvenile idiopathic arthritis (JIA) requires a combination of pharmacological, physical, and psychosocial therapies in order to induce disease remission, by controlling articular and systemic inflammation. This review aims to provide a comprehensive discussion on the biological therapies currently in use in the treatment of JIA referring to existing recommendations and clinical evidence. We also discuss on the emerging biological drugs actually under consideration.
AREAS COVERED
Recent findings on immunological mechanisms involved in the pathogenesis of the disease allowed us to identify several specific targets for biologic therapies. A systematic literature review was conducted between January 1997 and January 2020 on PubMed including national and international guidelines and recommendations, trials and case-control studies.
EXPERT OPINION
There is now a plethora of therapies that are directed against variable targets, and the physician has to choose the most appropriate available medication in order to achieve early and sustained remission with as few side effects as possible. Research is advancing very fast in order to be more and more specific in suppressing inflammatory pathways without harming natural defenses. Finally, pharmacoeconomic considerations will also be very important to deal with, considering the high cost of most of these molecules.
Topics: Adalimumab; Antirheumatic Agents; Arthritis, Juvenile; Biological Products; Child; Etanercept; Humans; Interleukin 1 Receptor Antagonist Protein; Neoplasms; Recombinant Fusion Proteins
PubMed: 32116038
DOI: 10.1080/14712598.2020.1733524 -
Arthritis & Rheumatology (Hoboken, N.J.) Aug 2021To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares.
METHODS
Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response.
RESULTS
One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction.
CONCLUSION
Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.
Topics: Adult; Aged; Aged, 80 and over; Arthralgia; Double-Blind Method; Female; Gout; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Middle Aged; Pain Measurement; Patient Reported Outcome Measures; Symptom Flare Up; Treatment Outcome; Triamcinolone
PubMed: 33605029
DOI: 10.1002/art.41699 -
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 -
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 -
Arthritis & Rheumatology (Hoboken, N.J.) Mar 2021
Topics: COVID-19; Humans; Interleukin 1 Receptor Antagonist Protein; Liver; SARS-CoV-2
PubMed: 32951346
DOI: 10.1002/art.41524