Macrophage Activation Syndrome In Patients Research Articles

Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis on anti-interleukin-1 or -6 therapy: more difficult to diagnose, not to control?

Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis on anti-interleukin-1 or -6 therapy: more difficult to diagnose, not to control?

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

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). 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. 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. 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.

Clinical features of macrophage activation syndrome in adult dermatomyositis:A single-center retrospective case-control study.

Little is known about the features of macrophage activation syndrome (MAS) in dermatomyositis, especially the association between rapidly progressive interstitial lung disease (RP-ILD) and MAS. To determine the characteristics of MAS in patients with dermatomyositis and their association with RP-ILD. This was a retrospective cohort study of 201 dermatomyositis patients at the First Affiliated Hospital of Zhejiang University over a 10-year period. A total of 22 (10.9%) patients were diagnosed with MAS. The rate of RP-ILD was significantly higher in patients with MAS than in those without MAS (81.8% vs. 17.4%, respectively, p < .001). Multivariate analysis indicated that RP-ILD (p = .019), ferritin level > 1685 ng/mL (p = .007) and hemoglobin < 100 g/L (p = .001) were independent risk factors for MAS. Furthermore, RP-ILD patients with MAS presented more cardiac injury (50.0% vs. 13.3%, respectively, p < .009), central nervous system dysfunction (42.8% vs. 3.4%, respectively, p < .001) and hemorrhage (38.9% vs. 3.3%, respectively, p = .003) than RP-ILD patients without MAS. The 90-day cumulative survival rate for patients with MAS was significantly lower than for those without MAS (18.2% vs. 82.1%, respectively, p < .001). MAS was a common and fatal complication of dermatomyositis in our cohort. MAS is closely related to RP-ILD in patients with dermatomyositis. When RP-ILD is present in dermatomyositis patients with abnormal laboratory findings, such as cytopenia and hyperferritinemia, the presence of MAS should be considered.

Type I interferon signature and cycling lymphocytes in macrophage activation syndrome.

BACKGROUNDMacrophage activation syndrome (MAS) is a life-threatening complication of Still's disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS.METHODWe profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies.RESULTSBulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell, and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 - both elevated in MAS patients - synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response.CONCLUSIONMAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.

Risk of Macrophage Activation Syndrome in Patients with Adult-Onset Still's Disease Treated with IL-1 and IL-6 Inhibitors: A Meta-analysis and Single-Center Experience.

Patients with adult-onset Still's disease (AOSD) are at risk of developing macrophage activation syndrome (MAS), a life-threatening condition. Some cases of MAS have been reported following the use of biological agents, highlighting the need to identify contributing factors. This study aims to examine the characteristics of MAS in patients with AOSD treated with anakinra (ANA) or tocilizumab (TCZ). A systematic search was conducted across four online databases to identify studies reporting the incidence rates of MAS in patients with AOSD treated with ANA or TCZ. Meta-analysis was performed using a random-effects model and the generic inverse variance method to estimate the pooled incidence rates. The difference in incidence rates of MAS between TCZ and ANA was assessed. Additionally, we analyzed laboratory data and clinical features of AOSD cases at our institution, stratifying them into two groups: those who developed MAS after TCZ administration and those who did not. Of the 455 screened articles, we included five ANA and six TCZ studies. The pooled incidence rates of MAS were 1.50% (95% confidence interval [CI], 0-3.36) for ANA (345 patients) and 14.01% (95% CI 4.51-23.51) for TCZ (94 patients). MAS incidence was significantly higher in the TCZ group (P = 0.01). Among the 17 patients from our institution, the six patients who developed MAS had significantly higher white blood cell and neutrophil counts, as well as elevated levels of lactate dehydrogenase, C-reactive protein, and ferritin before TCZ induction (P < 0.05). In patients with AOSD, the manifestation of MAS is influenced by multiple causative factors. Consequently, the administration of TCZ should be approached with caution, particularly in patients exhibiting elevated inflammatory markers. This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (Japan) as UMIN000049243.

Hemophagocytic Lymphohistiocytosis With Elevated Cytokines Related to Macrophage Activation After Liver Transplantation for Autoimmune Hepatitis: A Case Report

Hemophagocytic lymphohistiocytosis (HLH) is a rare but lethal complication of liver transplantation (LT). HLH is characterized by pathologic macrophage activation with hypercytokinemia, excessive inflammation, and tissue destruction, resulting in progressive organ dysfunction. HLH is also known as macrophage activation syndrome (MAS) when complicated by rheumatic or autoinflammatory diseases. Measuring several serum cytokines could be helpful in diagnosing HLH and MAS. Cytokines related to macrophage activation: neopterin, interleukin-18 (IL-18), and soluble tumor necrosis factor receptors (sTNF-R) I and II have not been assessed in patients with HLH complicated by LT. In this case, these cytokines were evaluated in the perioperative period of LT. The patient was a 24-year-old woman who underwent living-donor LT for acute worsening of autoimmune hepatitis. On postoperative day 12, the patient was diagnosed with HLH on the basis of the criteria. Plasma exchange, steroid pulse therapy, intravenous immunoglobulin and granulocyte-colony stimulating factor effectively inhibited progression to lethal HLH. When HLH occurred after LT, cytokine analysis showed that neopterin, IL-18, sTNFR-I, and II were elevated: cytokine storm. Of note, cytokine analysis on hospital admission also revealed elevated cytokine levels. Particularly, IL-18 levels were markedly elevated, suggesting that activation of the innate immune system was involved. These results revealed that a cytokine storm and macrophage activation developed before LT. Based on these findings, cytokine analysis related to macrophage activation may be useful for diagnosing and predicting HLH and MAS in patients with LT.

Under-Recognized Macrophage Activation Syndrome in Refractory Kawasaki Disease: A Wolf in Sheep's Clothing.

Recognition of macrophage activation syndrome (MAS) in patients with refractory Kawasaki disease (KD) can be challenging. This study aimed to investigate the incidence of MAS in patients with refractory KD and to compare the characteristics of refractory KD and MAS. Medical records of 468 patients diagnosed with KD from January 2010 to December 2019 were retrospectively reviewed. Of the 468 KD patients, 63 were enrolled in the study as a refractory KD group (n = 59) and an MAS group (n = 4). The incidence of MAS was 0.8% (4/468) in patients with KD and 6.3% (4/63) in patients with refractory KD. Compared to the refractory KD group, the MAS group had higher frequencies of incomplete KD, hepatosplenomegaly, third-line treatment, and MAS screening, and showed lower levels of albumin. No significant differences were found in other clinical and laboratory findings. In addition to four patients with MAS, five patients with refractory KD who received third-line treatment showed severe systemic inflammation and organ dysfunction, but only one in five patients underwent MAS screening, including ferritin levels. In conclusion, given the relatively high incidence of MAS in children with refractory KD and the similar phenotype between refractory KD and MAS, we propose that MAS screening should be included in routine laboratory tests for refractory KD.

Evaluation of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis: A Single Center Experience

Objectives Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile arthritis (sJIA), and early diagnosis is critical for survival. The objective of this study was to evaluate the 2016 MAS classification criteria in a Danish sJIA cohort and to compare different sets of criteria for the early identification of MAS including the HLH-2004 diagnostic guidelines, MS score, and the ferritin/ESR ratio. Methods Data was extracted from medical charts of 32 patients with sJIA from a single Danish paediatric rheumatology center diagnosed between January 2014 and June 2021. Patients who met the 2016 MAS classification criteria were classified as having MAS. From a receiver operating characteristic (ROC) plot, the area under the curve (AUC) was calculated for the prediction of patients with MAS according to the 2016 MAS classification criteria using either MS score or the ferritin/ESR ratio. Results Of the cohort, eight (25%) patients were classified as having MAS according to the 2016 MAS classification criteria compared to only three (9.4%) patients fulfilling the HLH-2004 diagnostic guidelines, all of which had recurrent MAS. The ferritin/ESR ratio showed the highest sensitivity (100%) but the lowest specificity (72.2%). In comparison, the MS score had a higher specificity (90.9%) for the identification of MAS according to the 2016 classification criteria. In our cohort, the most optimal cut-off point for the ferritin/ESR ratio was ≥19.4 (sensitivity: 100%, specificity: 72.2%) and ≥ -1.5 for the MS score (sensitivity: 71.4%, specificity: 91.7%), respectively. Conclusion The 2016 MAS classification criteria were a valuable tool in the discrimination of sJIA with and without MAS. The HLH-2004 diagnostic guidelines showed the lowest sensitivity, ferritin/ESR ratio, and the lowest specificity compared to the MS score where an acceptable high sensitivity and specificity was found.

Baseline clinical features predicting macrophage activation syndrome in patients with systemic adult-onset Still's disease receiving interleukin-6 inhibitor treatment.

Macrophage activation syndrome (MAS), a severe complication of systemic adult-onset Still's disease (AOSD), has been reported to occur during interleukin-6 (IL-6) inhibitor treatment. However, predictors for MAS development are unknown. Therefore, this study investigated predictive features for MAS development after starting IL-6 inhibitor treatment in systemic AOSD patients. In a single-center retrospective study involving systemic AOSD patients who were refractory to high-dose glucocorticoids with immunosuppressants and started IL-6 inhibitor treatment between April 2008 and March 2020, we compared the baseline clinical features between patients who developed AOSD flare with MAS features (MAS group) and those who did not (non-MAS group) during IL-6 inhibitor treatment. Only tocilizumab was used as an IL-6 inhibitor. Six of 14 refractory systemic AOSD patients developed AOSD flares with MAS features during tocilizumab treatment, including 4 who developed them shortly after initiation. The MAS group had significantly lower neutrophil counts, fibrinogen, and higher IL-18/C-reactive protein (CRP) ratio at starting tocilizumab (baseline) than the non-MAS group. Before starting tocilizumab, neutrophil counts were trending downward and upward in the MAS and non-MAS groups, respectively, with significant differences in changes. Receiver operating characteristic analysis showed that baseline neutrophil counts and fibrinogen and their changes before tocilizumab treatment and baseline IL-18/CRP ratio had significant discriminatory abilities for subsequent MAS development. We identified baseline laboratory features associated with MAS development after initiating an IL-6 inhibitor in refractory systemic AOSD patients. These features may reflect the suppression of IL-6 signaling, and further suppression of IL-6 signaling might trigger early-onset MAS.

Significance of hyperferritinemia as a diagnostic and prognostic biomarker

Ferritin is a complex protein composite (iron protein) that plays the role of the main intracellular iron depot in humans and animals, consisting of the protein apoferritin and the ferric atom in the composition of phosphate hydroxide. The reference value of ferritin in women is 200 μg/l, in men – 300 μg/l. Ferritin is a marker of total body iron stores, and low levels are specific for iron deficiency. Ferritin is also involved in immune processes and has both pro-inflammatory and immunosuppressive activity. Hyperferritinemia is a nonspecific symptom that occurs in a number of immunoinflammatory, infectious diseases, as well as during body iron stores overload. Hyperferritinemia is a criterion sign of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis, systemic lupus erythematosus and Kawasaki disease, as well as a predictive biomarker of adult-onset Still's disease. High ferritin levels occur in catastrophic antiphospholipid syndrome, as well as in infectious pathologies such as septic shock and COVID-19, including multisystem inflammatory syndrome associated with COVID-19. Ferritin concentration is an important parameter for assessing the activity and prognosis of the disease, which allows a rational approach to the choice of therapy in these patients.

Is There an Association Between Initial Clinical Manifestations and the Development of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis?

Is There an Association Between Initial Clinical Manifestations and the Development of Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis?

The spectrum of hemophagocytic lymphohistiocytosis: a retrospective study comparing adult macrophage activation syndrome to malignancy-associated hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening inflammatory syndrome that can be triggered by autoimmune diseases, malignancy, or infection. In rheumatologic patients, sHLH is referred to as macrophage activation syndrome (MAS). Differentiating between triggers is important for prompt treatment and prognosis. Data comparing subsets of sHLH are limited due to the rarity of this disease. We aim to explore differences in clinical features that may differentiate MAS from malignancy-associated HLH (mHLH) patients. We conducted a single-center retrospective study assessing clinical characteristics, laboratory parameters, treatment regimens and outcomes in 34 patients with sHLH over a 16 year period. We compared patients with MAS to those with mHLH. Hepatomegaly was not present in the MAS group but was present in the mHLH group (0 vs. 25%, p = 0.024). MAS patients had on average nearly double the concentration of platelets at 50.0 (IQR: 31.0–78.0 Kµ/L) vs. 29.0 Kµ/L (IQR: 14.0–37.5 Kµ/L), p = 0.003. Soluble IL-2R concentrations were four times lower in the MAS group with a median soluble IL-2R concentration of 6814.5 kU/L (IQR: 2101–2610 kU/L) vs. 27972.0 kU/L (IQR: 12,820–151,650 kU/L), p = 0.010. The MAS group fared better overall than the mHLH group but was not statistically significant (mortality 22 vs. 44%, p = 0.18). MAS and mHLH patients exhibited different laboratory parameters and clinical features, most notably differences in platelet counts, soluble IL-2R concentration and hepatomegaly, which may help differentiate these conditions early in their course.

Experience with macrophage activation syndrome associated with systemic lupus erythematosus: A single-center study from Pakistan

Objective: The objective of the study was to evaluate the clinical, laboratory manifestations, and associations of macrophage activation syndrome (MAS) in a cohort of Pakistani patients with systemic lupus erythematous and to compare it with a well-characterized cohort of active systemic lupus erythematosus (SLE) without MAS.Materials and Methods: Patients with a diagnosis of SLE admitted from January 2017 to July 2019 were retrospectively reviewed. MAS ascertained by either clinical criteria or bone marrow biopsy were studied. Demographics, clinical, and laboratory parameters of MAS patients were evaluated and compared with a cohort of non-MAS active SLE.Results: A total of 305 patients of SLE were evaluated, out of these 18 patients had a diagnosis of MAS, making a MAS prevalence of 5.9%. Mean age of the patients was 27.25 ± 10.16 years. Female comprised 13 (72%) of MAS group. Fever was the most common clinical presentation (100%), followed by splenomegaly (38.9%) and lymphadenopathy (33.3%). At least 5 (27.8%0 patients had MAS as their initial manifestation. Anemia (88.9%), thrombocytopenia (88.9%), leukopenia (72%), and pancytopenia (55.6%) were prominent laboratory parameters. Mean serum ferritin of 1584 ng/ml and mean triglyceride of 270 mg/dl were reported. On comparing with non-MAS cohort; younger age, fever, lymphadenopathy, splenomegaly, mucocutaneous features, any type of cytopenia, high aspartate aminotransferase (AST), low albumin, and lactate dehydrogenase, all showed significant association with MAS (P < 0.05).Conclusion: Fever and associated cytopenias coupled with raised AST are strong predictors of MAS in patients with SLE.

Evaluation of the relationship between pentraxin 3 (PTX3) rs2305619 (281A/G) and rs1840680 (1449A/G) polymorphisms and the clinical course of COVID-19.

Macrophage activation syndrome (MAS) is one of the main causes of morbidity and mortality in patients with coronavirus disease 2019 (COVID‐19). This study aimed to investigate the relationship between the pentraxin 3 (PTX3) gene polymorphisms rs2305619 (281A/G) and rs1840680 (1449A/G) and the development of MAS in patients with COVID‐19. The study included a total of 94 patients aged 18–45 who were diagnosed as having COVID‐19 between June and December 2020. PTX3 281A/G and 1449A/G polymorphism frequencies were evaluated. PTX3 281A/G allele and genotype frequencies did not deviate from Hardy–Weinberg (HW) equilibrium in the MAS or non‐MAS group (χ 2: 0.049, df: 2, p = 0.976, χ 2: 0.430, df: 2, p = 0.806). PTX3 1449A/G allele and genotype frequencies deviated significantly from HW equilibrium in the non‐MAS group (χ 2: 6.794, df: 2, p = 0.033) but not in the MAS group (χ 2: 2.256, df: 2, p = 0.324). The AG genotype was significantly more frequent in the non‐MAS group, while the AA genotype was significantly more frequent in the MAS group (χ 2: 11.099, df: 2, p= 0.004). Analysis of the PTX3 1449A/G polymorphism showed that individuals with the GG genotype had higher serum PTX3 levels than those with the AA and AG genotypes (p = 0.001 for both). Analysis of the PTX3 1449A/G polymorphism in patients with COVID‐19 showed that those with the AG genotype were relatively more protected from MAS compared with individuals with the AA genotype. In addition, lower serum PTX3 levels are observed in patients carrying the A allele.

Efficacy of Tocilizumab Therapy in Different Subtypes of COVID-19 Cytokine Storm Syndrome

Background: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. Methods: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In the MAS and CRS groups, treatment results were assessed depending on whether or not tocilizumab was used. Results: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/mL, p < 0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p = 0.043), RR = 2.1 (95% CI 1.0–4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p = 0.013), RR = 0.50 (95% CI 0.25–0.99). Conclusions: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients, it contributed to reduced mortality.

Macrophage activation syndrome in patients with adult-onset Still's disease under tocilizumab treatment: A single-center observational study.

Macrophage activation syndrome (MAS) developed under tocilizumab treatment poses a diagnostic challenge. This study aims to demonstrate the frequency and the clinical features of MAS developed in patients with adult-onset Still's disease (AOSD) receiving tocilizumab. The consecutive AOSD patients treated with tocilizumab in our institution from April 2008 to March 2020 were studied. The frequency of clinically diagnosed MAS during tocilizumab treatment, their conformity to the several criteria relevant for MAS, and laboratory characteristics compared to AOSD flare were investigated. Of the 20 AOSD patients treated with tocilizumab, six developed clinically diagnosed MAS, four immediately after starting tocilizumab and two after long-term treatment. Some of them had already met the MAS criteria before starting tocilizumab. At MAS diagnosis, although some did not meet the MAS criteria due to lack of fever and/or the lower ferritin levels, all consistently showed sharp increases in ferritin along with marked abnormal changes in two or more different markers of organ damage, unlike the AOSD flares. MAS is not a rare complication in AOSD patients receiving tocilizumab. The clinical similarities between systemic AOSD and MAS, and substantial alterations in MAS features by inhibition of interleukin-6 signaling may limit the utility of the existing diagnostic/classification criteria in diagnosing MAS under tocilizumab treatment. The emergence of abnormalities in MAS-related organ damage markers with a rapid elevation of ferritin should be considered as MAS development in AOSD patients receiving tocilizumab even if the patients are afebrile or have relatively low ferritin levels.

Sudden Hypotension and Increased Serum Interferon-γ and Interleukin-10 Predict Early Macrophage Activation Syndrome in Patients with Systemic Juvenile Idiopathic Arthritis

To identify clinical and laboratory predictors for early macrophage activation syndrome (MAS) associated with systemic juvenile idiopathic arthritis (sJIA). This is a retrospective cohort study of 149 patients with sJIA, of whom 27 had 31 episodes of MAS. We evaluated the clinical and laboratory features of patients with sJIA and MAS and compared them with those without MAS. We focused our analysis on the overall process of MAS development, especially MAS onset. As shown in previous studies, we found a high percentage of fever, absence of arthritis, and central nervous system dysfunction at MAS onset in our study cohort. We also found that 35% of patients with MAS had hypotension although not shock, and 22.6% of patients with MAS had gastrointestinal involvement at MAS onset. Compared with patients with MAS without hypotension, patients with MAS and hypotension had greater rates of admission to the intensive care unit; presented with more arthritis, serositis, pneumonia, and gastrointestinal involvement; and had greater white blood cell and absolute neutrophil counts and serum bilirubin levels and lower serum total protein. We confirmed laboratory markers such as platelet counts, lactate dehydrogenase, and aspartate aminotransferase can help to identify early MAS and that ferritin/erythrocyte sedimentation rate ratio of approximately 20.0 had a high diagnostic sensitivity and specificity for MAS. In addition, we discovered that the combination of interferon-γ >17.1 pg/mL and interleukin-10>7.8 pg/mL appeared to be a good cytokine pattern for the recognition of MAS onset. Sudden hypotension, elevated ferritin/erythrocyte sedimentation rate ratio, and the cytokine pattern of significantly increased interferon-γ and interleukin-10 levels are important markers for early identification of MAS in addition to the traditional characteristics of sJIA-associated MAS.

Risk of macrophage activation syndrome in patients with adult-onset Still's disease with skin involvement: A retrospective cohort study

Smallcase series and case reports indicated that atypical persistent pruritic eruptions (PPEs), another type of skin lesions seen in adult-onset Still's disease (AOSD), imply a worse prognosis than typical evanescent rashes. To investigate clinical characteristics and macrophage activation syndrome (MAS) occurrence in AOSD with PPEs. A retrospective cohort study analyzed 150 patients with AOSD with rashes at the First Affiliated Hospital of Zhejiang University from January 2013 to December 2019. Patients with AOSD with PPEs had higher lactate dehydrogenase (492.00 U/L vs 382.00 U/L; P<.001) and ferritin (6944.10ng/ml vs 4286.60ng/ml; P=.033), and lower fibrinogen (5.05g/L vs 5.77g/L; P=.014) than those with evanescent rashes. Patients with AOSD with PPEs had a higher incidence (17.4% vs 3.1%, P=.006) and cumulative event rate for MAS (P=.008) and tended to receive high-dose glucocorticoid (36% vs 20.3%; P=.036). Multivariate analysis indicated that PPEs (hazard ratio [HR], 5.519; 95% confidence interval [CI], 1.138-26.767; P=.034), aspartate aminotransferase of greater than 120 U/L (HR, 8.084; 95% CI, 1.728-37.826; P=.008), and splenomegaly (HR, 21.152; 95% CI, 2.263-197.711; P=.007) were independent risk factors for MAS. Single-center, retrospective nature, small sample size. PPEs indicated increased severity and MAS occurrence versus evanescent rashes. PPEs, aspartate aminotransferase of greater than 120 U/L, and splenomegaly were risk factors for MAS in AOSD with skin involvement.

Clinical analysis of macrophage activation syndrome in adult rheumatic disease: A multicenter retrospective study.

To evaluate the clinical and laboratory characteristics, prognostic factors, and outcome of adult rheumatic disease-associated macrophage activation syndrome (MAS). A multicenter retrospective study was performed across 4 tertiary hospitals in China between January 1, 2017 to December 31, 2019. There were 61 rheumatic disease patients with MAS enrolled into this retrospective clinical study. Fever and hyperferritinemia are the most frequent clinical feature and laboratory abnormality in MAS patients. Serum ferritin>6000ng/mL (odds ratio [OR]=9.46, 95% CI=2.53-47.13, P=.005) and hemophagocytosis in bone marrow smear (OR=11.12, 95%, CI=3.29-50.65, P=.001) were the 2 most prominent predictive factors indicating MAS occurrence. The 90-day all-cause mortality rate of all rheumatic disease patients with MAS was 22.9% (hazards ratio [HR]=2.15, 95% CI=0.81-6.78, P=.05). Platelets<100×109 /L (HR=3.23, 95% CI=2.51-4.81, P=.01) and ferritin>6000ng/mL (HR=6.12, 95% CI=2.93-16.27, P=.005) were independent predictors of poor outcome in rheumatic disease-associated MAS. Macrophage activation syndrome could be a fatal complication in rheumatic disease. Patients presenting with unexplained fever, serum ferritin>6000ng/mL, hepatosplenomegaly and cytopenia at baseline should raise the suspicion of MAS. The presence of serum ferritin>6000ng/mL, hepatosplenomegaly and low number of platelets was associated with poor outcome.

Macrophage activation syndrome in children with Kawasaki disease: diagnostic and therapeutic approaches.

Macrophage activation syndrome (MAS) is a rare, life-threatening complication of Kawasaki disease (KD). Early recognition and treatment of MAS are very important, but sometimes it is difficult to distinguish MAS from a severe form of KD. A PubMed search was performed in Clinical Queries using the key terms "macrophage activation syndrome or secondary hemophagocytic lymphohistiocytosis (HLH)" and "Kawasaki disease". KD patients with MAS show high intravenous immunoglobulin (IVIG) resistance and coronary complications. Mortality is also as high as MAS in other diseases. Persistent fever greater than 10days is highly associated with development of MAS in KD. Splenomegaly is observed in more than two-thirds of KD patients with MAS. Thrombocytopenia is often the earliest laboratory finding of MAS. Hyperferritinemia is highly specific and sensitive for detecting MAS in KD; so, ferritin levels should be checked if there are unexplained clinical exacerbations in KD patients. Given the under-recognition of MAS in KD, it is prudent to consider resistant KD as occult/subclinical MAS. Many KD patients with MAS have good outcomes on immune modulators. However, if KD patients fulfill the HLH-2004 diagnostic criteria, they may undergo longer and more intensive treatment than needed. The possible existence of MAS should be taken into account when a KD patient shows persistent fever, splenomegaly, thrombocytopenia, hyperferritinemia, or IVIG resistance. The under-diagnosis of MAS in patients with KD is an important issue to be addressed. Therapeutically, however, there is a possibility of over-treatment of MAS in patients with KD.