INTRODUCTION

Macrophage Activation Syndrome (MAS) is a rare but life threatening pro-inflammatory complication of multiple autoimmune diseases leading to cytokine storm. We report a case of MAS as a presenting manifestation of Systemic Lupus Erythematosus.

CASE REPORT

A 32-year-old female, newly diagnosed with Systemic Lupus Erythematosus (SLE), presents with a 3-month history of fever and joint pains, which began a few days after receiving her first dose of a viral vector COVID-19 vaccine. She later developed facial edema, and her fever became persistent and unremitting. Upon presentation, she was initially hypotensive, tachycardic, with distended neck veins, with periorbital edema and muffled heart sounds. Initial work-up revealed pericardial effusion, anemia, thrombocytopenia, elevated creatinine, hypoalbuminemia, hematuria, and pyuria. She was intubated, started on inotrope, and underwent pericardiocentesis. Patient was classified as SLE based on Systemic Lupus International Collaborating Clinics Classification (SLICC) Criteria despite negative antinuclear antibody (ANA). Nevertheless, she was started on IV steroids and hydroxychloroquine. She was eventually extubated after significant clinical improvement. Further work-up for MAS was however done due to persistent febrile episodes. Hyperferritinemia, hypertriglyceridemia, hypercholesterolemia, pancytopenia, transaminitis, and splenomegaly on imaging were noted. She was then started on methylprednisolone pulse therapy. After treatment, marked clinical improvement, as well as resolution of transaminitis and pancytopenia were noted.

CONCLUSION

A high index of suspicion for MAS should exist in a patient with pyrexia of unknown origin with concomitant autoimmune disease. In this disease that can lead to progressive organ failure, early diagnosis and management is crucial. This case report culminates the need for diagnostic and therapeutic guidelines that will help in the early diagnosis and immediate treatment of this debilitating condition.

Human ; Female ; Adult: 25-44 Yrs Old ; Lymphohistiocytosis, Hemophagocytic ; Macrophage Activation Syndrome ; Lupus Erythematosus, Systemic ; Autoimmune Diseases

Child ; Humans ; Arthritis, Juvenile/drug therapy* ; Macrophage Activation Syndrome/etiology* ; Antibodies, Monoclonal, Humanized/therapeutic use*

OBJECTIVES: To investigate the clinical manifestations and laboratory examination results of children with Kawasaki disease complicated by macrophage activation syndrome (KD-MAS), and to provide a basis for identifying early warning indicators for the early diagnosis and treatment of KD-MAS. METHODS: A retrospective study was performed on 27 children with KD-MAS (KD-MAS group) and 110 children with KD (KD group) who were admitted to Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2014 to January 2022. Clinical and laboratory data were compared between the two groups. The receiver operating characteristic (ROC) curve was used to investigate the value of laboratory markers with statistical significance in the diagnosis of KD-MAS. RESULTS: Compared with the KD group, the KD-MAS group had significantly higher incidence rates of hepatomegaly, splenomegaly, incomplete KD, no response to intravenous immunoglobulin, coronary artery damage, multiple organ damage, and KD recurrence, as well as a significantly longer length of hospital stay (P<0.05). Compared with the KD group, the KD-MAS group had significantly lower levels of white blood cell count, absolute neutrophil count, hemoglobin, platelet count (PLT), erythrocyte sedimentation rate, serum albumin, serum sodium, prealbumin, and fibrinogen (FIB), a significantly lower incidence rate of non-exudative conjunctiva, and significantly higher levels of C-reactive protein, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and serum ferritin (SF) (P<0.05). The ROC curve analysis showed that SF, PLT, FIB, and LDH had high value in the diagnosis of KD-MAS, with areas under the curve (AUC) of 0.989, 0.966, 0.932, and 0.897, respectively (P<0.001), and optimal cut-off values of 349.95 μg/L, 159×10⁹/L, 3.85 g/L, and 403.50 U/L, respectively. The combination of SF, PLT, FIB, and LDH had a larger AUC than PLT, FIB, and LDH alone in the diagnosis of KD-MAS (P<0.05), but there was no significant difference in the AUC between the combination of SF, PLT, FIB, and LDH and SF alone (P>0.05). CONCLUSIONS KD-MAS should be considered when children with KD have hepatosplenomegaly, no response to intravenous immunoglobulin, coronary artery damage, and KD recurrence during treatment. SF, PLT, FIB, and LDH are of high value in the diagnosis of KD-MAS, especially SF is of great significance in the diagnosis of KD-MAS.
Child ; Humans ; Immunoglobulins, Intravenous ; Macrophage Activation Syndrome/etiology* ; Mucocutaneous Lymph Node Syndrome/diagnosis* ; Retrospective Studies ; Blood Sedimentation ; Hepatomegaly

Infant, Newborn ; Humans ; Macrophage Activation Syndrome/diagnosis*

OBJECTIVE: To analyze and compare the clinical and laboratory characteristics of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD), and to evaluate the applicability of the 2016 European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization classification criteria for MAS complicating systemic juvenile idiopathic arthritis (sJIA) in different auto-immune diseases contexts and to propose new diagnostic predictive indicators. METHODS: A retrospective analysis was conducted on the clinical and laboratory data of 24 SLE patients with MAS (SLE-MAS) and 24 AOSD patients with MAS (AOSD-MAS) who were hospitalized at Peking University People's Hospital between 2000 and 2018. Age- and sex-matched SLE (50 patients) and AOSD (50 patients) diagnosed in the same period without MAS episodes were selected as controls. The cutoff values for laboratory indicators predicting SLE-MAS and AOSD-MAS were determined using receiver operating characteristic (ROC) curves. Furthermore, the laboratory diagnostic predictive values for AOSD-MAS were used to improve the classification criteria for systemic juvenile idiopathic arthritis-associated MAS (sJIA-MAS), and the applicability of the revised criteria for AOSD-MAS was explored. RESULTS: Approximately 60% of SLE-MAS and 40% of AOSD-MAS occurred within three months after the diagnosis of the underlying diseases. The most frequent clinical feature was fever. In addition to the indicators mentioned in the diagnosis criteria for hemophagocytic syndrome revised by the International Society for Stem Cell Research, the MAS patients also exhibited significantly elevated levels of aspartate aminotransferase and lactate dehydrogenase, along with a significant decrease in albumin. Hemophagocytosis was observed in only about half of the MAS patients. ROC curve analysis demonstrated that the optimal discriminative values for diagnosing MAS was achieved when SLE patients had ferritin level≥1 010 μg/L and lactate dehydroge-nase levels≥359 U/L, while AOSD patients had fibrinogen levels≤225.5 mg/dL and triglyceride levels≥2.0 mmol/L. Applying the 2016 sJIA-MAS classification criteria to AOSD-MAS yielded a diagnostic sensitivity of 100% and specificity of 62%. By replacing the less specific markers ferritin and fibrinogen in the 2016 sJIA-MAS classification criteria with new cutoff values, the revised criteria for classifying AOSD-MAS had a notable increased specificity of 86%. CONCLUSION Secondary MAS commonly occurs in the early stages following the diagnosis of SLE and AOSD. There are notable variations in laboratory indicators among different underlying diseases, which may lead to misdiagnosis or missed diagnosis when using uniform classification criteria for MAS. The 2016 sJIA-MAS classification criteria exhibit high sensitivity but low specificity in diagnosing AOSD-MAS. Modification of the criteria can enhance its specificity.
Adult ; Humans ; Child ; Macrophage Activation Syndrome/complications* ; Arthritis, Juvenile/diagnosis* ; Still's Disease, Adult-Onset/diagnosis* ; Retrospective Studies ; Lupus Erythematosus, Systemic/diagnosis* ; Fibrinogen ; Ferritins

Systemic lupus erythematosus (SLE) associated macrophage activation syndrome (MAS) is clinically severe, with a high mortality rate and rare neuropsychiatric symptoms. In the course of diagnosis and treatment, it is necessary to actively determine whether the neuropsychiatric symptoms in patients are caused by neuropsychiatric systemic lupus erythematosus (NPSLE) or macrophage activation syndrome. This paper retrospectively analyzed the clinical data of 2 cases of SLE associated MAS with neuropsychiatric lesions, Case 1: A 30-year-old female had obvious alopecia in 2019, accompanied by emaciation, fatigue and dry mouth. In March 2021, she felt weak legs and fell down, followed by fever and chills without obvious causes. After completing relevant examinations, she was diagnosed with SLE and given symptomatic treatments such as hormones and anti-infection, but the patient still had fever. The relevant examinations showed moderate anemia, elevated ferritin, elevated triglycerides, decreased NK cell activity, and a perforin positivity rate of 4.27%, which led to the diagnosis of "pre-hemophagocytic syndrome (HPS)". In May 2021, the patient showed mental trance and babble, and was diagnosed with "SLE-associated MAS"after completing relevant examinations. After treatment with methylprednisolone, anti-infection and psychotropic drugs, the patient's temperature was normal and mental symptoms improved. Case 2: A 30-year-old female patient developed butterfly erythema on both sides of the nose on her face and several erythema on her neck in June 2019, accompanied by alopecia, oral ulcers, and fever. She was diagnosed with "SLE" after completing relevant examinations, and her condition was relieved after treatment with methylprednisolone and human immunoglobulin. In October 2019, the patient showed apathy, no lethargy, and fever again, accompanied by dizziness and vomiting. The relevant examination indicated moderate anemia, decreased NK cell activity, elevated triglycerides, and elevated ferritin. The patient was considered to be diagnosed with "SLE, NPSLE, and SLE-associated MAS". After treatment with hormones, human immunoglobulin, anti-infection, rituximab (Mabthera), the patient's condition improved and was discharged from the hospital. After discharge, the patient regularly took methylprednisolone tablets (Medrol), and her psychiatric symptoms were still intermittent. In November 2019, she developed symptoms of fever, mania, and delirium, and later turned to an apathetic state, and was given methylprednisolone intravenous drip and olanzapine tablets (Zyprexa) orally. After the mental symptoms improved, she was treated with rituximab (Mabthera). Later, due to repeated infections, she was replaced with Belizumab (Benlysta), and she was recovered from her psychiatric anomalies in March 2021. Through the analysis of clinical symptoms, imaging examination, laboratory examination, treatment course and effect, it is speculated that the neuropsychiatric symptoms of case 1 are more likely to be caused by MAS, and that of case 2 is more likely to be caused by SLE. At present, there is no direct laboratory basis for the identification of the two neuropsychiatric symptoms. The etiology of neuropsychiatric symptoms can be determined by clinical manifestations, imaging manifestations, cerebrospinal fluid detection, and the patient's response to treatment. Early diagnosis is of great significance for guiding clinical treatment, monitoring the condition and judging the prognosis. The good prognosis of the two cases in this paper is closely related to the early diagnosis, treatment and intervention of the disease.
Humans ; Female ; Adult ; Rituximab/therapeutic use* ; Macrophage Activation Syndrome/etiology* ; Retrospective Studies ; Lupus Erythematosus, Systemic/drug therapy* ; Methylprednisolone/therapeutic use* ; Lupus Vasculitis, Central Nervous System ; Fever/drug therapy* ; Erythema/drug therapy* ; Hormones/therapeutic use* ; Anemia ; Alopecia/drug therapy* ; Triglycerides/therapeutic use* ; Ferritins/therapeutic use*

OBJECTIVE: Acute lung injury (ALI) is a serious respiratory dysfunction caused by pathogen or physical invasion. The strong induced inflammation often causes death. Tanshinone IIA (Tan-IIA) is the major constituent of Salvia miltiorrhiza Bunge and has been shown to display anti-inflammatory effects. The aim of the current study was to investigate the effects of Tan-IIA on ALI. METHODS: A murine model of lipopolysaccharide (LPS)-induced ALI was used. The lungs and serum samples of mice were extracted at 3 days after treatment. ALI-induced inflammatory damages were confirmed from cytokine detections and histomorphology observations. Effects of Tan-IIA were investigated using in vivo and in vitro ALI models. Tan-IIA mechanisms were investigated by performing Western blot and flow cytometry experiments. A wound-healing assay was performed to confirm the Tan-IIA function. RESULTS: The cytokine storm induced by LPS treatment was detected at 3 days after LPS treatment, and alveolar epithelial damage and lymphocyte aggregation were observed. Tan-IIA treatment attenuated the LPS-induced inflammation and reduced the levels of inflammatory cytokines released not only by inhibiting neutrophils, but also by macrophage. Moreover, we found that macrophage activation and polarization after LPS treatment were abrogated after applying the Tan-IIA treatment. An in vitro assay also confirmed that including the Tan-IIA supplement increased the relative amount of the M2 subtype and decreased that of M1. Rebalanced macrophages and Tan-IIA inhibited activations of the nuclear factor-κB and hypoxia-inducible factor pathways. Including Tan-IIA and macrophages also improved alveolar epithelial repair by regulating macrophage polarization. CONCLUSION This study found that while an LPS-induced cytokine storm exacerbated ALI, including Tan-IIA could prevent ALI-induced inflammation and improve the alveolar epithelial repair, and do so by regulating macrophage polarization.
Abietanes ; Acute Lung Injury/drug therapy* ; Animals ; Cytokine Release Syndrome ; Cytokines ; Inflammation/drug therapy* ; Lipopolysaccharides/toxicity* ; Macrophage Activation ; Macrophages ; Mice ; Triacetoneamine-N-Oxyl/pharmacology*

To investigate the clinical and immunological features of dermatomyositis (DM) complicated with macrophage activation syndrome (MAS). The demographic and clinical characteristics of five patients diagnosed with DM complicated with MAS hospitalized in the Department of Rheumatology and Immunology, Peking University People ' s Hospital from 2011 to 2021 were collected. The results of clinical manifestations, laboratory tests, immunological features, treatments and prognosis were analyzed and summarized. In this study, five female patients in Peking University People's Hospital with an average age of 63.8 (44.0-83.0) years and an average disease duration of 16.1 (1.5-48.0) months. All the patients had typical DM rash (such as heliotrope sign, V/shawl sign or Gottron's sign/papules). They all had muscle involvement (including myalgia or muscle weakness). Two patients had positive myositis-specific antibodies (MSAs), in which case 1 had anti-TIF1-γ antibody and case 5 had anti-NXP-2 antibody. Four patients had interstitial lung disease except case 3. All of the cases developed MAS in the active stage of DM. Common manifestations of MAS in these five patients included high-grade fever, cytopenia, decreased fibrinogen, elevated ferritin and increased soluble CD25. Case 1 presented with neutropenia (0.6×10⁹ /L), thrombocytopenia (26.0×10⁹ /L), hypofibrinogenemia (0.9 g/L), markedly elevated ferritin (26 331.0 μg/L), decreased NK cell activity. Case 2 had anaemia (hemoglobin 81.0 g/L), thrombocytopenia (55.0×10⁹ /L), hypertriglyceridemia (4.7 mmol/L), hypofibrinogenemia (1.2 g/L), elevated ferritin (>100 000.0 μg/L), hemophagocytosis in bone marrow. Case 3 had anaemia (hemoglobin 88 g/L), decreased fibrinogen (1.9 g/L), increased ferritin (>27 759.0 μg/L), splenomegaly, hemophagocytosis in bone marrow. Case 4 suffered from neutropenia(0.3×10⁹ /L), anaemia(hemoglobin 78 g/L), hypertriglyceridemia (4.2 mmol/L), hypofibrinogenemia (0.9 g/L), increased ferritin (>100 000.0 μg/L), and decreased NK cell activity. Case 5 presented anaemia (hemoglobin 60.0 g/L), thrombocytopenia (67.0×10⁹ /L), hypertriglyceridemia (12.7 mmol/L), decreased fibrinogen (1.1 g/L), and elevated ferritin (>923.0 μg/L). All the patients were treated with methylprednisone pulse therapy (200-500 mg) combined with cyclosporine while case 5 received rituximab after methylprednisone pulses. In addition, case 3 also received the combination of mycophenolate mofetil. Case 1 was given etoposide while case 4 was treated with cyclophosphamide and repeated plasmapheresis at the same time. Moreover, intravenous immunoglobulin was added meantime apart from case 3. The condition of four patients improved significantly, nevertheless case 4 experienced recurred pulmonary symptoms and died of respiratory failure. As for complications about infection, case 2 had bacterial infection with high level procalcitonin (PCT) before MAS treatment and condition was improved after empiric antibacterial therapy. Case 3 had cytomegalovirus DNAemia before diagnosis of MAS and viral titer turned negative after ganciclovir therapy. After treatment of MAS, four patients developed cytomegalovirus DNAemia except case 3, in which case 5 was co-infected with bacteria. To sum, DM complicated with MAS is relatively rare, and its patients are of ten in life-threatening condition. Early detection, treatment and prevention of infection during treatment are critical to improve the prognosis.
Humans ; Female ; Middle Aged ; Dermatomyositis/complications* ; Macrophage Activation Syndrome/complications* ; Afibrinogenemia/complications* ; Autoantibodies ; Neutropenia ; Thrombocytopenia/complications* ; Ferritins/therapeutic use* ; Hypertriglyceridemia/complications* ; Fibrinogen/therapeutic use*

OBJECTIVE: To described the clinical and laboratory features and outcome of 67 macrophage activation syndrome (MAS). METHODS: A total of 67 MAS patients from three centers from January 2007 to December 2017 were enrolled. Clinical and laboratory features, and response to therapy were analyzed. Predictive factors for remission and survival were explored. RESULTS: We identified a mean age of (36.1±16.3) years at diagnosis of MAS and a median connective tissue disease (CTD) duration of 8 months prior to MAS development. Among 67 MAS patients identified, underlying diseases included adult-onset Still's disease (AOSD) in 56.7% and systemic lupus erythematosus (SLE) in 30.0%. Fever and splenomegaly were found in 100.0% and 82.1% of the patients, respectively. Ferritinemia and elevation of serum soluble interleukin-2 receptor was seen in 100.0% and 93.2% of the patients. Serum levels of alanine aminotransferase, D-dimer, ferritin and C reactive protein were significantly higher in MAS associated with the AOSD patients than in MAS associated with the SLE patients. A significant decrease of erythrocyte sedimentation rate was found in MAS associated with AOSD, as compared with MAS associated with SLE. The most commonly used therapy was corticosteroids, which were initially administered in 100.0% of the patients. Intravenous immunoglobulin (IVIG) was administered in 91.0%, cyclosporine A in 64.2%, and etoposide in 46.3% of the patients, respectively. The induction therapy yielded a complete remission (CR) at the end of week 8 in 47.8% of the MAS patients. The overall mortality rate at the end of week 16 was 22.4%. The median serum levels of gamma-glutamyltransferase, alkaline phosphatase, total bilirubin and direct bilirubin were significantly lower in the patients who achieved complete remission at the end of week 8 than in those who did not, and splenomegaly was significantly less frequent (71.9% vs.91.4%, P=0.037). Both the mean age at diagnosis of MAS and the mean age at diagnosis of underlying CTD of the deceased patients were elder than those of the survived population (P=0.014 and P=0.017, respectively). The platelet count was significantly less in the deceased population as compared with the living population (P=0.018). No addition of cyclosporine A (P=0.004) was identified as risk factors associated with death in Logistic regression analysis. CONCLUSION MAS secondary to connective tissue disease is most common with AOSD and SLE. In terms of laboratory findings, there were considerable differences between the patients with underlying SLE and those with AOSD. Advanced age and low platelet counts are significant predictive factors for death, while treatment with cyclosporine may reduce the risk.
Adult ; Cyclosporine ; Humans ; Macrophage Activation Syndrome ; Middle Aged ; Retrospective Studies ; Still's Disease, Adult-Onset ; Treatment Outcome ; Young Adult

OBJECTIVETo study the clinical and laboratory features of macrophage activation syndrome (MAS) at the early stage of diagnosis, and to explore a method for early identification of MAS.

METHODSA retrospective analysis was performed for the demographic data, clinical and laboratory features, and treatment outcomes of 21 MAS patients.

RESULTSOf the 21 MAS patients, 14 had systemic juvenile idiopathic arthritis, 5 had Kawasaki disease (KD), and 2 had connective tissue disease (CTD) as primary diseases. The median time of MAS onset was 19 days. The KD patients had the shortest time of MAS onset, while the CTD patients had the longest onset time (P=0.009). The top 10 clinical symptoms were fever (95%), rash (86%), lymph node enlargement (67%), hemophagocytic phenomenon in bone marrow (63%), pulmonary disease (62%), serous effusion (62%), hepatomegaly (52%), cerebrospinal fluid abnormalities (50%), central nervous system damage (43%), and splenomegaly (38%). The median of hemoglobin level was lower than the normal value. The medians of C-reactive protein level and erythrocyte sedimentation rate were higher than the normal values. There were significant increases in serum ferritin, glutamic-pyruvic transaminase, aspartate aminotransferase, lactate dehydrogenase, and triglyceride. The median of fibrinogen level was lower than the normal value. There were significant increases in D-dimer, interleukin-6 (IL-6), interleukin-10 (IL-10), and interferon-γ (IFN-γ). Of the 21 patients, 20 were improved and discharged.

CONCLUSIONSIf patients with rheumatic disease have persistent fever, hepatic dysfunction, coagulation disorders, multiple organ impairment, significantly increased IL-10 and IFN-γ, and a persistent increase in serum ferritin, the development of MAS should be considered.

Adolescent ; C-Reactive Protein ; analysis ; Child ; Child, Preschool ; Cytokines ; blood ; Female ; Fibrin Fibrinogen Degradation Products ; analysis ; Humans ; Infant ; Macrophage Activation Syndrome ; blood ; diagnosis ; drug therapy ; Male ; Retrospective Studies