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European Journal of Medical Research Feb 2023At the end of 2021, the European Medicines Agency (EMA) expanded its approval for the recombinant human interleukin-1 (IL-1) receptor antagonist Anakinra for the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
At the end of 2021, the European Medicines Agency (EMA) expanded its approval for the recombinant human interleukin-1 (IL-1) receptor antagonist Anakinra for the treatment of COVID-19 patients with elevated soluble urokinase plasminogen activator receptor (suPAR). However, the role of Anakinra in COVID-19 remains unanswered, especially in patients receiving different forms of respiratory support. Therefore, the objective of this systematic review is to assess the safety and effects of Anakinra compared to placebo or standard care alone on clinical outcomes in adult hospitalized patients with SARS-CoV-2 infection.
METHODS
We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, medRxiv, and the Cochrane Central Register of Controlled Trials (CCSR)) and the WHO COVID-19 Global literature on coronavirus disease database to identify completed and ongoing studies from inception of each database to December 13, 2021. Since then, we monitored new published studies weekly up to June 30, 2022 using the CCSR. We included RCTs comparing treatment with Anakinra to placebo or standard care alone in adult hospitalized patients with SARS-CoV-2 infection.
RESULTS
We included five RCTs with 1,627 patients (n = 888, n = 739, mean age 59.63 years, 64% male). Random-effects meta-analysis was used to pool data. We found that Anakinra makes little or no difference to all-cause mortality at up to day 28 compared to placebo or standard care alone (RR 0.96, 95% CI 0.64-1.45; RD 9 fewer per 1000, 95% CI 84 fewer to 104 more; 4 studies, 1593 participants; I = 49%; low certainty of evidence).
CONCLUSIONS
Anakinra has no effect on adult hospitalized patients with SARS-CoV-2 infection regarding mortality, clinical improvement and worsening as well as on safety outcomes compared to placebo or standard care alone.
TRIAL REGISTRATION
PROSPERO Registration Number: CRD42021257552.
Topics: Adult; Humans; Male; Middle Aged; Female; COVID-19; Interleukin 1 Receptor Antagonist Protein; SARS-CoV-2
PubMed: 36841793
DOI: 10.1186/s40001-023-01072-z -
European Review For Medical and... Dec 2021Rheumatoid arthritis (RA) can be described as a chronic, inflammatory, progressive, autoimmune disorder characterized by generalized inflammation of the synovial joints,...
OBJECTIVE
Rheumatoid arthritis (RA) can be described as a chronic, inflammatory, progressive, autoimmune disorder characterized by generalized inflammation of the synovial joints, which hereby triggers the progressive erosion of both cartilage and bone. Anakinra is a recombinant form of human IL-1 receptor antagonist which targets the type I IL-1 receptor. In the present systematic review, we intend to evaluate the effectiveness and adverse effects of interleukin-1 antagonists in the treatment of rheumatoid arthritis.
MATERIALS AND METHODS
The database search was carried out using PubMed (Medline), Web of Science (Clarivate), Embase, Scopus, and Cochrane Library for the existing studies. A total of 3912 relevant articles were identified as per the search strategy. Out of them, 854 duplicate records and further 3024 records were excluded after going through their titles and abstracts. Further, out of 42 articles left, we excluded 32 more articles matching our inclusion criteria and excluding the reviews and case studies. Finally, we included 10 relevant studies that focused on both the effectiveness and adverse effects of interleukin-1 antagonists during the treatment of adult patients with rheumatoid arthritis in the present analysis. Nine out of 10 included studies are randomized trials (RCT) except for 1 study, which was an extension study.
RESULTS
The results showed an ACR20 response at week 12 and were the most common primary outcome measure in the present review. Various secondary outcome measures studied were changed from baseline at week 24 in individual ACR components. ACR50 and ACR70 responses at subsequent weeks (12 and 24), ESR components, HAQ score, CRP levels, and ESR. Notably, more improvement was observed with anakinra in comparison to placebo for achieving ACR50 and ACR70 responses at 24 weeks. Premature withdrawal of participants was observed in almost all the studies. Adverse drug reactions were attributed to be the most common reason followed by loss of efficacy for withdrawal of patients from the treatment. The infectious episode was another common adverse effect observed in both anakinra and placebo groups. Some malignancies were also documented in the included researches of this systematic analysis. We observed a lower overall incidence of malignancies for the studies screened compared with that of the general population.
CONCLUSIONS
This review demonstrated that anakinra is safe, effective, and well-tolerated, with no significant difference in adverse effects compared to placebo in rheumatoid arthritis patients.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Interleukin 1 Receptor Antagonist Protein; Methotrexate; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34982445
DOI: 10.26355/eurrev_202112_27630 -
The Journal of Rheumatology May 2024To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD).
METHODS
Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series.
RESULTS
Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, 36%), 73% (95% CI 58-84%, 66%), and 77% (95% CI 29-97%, 82%) and CS discontinuation was 57% (95% CI 29-81%, 66%), 47% (95% CI 18-78%, 79%), and 34% (95% CI 6-81%, 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation ( = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy.
CONCLUSION
Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.
Topics: Adult; Humans; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Biological Products; Interleukin 1 Receptor Antagonist Protein; Remission Induction; Still's Disease, Adult-Onset; Treatment Outcome
PubMed: 38302170
DOI: 10.3899/jrheum.2023-0995 -
Rheumatology (Oxford, England) Dec 2021Acute respiratory distress syndrome and cytokine release syndrome are the major complications of coronavirus disease 2019 (COVID-19) associated with increased mortality... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Acute respiratory distress syndrome and cytokine release syndrome are the major complications of coronavirus disease 2019 (COVID-19) associated with increased mortality risk. We performed a meta-analysis to assess the efficacy and safety of anakinra in adult hospitalized non-intubated patients with COVID-19.
METHODS
Relevant trials were identified by searching literature until 24 April 2021 using the following terms: anakinra, IL-1, coronavirus, COVID-19, SARS-CoV-2. Trials evaluating the effect of anakinra on the need for invasive mechanical ventilation and mortality in hospitalized non-intubated patients with COVID-19 were included.
RESULTS
Nine studies (n = 1119) were eligible for inclusion in the present meta-analysis. Their bias risk with reference to the assessed parameters was high. In pooled analyses, anakinra reduced the need for invasive mechanical ventilation (odds ratio (OR): 0.38, 95% CI: 0.17-0.85, P = 0.02, I2 = 67%; six studies, n = 587) and mortality risk (OR: 0.32, 95% CI: 0.23-0.45, P < 0.00001, I2 = 0%; nine studies, n = 1119) compared with standard of care therapy. There were no differences regarding the risk of adverse events, including liver dysfunction (OR: 0.75, 95% CI: 0.48-1.16, P > 0.05, I2 = 28%; five studies, n = 591) and bacteraemia (OR: 1.07, 95% CI: 0.42-2.73, P > 0.05, I2 = 71%; six studies, n = 727).
CONCLUSIONS
Available evidence shows that treatment with anakinra reduces both the need for invasive mechanical ventilation and mortality risk of hospitalized non-intubated patients with COVID-19 without increasing the risk of adverse events. Confirmation of efficacy and safety requires randomized placebo-controlled trials.
Topics: Humans; Interleukin 1 Receptor Antagonist Protein; Receptors, Interleukin-1; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33999135
DOI: 10.1093/rheumatology/keab447 -
Frontiers in Immunology 2023This scoping review explores the effectiveness of IL-1 pathway inhibitors in managing PSTPIP1-associated inflammatory diseases (PAID). These diseases are marked by...
INTRODUCTION
This scoping review explores the effectiveness of IL-1 pathway inhibitors in managing PSTPIP1-associated inflammatory diseases (PAID). These diseases are marked by abnormal IL-1 pathway activation due to genetic mutations.
METHODS
Our methodology adhered to a pre-published protocol and involved a thorough search of MEDLINE and EMBASE databases up to February 2022, following the Joanna Briggs Institute Reviewer's Manual and the PRISMA Extension for Scoping Reviews. The review included studies reporting on IL-1 pathway inhibitor use in PAID patients.
RESULTS
From an initial pool of 5,225 articles, 36 studies involving 43 patients were selected. The studies predominantly used observational designs and exhibited diversity in patient demographics, treatment approaches, and outcomes. Anakinra and canakinumab demonstrated promise in treating sterile pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) and PSTPIP1-associated myeloid-related-proteinemia inflammatory (PAMI) syndromes, with scant data on other syndromes. Notably, there was a paucity of information on the adverse effects of these treatments, necessitating cautious interpretation of their safety profile.
CONCLUSION
Current evidence on IL-1 pathway inhibitors for PAID is primarily from observational studies and remains limited. Rigorous research with larger patient cohorts is imperative for more definitive conclusions. Collaborative efforts among specialized research centers and international health initiatives are key to advancing this field.
Topics: Humans; Acne Vulgaris; Adaptor Proteins, Signal Transducing; Antibodies, Monoclonal, Humanized; Arthritis, Infectious; Cytoskeletal Proteins; Interleukin 1 Receptor Antagonist Protein; Interleukin-1
PubMed: 38259483
DOI: 10.3389/fimmu.2023.1339337 -
Reviews in Medical Virology May 2022As the pandemic progresses, the pathophysiology of coronavirus disease 2019 (COVID-19) is becoming clearer and the potential for immunotherapy is increasing. However,... (Meta-Analysis)
Meta-Analysis Review
As the pandemic progresses, the pathophysiology of coronavirus disease 2019 (COVID-19) is becoming clearer and the potential for immunotherapy is increasing. However, clinical efficacy and safety of immunosuppressants (including tocilizumab, sarilumab and anakinra) treatment in COVID-19 patients are not yet known. We searched PubMed, Embase Medline, Web of Science and MedRxiv using specific search terms in studies published from 1 January 2020 to 20 December 2020. In total, 33 studies, including 3073 cases and 6502 controls, were selected for meta-analysis. We found that immunosuppressant therapy significantly decreased mortality in COVID-19 patients on overall analysis (odds ratio = 0.71, 95% confidence interval = 0.57-0.89, p = 0.004). We also found that tocilizumab and anakinra significantly decreased mortality in patients without any increased risk of secondary infection. In addition, we found similar results in several subgroups. However, we found that tocilizumab therapy significantly increased the risk of fungal co-infections in COVID-19 patients. This represents the only systematic review and meta-analysis to investigate the efficacy and secondary infection risk of immunosuppressant treatment in COVID-19 patients. Overall, immunosuppressants significantly decreased mortality but had no effect on increased risk of secondary infections. Our analysis of tocilizumab therapy showed a significantly increased risk of fungal co-infections in these patients.
Topics: Antibodies, Monoclonal, Humanized; Coinfection; Humans; Immunosuppressive Agents; Interleukin 1 Receptor Antagonist Protein; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 34558756
DOI: 10.1002/rmv.2295 -
Infection & Chemotherapy Jun 2021This study aims to assess anakinra's safety and efficacy for treating severe coronavirus disease 2019 (COVID-19). Numerous electronic databases were searched and finally... (Review)
Review
This study aims to assess anakinra's safety and efficacy for treating severe coronavirus disease 2019 (COVID-19). Numerous electronic databases were searched and finally 15 studies with a total of 3,530 patients, 757 in the anakinra arm, 1,685 in the control arm were included. The pooled adjusted odds ratio (OR) for mortality in the treatment arm was 0.34 (95% confidence interval [CI], 0.21 - 0.54, I² = 48%), indicating a significant association between anakinra and mortality. A significant association was found regarding mechanical ventilation requirements in anakinra group compared to the control group OR, 0.68 (95% CI, 0.49 - 0.95, I² = 50%). For the safety of anakinra, we evaluated thromboembolism risk and liver transaminases elevation. Thromboembolism risk was OR, 1.59 (95% CI, 0.65 - 3.91, I² = 0%) and elevation in liver transaminases with OR was 1.35 (95% CI, 0.61 - 3.03, I² = 76%). Both were not statistically significant over the control group. Anakinra is beneficial in lowering mortality in COVID-19 patients. However, these non-significant differences in the safety profile between the anakinra and control groups may have been the result of baseline characteristics of the intervention group, and further studies are essential in evaluating anakinra's safety profile.
PubMed: 34216117
DOI: 10.3947/ic.2021.0016 -
Laryngoscope Investigative... Dec 2020The study systematically reviewed the existing literature on the management of autoimmune inner ear disease (AIED). (Review)
Review
OBJECTIVES
The study systematically reviewed the existing literature on the management of autoimmune inner ear disease (AIED).
STUDY DESIGN
Systematic review.
METHODS
We performed a literature search of Embase, NCBI, Cochrane, and Web of Science databases from April 1990 to April 2020. Inclusion criteria included studies that were retrospective or prospective in nature evaluating the treatment of AIED with audiometric data measuring hearing outcomes during treatment. Hearing improvement was the primary study outcome and improvement in vestibular symptoms was the secondary study outcome.
RESULTS
Sixteen of 412 candidate articles were included in our study. Systemic steroid treatment is most commonly described. Alternative treatment modalities included intratympanic steroid treatment, methotrexate, cyclophosphamide, azathioprine, infliximab, etanercept, adalimumab, golimumab, methylprednisolone, rituximab, and anakinra.
CONCLUSION
Systemic corticosteroids are the first line treatment of AIED. Intratympanic steroids are a potential adjuvant or alternative treatment for patients who cannot tolerate or become refractory to steroid treatment. Steroid nonresponders may benefit from biologic therapy. Alternative treatment modalities including nonsteroidal immunosuppressants and biologics have been studied in small cohorts of patients with varying results. Prospective studies investigating the efficacy of biologic and nonsteroidal therapy are warranted.
LEVEL OF EVIDENCE
2.
PubMed: 33364414
DOI: 10.1002/lio2.508 -
Genes Aug 2023PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as... (Review)
Review
PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, previously known as Hyperzincemia/Hypercalprotectinemia (Hz/Hc) syndrome, is a recently described, rare auto-inflammatory disorder caused by specific deleterious variants in the gene (p.E250K and p.E257K). The disease is characterized by chronic systemic inflammation, cutaneous and osteoarticular manifestations, hepatosplenomegaly, anemia, and neutropenia. Increased blood levels of MRP 8/14 and zinc distinguish this condition from other PSTPIP1-associated inflammatory diseases (PAID). The aim of this systematic review is to provide a comprehensive overview of the disease phenotype, course, treatment, and outcome based on reported cases. This systematic review adheres to the PRISMA guidelines (2020) for reporting. A literature search was performed in Embase, Medline, and Web of Science on 13 October 2022. The quality of the case reports and case series was assessed using the JBI checklists. Out of the 43 included patients with PAMI syndrome, there were 24 females and 19 males. The median age at onset was 3.9 years. The main clinical manifestations included anemia (100%), neutropenia (98%), cutaneous manifestations (74%), osteoarticular manifestations (72%), splenomegaly (70%), growth failure (57%), fever (51%), hepatomegaly (56%), and lymphadenopathy (39%). Systemic inflammation was described in all patients. Marked elevation of zinc and MRP 8/14 blood levels were observed in all tested patients. Response to treatment varied and no consistently effective therapy was identified. The most common therapeutic options were corticosteroids (N = 30), anakinra (N = 13), cyclosporine A (N = 11), canakinumab (N = 6), and anti-TNF (N = 14). Hematopoietic stem cell transplantation has been recently reported to be successful in five patients. Our review highlights the key characteristics of PAMI syndrome and the importance of considering this disease in the differential diagnosis of patients presenting with early-onset systemic inflammation and cytopenia.
Topics: Female; Male; Humans; Tumor Necrosis Factor Inhibitors; Neutropenia; Diagnosis, Differential; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37628706
DOI: 10.3390/genes14081655 -
Therapeutic Advances in Musculoskeletal... 2021The past decade has seen increasingly rapid advances in understanding the pathogenic nature of adult-onset Still's disease (AOSD) and its shared symptoms with the... (Review)
Review
INTRODUCTION
The past decade has seen increasingly rapid advances in understanding the pathogenic nature of adult-onset Still's disease (AOSD) and its shared symptoms with the systemic juvenile idiopathic arthritis (sJIA). Interleukin-1 (IL-1) blocking agents are key elements in the treatment. In this updated systematic review, we focus on studies on efficacy and safety of IL-1 blockers published in the past 5 years and review on latest available therapies.
METHODS
We conducted searches using Medline, Biosis, Embase, and Cochrane databases between 2016 and 2021 using the terms AOSD, IL1, IL-18, canakinumab, anakinra, tadekinig, and rilonacept and if applicable their trade names. Duplicates, case reports, and manuscripts with incomplete data were excluded.
RESULTS
Of the 1013 screened publications, 17 were eligible after careful selection. We only found two published randomized controlled studies in the past 5 years. Review manuscripts of rare diseases, like our work, usually rely on retrospective studies and case series. Anakinra and canakinumab can be successfully used as first- or further-line treatment in patients with AOSD refractory to steroids. A homogeneous outcome is not established yet. Thus, a combination of clinical and laboratory tests can support the experienced clinician in the decision-making process.
CONCLUSION
The approval of IL-1 inhibitors for AOSD brought us into a new era in the treatment of AOSD. The overall efficacy-safety profile of the IL-1 inhibitors is favorable reflecting a targeted approach as standard of care. We can expect that the successful treatment of AOSD with IL-1 inhibition will facilitate further clinical and basic research with impact on other auto-inflammatory and hyper-inflammatory conditions.
PubMed: 34868356
DOI: 10.1177/1759720X211059598