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Annals of the Rheumatic Diseases Oct 2023Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most...
The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
OBJECTIVE
Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the of diagnosis, treatment and monitoring of HLH/MAS.
METHODS
A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.
RESULTS
The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.
CONCLUSION
These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
Topics: Child; Adult; Humans; United States; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Rheumatology; Consensus
PubMed: 37487610
DOI: 10.1136/ard-2023-224123 -
Arthritis & Rheumatology (Hoboken, N.J.) Oct 2023Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most...
The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS).
OBJECTIVE
Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS.
METHODS
A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.
RESULTS
The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.
CONCLUSION
These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
Topics: Adult; Child; Humans; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Consensus; Physicians; Advisory Committees
PubMed: 37486733
DOI: 10.1002/art.42636 -
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 -
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 -
The Journal of Tehran Heart Center Oct 2023Among its functions, brain-derived neurotrophic factor (BDNF) regulates endothelial and macrophage activation, possibly playing a role in atherosclerotic plaque... (Review)
Review
BACKGROUND
Among its functions, brain-derived neurotrophic factor (BDNF) regulates endothelial and macrophage activation, possibly playing a role in atherosclerotic plaque pathophysiology. Given contradicting reports, this study sought to investigate whether blood levels of BDNF differed between patients with coronary heart disease (CHD) and controls.
METHODS
We explored PubMed, Embase, Web of Science, and Cochrane Library for studies comparing BDNF blood levels in patients with CHD and controls. Random-effect meta-analysis was conducted to calculate the standardized mean differences (SMD) and 95% confidence intervals (CI). The Newcastle-Ottawa scale was used to evaluate the quality of included articles, and statistical analyses were conducted using R version 4.0.4.
RESULTS
The final analysis comprised 12 investigations covering 1422 CHD cases and 929 controls with mean ages of 59.66±13.56 and 53.78±13.61 years, respectively. The initial analyses revealed a tendency toward low levels of BDNF in the CHD group compared with the control group (SMD= -0.41; 95% CI, -1.12 to 0.30; P=0.26). After the removal of outliers, the difference achieved statistical difference (SMD= -0.56; 95% CI, -0.93 to -0.19; P<0.01). Subgroup analysis demonstrated no significant difference between serum and plasma BDNF levels (P=0.54); however, subgroup analyses of studies investigating plasma BDNF showed that patients with CHD had significantly lower BDNF levels.
CONCLUSION
Serum and plasma BDNF concentrations were considerably lower in patients with CHD than in healthy controls. Further studies of higher quality are required on the potential role of BDNF as a biomarker of CHD pathophysiology and severity.
PubMed: 38680638
DOI: 10.18502/jthc.v18i4.14823 -
International Immunopharmacology Jun 2024To evaluate the efficacy and safety of Janus kinases inhibitors (JAKi) for adult-onset Still's disease (AOSD) patients. (Review)
Review
OBJECTIVE
To evaluate the efficacy and safety of Janus kinases inhibitors (JAKi) for adult-onset Still's disease (AOSD) patients.
METHODS
We searched the Embase, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and the China National Knowledge Infrastructure (CNKI) from inception up to 22 October 2023. The results were supplemented by a backward search of relevant publications. Two authors independently selected trials. The available studies were comprehensively reviewed and analysed.
RESULTS
A total of 9 studies with a total of 35 patients were included in the review. Of these patients, 17 (48.6%) patients were treated with tofacitinib, 14 (40%) with baricitinib, 4 (11.4%) with ruxolitinib and 1 (2.9%) with upadacitinib. After treatment with JAKi, 17 (48.6%) patients showed complete remission, 12 (34.3%) patients showed partial remission, and 7 (20%) patients showed loss of efficacy or relapse. The use of ruxolitinib showed a remission rate of 100% in AOSD patients with macrophage activation syndrome (MAS). The incidence of adverse events (AEs) reported were mild and rare overall. Most AEs were abnormal lipid parameters (9.7%), bacterial pneumonia (3.2%), organised pneumonia (3.2%), diarrhoea (3.2%), increased heart rate (3.2%), menometrorrhagia (3.2%) and leukopenia (3.2%). One patient died from bacterial pneumonia.
CONCLUSION
JAKi therapy may be an option for patients with AOSD, especially for refractory AOSD. For patients with AOSD complicated by MAS, ruxolitinib seems to be a better choice than other JAKi agents. Although our study shows that JAKi are well tolerated in AOSD patients, we still need to be on the lookout for fatal infections.
PubMed: 38870881
DOI: 10.1016/j.intimp.2024.112451 -
RMD Open Feb 2024In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), histopathological assessment of affected tissue is often necessary for diagnosis and...
BACKGROUND
In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), histopathological assessment of affected tissue is often necessary for diagnosis and assessment of disease extent. There is a requirement for validated non-invasive biomarkers to avoid the need for serial tissue biopsies.
METHODS
A systematic review of scientific databases from 2012 until present was performed to identify studies fulfilling the inclusion criteria. Studies were assessed for quality using the Strengthening the Reporting of Observational Studies in Epidemiology checklist for cohort, case-control and cross-sectional studies and the Risk of Bias Assessment tool for Non-randomised Studies, or the Cochrane Risk of Bias tool 2.0 for randomised controlled trials. A descriptive synthesis of the data for non-invasive (blood-based or urinary) biomarkers of AAV-related disease activity and organ damage was performed.
RESULTS
Twenty-two high quality studies were included. These articles reported the value of blood-based and urinary biomarkers including anti-neutrophil cytoplasmic antibodies, immune cells, complement factors, gene expression profiles, cytokines, chemokines and other proteins in the assessment of disease activity and/or organ damage in patients with AAV. Many of these biomarkers involve the alternative complement pathway, neutrophil activation and macrophage activation.
CONCLUSION
This is the first contemporary systematic review synthesising the value of non-invasive biomarkers of AAV-related disease activity and organ damage. The incorporation of individual markers in combined biomarker profiles might enhance clinical decision-making. Many unmet needs were identified; few studies involve oeosinophilic granulomatosis with polyangiitis and patients with childhood-onset AAV. Further validation of the candidate biomarkers is warranted in large prospective studies to bridge the existing knowledge gaps and apply precision health to systemic vasculitis.
Topics: Humans; Child; Granulomatosis with Polyangiitis; Prospective Studies; Cross-Sectional Studies; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biomarkers; Antibodies, Antineutrophil Cytoplasmic; Cytokines
PubMed: 38341193
DOI: 10.1136/rmdopen-2023-003579 -
Rheumatology International Jul 2024We aimed to review the literature on the clinical presentation, renal pathology, treatment, and outcome of renal manifestations in adult-onset Still's disease (AOSD).
OBJECTIVE
We aimed to review the literature on the clinical presentation, renal pathology, treatment, and outcome of renal manifestations in adult-onset Still's disease (AOSD).
METHODS
We used PRISMA guidelines for our systematic review and included all English-language original articles from inception till September 15, 2023, on AOSD and kidney involvement in any form. Data on patient demographics, diagnostic criteria, clinical presentation, renal pathology, treatment employed including dialysis, outcome, cause of death were collected and analyzed.
RESULTS
The median age at the diagnosis of renal issues was 37, with a higher prevalence among females (58.1%). Among the cases, 28 experienced renal problems after being diagnosed with AOSD, 12 had simultaneous diagnoses of renal issues and AOSD, and in 4 cases, renal problems appeared before AOSD diagnosis. Out of the 44 cases, 36 underwent renal biopsy, revealing various pathology findings including AA amyloidosis (25%), collapsing glomerulopathy (11.4%), thrombotic microangiopathy (TMA) (11.4%), IgA nephropathy (9.1%), minimal change disease (6.8%), and others. Some cases were clinically diagnosed with TMA, proximal tubular dysfunction, or macrophage activation syndrome-related acute kidney injury. Treatment approaches varied, but glucocorticoids were commonly used. Renal involvement was associated with increased mortality and morbidity, with 6 out of 44 patients passing away, 4 progressing to end-stage renal disease (ESRD), and data on 2 cases' outcomes not available.
CONCLUSION
Renal manifestations in AOSD are diverse but rarely studied owing to the rarity of the disease. Studies with larger data would be essential to study further on the pathogenesis and implications.
Topics: Humans; Still's Disease, Adult-Onset; Kidney Diseases; Adult; Nephrosis, Lipoid; Kidney; Thrombotic Microangiopathies; Female; Amyloidosis; Glomerulonephritis, IGA; Glucocorticoids
PubMed: 38625385
DOI: 10.1007/s00296-024-05578-5 -
Modern Rheumatology May 2024This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA).
OBJECTIVES
This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA).
METHODS
Studies published between 2000 and 2021 were searched using PubMed, Embase, Cochrane, Ichushi-Web and clinical trial registries. The risk of bias was assessed according to the manual for development clinical practice guidelines by Minds, a project to promote evidence-based medicine in Japan.
RESULTS
Seven observational studies were included. American College of Rheumatology pediatric 30/50/70 responses at 3, 6 and 12 months were 64.8%/50.3%/27.9%, 85.7%/71.4%/42.9% and 80.0%/50.0%/40.0%, respectively. Outcomes on systemic symptoms, joint symptoms and activities of daily living were not obtained. No macrophage activation syndrome or infusion reaction occurred. Serious infection occurred in 2.6% of cases.
CONCLUSIONS
Abatacept improved the disease activity index. In addition, abatacept was as safe as interleukin-6 (IL -6) and IL-1 inhibitors. However, both the efficacy and safety data in this systematic review should be reviewed with caution because their quality of evidence is low or very low. Further studies are needed to confirm the efficacy and safety of abatacept for systemic JIA, especially its efficacy on joint symptoms.
PubMed: 38753302
DOI: 10.1093/mr/roae046