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European Journal of Haematology Sep 2023Haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) has a potentially high mortality rate. Anakinra, an interleukin-1 receptor antagonist,...
BACKGROUND
Haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) has a potentially high mortality rate. Anakinra, an interleukin-1 receptor antagonist, is now recommended early in HLH/MAS, with intravenous (IV) use proposed in critically unwell patients. This systematic review establishes the literature relating to IV anakinra in secondary HLH/MAS (sHLH/MAS).
METHODS
We screened Embase, PubMed, and Medline, including all reports of IV anakinra for HLH or MAS. We extracted age, HLH/MAS trigger, continuous infusion or bolus dosing, and survival.
RESULTS
Twenty-nine case reports/series identified 87 patients (median age 22 years, range 22 months to 84 years), all with sHLH. Amongst identifiable triggers, 43% were systemic infection, 33% rheumatological, 9% oncological. Children had predominantly a rheumatological trigger (48%), whilst adults were more commonly infection-driven (50%). Overall, rheumatologically triggered disease showed greater survival (83.3%), particularly compared with oncological triggers (42.9%). Children had a greater survival, particularly under 10 years (83%, vs. adults, 63%).
CONCLUSIONS
Despite IV anakinra recipients likely to be critically unwell, this cohort had similar disease triggers and survival compared to large historical cohorts, and enhances awareness of age and trigger-specific survival patterns. IV anakinra had a wide therapeutic dosing range and tolerability, regardless of trigger, demonstrating substantial utility in severe sHLH/MAS.
Topics: Adult; Child; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Interleukin 1 Receptor Antagonist Protein; Sepsis; Rheumatic Diseases
PubMed: 37344166
DOI: 10.1111/ejh.14029 -
Rheumatology International May 2020Macrophage activation syndrome (MAS) is a potentially fatal complication of a number of rheumatological conditions, but few studies assessed it in juvenile... (Review)
Review
Macrophage activation syndrome (MAS) is a potentially fatal complication of a number of rheumatological conditions, but few studies assessed it in juvenile dermatomyositis (JDM). Indeed, MAS is not considered as a frequent complication of JDM, but its occurrence could be under-estimated. In order to address this issue, we performed a revision of the available medical literature, describing and assessing patients with both MAS and JDM. After retrieving 253 records initially, 11 papers were selected as appropriate for our research objective, which provided a total of 12 patients affected with both MAS and JDM. Our pooled case series suggested that MAS in JDM may not be very rare, even though no final conclusion about its incidence and mortality rate can be made. However, JDM-related MAS seems to be difficult to treat, since methylprednisolone pulse therapy alone was not sufficient in most cases. Moreover, MAS in JDM patients often occurred at the onset of the rheumatic disease, before the final diagnosis of JDM could be established. Finally, MAS criteria validated for systemic Juvenile Idiopathic Arthritis (sJIA) resulted to be a very useful guidance to diagnose MAS in JDM patients as well, but their reliability may not be absolute. Therefore, cohort and multicenter studies are needed to assess the incidence and improve the diagnostic criteria for MAS in JDM patients.
Topics: Adolescent; Child; Child, Preschool; Dermatomyositis; Female; Humans; Macrophage Activation Syndrome; Male
PubMed: 31529231
DOI: 10.1007/s00296-019-04442-1 -
Obesity Reviews : An Official Journal... Nov 2019Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes...
Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes (T2D). The role of the immune system in skeletal muscle (SM) inflammation and insulin sensitivity is not yet well characterized. As SM IR is an important determinant of glycaemia, it is critical that the muscle-immune phenotype is mapped to help design interventions to target T2D. This systematic review synthesized the evidence for SM macrophage content and phenotype in humans and murine models of obesity, and the association of muscle macrophage content and phenotype with IR. Results were synthesized narratively, as we were unable to conduct a meta-analysis. We included 28 studies (n=10 human, n=18 murine), and all studies detected macrophage markers in SM. Macrophage content was positively associated with IR. In humans and mice, there was variability in muscle macrophage content and phenotype in obesity. Overall certainty in the evidence was low due to heterogeneity in detection methods and incompleteness of data reporting. Macrophages are detected in human and murine SM in obesity and a positive association between macrophage content and IR is noted; however, the standardization of markers, detection methods, and reporting of study details is warranted to accurately characterize macrophages and improve the potential for creating specific and targeted immune-based therapies in obesity.
Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Clamp Technique; Humans; Inflammation; Insulin Resistance; Macrophage Activation; Macrophages; Mice; Muscle, Skeletal; Obesity
PubMed: 31410961
DOI: 10.1111/obr.12922 -
Pediatric Rheumatology Online Journal Dec 2015Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile... (Review)
Review
BACKGROUND
Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment.
METHODS
A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines.
RESULTS
27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra.
CONCLUSION
MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.
Topics: Adrenal Cortex Hormones; Arthritis, Juvenile; Biomarkers; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Macrophage Activation Syndrome
PubMed: 26634252
DOI: 10.1186/s12969-015-0055-3 -
Cureus Oct 2021Among the autoimmune (AI) diseases, systemic lupus erythematosus (SLE) is known to mimic various disease processes and this can lead to under-diagnosis of macrophage... (Review)
Review
Among the autoimmune (AI) diseases, systemic lupus erythematosus (SLE) is known to mimic various disease processes and this can lead to under-diagnosis of macrophage activation syndrome (a dire complication). We aimed at performing a systematic review to identify trigger factors that could lead to the development of macrophage activation syndrome (MAS) in patients with SLE as well as identify factors that can affect mortality. We searched the following databases to extract relevant articles: PubMed, ScienceDirect, Cochrane library, Pro-Quest, and Google Scholar. We used search terms including but not limited to hemophagocytic syndromes OR hemophagocytic lymphohistiocytosis OR macrophage activation syndrome OR HLH OR secondary hemophagocytic lymphohistiocytosis AND systemic lupus erythematosus OR SLE. We screened the articles first by titles and abstracts and later by full text. After the application of our eligibility criteria, we identified eight studies to include in our final synthesis. The studies showed that lupus flare itself, as well as, time to onset and high systemic lupus erythematosus disease activity index (SLEDAI) scores, were major risk factors that led to the development of MAS. In addition, infections followed by drugs, underlying malignancy, and pregnancy were other potential trigger factors identified. Studies also detected that MAS development led to high intensive care unit (ICU) admissions and in-hospital mortalities with C-reactive protein (CRP) levels, age, presence of infection, leukopenia, thrombocytopenia, MAS throughout the hospital stay, and high liver function tests (LFTs) as signs of poor prognosis. Additionally, ferritin levels, LFTs, and triglyceride levels formed an important part of diagnostic criteria. However, our review was limited due to the absence of prospective studies and heterogeneity in the studies seen. More studies need to be done to identify various factors leading to hemophagocytic lymphohistiocytosis (HLH) in autoimmune diseases with validated criteria for MAS secondary to autoimmune diseases.
PubMed: 34804679
DOI: 10.7759/cureus.18822 -
Clinical Rheumatology Dec 2018Our aim was to report our experiences of pediatric macrophage activation syndrome (MAS) patients treated with anakinra and to review previous studies reporting anakinra... (Review)
Review
Our aim was to report our experiences of pediatric macrophage activation syndrome (MAS) patients treated with anakinra and to review previous studies reporting anakinra treatment in pediatric MAS patients associated with systemic juvenile idiopathic arthritis (sJIA) or autoinflammatory diseases (AIDs). The study group consisted of pediatric MAS patients due to sJIA or AIDs, followed up in the Pediatric Rheumatology Unit of Hacettepe University between January 2015 and January 2017 and treated with anakinra (anti-IL1). We conducted a systematic review of the published literature involving pediatric MAS patients associated with sJIA or AIDs, treated with anakinra. Thirteen sJIA patients and two AIDs patients were included the study. Nineteen MAS episodes were observed in 15 patients. Anakinra (2 mg/kg/day) was started in with a median 1 day after admission. Clinical symptoms resolved, and laboratory findings normalized within median (minimum-maximum) 2 (1-4) and 6 (4-9) days, respectively after the introduction of anakinra. Steroid treatment was stopped in a median of 10 (4-13) weeks after the initiation of anakinra treatment. Patients were followed up for a median of 13 (6-24) months. Two patients developed recurrent MAS episodes when the anakinra dose was reduced, while the other patients achieved remission. In the literature review, we identified nine articles, describing 35 pediatric MAS patients associated with sJIA or AIDs and treated with anakinra. Except for two, all the patients reached remission. Our study and systematic literature review may help to improve the knowledge on the role of anakinra treatment in the management of MAS.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Male; Arthritis, Juvenile; Autoimmunity; Inflammation; Interleukin 1 Receptor Antagonist Protein; Macrophage Activation Syndrome; Patient Safety; Remission Induction; Treatment Outcome
PubMed: 29663156
DOI: 10.1007/s10067-018-4095-1 -
Experimental & Molecular Medicine Mar 2024Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a life-threatening immune disorder triggered by rheumatic disease, infections,... (Review)
Review
Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a life-threatening immune disorder triggered by rheumatic disease, infections, malignancies, or medications. Characterized by the presence of hemophagocytic macrophages and a fulminant cytokine storm, sHLH/MAS leads to hyperferritinemia and multiorgan failure and rapidly progresses to death. The high mortality rate and the lack of specific treatments necessitate the development of a new drug. However, the complex and largely unknown immunopathologic mechanisms of sHLH/MAS, which involve dysfunction of various immune cells, diverse etiologies, and different clinical contexts make this effort challenging. This review introduces the terminology, diagnosis, and clinical features of sHLH/MAS. From a translational perspective, this review focuses on the immunopathological mechanisms linked to various etiologies, emphasizing potential drug targets, including key molecules and signaling pathways. We also discuss immunomodulatory biologics, existing drugs under clinical evaluation, and novel therapies in clinical trials. This systematic review aims to provide insights and highlight opportunities for the development of novel sHLH/MAS therapeutics.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Macrophages
PubMed: 38448692
DOI: 10.1038/s12276-024-01182-6 -
European Neuropsychopharmacology : the... Aug 2023Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced... (Meta-Analysis)
Meta-Analysis Review
Clozapine presents immunoregulatory properties not well understood. To address this issue, we performed this systematic review to evaluate the immune alterations induced by clozapine and its relationship with the drug's clinical response and compare it with other antipsychotics. Our systematic review has selected nineteen studies meeting the inclusion criteria, from which eleven were included in the meta-analysis, totalizing 689 subjects distributed over three different comparisons. The results revealed that clozapine treatment activates the compensatory immune-regulatory system (CIRS) (Hedges's g = +1.049; CI +0.62 - +1.47, p < 0.001) but has no effects on the immune-Inflammatory Response System (IRS) (Hedges's g= -0.27; CI -1.76 - +1.22, p = 0.71), M1 macrophage (Hedges's g= -0.32; CI -1.78 - +1.14, p = 0.65) and Th1 (Hedge's g = 0.86; CI -0.93 - +1.814, p = 0.07) profiles. Comparing clozapine-treated patients with other anti-psychotics-treated, plasma levels of interleukin (IL)-6 were greater in the clozapine group (Hedge's g = 0.75; CI 0.35 - 1.15, p<0.001). In addition, higher IL-6 plasma levels after four weeks of clozapine treatment were related to the development of clozapine-induced fever; however, IL-6 levels recovered to baseline in 6-10 weeks due to an unexplained compensatory mechanism. In conclusion, our results show that clozapine treatment causes a time-dependent mixed immune profile characterized by increased IL-6 levels and CIRS activation, which may contribute to this drug mechanism of action and adverse effects. Future studies must be designed to investigate the relationship between clozapine-induced immune alterations and symptom remission, treatment resistance, and adverse effects, given the importance of this drug for treating resistant schizophrenia.
Topics: Humans; Clozapine; Schizophrenia; Interleukin-6; Antipsychotic Agents; Oxidative Stress
PubMed: 37148631
DOI: 10.1016/j.euroneuro.2023.04.003 -
Pediatric Blood & Cancer Mar 2023Risk factors of mortality in critically ill children with hemophagocytic lymphohistiocytosis (HLH) are not well described. This systematic review aims to determine... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Risk factors of mortality in critically ill children with hemophagocytic lymphohistiocytosis (HLH) are not well described. This systematic review aims to determine overall mortality of critically ill children with HLH, and describes etiologies, treatment, and pediatric intensive care unit (PICU) support employed.
DATA SOURCES
PubMed, Embase, Web of Science, CINAHL, and Cochrane Library from inception until February 28, 2022.
STUDY SELECTION
Observational studies and randomized controlled trials reporting children aged 18 years or below, diagnosed with HLH and admitted to the PICU.
DATA EXTRACTION
Etiologies, treatment modalities, PICU therapies, and mortality outcomes were summarized. Random-effects meta-analysis was performed.
DATA SYNTHESIS
Total 36 studies (total patients = 493, mean age: 49.5 months [95% confidence interval (CI): 30.9-79.5]) were included. Pooled mortality rate was 32.6% (95% CI: 23.4-42.4). The most frequent etiologies for HLH were infections (53.3%) and primary HLH (12.8%), while the remaining cases were due to other causes of secondary HLH, including autoimmune diseases, malignancy, and drug-induced and idiopathic HLH. Pooled mortality rate was higher in primary than secondary HLH (72.2%, 95% CI: 57.8-84.5 vs. 23.9%, 95% CI: 14.4-35.02; p < .01). Univariate analysis found that treatment with etoposide was associated with higher mortality, while intravenous immunoglobulins (IVIGs) were associated with lower mortality. Conversely, multivariable analysis adjusted for etiology demonstrated no association between etoposide and IVIG use, and mortality. Twenty-one studies (total patients = 278) had detailed information on PICU therapies. Mechanical ventilation (MV), continuous renal replacement therapy, and inotropes were used in 107 (38.5%), 66 (23.7%), and 51 patients (18.3%), respectively. Need for MV was associated with increased risk of mortality (mean difference = 28%, 95% CI: 9-47).
CONCLUSION
Critically ill children with HLH have high mortality rates and require substantial PICU support. Collaborative work between multiple centers with standardized data collection can potentially provide more robust data.
Topics: Humans; Child; Child, Preschool; Lymphohistiocytosis, Hemophagocytic; Etoposide; Critical Illness; Retrospective Studies; Intensive Care Units, Pediatric; Immunoglobulins, Intravenous
PubMed: 36579732
DOI: 10.1002/pbc.30122 -
Materials (Basel, Switzerland) Oct 2022Immunomodulatory biomaterials have the potential to stimulate an immune response able to promote constructive and functional tissue remodeling responses as opposed to... (Review)
Review
UNLABELLED
Immunomodulatory biomaterials have the potential to stimulate an immune response able to promote constructive and functional tissue remodeling responses as opposed to persistent inflammation and scar tissue formation. As such, the controlled activation of macrophages and modulation of their phenotype through implant surface modification has emerged as a key therapeutic strategy.
METHODS
Online databases were searched for in vitro studies between January 1991 and June 2020 which examined the effect of titanium implant surface topography on the adherent macrophage phenotype at either the gene or protein level.
RESULTS
Thirty-nine studies were subsequently included for review. Although there was significant heterogeneity between studies, treatment of titanium surfaces increased the surface roughness or hydrophilicity, and hence increased macrophage attachment but decreased cell spreading. Physical coating of the titanium surface also tended to promote the formation of cell clusters. Titanium and titanium-zirconium alloy with a micro- or nano-scale rough topography combined with a hydrophilic surface chemistry were the most effective surfaces for inducing an anti-inflammatory phenotype in adherent macrophages, as indicated by significant changes in cytokine gene expression and or cytokine secretion profiles.
CONCLUSIONS
The published data support the hypothesis that incorporation of specific topographical and physiochemical surface modifications to titanium can modulate the phenotypic response of adherent macrophages.
PubMed: 36295379
DOI: 10.3390/ma15207314