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Objectives: The aim of this study was to identify potential predictors of the disease course of systemic juvenile idiopathic arthritis (sJIA) at the time of diagnosis. Methods: This retrospective observational study was conducted in patients diagnosed with sJIA in our hospital between April 2009 and October 2023. The relationship between the disease course of sJIA patients and demographic, clinical, laboratory findings and complications was analysed. Results: Of the 51 patients diagnosed with sJIA, 26 (51%) patients had monocyclic, 7 (13.7%) polycyclic, and 18 (35.2%) persistent disease course. The presence of arthritis, polyarticular involvement, and hip involvement at the time of diagnosis were associated with persistent disease course (P = .009, P = .003, P = .003). Serositis and higher white blood cell and neutrophil counts at the time of diagnosis were associated with a monocyclic disease course (P = .034,.002,.008). However, no significant correlation was found between macrophage activation syndrome and disease course (P = 1). Conclusions: sJIA patients with polyarthritis and hip involvement at disease onset may develop a persistent course. Although macrophage activation syndrome is an important complication of sJIA, its effect on the course of the disease was not found in this study. [ABSTRACT FROM AUTHOR]

Objectives: Given the limited tocilizumab (TCZ) treatment data for systemic juvenile idiopathic arthritis (sJIA) in China, we evaluated the long-term efficacy and safety of TCZ in Chinese patients with sJIA. Method: In this multicentre, interventional Phase IV study, patients with sJIA and inadequate clinical response to non-steroidal anti-inflammatory drugs/corticosteroids received TCZ infusions every 2 weeks based on body weight (< 30 kg, 12 mg/kg; ≥ 30 kg, 8 mg/kg), over a 52-week open-label period and an 8-week safety follow-up period. The primary endpoint was the proportion of patients with a JIA American College of Rheumatology (ACR) 30 response and absence of fever at Week 12. Results: Sixty-two patients were enrolled and treated (12-mg/kg group, 34; 8-mg/kg group, 28). At Week 12, 87.1% (95% confidence interval 78.8%–95.4%) of patients had JIA ACR 30 response and absence of fever; Week 52 results were similar. The proportion of JIA ACR 30/50/70/90 responders rapidly increased at Week 12, up to Week 52. High-sensitivity C-reactive protein (hsCRP) levels decreased within 4 weeks; 44/58 patients (75.9%) with elevated baseline hsCRP recovered at Week 52. Childhood Health Assessment Questionnaire pain scores, disability index scores, and mean corticosteroid dose decreased over time. Height standard deviation score changes at Week 52 indicated catch-up growth. Most adverse events (AEs) were mild (serious AE incidence, 17.7%). No deaths or macrophage activation syndrome occurred. Conclusion: This is the first multicentre trial to report the efficacy and safety of TCZ in Chinese patients with sJIA at 52 weeks. No new safety concerns were found. Key points • This is the first multicentre trial providing strong evidence for tocilizumab (TCZ) treatment for systemic juvenile idiopathic arthritis (sJIA) in China. • The study reported TCZ had good efficacy and favourable safety profiles in Chinese sJIA patients in the long term (52 weeks). • TCZ treatment showed rapid disease control, which was maintained over time, catch-up growth benefits in patients, tapering and discontinuation of corticosteroids, and improved quality of life. [ABSTRACT FROM AUTHOR]

Objective: This study aims to assess current diagnostic and management for systemic Juvenile Idiopathic Arthritis (sJIA) among physicians, evaluate the challenges encountered in diagnosis and treatment, and identify the educational needs and professional development engagements of physicians managing sJIA. Methods: A nationwide survey was conducted from November 2023 to March 2024 across tertiary and secondary pediatric and general hospitals in China. The survey targeted physicians with at least three years of specialty experience, resulting in 310 valid responses from 25 provinces, autonomous regions, and municipalities. The survey collected data on diagnostic practices, treatment approaches, and professional development related to sJIA. Data collection was facilitated through WeChat, and statistical analysis was performed using descriptive statistics. Ethical approval was obtained from the Ethics Committee of Beijing Children's Hospital, with informed consent provided electronically by participants. Results: The survey indicated that all physicians encountered suspected or confirmed cases of sJIA, highlighting its prevalence and the diagnostic challenges associated. Regarding diagnostic standards, 53.9% of physicians used the "Consensus on the Diagnosis and Treatment of sJIA and Macrophage Activation Syndrome," 18.1% followed the International League of Associations for Rheumatology (ILAR) standards, and 24.8% adhered to the Pediatric Rheumatology International Trials Organization (PRINTO) standards. In treatment strategies, glucocorticoids and IL-6 receptor monoclonal antibodies were extensively used, with the latter receiving "excellent" and "satisfactory" ratings of 46.5% and 36.1%, respectively, demonstrating high efficacy and acceptance. Main challenges included high treatment costs, complexity of diagnosis, patient compliance issues, and potential long-term side effects of biologics. Additionally, 126 doctors (40.7%) actively participated in more than three academic conferences or systematic learning courses related to sJIA, indicating a strong demand for ongoing education, particularly in new treatment developments and diagnostic skills. Conclusion: The findings emphasize the necessity for standardized diagnosis and customized treatment plans tailored to patient-specific conditions in managing sJIA. Key Points • The survey highlights the prevalence and clinical challenges of sJIA among physicians, emphasizing the importance of vigilant diagnosis, multi-system involvement, and differential diagnosis to improve treatment outcomes and patient quality of life. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to characterize and investigate the safety and efficacy of Plonmarlimab, a novel anti‐granulocyte‐macrophage colony‐stimulating factor (anti‐GM‐CSF) neutralizing antibody, on the treatment of macrophage activation syndrome (MAS), a life‐threatening systemic inflammatory disease, in pre‐clinical models. Methods: The binding affinity was evaluated using Biacore. The neutralizing activity was measured through the blockade of ligand–receptor interaction, inhibition of STAT5 phosphorylation and suppression of TF‐1 cell proliferation. The efficacy of Plonmarlimab was evaluated in a humanized MAS model, which was established by engrafting human umbilical cord blood (UCB) cells into NOG‐EXL mice. Additionally, the safety profile of Plonmarlimab was investigated in cynomolgus monkeys. Results: At the molecular level, Plonmarlimab showed sub‐nanomolar binding affinity with human GM‐CSF and effectively blocked the binding of GM‐CSF to its receptor. At the cellular level, Plonmarlimab dose‐dependently inhibited intracellular STAT5 phosphorylation and suppressed GM‐CSF‐induced TF‐1 proliferation. In the UCB‐engrafted NOG‐EXL MAS mouse model, Plonmarlimab treatment significantly ameliorated disease progression, demonstrated by the improvements in body weight loss, anaemia and some histopathological features. Furthermore, Plonmarlimab was well tolerated up to 150 mg/kg weekly in monkeys with no reported adverse effects. Conclusions: Plonmarlimab is a highly potent GM‐CSF blocking antibody and has demonstrated promising efficacy in a pre‐clinical MAS model with a favourable safety profile, supporting its clinical development. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome (MAS) is one of the most severe complications of systemic juvenile idiopathic arthritis (sJIA). Around 10% of patients with sJIA exhibit systemic symptoms accompanied by macrophage activation syndrome (MAS), but it may occur subclinically in another 30–40%. In this article, we present a case of a 3-year-old girl diagnosed with sever MAS as an onset of sJIA complicated by disseminated intravascular coagulation (DIC). First symptoms of sJIA were observed about 5 months before setting the diagnose, and it was resembling urticaria. A comprehensive allergological diagnostics were conducted, but no cause for the skin changes was identified. A few weeks before admission to the hospital, the girl was presented with a high fever. During the hospital stay, viral, bacterial, and fungal infections were ruled out. However, the findings indicated significantly elevated markers of inflammation (ferritin, CRP, ESR) in the conducted tests. Meanwhile, swelling of the feet and ankle joints was also observed. Based on Ravelli criteria, we set the diagnosis of MAS in a course of sJIA. We implemented treatment with steroid pulses, followed by cyclosporine; however, her clinical condition did not improve. Despite intensive treatment, skin petechiae were observed twice, and laboratory tests revealed a very high INR along with an extremely low level of fibrinogen. The patient required multiple plasma transfusions and clotting factor administrations. Due to the severe condition of the girl, we initiated biological treatment with anakinra, after which the child's condition gradually improved. In this case, we want to present how dynamic and life-threatening the course of MAS can be. In the discussion, we are also comparing our approach and the applied treatment with the currently available knowledge. [ABSTRACT FROM AUTHOR]

The characteristic expansion of T CD38high/HLA‐DR+CD8+ lymphocytes observed in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) proved able to distinguish HLH/MAS from sepsis and systemic juvenile idiopathic arthritis. However, the performance of this marker in differentiating HLH/MAS from other pediatric febrile conditions with similar clinical onset and yet entirely different treatments remains unexplored. CD38high/HLA‐DR+CD8+ frequencies measured in the peripheral fresh blood of pediatric patients attended for suspicion of HLH/MAS were retrospectively recorded and clinical characteristics were retrieved. CD38high/HLA‐DR+CD8+ frequencies in HLH/MAS patients (15 patients; median: 22.0%, IQR: 11.0–49.0%) were compared with those who presented febrile conditions other‐than‐HLH (28 patients; median: 13.0%, IQR: 3.9–28.7%; p = 0.24). HLH and non‐HLH patients were subsequently regrouped based on the presence of an identified infection (22 patients; median: 27.0%, IQR: 15.2‐72.1%) and compared with those without infections (21 patients; median: 7.6%, IQR: 3.7–24.3%; p = 0.0035). CD38high/HLA‐DR+CD8+ percentages were significantly higher only in the infection group compared with the noninfection one, with a patent pathogen‐specific expansion in Epstein–Barr virus primoinfection and visceral leishmaniasis regardless of the presence of HLH. CD38high/HLA‐DR+CD8+ frequencies do not appear as an HLH‐specific marker as they naturally expand in other clinical situations that are common in childhood and may mimic HLH initial presentation. [ABSTRACT FROM AUTHOR]

UNC13 family (also known as Munc13) proteins are evolutionarily conserved proteins involved in the rapid and regulated secretion of vesicles, including synaptic vesicles and cytotoxic granules. Fast and regulated secretion at the neuronal and immunological synapses requires multiple steps, from the biogenesis of vesicles to membrane fusion, and a complex array of proteins for each step. Defects at these steps can lead to various genetic disorders. Recent studies have shown multiple roles of UNC13D in the secretion of cytotoxic granules by immune cells. Here, the molecular structure and detailed roles of UNC13D in the biogenesis, tethering, and priming of cytotoxic vesicles and in endoplasmic reticulum are summarized. Moreover, its association with immune diseases, including familial hemophagocytic lymphohistiocytosis type 3, macrophage activation syndrome, juvenile idiopathic arthritis, and autoimmune lymphoproliferative syndrome, is reviewed. Finally, the therapeutic application of CRISPR/Cas9-based gene therapy for genetic diseases is introduced. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) is a serious complication in systemic juvenile idiopathic arthritis (SJIA). This study aimed to identify the clinical characteristics and prognosis of SJIA-ILD. Methods: A two-center retrospective cohort study was conducted on patients newly diagnosed with SJIA in China from October 2010 to December 2021. Clinical characteristics, laboratory parameters, outcomes, and relapse rates were compared between ILD and non-ILD groups. Results: A total of 176 children with SJIA were included, including 35 in ILD group and 141 in non-ILD group. The median age at onset of SJIA was 5.8 years (range 4.4–9.5) in patients with SJIA-ILD. It exhibited higher incidences of cervical spine (28.6%) and hip involvement (40.0%) in ILD group (P = 0.031 and P = 0.029, respectively). The incidence of macrophage activation syndrome (MAS) in ILD group reached up to 40%, significantly elevated than that in non-ILD group (P = 0.047). Children with ILD demonstrated a stronger inflammatory response and were more prone to developing lymphopenia (P = 0.009), requiring more combination therapy (P = 0.006) to control disease activity. 54.3% of patients received biologic therapies, with only three patient receiving biologics (one with IL-6 blockade, two with TNF inhibitor) prior to ILD onset and none receiving IL-1 blockade. The median follow-up duration was 6.0 years (range 3.9–9.5). The proportions of patients with SJIA-ILD achieving clinical inactive disease without glucocorticoids within 6 to 12 months of the treatment were significantly lower than control group (45.7% vs. 70.2%, P = 0.006). In ILD group, only 54.3% of patients achieved complete remission, and 17.1% were in a non-remission state, among whom two deaths from respiratory failure. There was no significant difference in disease relapse rates between the two groups (P > 0.05). Conclusions: Patients with SJIA-ILD exhibited heightened inflammation, increased hip joint and cervical spine involvement, and were more susceptible to developing lymphopenia and MAS, suggesting a relatively poor prognosis. They required a prolonged time to control inflammation and more aggressive treatment strategies to achieve inactive status. The unsatisfactory rate of complete remission highlighted an urgent need for focused clinical strategies. [ABSTRACT FROM AUTHOR]

The document discusses the use of blinatumomab in patients with CD19 positive B-ALL and hepatic dysfunction. Blinatumomab, a bispecific monoclonal antibody, has shown favorable survival benefits in B-ALL patients, especially those who cannot tolerate conventional chemotherapy. The document presents three cases where blinatumomab was used in patients with hepatic dysfunction, showing varying outcomes and highlighting the need for further research to confirm its safety and efficacy in this patient population. [Extracted from the article]

This article presents a case study of a 40-year-old man who presented with symptoms of fevers, sore throat, fatigue, weakness, and joint pains. After ruling out common respiratory viruses and streptococcus infection, further examination revealed musculoskeletal findings and elevated inflammatory markers, suggesting a possible rheumatologic cause. The patient was diagnosed with adult-onset Still's disease, a rare inflammatory condition characterized by fevers, rash, and joint pain. Treatment options discussed include nonsteroidal anti-inflammatory drugs, biologic agents, disease-modifying antirheumatic drugs, and interleukin inhibitors. The article emphasizes the need for effective immunomodulatory therapy and further research in this area. [Extracted from the article]

Objective: Our objective was to evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)‐associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in patients with sJIA from an established cohort. Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as P < 0.05 after 100,000 permutations. Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome‐derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein‐altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (P = 0.020) and ultrarare variants (MAF < 0.001) of STXBP2 (P = 0.006) and UNC13D (P = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (P = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (P = 0.007), driven largely by digenic combinations involving LYST. Conclusion: We identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS). Methods Demographic, clinical and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen paediatric rheumatology centres across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment. Results One hundred and sixty-two patients were included in the study. Forty-five of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72–232) vs 199 (130–371) 109/l], ferritin level on admission [1107 (676–2050) vs 2863 (1193–9562) ng/ml], C-reactive protein level [15.4 (2.9–56) vs 90 (32–160) mg/l], erythrocyte sedimentation rate [13 (3–36) vs 43.5 (13–77) mm/h] and fever duration [5 (4–7.5) vs 10 (7–14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals. Conclusion Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met. [ABSTRACT FROM AUTHOR]

To investigate the efficacy of the doxorubicin-etoposide-methylprednisolone, DEP) regimen as an effective treatment for adult Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease and analyze prognosis in these patients. Fifty-eight adult patients diagnosed with Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease admitted to Beijing Friendship Hospital from 1st Jan. 2018 to 31st Dec. 2022 were retrospectively included in this study. Patients were grouped according to previous treatment. Clinical data and laboratory characteristics of patients were retrospectively analyzed. The efficacy was evaluated every 2 weeks after initiating the first course of the DEP regimen and until the last inpatient or 31st Dec. 2023. 26 patients were included in Group A and 32 patients were included in Group B due to the previous treatment. After the first course of the DEP regimen, the overall response rate of all patients was 82.8%, with 13.8% in complete response and 69% in partial response. There was no significant statistical objective response rate between the two groups after the DEP regimen, except at 2-week. Serum ferritin, sCD25, ALT, AST, and DBIL concentrations were significantly lower at 2, 4 and 6-week than pre-treatment (P < 0.05). The overall mortality rate is 20.7% (12/58). Importantly, advanced age, initial level of HB and PLT, and central nervous system (CNS) involvement were independent poor risk factors affecting OS in bivariate analysis. The DEP regimen is effective for adult HLH secondary rheumatic disease with a high overall rate and accepted side effects. [ABSTRACT FROM AUTHOR]

Objective: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. Method: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. Results: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with reelevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. Conclusion: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient’s immune function. [ABSTRACT FROM AUTHOR]

Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory condition with onset in childhood. It is sporadic, but elements of its stereotypical innate immune responses are likely genetically encoded by both common variants with small effect sizes and rare variants with larger effects. Genomic investigations have defined the unique genetic architecture of sJIA. Identification of the class II HLA locus as the strongest sJIA risk factor for the first time brought attention to T lymphocytes and adaptive immune mechanisms in sJIA. The importance of the human leukocyte antigen (HLA) locus was reinforced by recognition that HLA-DRB1*15 alleles are strongly associated with development of drug reactions and sJIA-associated lung disease (sJIA-LD). At the IL1RN locus, genetic variation relates to both risk of sJIA and may also predict non-response to anakinra. Finally, rare genetic variants may have critical roles in disease complications, such as homozygous LACC1 mutations in families with an sJIA-like illness, and hemophagocytic lymphohistiocytosis (HLH) gene variants in some children with macrophage activation syndrome (MAS). Genetic and genomic analysis of sJIA holds great promise for both basic discovery of the course and complications of sJIA, and may help guide personalized medicine and therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-T cell therapies have been approved by FDA to treat relapsed or refractory hematological malignancies. However, the adverse effects of CAR-T cell therapies are complex and can be challenging to diagnose and treat. In this review, we summarize the major adverse events, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR T-cell associated HLH (carHLH), and discuss their pathophysiology, symptoms, grading, and diagnosis systems, as well as management. In a future outlook, we also provide an overview of measures and modifications to CAR-T cells that are currently being explored to limit toxicity.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0 years (IQR 11.9–16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%) discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%) patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7 years (IQR 0.8–4.4). Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency. What is known? • Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) is a rare complication of inflammatory bowel disease (IBD). • HLH/MAS has been described in adult patients with IBD while pediatric cases are only anecdotal. What is new? • HLH/MAS primarily develops during adolescence in children with early-onset IBD and its prognosis is usually favorable. • HLH/MAS is generally triggered by an infection in children with IBD who are on immunosuppressant treatment. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multisystemic disease characterized by non-caseating granulomas of unknown etiology. While pulmonary manifestations are present in 90% of cases, extrapulmonary sarcoidosis cases are rare and diagnosis is often challenging due to atypical clinical course. Here, we aim to present a case of extrapulmonary sarcoidosis diagnosed after excluding Macrophage Activation Syndrome and lymphoma during clinical follow-up.

Macrophage activation syndrome (MAS), is a severe and fatal complication of various pediatric inflammatory disorders. Kabuki syndrome (KS), mainly caused by lysine methyltransferase 2D (KMT2D; OMIM 602113) variants, is a rare congenital disorder with multi-organ deficiencies. To date, there have been no reported cases of MAS in patients with KS. This report describes a case of a 22-year-old male with Kabuki syndrome (KS) who developed MAS. This unique case not only deepens the understanding of the involvement of KMT2D in immune regulation and disease, but expands the phenotype of the adult patient to better understand the natural history, disease burden, and management of patients with KS complicated with autoimmune disorders. [ABSTRACT FROM AUTHOR]

Objective(s): Polycystic ovary syndrome (PCOS) is a complex metabolic and endocrine disorder associated with chronic inflammation. However, the effect of Δ tetrahydrocannabinol-9 (THC) on PCOS has not been evaluated. Therefore, this study aimed to investigate the immunomodulatory effects of THC in an animal model of PCOS. Materials and Methods: Twenty female Sprague-Dawley rats, aged 4 weeks, were divided into four groups. The control group received a normal diet, the sham group received a vehicle (carboxymethyl cellulose), the PCOS group received a high-fat diet (HFD) for 16 weeks followed by letrozole for 4 weeks, and the THC group received an HFD for 16 weeks followed by letrozole+THC (0.02 mg/kg) for 4 weeks. Results: The PCOS animals exhibited significantly higher levels of testosterone, insulin, triglycerides, and total cholesterol, along with elevated inflammatory and oxidative stress markers compared to the control group. Flow cytometry and real-time PCR analysis revealed an increase in M1 macrophage markers and a decrease in M2 macrophage markers compared to the control group. However, the administration of a low dose of THC mitigated these disturbances. Conclusion: Low-dose THC improved inflammatory responses and shifted the balance of M1/M2 macrophage markers towards M2 macrophages in the animal model of PCOS. [ABSTRACT FROM AUTHOR]

Objective: To improve our understanding of systemic lupus erythematosus (SLE)‐macrophage activation syndrome (MAS). Methods: A systematic review was performed, to retrieve all those papers on patients with SLE‐MAS, in individual or aggregated form. The data in each of these medical records were extracted and analyzed to identify the characteristics of SLE‐MAS. Results: A total of 86 SLE‐MAS patients were included (25 males and 61 females. The mean (±standard error of the mean) age was 31.21 ± 1.694 years. MAS occurred as the initial presentation of SLE in 47 people (54.65%) and during the course of SLE in 39 (45.35%). A coinfection was reported in 23 (26.74%) patients. The mean Lupus Erythematosus Disease Activity Index 2000 (SLEDAI‐2K) score was 16.54 ± 0.9462. Overall, 10 patients (11.63%) died. The SLEDAI‐2K score was higher in patients with MAS as an initial manifestation of SLE than in those where MAS occurred during the course of SLE. The proportion of patients receiving steroid pulse therapy was lower in patients with coinfections. The deceased group demonstrated lower platelet and ferritin levels. Multiple regression analysis revealed that age and thrombocytopenia were independent factors associated with poor prognosis. In receiver operating characteristic analysis, a platelet count cutoff value of ≤47 × 109/L was a predictor of poor outcome. Conclusions: SLE‐MAS patients demonstrated high lupus activity, and lupus activity was especially higher in patients with MAS as an initial manifestation. Lupus activity was the predominant trigger of lupus MAS. Thrombocytopenia was an independent factor for poor prognosis. Highlights: Lupus activity was especially high in patients with macrophage activation syndrome (MAS) as an initial manifestation.Lupus activity is the predominant trigger for lupus‐MAS.Thrombocytopenia is a predictor of poor prognosis in patients with systemic lupus erythematosus‐MAS. [ABSTRACT FROM AUTHOR]

There has been no severity evaluation model for pediatric patients with hemophagocytic lymphohistiocytosis (HLH) that uses readily available parameters. This study aimed to develop a novel model for predicting the early mortality risk in pediatric patients with HLH using easily obtained parameters whatever etiologic subtype. Patients from one center were divided into training and validation sets for model derivation. The developed model was validated using an independent validation cohort from the second center. The prediction model with nomogram was developed based on logistic regression. The model performance underwent internal and external evaluation and validation using the area under the receiver operating characteristic curve (AUC), calibration curve with 1000 bootstrap resampling, and decision curve analysis (DCA). Model performance was compared with the most prevalent severity evaluation scores, including the PELOD-2, P-MODS, and pSOFA scores. The prediction model included nine variables: glutamic-pyruvic transaminase, albumin, globulin, myohemoglobin, creatine kinase, serum potassium, procalcitonin, serum ferritin, and interval between onset and diagnosis. The AUC of the model for predicting the 28-day mortality was 0.933 and 0.932 in the training and validation sets, respectively. The AUC values of the HScore, PELOD-2, P-MODS and pSOFA were 0.815, 0.745, 0.659 and 0.788, respectively. The DCA of the 28-day mortality prediction exhibited a greater net benefit than the HScore, PELOD-2, P-MODS and pSOFA. Subgroup analyses demonstrated good model performance across HLH subtypes. The novel mortality prediction model in this study can contribute to the rapid assessment of early mortality risk after diagnosis with readily available parameters. [ABSTRACT FROM AUTHOR]

Objective. To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA). Methods. We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory, and radiographic data were collected from the medical record and reviewed with each patient's primary medical team. Results. Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy, but all the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n = 5), rash (n = 5), and arthritis (n = 4) developed after surgical intervention in all the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n = 5), elevated interleukin 18 levels (n = 5), baseline eosinophilia prior to initiation of biologic disease-modifying antirheumatic drugs (n = 4), and positivity for HLA-DRB1*15:01 alleles (n = 4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease. Conclusion. We identified an association between CHD and severe forms of sJIA. Although these findings will need to be confirmed in larger, multicenter cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD. [ABSTRACT FROM AUTHOR]

Objective: To study the prevalence of macrophage activation syndrome (MAS) in children with Kawasaki disease (KD) and to devise a classification tree for predicting MAS in early KD based on easily available clinical and laboratory information using artificial intelligence (AI) technology. Methods: A cross-sectional observational study was conducted (March 2020–October2021) during which hospitalized children aged 1–18 years with KD were consecutively enrolled. Those with a positive RTPCR test or IgM/IgG serology for COVID-19 were excluded. The clinical and laboratory profiles of children with and without MAS were studied. A multivariable logistic regression (LR) model was developed utilizing backward elimination method to determine the relationship between select candidate predictor variables and MAS in patients with KD. A classification tree was created based on these using artificial intelligence algorithms. Results: Sixty-two children were diagnosed with KD during the study period, of these, 42 children with KD were included; 14 (33.3 %) were diagnosed with MAS. The median (IQR) duration of fever (days) was significantly more in MAS than those without MAS [7 (5, 15) vs 5 (5, 9), P < 0.05]. Serum albumin (g/dL) was significantly lower in those with MAS [2.3 (2.2, 2.7) vs 2.8 (2.3, 3.1), P = 0.03]. The classification tree constructed using the AI-based algorithm predicted that in children with KD who had myocardial dysfunction, serum albumin < 2.8 g/dL and fever > 6 days duration at admission had an increased likelihood of developing MAS. In children without myocardial dysfunction, alanine transaminase (ALT) levels > 70 U/L and fever > 5 days were equally predictive of MAS. Conclusion: Nearly one-third of the children with KD had MAS. Clinicians should consider screening all children with KD for MAS at admission. A classification tree based on the presence of myocardial dysfunction, duration of fever > 6 days, ALT levels and hypoalbuminemia can identify MAS in the course of KD. [ABSTRACT FROM AUTHOR]

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed. [ABSTRACT FROM AUTHOR]

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH. Methods: An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators. Results: A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment. Conclusion: The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy. [ABSTRACT FROM AUTHOR]

Introduction: Interleukin-18 (IL-18), a pro-inflammatory cytokine belonging to the IL-1 Family, is a key mediator ofautoinflammatory diseases associated with the development of macrophage activation syndrome (MAS). High levels of IL-18 correlate with MAS and COVID-19 severity and mortality, particularly in COVID-19 patients with MAS. As an inflammation inducer, IL-18 binds its receptor IL-1 Receptor 5 (IL-1R5), leadingto the recruitment of the co-receptor, IL-1 Receptor 7 (IL-1R7). This heterotrimeric complex subsequentlyinitiates downstream signaling, resulting in local and systemic inflammation. Methods: We reported earlier the development of a novel humanized monoclonal anti-human IL-1R7 antibody whichspecifically blocks the activity of human IL-18 and its inflammatory signaling in human cell and wholeblood cultures. In the current study, we further explored the strategy of blocking IL-1R7 inhyperinflammation in vivo using animal models. Results: We first identified an anti-mouse IL-1R7 antibody that significantly suppressed mouse IL-18 andlipopolysaccharide (LPS)-induced IFNg production in mouse splenocyte and peritoneal cell cultures. Whenapplied in vivo, the antibody reduced Propionibacterium acnes and LPS-induced liver injury and protectedmice from tissue and systemic hyperinflammation. Importantly, anti-IL-1R7 significantly inhibited plasma,liver cell and spleen cell IFNg production. Also, anti-IL-1R7 downregulated plasma TNFa, IL-6, IL-1b,MIP-2 production and the production of the liver enzyme ALT. In parallel, anti-IL-1R7 suppressed LPSinducedinflammatory cell infiltration in lungs and inhibited the subsequent IFNg production andinflammation in mice when assessed using an acute lung injury model. Discussion: Altogether, our data suggest that blocking IL-1R7 represents a potential therapeutic strategy to specificallymodulate IL-18-mediated hyperinflammation, warranting further investigation of its clinical application intreating IL-18-mediated diseases, including MAS and COVID-19. [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the clinical usefulness of the systemic score in the prediction of life‐threatening evolution in Still disease. We also aimed to assess the clinical relevance of each component of the systemic score in predicting life‐threatening evolution and to derive patient subsets accordingly. Methods: A multicenter, observational, prospective study was designed including patients included in the Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale Adult‐Onset Still Disease Study Group and the Autoinflammatory Disease Alliance Network Still Disease Registry. Patients were assessed to see if the variables to derive the systemic score were available. The life‐threatening evolution was defined as mortality, whatever the clinical course, and/or macrophage activation syndrome, a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis. Results: A total of 597 patients with Still disease were assessed (mean ± SD age 36.6 ± 17.3 years; male 44.4%). The systemic score, assessed as a continuous variable, significantly predicted the life‐threatening evolution (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.07–1.42; P = 0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life‐threatening evolution (OR 3.36; 95% CI 1.81–6.25; P < 0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR 1.68; 95% CI 1.48–2.67; P = 0.031) and lung disease (OR 2.12; 95% CI 1.14–4.49; P = 0.042) both significantly predicted life‐threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations. Conclusion: The clinical utility of the systemic score was shown in identifying Still disease at a higher risk of life‐threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome (MAS) is a life-threatening systemic hyperinflammatory syndrome triggered by various infections, particularly viral infections, autoimmune disorders, and malignancy. The condition is characterized by an increased production of proinflammatory cytokines resulting in a cytokine storm and has been associated with poor clinical outcomes. During the COVID-19 pandemic, patients with severe manifestations developed features similar to those of MAS, although these characteristics remained well defined within the lung. Additionally, other viral infections including EBV, the herpes family of viruses, hepatitis viruses, influenza, HIV, and hemorrhagic fevers can be complicated by MAS. The diagnosis and management of the condition remain challenging due to the lack of consensus on specific guidelines, especially among the adult population. Currently, therapeutic options primarily rely on medications that are typically used to treat primary hemophagocytic lymphohistiocytosis, such as corticosteroids and etoposide. In addition, cytokine-targeted therapies present promising treatment options. The objective of this review is to discuss the emergence of MAS in the context of viral infections including, but not limited to, its occurrence in COVID-19. [ABSTRACT FROM AUTHOR]

This article discusses the relationship between the timing of tocilizumab (TCZ) introduction and its glucocorticoid-sparing effects on adult-onset Still's disease (AOSD). A retrospective observational study was conducted on AOSD patients who received TCZ and high-dose glucocorticoids for remission-induction therapy. The study found that early introduction of TCZ within 3 weeks of initiating glucocorticoid treatment effectively reduced the glucocorticoid dose requirement without increasing adverse events or the risk of macrophage activation syndrome. However, further research is needed to determine the efficacy of early TCZ introduction in AOSD treatment. [Extracted from the article]

Introduction: Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. Methods: This multicenter retrospective study investigated the etiologies, survival, and prognostic factors of HLH, including the utility of HLH-2004 criteria and HScore in real-life clinical practice. Results: A total of 147 HLH patients were identified by using a combination of hemophagocytosis identification in bone marrow and the HLH-related international classification disease-10. A total of 116 (78.9%) patients fulfilled the HLH diagnosis by HScore, while 91 (61.9%) patients fulfilled 5 of 8 HLH-2004 criteria. In Thailand, the clinical application of HLH-2004 criteria needed to be reduced from 8 to 6 due to a lack of sCD25 and natural killer cell activity tests. Using the adapted HLH-2004 with a cutoff value of 4 resulted in 132 (89.9%) cases meeting the diagnostic criteria. Among these 132 confirmed HLH patients by using adapted HLH-2004, HLH was triggered by infection (29.5%), autoimmune disease (12.9%), malignancy (40.9%), and unknown cause (16.7%). Median overall survival of HLH patients was extremely short (67 days). Ferritin >6,000 μg/L, HLH from infection, malignancy, and unknown etiology were demonstrated as independent prognostic factors for inferior survival (hazard ratio [HR] 2.47; 95% confidence interval [CI] 1.39–4.37, HR 4.69; 95% CI 1.38–15.92, HR 6.09; 95% CI 1.84–20.14, and HR 6.02; 95% CI 1.64–22.05, respectively). Conclusion: Ferritin is a helpful biomarker for HLH diagnosis and prognostic prediction. Autoimmune disease-triggered HLH has favorable outcomes. Future prospective study is required to verify the use of the adapted HLH-2004 criteria. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Macrophage activation syndrome (MAS) associated with Primary Sjogren's syndrome is a rare entity. The following are our observations on a patient of Indian origin who presented with features of cholestatic jaundice and was diagnosed with MAS. We also discuss the challenges faced during its management. Case description: A 53-year-old woman presented with generalized weakness and yellowish discoloration of skin, sclera, and urine for 1 month. She was evaluated for various etiologies of acute hepatitis. During this, the autoimmune profile was suggestive of Primary Sjogren's syndrome. Despite starting appropriate treatment, her liver dysfunction worsened, and her fever persisted. Further workup revealed high ferritin, triglycerides, and lactate dehydrogenase (LDH). Secondary hemophagocytic lymphohistiocytosis (sHLH) was suspected, and biopsies from the liver and bone marrow were performed. Macrophages, lymphocytes, and histiocytes were present in the marrow. Hence, she was diagnosed with MAS associated with portosystemic shunts (PSS) with liver dysfunction. She was treated with steroids, etoposide, cyclosporine, and intravenous immunoglobulin (IVIg). Despite best efforts, there was no clinical improvement, and she was discharged against medical advice. Six weeks later, she succumbed to her illness at home. Conclusion: Macrophage activation syndrome is a rare entity. The mortality is very high, especially when initial ferritin levels are elevated and also if they do not respond to steroids. [ABSTRACT FROM AUTHOR]

NSG-SGM3 and NOG-EXL mice combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines, resulting in marked expansion of myeloid populations upon humanization with CD34+ hematopoietic stem cells (HSCs). Humanized NSG-SGM3 mice typically develop a lethal macrophage activation syndrome and mast cell hyperplasia that limit their use in long-term studies (e.g., humanization followed by tumor xenotransplantation). It is currently unclear to what extent humanized NOG-EXL mice suffer from the same condition observed in humanized NSG-SGM3 mice. We compared the effects of human CD34+ HSC engraftment in these two strains in an orthotopic patient-derived glioblastoma model. NSG-SGM3 mice humanized in-house were compared to NOG-EXL mice humanized in-house and commercially available humanized NOG-EXL mice. Mice were euthanized at humane or study endpoints, and complete pathological assessments were performed. A semiquantitative multiparametric clinicopathological scoring system was developed to characterize chimeric myeloid cell hyperactivation (MCH) syndrome. NSG-SGM3 mice were euthanized at 16 weeks after humanization because of severe deterioration of clinical conditions. Humanized NOG-EXL mice survived to the study endpoint at 22 weeks after humanization and showed less-severe MCH phenotypes than NSG-SGM3 mice. Major differences included the lack of mast cell expansion and limited tissue/organ involvement in NOG-EXL mice compared to NSG-SGM3 mice. Engraftment of human lymphocytes, assessed by immunohistochemistry, was similar in the two strains. The longer survival and decreased MCH phenotype severity in NOG-EXL mice enabled their use in a tumor xenotransplantation study. The NOG-EXL model is better suited than the NSG-SGM3 model for immuno-oncology studies requiring long-term survival after humanization. [ABSTRACT FROM AUTHOR]

Objectives: To present a rare case of neonatal lupus erythematosus (NLE) associated with suspected hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Case presentation: A female infant weighing 2,995 g was born to a mother without medical history of any disease. At birth, the patient had erythematous papules on her face and trunk. She was admitted at 1 day of age with elevated C-reactive protein levels. The patient was diagnosed with NLE based on the presence of anti-Ro/SSA and anti-La/SSB antibodies. Thereafter, it became clear that the antibody levels in her mother were also elevated. At 20 days of age, the infant showed elevated transaminases, ferritin, triglyceride, and soluble interleukin-2 receptor levels. Although HLH or MAS was suspected, she did not fulfill the diagnostic criteria. Thereafter, these abnormal values spontaneously improved, and the skin rash improved with the use of topical steroids. The patient was discharged at 39 days of age. At 1 year of age, the patient's growth and development were normal. Conclusion: NLE should be considered in infants with an unexplained skin rash at birth. When a diagnosis is made, close observation of the infant's clinical features is needed to determine whether they will develop HLH or MAS. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome (MAS) is potentially fatal; so, early diagnosis and timely treatment are essential. However, detecting MAS is sometimes challenging because its principal features can be observed in other pediatric diseases that cause severe inflammation. Cytokine storm due to immune dysregulation represents the clinical and laboratory features of MAS that are included in the diagnostic criteria. Most cases of MAS occur as an underlying condition worsens and progresses. Therefore, a patient with autoimmune or autoinflammatory disease who shows unexplained clinical deterioration despite appropriate management should be considered at high risk for MAS (i.e., occult MAS). The basic principles of treatment are control of triggering factors, supportive care, and relief of hyperinflammation. Systemic steroids and cyclosporine A are frequently used as a first-line treatment. For the treatment of refractory MAS, cytokine-specific biologic agents such as anakinra have recently become preferred over traditional immunosuppressive agents such as etoposide. MAS might be underrecognized in pediatric patients with infectious and inflammatory diseases due to its diverse clinical presentations. Clinical suspicion of MAS is of the utmost importance for early recognition of the disease. [ABSTRACT FROM AUTHOR]

As indications for immune checkpoint inhibitors for breast cancer continue to expand, rare toxicities will emerge that require careful consideration and multidisciplinary management. We report the case of a 40-year-old female receiving neoadjuvant pembrolizumab and chemotherapy for locally advanced triple-negative breast cancer who developed cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH). CRS/HLH secondary to pembrolizumab are scarcely documented in the literature and, to our knowledge, have never been reported in the context of neoadjuvant treatment for breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Emapalumab is a fully human monoclonal antibody that targets free and receptor-bound interferon-gamma (IFNγ), neutralizing its biological activity. IFNγ levels differ by orders of magnitude between patients with primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS; a form of secondary HLH) in systemic juvenile idiopathic arthritis (sJIA). Therefore, this study aimed to develop a population pharmacokinetic model for emapalumab across a patient population with a wide range of total (free and emapalumab-bound) IFNγ levels using observations from patients with primary HLH or MAS in sJIA in clinical trials. Methods: Pharmacokinetic data were pooled (n = 58; 2709 observations) from studies enrolling patients administered emapalumab for primary HLH or MAS in sJIA. Patients with primary HLH were administered emapalumab 1 mg/kg (potentially increasing to 3, 6, and up to 10 mg/kg based on clinical response) every 3 days. Patients with MAS in sJIA were administered emapalumab 6 mg/kg, followed by 3 mg/kg every 3 days until day 15 and twice weekly until day 28. An earlier population PK model was re-parameterized using this data. Results: The final model for emapalumab comprised a 2-compartment model with first-order elimination. Emapalumab clearance remains constant when the total IFNγ concentration (free and emapalumab-bound) is < ~ 10,000 pg/ml but increases proportionally to total IFNγ concentration above this threshold. Emapalumab clearance was estimated to be 0.00218, 0.00308, 0.00623 and 0.01718 l/h at total serum IFNγ concentrations of 103, 104, 105 and 106 pg/ml, respectively, with corresponding terminal half-lives of 19.2, 13.8, 7.18 and 3.12 days for a 1-year-old patient weighing 10 kg with primary HLH. The median terminal half-life for emapalumab in patients with MAS in sJIA was estimated to be 24.0 (range, 6.13–32.4) days, which is similar to observations in healthy volunteers. Conclusions: Emapalumab pharmacokinetics in patients with primary HLH and MAS in sJIA were described by a two-compartment model with fixed allometric exponents and an age-related effect. Differences in total IFNγ levels between patients with primary HLH and MAS may affect emapalumab pharmacokinetics, suggesting that each indication may require different dosing to rapidly control hyperinflammation. Trial registration: Clinicaltrials.gov identifiers: NCT01818492, NCT03311854 and NCT02069899. Plain Language Summary: Patients with a rare condition called hemophagocytic lymphohistiocytosis (HLH) produce excessive amounts of a molecule called interferon-gamma. Excessive interferon-gamma causes extreme (or hyper) inflammation, which can be fatal. A drug called emapalumab can be used to block the action of interferon-gamma. However, we need to understand how the concentration of emapalumab in the blood changes over time to ensure that the correct dose is administered when attempting to control interferon-gamma-driven hyperinflammation in patients with HLH. Because HLH is a rare condition, data from a small number of patients were used to create a mathematical model that predicts emapalumab concentrations in the blood at various times after it is administered. Importantly, the amount of interferon-gamma observed in patients with different types of HLH is highly variable, which can alter how quickly emapalumab is removed from the blood. The higher interferon-gamma levels go above a certain threshold, the faster emapalumab is removed. In particular, interferon-gamma levels generally only exceed this threshold in patients with a familial or genetic form of HLH (primary HLH). Interferon-gamma levels in patients with a type of HLH called macrophage activation syndrome, which can occur in patients with systemic juvenile idiopathic arthritis (sJIA), do not usually cross the threshold associated with faster removal of emapalumab. This means that higher dosing may be required for patients with primary HLH compared with patients who have macrophage activation syndrome in sJIA to expedite control of hyperinflammation because of differences in the rate at which emapalumab is removed from the blood. [ABSTRACT FROM AUTHOR]

Macrophage activation syndrome (MAS) is a life-threatening condition, characterized by cytopenia, multi-organ dysfunction, and coagulopathy associated with excessive activation of macrophages. In this study, we investigated the roles of alpha2-antiplasmin (α2AP) in the progression of MAS using fulminant MAS mouse model induced by toll-like receptor-9 agonist (CpG) and D-(+)-galactosamine hydrochloride (DG). α2AP deficiency attenuated macrophage accumulation, liver injury, and fibrin deposition in the MAS model mice. Interferon-γ (IFN-γ) is associated with macrophage activation, including migration, and plays a pivotal role in MAS progression. α2AP enhanced the IFN-γ-induced migration, and tissue factor production. Additionally, we showed that fibrin-induced macrophage activation and tumor necrosis factor-α production. Moreover, the blockade of α2AP by neutralizing antibodies attenuated macrophage accumulation, liver injury, and fibrin deposition in the MAS model mice. These data suggest that α2AP may regulate IFN-γ-induced responses and be associated with macrophage activation and fibrin deposition in the MAS progression. α2-Antiplasmin deficiency attenuated macrophage accumulation and activation in the macrophage activation syndrome model mice. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objectives: Crimean‐Congo haemorrhagic fever (CCHF) is a zoonotic viral infection which is an important public health problem in Turkey. CCHF causes fever and bleeding and can lead to severe health outcomes. The study aims to report a case of a male patient with severe CCHF, hemophagocytic lymphohistiocytosis (HLH) treated with steroids and portal vein thrombosis. Case Report: A 37‐year‐old man was admitted to the emergency department with complaints of high fever, headache, myalgia and diarrhoea. The patient travelled to the endemic region of Turkey. In laboratory findings, thrombocytopenia, abnormal liver function tests and elevated coagulation parameters were observed. Real‐time polymerase chain reaction assay was used for diagnosis of CCHF. Hypofibrinogenemia, hypertriglyceridemia, elevated ferritin and d‐dimer levels were observed in the clinical follow‐up. Prednisolone treatment was performed due to considered the diagnosis of HLH. Portal vein thrombosis was detected on abdominal computed tomography scan. He was successfully treated with ribavirin, corticosteroids, anticoagulant and supportive therapy. Conclusion: The clinical presentation of CCHF can range from self‐limiting flu‐like to severe symptoms possibly fatal. Acute portal vein embolism is a rare complication that has not been reported before to our knowledge. Corticosteroids may be a life‐saving treatment for CCHF patients presenting with HLH. [ABSTRACT FROM AUTHOR]

Background: Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH‐2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. Methods: In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité—Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 μg/L) and underwent bone marrow biopsy during their ICU course. Results: Two hundred fifty‐two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH‐2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. Conclusions: Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH‐2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Mixed connective tissue disease (MCTD) is a rare entity in children. There is a paucity of studies on juvenile‐onset MCTD (jMCTD) worldwide especially from Southeast Asia. Objectives: To describe clinical and laboratory features of jMCTD diagnosed at pediatric rheumatology centers across India. Methods: A predesigned detailed case proforma in an excel format was prepared and was sent to all the Pediatric Rheumatology centers in India. Eleven centers provided the clinical and laboratory data of their jMCTD patients, which was then compiled and analyzed in detail. Results: Thirty‐one jMCTD patients from 11 centers were included in the study. Our cohort had 27 females and four male patients over 12 months (August 2021 to July 2022). The median age at presentation was 12 years (range 5–18 years) and the median duration of symptoms was 24 months at diagnosis (range 2–96 months). The common features included arthritis (90%), malar rash (70.9%), and Raynaud's phenomenon (70.9%). At a mean follow‐up of 43 months (range 1–168 months), 45% of them were in remission. There were two deaths reported, due to macrophage activation syndrome and sepsis respectively. Conclusion: We present the largest multicenter experience on jMCTD from the Indian subcontinent. The study's findings serve as a crucial stepping stone toward unraveling the complexities of jMCTD and improving patient care and management strategies. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein–Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients. [ABSTRACT FROM AUTHOR]