Early identification of macrophage activation syndrome secondary to systemic lupus erythematosus with machine learning.

OBJECTIVE: The macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE) is a severe and life-threatening complication. Early diagnosis of MAS is particularly challenging. In this study, machine learning models and diagnostic scoring card were developed to aid in clinical decision-making using clinical characteristics. METHODS: We retrospectively collected clinical data from 188 patients with either SLE or the MAS secondary to SLE. 13 significant clinical predictor variables were filtered out using the Least Absolute Shrinkage and Selection Operator (LASSO). These variables were subsequently utilized as inputs in five machine learning models. The performance of the models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), F1 score, and F2 score. To enhance clinical usability, we developed a diagnostic scoring card based on logistic regression (LR) analysis and Chi-Square binning, establishing probability thresholds and stratification for the card. Additionally, this study collected data from four other domestic hospitals for external validation. RESULTS: Among all the machine learning models, the LR model demonstrates the highest level of performance in internal validation, achieving a ROC-AUC of 0.998, an F1 score of 0.96, and an F2 score of 0.952. The score card we constructed identifies the probability threshold at a score of 49, achieving a ROC-AUC of 0.994 and an F2 score of 0.936. The score results were categorized into five groups based on diagnostic probability: extremely low (below 5%), low (5-25%), normal (25-75%), high (75-95%), and extremely high (above 95%). During external validation, the performance evaluation revealed that the Support Vector Machine (SVM) model outperformed other models with an AUC value of 0.947, and the scorecard model has an AUC of 0.915. Additionally, we have established an online assessment system for early identification of MAS secondary to SLE. CONCLUSION: Machine learning models can significantly improve the diagnostic accuracy of MAS secondary to SLE, and the diagnostic scorecard model can facilitate personalized probabilistic predictions of disease occurrence in clinical environments.

An unusual case of adult-onset still's disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. CASE PRESENTATION: A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). CONCLUSION: Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.

Heterogeneity of macrophage activation syndrome and treatment progression.

Macrophage activation syndrome (MAS) is a rare complication of autoimmune inflammatory rheumatic diseases (AIIRD) characterized by a progressive and life-threatening condition with features including cytokine storm and hemophagocytosis. Predisposing factors are typically associated with microbial infections, genetic factors (distinct from typical genetically related hemophagocytic lymphohistiocytosis (HLH)), and inappropriate immune system overactivation. Clinical features include unremitting fever, generalized rash, hepatosplenomegaly, lymphadenopathy, anemia, worsening liver function, and neurological involvement. MAS can occur in various AIIRDs, including but not limited to systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), systemic lupus erythematosus (SLE), Kawasaki disease (KD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), etc. Although progress has been made in understanding the pathogenesis and treatment of MAS, it is important to recognize the differences between different diseases and the various treatment options available. This article summarizes the cell types and cytokines involved in MAS-related diseases, the heterogeneity, and treatment options, while also comparing it to genetically related HLH.

Serum Mac-2 binding protein glycosylation isomer and galectin-3 levels in adult-onset Still's disease and their association with cytokines.

Background: Autoinflammation with cytokine dysregulation may be implicated in the pathophysiology of adult-onset Still's disease (AOSD); however, the relationship between galectins and cytokines in patients with active AOSD remains unknown. We aimed to examine the relationship between circulating cytokines/chemokines and galectin-3 (Gal-3) or its ligand, Mac-2 binding protein glycosylation isomer (M2BPGi), in Japanese patients with AOSD. Methods: We recruited 44 consecutive patients diagnosed with AOSD according to the Yamaguchi criteria, 50 patients with rheumatoid arthritis (RA) as disease controls, and 27 healthy participants. Serum M2BPGi levels were directly measured using a HISCL M2BPGi reagent kit and an automatic immunoanalyzer (HISCL-5000). Serum Gal-3 concentrations were measured by enzyme-linked immunosorbent assay. The serum levels of 69 cytokines were analyzed in patients with AOSD using a multi-suspension cytokine array. We performed a cluster analysis of each cytokine expressed in patients with AOSD to identify specific molecular networks. Results: Significant increases in the serum concentrations of Gal-3 and M2BPGi were found in the serum of patients with AOSD compared with patients with RA and healthy participants (both p <0.001). There were significant positive correlations between serum Gal-3 levels and AOSD disease activity score (Pouchot score, r=0.66, p <0.001) and serum ferritin levels. However, no significant correlations were observed between serum M2BPGi levels and AOSD disease activity scores (Pouchot score, r = 0.32, p = 0.06) or serum ferritin levels. Furthermore, significant correlations were observed between the serum levels of Gal-3 and various inflammatory cytokines, including interleukin-18, in patients with AOSD. Immunosuppressive treatment in patients with AOSD significantly reduced serum Gal-3 and M2BPGi levels (p = 0.03 and 0.004, respectively). Conclusions: Although both Gal-3 and M2BPGi were elevated in patients with AOSD, only Gal-3 was a useful biomarker for predicting disease activity in AOSD. Our findings suggest that circulating Gal-3 reflects the inflammatory component of AOSD, which corresponds to proinflammatory cytokine induction through inflammasome activation cascades.

Macrophage activation syndrome in a Sudanese child: a case report from Sudan.

Introduction and importance: Macrophage activation syndrome (MAS) is a severe form of hemophagocytic lymphohistiocytosis that is frequently associated with either a flare-up of rheumatologic diseases, or infection and is characterized by intermittent fever, organomegaly, and multisystem dysfunction. Early diagnosis and treatment are crucial for outcome improvement. Case presentation: The authors present a 9-year-old male with systemic onset juvenile idiopathic arthritis who presented with fever, vomiting, and nose bleeding, as well as being jaundiced, and having hepatomegaly and ascites. Pancytopenia, hepatic dysfunction, and elevated ferritin levels were discovered, along with negative virological and immunological tests. He was given broad-spectrum antibiotics, and a high-dose steroid showed a good response, and he was discharged about a week later. Clinical discussion: It is hypothesized that decreased natural killer cells' function could lead to the inability to clear the infection, and subsequent lymphocytes-induced macrophages activation. Despite being beneficial in this case, steroids led to no improvement in other similar cases. Conclusion: MAS is a real life-threatening complication for patients with systemic Juvenile idiopathic arthritis (sJIA), and early diagnosis and prompt initial treatment can both offer a favourable result against such syndrome.

New discoveries in the genetics and genomics of systemic juvenile idiopathic arthritis.

INTRODUCTION: 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. AREAS COVERED: 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). EXPERT OPINION: 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.

Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: two rare sides of the same devastating coin.

Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

Does your unwell patient have haemophagocytic lymphohistiocytosis?

Haemophagocytic lymphohistiocytosis is a severe systemic hyperinflammatory syndrome characterised by dysregulation of immune cells and excessive production of cytokines, also known as a cytokine storm. It has distinctive clinical features with fever, hyperferritinaemia and falling blood counts. In adults, this usually occurs secondary to an underlying driver or trigger including infection, malignancy or rheumatic diseases. Prompt treatment with immunomodulatory therapy, including corticosteroids and the recombinant IL-1 receptor antagonist anakinra, is recommended to switch off the cytokine storm. Etoposide-based regimens are sometimes needed, and newer therapies such as emapalumab and JAK inhibitors are increasingly being used. The incidence of haemophagocytic lymphohistiocytosis has increased significantly over the last 20 years which may partly reflect increased awareness of the condition. Although relatively rare, haemophagocytic lymphohistiocytosis can be encountered by a broad range of hospital physicians, so knowing how to diagnose and treat this condition is essential. This article reviews the pathogenesis, clinical features, causes, diagnosis and treatment of haemophagocytic lymphohistiocytosis to improve physician recognition and management of this condition to improve future patient outcomes.

Concept and Diagnostic Challenges of Renal-Limited Hemophagocytic Syndrome/Macrophage Activation Syndrome.

Hemophagocytic syndrome/macrophage activation syndrome (HPS/MAS) is a serious clinical condition that frequently leads to multiple organ failure, including acute kidney injury (AKI). Although the pathogenesis of AKI is not yet fully understood, it is believed to result from uncontrolled activation of the immune system involving macrophages and cytotoxic lymphocytes. Renal histology in HPS/MAS often presents with characteristic foamy glomerular lesions (glomerular lipidosis) with massive macrophage infiltration, known as histiocytic glomerulopathy. In this review, we introduce the recently proposed concept of renal-limited HPS/MAS as a novel etiology of histiocytic glomerular lipidosis. Patients with renal-limited HPS/MAS often develop AKI but do not fulfill the diagnostic criteria for HPS/MAS because their systemic manifestations are less severe. Therefore, the diagnosis largely depends on characteristic histological findings, that is, diffuse and global glomerular accumulation of foamy macrophages and cytotoxic lymphocytes accompanied by the interaction of these cells as well as the exclusion of various differential diseases. Although there are no established therapeutic regimens, these patients receive various types of therapies, including high-dose glucocorticoids, immunosuppressants, or anti-interleukin-1 drug, and generally achieve favorable outcomes. We summarized the concept, diagnostic challenges, and recent topics of this disease entity and discussed treatment options based on our own experiences.

Marginal Zone Lymphoma Manifesting as Macrophage Activation Syndrome: A Case Report.

Macrophage activation syndrome (MAS) is a form of secondary hemophagocytic lymphohistiocytosis (HLH) when it occurs in the context of rheumatologic disorders. HLH is a rare and potentially life-threatening syndrome characterized by excessive immune system activation. It is mainly seen in children and can be genetic based or related to infections, malignancies, rheumatologic disorders, or immunodeficiency syndromes. MAS can present with nonspecific symptoms, leading to a delay in diagnosis. This report describes a case of a 64-year-old female with marginal zone lymphoma and systemic lupus erythematosus who presented with a purpuric rash and acute kidney injury. She underwent a kidney biopsy and was diagnosed with MAS. This case highlights the importance of promptly recognizing MAS's symptoms and signs, allowing timely diagnosis and early therapeutic intervention. This potentially fatal condition tends to respond well to rapid treatment initiation with corticosteroids and to address the underlying condition.

Corrigendum: HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

[This corrects the article DOI: 10.3389/fimmu.2024.1282804.].

Canakinumab in the treatment of systemic juvenile idiopathic arthritis: a retrospective single center study in China.

Objective: Systemic juvenile idiopathic arthritis (sJIA) is characterized by excessive production of proinflammatory cytokines. As an anti-IL-1 agent, canakinumab has been approved in the USA and Europe for the treatment of sJIA patients aged ≥2 years. However, the use of canakinumab has never been reported in China. In this study, we aimed to assess the efficacy and safety of canakinumab in Chinese patients with sJIA. Methods: A total of 11 patients with sJIA who were treated with canakinumab were included in this study. Clinical data were collected retrospectively from medical records. Efficacy was evaluated by the systemic juvenile arthritis disease activity score (sJADAS). The follow-up was performed at canakinumab initiation, at months 1, 3, 6, 9 and 12, or at the last follow-up. Results: Of the 11 patients enrolled, 91.0% (10/11) had previously received treatment with tocilizumab. The mean duration of canakinumab was 9 (3-18) months. 45.5% (5/11) of patients showed complete response, 45.5% (5/11) showed partial response, and 9.0% (1/11) showed no response. 18.2% (2/11) experienced disease flare during the treatment with canakinumab. 81.8% (9/11) of patients successfully reduced the dose of corticosteroids, with six discontinuing corticosteroids. 45.6% (5/11) of patients experienced infection. No serious adverse events occurred during the treatment with canakinumab. Conclusions: Canakinumab may be effective and tolerable for Chinese sJIA patients, helping to reduce the dosage of corticosteroids. However, additional researches on large samples are required to evaluate its efficacy and safety.

Hemophagocytic Lymphohistiocytosis (HLH) in Patients with Tick-Borne Illness: A Scoping Review of 98 Cases.

Hemophagocytic lymphohistiocytosis (HLH) secondary to tick-borne infections is a rare but potentially life-threatening syndrome. We performed a scoping review according to PRISMA guidelines to systematically analyze the existing literature on the topic. A total of 98 patients were included, with a mean age of 43.7 years, of which 64% were men. Most cases, 31%, were reported from the USA. Immunosuppression was present in 21.4%, with the most common cause being previous solid organ transplantation. Constitutional symptoms were the most common, observed in 83.7% of the patients, while fever was reported in 70.4% of cases. Sepsis was present in 27.6%. The most common laboratory abnormalities in this cohort were thrombocytopenia in 81.6% of patients, while anemia, leukopenia, and leukocytosis were observed in 75.5%, 55.1%, and 10.2%, respectively. Liver enzyme elevation was noted in 63.3% of cases. The H-score was analyzed in 64 patients, with the mean value being 209, and bone marrow analysis was performed in 61.2% of patients. Ehrlichia spp. was the main isolated agent associated with HLH in 45.9%, followed by Rickettsia spp. in 14.3% and Anaplasma phagocytophilum in 12.2%. Notably, no patient with Powassan virus infection or Lyme borreliosis developed HLH. The most common complications were acute kidney injury (AKI) in 35.7% of patients, shock with multiple organ dysfunction in 22.5%, encephalopathy/seizure in 20.4%, respiratory failure in 16.3%, and cardiac complications in 7.1% of patients. Treatment included antibiotic therapy alone in 43.9%, while 5.1% of patients were treated with immunosuppressants alone. Treatment with both antibiotics and immunosuppressants was used in 51% of patients. Appropriate empiric antibiotics were used in 62.2%. In 43.9% of cases of HLH due to tick-borne disease, patients received only antimicrobial therapy, and 88.4% of those recovered completely without the need for immunosuppressive therapy. The mortality rate in our review was 16.3%, and patients who received inappropriate or delayed empiric therapy had a worse outcome. Hence, we suggest empiric antibiotic treatment in patients who are suspected of having HLH due to tick-borne disease or in whom diagnostic uncertainty persists due to diagnostic delay in order to minimize mortality.

Acute Heart Failure in the Course of Macrophage Activation Syndrome Due to Newly Diagnosed Systemic Lupus Erythematosus: Case Presentation and Literature Review.

Macrophage activation syndrome is an uncommon yet dangerous and potentially fatal complication of many rheumatic diseases, inducing multiple organ failure, including, although rarely, acute heart failure. In the following paper, we present a case of a 37-year-old woman who, in a short period of time after a gynecological procedure due to fetal death, developed full-blown lupus erythematosus leading to early stages of macrophage activation syndrome with acute heart failure as its main clinical manifestation. We also include herein a brief literature review of the current understanding of diverse macrophage populations and their functions in various organs (focusing especially on the heart muscle), as well as a summary of different attempts at composing concise criteria for diagnosing macrophage activation syndrome.

A MASsive attack: a pediatric case of macrophage activation syndrome complicated by DIC as an onset of systemic juvenile idiopathic arthritis successfully treated with anakinra and review of the literature.

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.

Internalisation of neutrophils extracellular traps by macrophages aggravate rheumatoid arthritis via Rab5a.

OBJECTIVES: Although elevated levels of neutrophil extracellular traps (NETs) have been reported in patients with rheumatoid arthritis (RA), the role of NETs in RA and the relationship between NETs and macrophages in the pathogenesis of RA requires further research. Here, we sought to determine the role of NETs in RA pathogenesis and reveal the potential mechanism. METHODS: Neutrophil elastase (NE) and myeloperoxidase (MPO)-DNA were measured in human serum and synovium. NETs inhibitor GSK484 was used to examine whether NETs involved with RA progression. We stimulated macrophages with NETs and detected internalisation-related proteins to investigate whether NETs entry into macrophages and induced inflammatory cytokines secretion through internalisation. To reveal mechanisms mediating NETs-induced inflammation aggravation, we silenced GTPases involved in internalisation and inflammatory pathways in vivo and in vitro and detected downstream inflammatory pathways. RESULTS: Serum and synovium from patients with RA showed a significant increase in NE and MPO, which positively correlated to disease activity. Inhibiting NETs formation alleviated the collagen-induced arthritis severity. In vitro, NETs are internalised by macrophages and located in early endosomes. Rab 5a was identified as the key mediator of the NETs internalisation and inflammatory cytokines secretion. Rab 5a knockout mice exhibited arthritis alleviation. Moreover, we found that NE contained in NETs activated the Rab5a-nuclear factor kappa B (NF-κB) signal pathway and promoted the inflammatory cytokines secretion in macrophages. CONCLUSIONS: This study demonstrated that NETs-induced macrophages inflammation to aggravate RA in Rab 5a dependent manner. Mechanically, Rab5a mediated internalisation of NETs by macrophages and NE contained in NETs promoted macrophages inflammatory cytokines secretion through NF-κB-light-chain-enhancer of activated B cells signal pathway. Therapeutic targeting Rab 5a or NE might extend novel strategies to minimise inflammation in RA.

Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis on anti-interleukin-1 or -6 therapy.

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 pediatric rheumatology centers 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. 45 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.

Disseminated Histoplasmosis Mimicking Macrophage Activation Syndrome in a Patient With Rheumatoid Arthritis.

Infections caused by Histoplasma capsulatum typically do not produce symptoms. However, in individuals who are immunocompromised, progressive disseminated histoplasmosis may occur. A 67-year-old female, with lengthy history of immunosuppression due to management of rheumatoid arthritis, reported a two-month history of fatigue, headaches, and intermittent fevers following hip surgery. Due to the concern for macrophage activation syndrome and hemophagocytic lymphohistiocytosis, a bone marrow biopsy was performed. However, the results indicated the presence of Histoplasma, which was supported by the presence of Histoplasma antigens in the serum and urine, Histoplasma antibodies in the serum, positive (1,3)-beta-D-glucan results, and fungal blood cultures. The patient initially received amphotericin B, but it was switched to itraconazole due to adverse effects. The patient remains on itraconazole therapy and follows as an outpatient with an infectious diseases specialist.

Neutrophil activation biomarker pentraxin 3 for diagnosis and monitoring of macrophage activation syndrome occurrence in adult-onset Still's disease.

Macrophage activation syndrome (MAS) is a potentially fatal consequence of adult-onset Still's disease (AOSD), driven by a cytokine storm. Efficient early diagnosis of AOSD-associated MAS requires a sensitive and specific biomarker. In this study, we demonstrated that pentraxin 3 (PTX3), an acute phase protein, was associated with AOSD disease activity and served as a biomarker for AOSD-MAS. PTX3 levels were significantly increased in AOSD patients compared to other autoimmune diseases and healthy controls. Plasma PTX3 levels showed positive correlations with inflammatory markers, the systemic score and the HScore. In active AOSD with MAS, PTX3 levels were higher compared to those in non-AOSD haemophagocytic lymphohistiocytosis (HLH) patients. Moreover, the PTX3's area under the curve value for distinguishing AOSD with MAS exceeded that of soluble interleukin-2 receptor, ferritin and C-reactive protein. Furthermore, plasma levels of PTX3 were associated with circulating NET-DNA levels. To fully understand the underlying mechanism of PTX3 prompting AOSD and AOSD-MAS progression, we discovered that neutrophils exhibited enhanced NET formation and mitogen-activated protein kinases (MAPK) pathway activation upon PTX3 stimulation. More importantly, PTX3-induced NET formation was effectively dampened by MAPK pathway inhibitors. These findings collectively revealed that PTX3 has a favorable correlation with disease activity and may serve as a potential biomarker to differentiate AOSD patients with MAS. Additionally, PTX3 induces NET release via the MAPK pathway, suggesting a pathogenic role in AOSD-MAS.