Systemic Juvenile Idiopathic Arthritis and Secondary Macrophage Activation Syndrome in Latvia from 2009 to 2020: A Nationwide Retrospective Study.

Background and Objectives: Systemic juvenile idiopathic arthritis (sJIA) is a distinctive JIA subtype with mostly nonspecific systemic clinical features, which can be a diagnostic challenge. This study aimed to analyze our experience with sJIA in Latvia for twelve years: assessing clinical and epidemiological characteristics, the efficacy of therapy, and disease outcomes, including the development of macrophage activation syndrome (MAS). Materials and methods: This is a descriptive study in which we conducted a retrospective case review of all patients with sJIA diagnosis admitted to the only pediatric tertiary centre in Latvia during the period 2009-2020. Results: sJIA was diagnosed in 35 patients with a mean annual incidence rate of 0.85 patients per 100,000 children. Major clinical signs at the first visit were: fever, rash, arthritis, and lymphadenopathy. Almost half of the patients, 48.5%, had a monocyclic disease course, and only 20% of patients had persistent disease. MAS developed in 28.6% of patients. Biological therapy was administered to 48.6% of patients, mostly by tocilizumab, which induced remission in 75% after one year, and in 81.2% after two years without any serious therapy-related complications. In our study, none of the patients had interstitial lung disease, drug reaction with eosinophilia and systemic symptoms (DRESS)-like syndrome, or fatal disease. Conclusions: The incidence and clinical characteristics of sJIA correlate with the literature findings, although MAS was more common than described in other studies. There is a tendency for the persistent disease to decrease with the use of biological therapy. Tocilizumab is an efficient choice of treatment with a good safety profile.

Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease.

OBJECTIVE: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD). METHODS: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. RESULTS: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. CONCLUSION: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

Frequency of Interleukin-6 rs1800795 (-174G/C) and rs1800797 (-597G/A) Polymorphisms in COVID-19 Patients in Turkey Who Develop Macrophage Activation Syndrome.

Severe acute respiratory syndrome coronavirus 2 has infected over 100 million people since it appeared in Wuhan, China, just one year ago. This study aimed to evaluate the relationship between interleukin-6 (IL-6) gene polymorphisms -174G/C and -597G/A and coronavirus disease 2019 (COVID-19) course. The study included 70 patients aged 18-45 years who were diagnosed with COVID-19 in Turkey between March and November 2020 and hospitalized in our hospital. Of these, 40 patients required intensive care admission due to macrophage activation syndrome (MAS), and 30 patients did not develop MAS or acute respiratory distress syndrome. The frequencies of the IL-6-174G/C and -597G/A polymorphisms were determined. There were significant differences between the groups in terms of the -174G/C allele and genotype frequency according to the Hardy-Weinberg equilibrium (χ2 = 10.029, df = 1, P = 0.002 and χ2 = 9.998, df = 1, P = 0.002, respectively). The frequency of the GG genotype was significantly higher in the MAS group than in the non-MAS group (P = 0.002). The G allele was also significantly more frequent in the MAS group than in the non-MAS group (P = 0.032). Analysis of the -174G/C polymorphism in patients with MAS showed that the G allele may be a risk factor for increased serum IL-6 levels and progression to MAS.

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

BACKGROUND: Small case 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. OBJECTIVE: To investigate clinical characteristics and macrophage activation syndrome (MAS) occurrence in AOSD with PPEs. METHODS: 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. RESULTS: Patients with AOSD with PPEs had higher lactate dehydrogenase (492.00 U/L vs 382.00 U/L; P < .001) and ferritin (6944.10 ng/ml vs 4286.60 ng/ml; P = .033), and lower fibrinogen (5.05 g/L vs 5.77 g/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. LIMITATIONS: Single-center, retrospective nature, small sample size. CONCLUSION: 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.

Macrophage activation syndrome in pediatrics: 10 years data from an Indian center.

AIMS: Macrophage activation syndrome (MAS) is a dreaded complication of systemic inflammatory diseases and is most commonly seen in systemic juvenile idiopathic arthritis (sJIA). We evaluate the clinical features, laboratory findings and outcomes in pediatric MAS, assess the response to different pharmacological therapies, and finally identify possible factors associated with an unfavorable outcome. METHODS: This is a retrospective analysis of data from patients diagnosed as having MAS, admitted between July 2008 and April 2018 into the Department of Pediatric Rheumatology, Institute Of Child Health Kolkata. The data noted were the clinical and laboratory features, treatment details, responses to therapy and outcomes. RESULTS: Thirty-one patients were diagnosed as having MAS. Primary illness was sJIA in 26 (84%), systemic lupus erythematosus in 4 (13%) and Kawasaki disease (KD) in 1 (3%). All had fever with varying degrees of multisystemic involvement. Hyperferritinemia was universally present. Pulse methylprednisolone with cyclosporine was used for treating the majority. Ten patients (32%) expired. CONCLUSION: Macrophage activation syndrome is a near fatal complication with protean manifestations and multiorgan dysfunction. Hyperferritinemia is characteristic, higher values being associated with increased mortality. Cases resistant to steroids and cyclosporine had a poor prognosis. Late presentations with multiorgan dysfunction were associated with the poorest outcomes.

Clinical characteristics and comorbidities in adult-onset Still's disease using a large US administrative claims database.

OBJECTIVES: We aimed to describe clinical characteristics, treatment patterns and major comorbidities of a US-based adult-onset Still's disease (AOSD) cohort. METHODS: Administrative claims data from Truven MarketScan were collected from 2009 to 2015. An AOSD case was defined as ≥1 M06.1 International Classification of Diseases 10th revision (ICD-10) medical claim code. We extracted data for the AOSD cohort (n = 106) and 1:5 matched controls (n = 530) without AOSD. Outcomes of interest and a novel claims-based set of Yamaguchi criteria were identified by relevant ICD 9th revision (ICD-9) and ICD-10 codes. Bivariate descriptive analyses were conducted on all variables. Comorbidity rates and rate ratios were calculated in AOSD cases and matched controls. Statistical significance of cohort differences was determined to compare AOSD cases and matched controls. RESULTS: The AOSD cohort, with a mean age of 43.08 (standard deviation, s.d. 13.9) years and with female predominance (68.9%) was observed over a mean of 750.12 (637.6) days. A total of 35.9% of AOSD patients fulfilled claims-based Yamaguchi criteria compared with 0.4% matched controls (P< 0.05). We identified severe AOSD-related complications, including macrophage activation syndrome (4.7%) and acute respiratory distress syndrome (12.3%). Treatment commonly involved systemic glucocorticoids (62.2%), MTX (51%) and anakinra (24.5%). Compared with matched controls, serious infections were significantly increased (rate ratio 2.58, 95% CI: 1.53, 4.37, P = 0.0004), while hyperlipidaemia (0.54, 95% CI: 0.35, 0.85; P = 0.008) and obesity (0.30, 95% CI: 0.15, 0.62; P = 0.001) were significantly decreased in AOSD patients. CONCLUSION: We characterized a first US-based AOSD cohort using a large national administrative claims database, and identified key complications, treatments and comorbidities.

The frequency of macrophage activation syndrome and disease course in systemic juvenile idiopathic arthritis.

Objectives: The aim of this study was to demonstrate the frequency of macrophage activation syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) cases, to compare the laboratory tests at the time of diagnosis of sJIA and MAS and to see whether sJIA cases complicated with MAS follow a more severe disease course in the long-term follow-up.Methods: Files of children with sJIA that were followed between May 2010 and September 2017 were reviewed.Results: The cohort consisted of 53 sJIA cases. Mean duration of follow-up was 39.0 ± 24.1 months. The frequency of MAS was 33.9%. Initial laboratory tests at the time of diagnosis of sJIA were compared in between patients with MAS and without MAS. Only ferritin and fibrinogen levels showed significant differences in between the groups (p < .01). Patients who developed MAS had higher ferritin (4482 mg/dL) and lower fibrinogen (371 mg/dL) values than patients without MAS (ferritin 2060 mg/dL, fibrinogen 466 mg/dL) at the time of diagnosis of sJIA. Long-term follow-up results showed that monocyclic course was observed in 45.2%, polycyclic course in 30.1% and persistent course in 24.5% of the cases. It was seen that patients with MAS segregated equally into three groups.Conclusions: Higher ferritin and relatively lower fibrinogen levels at the time of diagnosis of sJIA may be early warning signs of an impending MAS. sJIA patients who develop MAS do not seem to warrant more guarded prognosis in the long-term follow-up.

Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: Characterization and Risk Factors.

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD). METHODS: Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. RESULTS: Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-γ-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD. CONCLUSION: Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.

Evaluation of macrophage activation syndrome in hospitalised patients with Kikuchi-Fujimoto disease based on the 2016 EULAR/ACR/PRINTO classification criteria.

BACKGROUND: To evaluate the impact of macrophage activation syndrome (MAS) on clinical features in patients with Kikuchi-Fujimoto disease (KFD) and to compare the features of MAS in KFD with those of adult-onset Still's disease (AOSD) and systemic lupus erythematosus (SLE). METHODS: The medical records of febrile patients hospitalised with KFD between November 2005 and April 2017 were reviewed. Patients fulfilling the 2016 classification criteria for MAS were classified as having MAS. Clinical and laboratory features of patients with KFD with and without MAS were evaluated. Poor hospitalisation outcomes were defined as intensive care unit admission or in-hospital mortality. The treatment outcomes of MAS in KFD, AOSD, and SLE were also compared. RESULTS: Among 78 patients hospitalised with KFD, 24 (30.8%) patients had MAS during admission. Patients with KFD and MAS more frequently required glucocorticoid treatment (66.7% vs 40.7%, p = 0.036) and had longer hospital stays than patients with KFD without MAS (12.5 vs 8.5 days, p<0.001). In addition, patients with MAS had worse hospitalisation outcomes than patients without MAS (29.2% vs. 0.0%, p<0.001). Among patients with MAS in KFD, AOSD, and SLE, the number of patients requiring glucocorticoid treatment after 3 months was significantly lower among patients with MAS and KFD (KFD 33.3%, AOSD 88.9%, SLE 100%, p<0.001). CONCLUSIONS: The presence of MAS in KFD was associated with adverse clinical outcomes including higher steroid usage and worse hospitalisation outcomes. However, compared to those with AOSD and SLE, patients with MAS and KFD were less likely to require long-term glucocorticoid treatment.

Macrophage Activation Syndrome in Patients Affected by Adult-onset Still Disease: Analysis of Survival Rates and Predictive Factors in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale Cohort.

OBJECTIVE: Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, which can complicate adult-onset Still disease (AOSD). We investigated AOSD clinical features at the time of diagnosis, to assess predictors of MAS occurrence. Further, we analyzed the outcomes of patients with AOSD who experience MAS. METHODS: Patients with AOSD admitted to any Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale center were retrospectively analyzed for features typical of AOSD, MAS occurrence, and their survival rate. RESULTS: Of 119 patients with AOSD, 17 experienced MAS (12 at admission and 5 during followup). Twelve patients with MAS at first admission differed from the remaining 107 in prevalence of lymphadenopathy and liver involvement at the time of diagnosis. In addition, serum ferritin levels and systemic score values were significantly higher in the patients presenting with MAS. At the time of diagnosis, the 5 patients who developed MAS differed from the remaining 102 in the prevalence of abdominal pain, and they showed increased systemic score values. In the multivariate analysis, lymphadenopathy (OR 7.22, 95% CI 1.49-34.97, p = 0.014) and abdominal pain (OR 4.36, 95% CI 1.24-15.39, p = 0.022) were predictive of MAS occurrence. Finally, MAS occurrence significantly reduced the survival rate of patients with AOSD (p < 0.0001). CONCLUSION: MAS occurrence significantly reduced the survival rate in patients with AOSD. Patients with MAS at baseline presented an increased prevalence of lymphadenopathy and liver involvement, as well as high serum ferritin levels and systemic score values. The presence of lymphadenopathy and abdominal pain was associated with MAS occurrence.

Significance of Hyperferritinemia in Hospitalized Adults.

BACKGROUND: Although high ferritin levels are associated with iron overload, it is known that ferritin is also an acute-phase reactant that may be elevated in conditions associated with acute and chronic inflammation. In addition, an elevated ferritin level is a criterion for the diagnosis of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Therefore, the significance of elevated serum ferritin is often unclear. As HLH/MAS is a medical emergency, prompt diagnosis is important to guide appropriate treatment. MATERIALS AND METHODS: To study the spectrum of diagnoses associated with elevated serum ferritin, we did a retrospective review of adult patients admitted to our academic medical center from 2008-2012 with serum ferritin levels greater than 2,000ng/mL. The degree of hyperferritinemia was compared to different diagnoses and selected laboratory values. RESULTS: A total of 333 patients were identified with a serum ferritin level >2,000ng/mL. Hepatocellular injury was the most prevalent diagnosis with n = 126; infection was next with n = 96. Eleven patients were diagnosed with HLH/MAS. CONCLUSIONS: Elevated ferritin, as an isolated finding, was not a specific marker for the diagnosis of HLH/MAS. However, as a group, HLH/MAS patients had the highest mean and median ferritin values.

Subtype frequencies, demographic features, and remission rates in juvenile idiopathic arthritis - 265 cases from a Turkish center.

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children. It is a group of heterogeneous disorders that have chronic arthritis as a common feature. It has a worldwide distribution and many studies have shown that subtype frequencies in JIA seem to be showing geographical distribution. The aim of this study was to define subtype frequencies, demographic features, and the rates of macrophage activation syndrome, uveitis and remission in Turkish JIA patients. The files of all JIA patients (378 cases) that were being followed in Pediatric Rheumatology Clinic of our institution, between May 2010 and February 2016 were reviewed. Two hundred and sixty-five patients were included into the study. Gender, JIA subtype, age at diagnosis, age at the initial symptoms, JIA medications, uveitis presence, JIA status at the time of enrollment were recorded from the files. There were 87 enthesitis related arthritis, 87 oligoarthritis (81 persistent, 6 extended), 36 rheumatoid factor (RF) negative polyarthritis, 35 systemic arthritis, 10 RF-positive polyarthritis, 5 psoriatic arthritis and 5 undifferentiated arthritis cases. Mean age at diagnosis was 9.9 ± 4.9 years and male/female ratio was 1.05. Uveitis was found in 4.5% of the cases. Biologics were used in 26% of the patients. At the time of enrollment, 69% of the patients were under remission while 31% of them were active. Systemic arthritis and persistent oligoarthritis cases were the groups that most commonly achieved remission, while patients with polyarticular involvement, namely RF positive polyarthritis, RF negative polyarthritis and extended oligoarthritis patients were the groups with high number of active patients. In conclusion, JIA is a heterogeneous group of disorder, and differences in subtype frequencies from country to country make it even more heterogeneous disease. Patients with polyarticular involvement may need early and aggressive treatment to control the disease activity.

Linfohistiocitosis hemofagocítica: análisis de 18 casos / Hemophagocytic lymphohistiocytosis: Analysis of 18 cases

Antecedentes y objetivo: La hemophagocytic lymphohistiocytosis (HLH, «linfohistiocitosis hemofagocítica») es una entidad grave, producida por una incorrecta regulación de la respuesta inmunológica frente a diversos estímulos del sistema inmunitario. Su diagnóstico y tratamiento precoz suponen un reto para el clínico. Pacientes y método: Hemos realizado un estudio descriptivo retrospectivo de los pacientes adultos diagnosticados de HLH, según los criterios de la Histiocyte Society, entre los años 2010 y 2015 en nuestra institución, analizando sus características clínicas, el estudio diagnóstico-etiológico y su evolución. Resultados: Se analizaron 18 pacientes. La mediana de tiempo al diagnóstico fue de 24 días. La etiología fue neoplásica en 8 casos (hematológica en 7), infecciosa en 6 (leishmaniasis visceral en 4), inflamatoria en uno, y en los 3 restantes, idiopática. Se realizó tratamiento en 16 pacientes con corticoides, asociando ciclosporina en 2, inmunoglobulinas en uno, y etopósido con tacrolimus en otro. Conclusiones: Destacamos la escasa utilización de etopósido en el tratamiento dirigido, el actualmente recomendado. La mortalidad global fue del 44%, asociada a la etiología neoplásica principalmente (67 frente a 16,6% de mortalidad en la etiología infecciosa, p < 0,05) (AU)

Background and objective: Hemophagocytic lymphohistiocytosis (HLH) is a serious condition, caused by an improper regulation of the immune response to different stimuli of the immune system. Early diagnosis and treatment are a challenge for the clinician. Patients and method: We conducted a retrospective study at our institution between 2010 and 2015, of adult patients diagnosed with HLH, in accordance with the criteria of the Histiocyte Society, analyzing their clinical characteristics, diagnostic and etiological studies and the outcome. Results: Eighteen patients were analyzed. Median time to diagnosis was 24 days. We found neoplastic etiology in 8 cases (7 hematologic), while it was infection-related in 6 (4 visceral leishmaniasis), and an inflammatory disease in one. In the remaining 3, an underlying cause for the HLH was not found. Course of treatment was corticosteroids in 16 patients, associated with cyclosporine in 2 of them, one received immunoglobulins, while another received etoposide with tacrolimus. Conclusions: We emphasize the scarce use of etoposide therapy, the currently recommended treatment. Overall mortality was 44%, mainly associated with neoplastic etiology (67 compared to 16.6% mortality in infection-related etiology, P < 0,05) (AU)

Epidemiological study of adult-onset Still's disease using a Japanese administrative database.

Adult-onset Still's disease (AOSD) is a rare disease, and large epidemiological studies of this disease are limited. Furthermore, it has been difficult to show the incidence and characteristics of severe AOSD complications due to the rarity of this disease. The aim of our study was to describe the demographics of AOSD and the incidence and characteristics of severe complications. Using a large Japanese administrative database, we identified hospitalized patients with AOSD and described the demographics. We also calculated the incidence of severe complications (i.e., macrophage activation syndrome [MAS] and disseminated intravascular coagulation [DIC]) and in-hospital mortality in AOSD patients, and then analyzed the age-controlled difference between men and women. We identified 513 patients with AOSD (mean age: 53.1 years; women 64.1 %). According to the age distribution, there was no distinct peak age. The thirties and the sixties were relatively large age groups. There were 76 patients of AOSD with MAS or DIC observed in this study. The incidence of severe complications was 14.8 %, 95 % CI [11.9, 18.2]. Women were more likely to have severe complications than men after controlling for age (odds ratio: 2.07; [1.14, 3.73]; p = 0.014). AOSD does not predominantly affect young adults in our study population. Elderly AOSD patients can be observed more than before due to global population aging. Severe complications are more likely to occur in women than in men.

Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial.

OBJECTIVE: To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated intravascular coagulation, hepatobiliary dysfunction, cytopenias, and hyperferritinemia. Hence, sepsis patients with macrophage activation syndrome features may benefit from interleukin-1 receptor blockade. DESIGN: Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis. SETTING: Multicenter study recruiting through 91 centers from 11 countries in Europe and North America. PATIENTS: Sepsis patients with multiorgan dysfunction syndrome and/or shock (original study) were regrouped based on the presence or the absence of concurrent hepatobiliary dysfunction and disseminated intravascular coagulation as features of macrophage activation syndrome. The non-hepatobiliary dysfunction/disseminated intravascular coagulation group included patients with only hepatobiliary dysfunction, only disseminated intravascular coagulation, or neither. INTERVENTION: Treatment with anakinra or placebo. MEASUREMENTS AND MAIN RESULTS: Main outcome was 28-day mortality. Descriptive and comparative statistics were performed. Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent hepatobiliary dysfunction/disseminated intravascular coagulation was noted in 43 patients (5.6% of total; 18-75 years old; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non-hepatobiliary dysfunction/disseminated intravascular coagulation patients (71.4% vs 70.8%; p = 0.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in hepatobiliary dysfunction/disseminated intravascular coagulation patients (65.4% anakinra vs 35.3% placebo), with hazard ratio for death 0.28 (0.11-0.71; p = 0.0071) for the treatment group in Cox regression. CONCLUSIONS: In this subgroup analysis, interleukin-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation. A prospective randomized trial using features of macrophage activation syndrome for mortality risk stratification should be undertaken to confirm the role of interleukin-1 blockage.

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab.

OBJECTIVE: In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence. METHODS: An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC-specified adverse event terms to identify potential MAS events. These were then adjudicated as "probable MAS," "possible MAS," or "MAS unlikely," using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient-years. RESULTS: Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab-treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab-treated patients (2.8 per 100 patient-years) and placebo-treated patients (7.7 per 100 patient-years), the difference was not significant (-4.9 [95% confidence interval -15.6, 5.9]). There were 3 deaths due to MAS-related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab. CONCLUSION: Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.

Macrophage Activation Syndrome.

Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic disorders that occurs most commonly in systemic juvenile idiopathic arthritis. In recent years, there have been several advances in the understanding of the pathophysiology of MAS. Furthermore, new classification criteria have been developed. Although the place of cytokine blockers in the management of MAS is still unclear, interleukin-1 inhibitors represent a promising adjunctive therapy, particularly in refractory cases.

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

OBJECTIVE: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. METHODS: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. RESULTS: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. CONCLUSION: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.