Macrophage Activation Syndrome Research Articles

Drugs for paediatric hyperinflammatory syndromes

BackgroundMany syndromes are associated with exaggerated inflammation. Children with hyperinflammatory syndromes often present with vague and non-specific symptoms that pose diagnostic and management challenges. The recent literature seems biased towards referring these syndromes only to the multisystem inflammatory syndrome in children (MIS-C) that is associated with COVID-19. The purpose of this paper is to provide an updated narrative review on the pathophysiology, manifestations and management approaches for common hyperinflammatory syndromes.MethodsAn extensive PubMed search of all publications in the English literature was performed with Clinical Queries for various hyperinflammatory syndromes and conditions using the undermentioned Medical Subject Headings: “hyperinflammation”, “hyperinflammatory syndromes”, “sepsis syndrome”, “severe inflammatory response syndrome” and “acute respiratory distress syndrome”. Categories were limited to reviews and clinical trials for the age range from birth to 18 years.ResultsThe criteria, presentation and management of these hyperinflammatory syndromes are described. Hyperinflammatory syndromes refer to a basket of inflammatory syndromes often associated with multisystem involvement and aberrant cytokine release and should be differentiated from autoinflammatory, autoimmune and hyperimmune syndromes. The major subtypes of hyperinflammatory syndromes, including macrophage activation syndrome, haemophagocytic lymphohistiocytosis, cytokine release syndrome and cytokine storm syndrome, are described. MIS-C associated with SARS-CoV-2 represents the latest addition. It must be understood that the syndrome is not exclusive to COVID-19 but could be caused by various viral infections. Early recognition, prompt and proactive treatment can reduce potential complications and improve outcomes and survival rates in paediatric patients. Anti-inflammatory medications for the management of these syndromes are described.ConclusionThe incidence of these hyperinflammatory conditions is generally low in comparison to other disease conditions. Except for paediatric inflammatory multisystem syndrome/MIS-C, the mortality is high and the hospital stay is prolonged in affected patients. Acute and critical care physicians must be aware of these conditions and their initial management. Corticosteroids are often used in the initial phrase but various disease-specific drugs and biologics are needed in subsequent management and expert management of these often-difficult conditions is crucial.

OP0194 COMBINATION ANAKINRA AND TOCILIZUMAB TO TREAT REFRACTORY MACROPHAGE ACTIVATION SYNDROME TRIGGERED BY ADULT-ONSET STILL’S DISEASE.

BackgroundAdult-onset Still’s disease (AOSD) is associated with the development of macrophage activation syndrome (MAS) [1], sometimes termed secondary haemophagocytic lymphohistiocytosis (sHLH), a severe hyperinflammatory state with high mortality. Successful management of AOSD and MAS is contingent on early identification and treatment of the syndromes and any triggers, with aggressive immunosuppression in acutely unwell patients [2].ObjectivesTo describe the case of a patient with newly diagnosed AOSD who developed severe MAS requiring ICU admission and immunosuppression with high-dose glucocorticoids, tocilizumab and anakinra.MethodsCase reportResultsA 24-year-old woman attended hospital with a 4 month history of fever, arthralgia, rash and later dry cough. She became hypoxic and was admitted to the ICU for ventilation and vasopressor support. Imaging revealed splenomegaly, pleural effusions and lung consolidation but there was no response to antibiotics and no clear evidence of infection. Cytomegalovirus (CMV) DNA was initially absent, with IgG avidity indicating prior exposure. Bloods confirmed significant inflammation (CRP 107 mg/L, ferritin 6154 μg/L, ESR 47mm/hr) without disordered haematopoiesis. A bone marrow aspirate showed no haemophagocytosis. After extensive investigation a diagnosis of AOSD was made given the fulfilment of the Yamaguchi criteria and absence of evidence of an alternative driver of inflammation.The patient deteriorated further, with deranged liver chemistry, rising CRP, triglycerides and ferritin (>100,000 μg /L), and trilineage cytopenia raising concern for MAS. This was managed by treating the presumed trigger (AOSD) with intravenous methylprednisolone (IVMP, 3x 500mg then 32mg daily) and anakinra (100mg twice daily). She developed a CMV viraemia that progressed despite aciclovir and later valganciclovir, which was switched to foscarnet and CMV immunoglobulin. The viraemia then stabilised and improved.Due to persistent pyrexia, tachycardia, and elevated inflammatory markers, further IVMP (3x250mg), increased anakinra doses (100mg IV TDS) and intravenous immunoglobulin (2x60g) were given. A repeat bone marrow biopsy was consistent with MAS and testing for HLH-associated genes was negative.The patient became increasingly hypoalbuminaemic and oedematous, developing acute kidney injury requiring continuous haemodiafiltration in the ICU. Anakinra was increased to 500mg daily in divided doses. The blood counts improved transiently, before the ferritin rose sharply again, with fevers and broad-spectrum antimicrobials continuing. Cytokine profile testing at this point revealed significant elevation in IL-1b and IL-6. Tocilizumab 8mg/kg fortnightly was added to existing therapy.After tocilizumab initiation the inflammatory markers, blood counts and clinical state improved, though the patient remained hypertensive despite numerous antihypertensives. She left the ICU ten weeks after initial presentation. Corticosteroids and anakinra were weaned and she was discharged on tocilizumab monotherapy. Renal function did not return, and she continues outpatient haemodialysis.ConclusionThe evidence base for effective therapies in MAS is poor. Reports exist of the use of either anakinra or tocilizumab [3] but not both agents in combination. In this case, cytokine blockade with both agents produced significant clinical improvement in a critically unwell patient.

POS1216 POTENTIAL PREDICTORS OF OUTCOME FOR ANAKINRA TREATMENT IN COVID-19 PATIENTS WITH MACROPHAGE ACTIVATION SYNDROME

BackgroundA hyperinflammatory response compatible with features of macrophage activation syndrome (MAS) contributes to this worse outcome in patients with Coronavirus Disease 2019 (COVID-19). Glucocorticoids have become the standard of care for those requiring oxygen support or mechanical ventilation. More targeted anti-inflammatory treatments with tocilizumab and anakinra have also been shown to be effective.ObjectivesMore studies are being awaited to clarify the features of patients who would benefit more, and we investigated the characteristics of the surviving and dead patients who received anakinra.MethodsThe records of hospitalized adult patients between March 2020 and May 2021 in a tertiary referral center were evaluated. Diagnosis of COVID-19-related MAS was based on the expert opinion and preliminary criteria developed by our group that patients with a score of ≥45 were accepted COVID-19-related MAS.1 Patients who received anakinra constituted the study group. Anakinra dose was determined according to the clinical and inflammatory parameters; and doses varied between daily 100-300 mg SC to 400-800 mg IV.Laboratory data of surviving and died patients were comparatively analyzed by using the ANCOVA method on the relevant days (baseline, anakinra-onset day, first response to anakinra treatment, and discharge or death). The temporal variation (drug onset day-first response day, drug onset day-discharge, or death day) was evaluated using the ANOVA method. A 50% reduction of CRP compared to the anakinra start day was accepted as the first response to the treatment.ResultsOut of 1080 hospitalized patients, 218 (151 male, 67 female, mean age 60.0±14.1) who received anakinra were identified. Among them, 125 (57.3%) patients were followed in the ward, 21 (9.6%) did not need oxygen treatment during the hospitalization; 69 (31.6%) patients were followed at ICU, 40 of them were intubated, 30 (13.7%) died in ICU. Anakinra had been started in a mean of 4.8 days of hospitalization. Twenty had tocilizumab initially and then received anakinra because of ongoing inflammatory parameters. The majority (83.5%) received steroid treatment (79.5% methylprednisolone, 5% of dexamethasone), and 6 received one IV pulse 250 mg of methylprednisolone; 36 (16.5%) were followed before September 2020 and received anakinra without steroids because of the standard of care at that period. Only CRP was different between the alive and dead patients for the baseline parameters (p=0.05). On the first day of drug treatment, CRP and procalcitonin values were significantly higher in dead patients (Table 1). A 50% decrease in CRP level was achieved in 3.1 days in survivors and 4.7 days in dead patients. D-dimer (p=0.018), CRP (p=0.006), LDH (p=0.003), procalcitonin (p=0.005), creatinine kinase (p=0.001), and fibrinogen levels (p=0.05) were significantly different between the surviving and dead patients when the measurements between the first drug administration day and response day were compared. Neutrophil, lymphocyte count, ferritin, D-dimer, CRP, LDH, AST, procalcitonin, creatinine kinase, and fibrinogen levels were significantly different between the patients when the parameters between the first drug administration day and discharge/death day were compared. Dead patients had higher CRP values and they did not show a continuing CRP decrease with the steroids and anakinra (Figure 1).ConclusionRetrospective analysis of 218 patients suggests that starting anakinra earlier in hospitalized patients may provide better results, and a decrease in CRP, ferritin, D-dimer values, as well as an increase in lymphocyte count, are associated with favorable outcomes. Increasing values of D-dimer and troponin during treatment are associated with worse outcomes, possibly indicating cardiovascular and thrombotic pathologies not responding to anakinra. Changes in the CRP values are found to help monitor the response to anakinra. Other inflammatory pathways could be targeted in those who are not responding to appropriate doses of anakinra within 5 days.Disclosure of InterestsNone declared

Short-term, low-dose etoposide in refractory adult-onset Still’s disease-associated macrophage activation syndrome

In this study, we modified the classical regimen of the hemophagocytic lymphohistiocytosis-04 protocol and evaluated the efficacy and safety of short-term, low-dose etoposide in patients with refractory macrophage activation syndrome (MAS) associated with adult-onset Still's disease (AOSD). A total of 17 patients with refractory AOSD-associated MAS were enrolled and received short-term, low-dose etoposide (100mg twice a week for four times). Another 11 patients, who were not treated with etoposide, were included as historical controls. Patient information, such as clinical manifestations, laboratory results, treatments, and short-term prognosis, were recorded and analyzed. In this case series, 88.24% of the patients with MAS who were treated with short-term, low-dose etoposide had a favorable response in 3weeks, which was significantly higher (p = 0.017) than that in the patients with MAS who were treated without etoposide (45.45%). The 90-day survival rate after the onset of MAS was significantly higher (p = 0.0029) among the patients in the short-term etoposide group (16/17, 94.12%) than in the control group (5/11, 45.45%). The regimen of short-term (2weeks), low-dose etoposide was highly effective in the treatment for patients with refractory AOSD-associated MAS with an acceptable safety profile. Key Points • There is no high level evidence to guide the management of refractory MAS-associated AOSD patients. • This study was the first to propose and confirm the efficacy and safety of short-term, low-dose etoposide in the treatment of refractory MAS-associated AOSD patients.

Serosal involvement in adult-onset Still's disease: A multicentre and retrospective study.

This study evaluated the characteristics of serosal involvement in adult-onset Still's disease (AOSD). Patients meeting the Yamaguchi classification criteria were classified into AOSD with and without serosal involvement according to their manifestations and sonography/radiography. Clinical data was retrospectively reviewed from 102 patients with AOSD in two centres. Forty-two patients (41.2%) had serosal involvement. The frequencies of pulmonary infiltrate and impaired liver function were significantly higher in patients with serosal involvement (p = .002 and p = .007, respectively), who also had a higher modified systemic score (p = .009). In addition, the percentages of CD3+ T cells (p < .001) and, especially, the CD8+ T cells (p = .004) were significantly increased in the peripheral blood of AOSD patients with serosal involvement. Notably, patients with serosal involvement were more likely to develop macrophage activation syndrome (p = .047) and a chronic pattern (p = .016) during the follow-up. Patients with serosal involvement demonstrated the more severe disease activity and different immune phenotypes; these patients were more likely to develop macrophage activation syndrome, and they may require more aggressive treatment at an early time to control their systemic inflammation.

Clinical presentation, outcome, and prognostic markers in patients with intravascular large B-cell lymphoma, a lymphoma study association (LYSA) retrospective study.

BackgroundIntravascular large B‐cell lymphoma (lVLBCL) is a very rare type of large B‐cell lymphoma.MethodsWe conducted a retrospective study on IVLBCL patients treated from 2000 to 2016 in LYSA cooperative group centers.ResultsSixty‐five patients were identified in 23 centers. Median age at diagnosis was 69 years (range 23–92). Thirty‐four patients (64%) had an IPI score >3 and 40 patients (67%) had a performance status ≥2. The most frequent extra‐nodal locations were bone marrow (n = 34; 52%), central nervous system (n = 25; 39%), and skin (n = 21; 33%). Nodal involvement and endocrine system were observed in 34% (n = 22) and 18% (n = 12) of all cases, respectively. Twenty‐six patients (41%) had macrophage activation syndrome. Tumor cells were frequently CD5 positive (52%) with a non‐germinal center origin (86%). BCL2 was expressed in 87% of all samples analyzed (n = 20) and 43% of patients had a MYC/BCL2 double expression. Fifty‐six patients were treated with a regimen of chemotherapy containing rituximab, among whom 73% reached complete remission. The median progression‐free survival (PFS) and median overall survival (OS) were 29.4 months and 63.8 months, respectively. History of autoimmune disorder (Hazard ratio [HR] 3.3 [1.4–7.8]; p < 0.01), nodal involvement (HR 2.6 [1.4–5.1]; p < 0.01), lack of anthracycline (HR 0.1 [0–0.4] for use; p < 0.001), or no intensification at first‐line regimen (p = 0.02) were associated with worse PFS. High‐dose methotrexate use was not associated with better PFS or OS.ConclusionsOur study highlights the aggressive clinical picture of IVLBCL, in particular the frequency of macrophage activation syndrome, and the need for new therapies despite a response to R‐CHOP‐like regimen similar to non‐intravascular diffuse large B‐cell lymphomas.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials

BackgroundThrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions.MethodsWe applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin.ResultsFour computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83–136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26–137.75], p < 0.0001).ConclusionsFour computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership (www.pedsepsis.pitt.edu) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Macrophage activation syndrome in rheumatic disease: Clinical characteristics and prognosis of 20 adult patients.

ObjectivesMacrophage activation syndrome (MAS) is a hyperinflammatory condition that is known to be secondary hemophagocytic lymphohistiocytosis (HLH) in patients with rheumatic disease. The aim of study was to evaluate the clinical manifestations and outcomes in patients with MAS with rheumatic disease.Materials and methodsWe performed a retrospective study of 20 adult patients who were diagnosed with MAS from 2012 to 2020. MAS was classified according to the HLH-2004 criteria. Patients’ information, including clinical features, laboratory findings, and treatment regimens, was collected, and the overall survival rate was estimated by the Kaplan–Meier method.ResultsTwenty patients (18 women, 35.6 ± 18.3 years) who met the HLH-2004 criteria also fulfilled the 2016 EULAR/ACR/PRINTO classification criteria for MAS, and HScore was higher than 169 (mean, 241.1). Fourteen patients with systemic lupus erythematosus and 6 patients with adult-onset Still’s disease were included. All patients were treated initially with corticosteroids, and 16 patients required additional immunosuppressants. The overall survival at 3 and 6 months was 75.2% and 64.3%. In survivors, renal impairment was less common (7.7% versus 71.4%, p = 0.007), the levels of AST (364.0 versus 81.0 IU/L, p = 0.019) and LDH (1346.0 versus 343.0IU/L, p = 0.014), and platelet count (90.0 versus 43.0 × 109/L, p = 0.02) were higher in compared to non-survivors. Nine patients had opportunistic infections, five of whom died during admission.ConclusionThe mortality of patients with MAS associated with rheumatic disease remains high. Renal impairment, levels of AST and LDH, and platelet count might be associated with prognosis.

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.

Expansion of CD4dimCD8+ T cells characterizes macrophage activation syndrome and other secondary HLH

AbstractCD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (HLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Peripheral blood mononuclear cells from children with inactive systemic juvenile idiopathic arthritis (sJIA, n = 17), active sJIA (n = 27), MAS in sJIA (n = 14), infection-associated HLH (n = 7), and with other forms of sHLH (n = 9) were analyzed by flow cytometry. Compared with patients with active sJIA, in patients with MAS and sHLH of different origins, beside a significant increase in the frequency of CD38high/HLA-DR+CD8+ T cells, we found a significant increase in the frequency of CD8+ T cells expressing the CD4 antigen (CD4dimCD8+ T cells). These cells expressed high levels of the activation markers CD38 and HLA-DR, suggesting they were a subset of CD38high/HLA-DR+CD8+ T cells, as well as of the activation/exhaustion markers CD25, PD1, CD95, and interferon-γ. The frequency of CD4dimCD8+ T cells strongly correlated with most of the laboratory parameters of MAS severity and with circulating levels of CXCL9 and interleukin-18. These findings were confirmed in a prospective replication cohort in which no expansion of any particular T-cell receptor Vβ family in CD3+ T cells of patients with sHLH was found. Finally, frequency of CD4dimCD8+, but not of CD38high/HLA-DR+CD8+ T cells, significantly correlated with a clinical severity score, further supporting the involvement of these cells in MAS/sHLH pathogenesis.

A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD.

Allogeneic hematopoietic cell transplantation (allo-HSCT) is a reconstruction process of hematopoietic and immune functions that can be curative in patients with hematologic malignancies, but it carries risks of graft-versus-host disease (GVHD), thrombotic microangiopathy (TMA), Epstein–Barr virus (EBV) infection, cytomegalovirus infection, secondary hemophagocytic lymphohistiocytosis (sHLH), macrophage activation syndrome (MAS), bronchiolitis obliterans, and posterior reversible encephalopathy syndrome (PRES). Gastrointestinal graft-versus-host disease (GI GVHD), a common complication of allo-HSCT, is one of the leading causes of transplant-related death because of its high treatment difficulty, which is affected by preimplantation, antibiotic use, dietary changes, and intestinal inflammation. At present, human trials and animal studies have proven that a decrease in intestinal bacterial diversity is associated with the occurrence of GI GVHD. Metabolites produced by intestinal bacteria, such as lipopolysaccharides, short-chain fatty acids, and secondary bile acids, can affect the development of GVHD through direct or indirect interactions with immune cells. The targeted damage of GVHD on intestinal stem cells (ISCs) and Paneth cells results in intestinal dysbiosis or dysbacteriosis. Based on the effect of microbiota metabolites on the gastrointestinal tract, the clinical treatment of GI GVHD can be further optimized. In this review, we describe the mechanisms of GI GVHD and the damage it causes to intestinal cells and we summarize recent studies on the relationship between intestinal microbiota and GVHD in the gastrointestinal tract, highlighting the role of intestinal microbiota metabolites in GI GVHD. We hope to elucidate strategies for immunomodulatory combined microbiota targeting in the clinical treatment of GI GVHD.

Interpreting Rheumatology Laboratory Tests

Interpreting Rheumatology Laboratory Tests

Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors, including endolysosomal TLRs and a STING dependent sensing pathway.

Abstract We have studied the biochemistry and genetics of Phospholipase D3 (PLD3) and PLD4 because polymorphisms of these proteins have been associated with several important inflammatory and autoimmune diseases, including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus and Alzheimer’s disease. We found that both PLD3 and PLD4 are 5’ exonucleases able to degrade both ssDNA and ssRNA. Deficiency in PLD3, PLD4 or both results in a variety of inflammatory defects, with the most serious being lethal hemophagocytic lymphohistiocytosis (HLH) in double knockout mice. Pld3−/−Pld4−/− mice represent a unique spontaneous model of HLH apparently independent of microbes, whereas Pld4−/− mice develop a range of phenotypes depending upon genetic background ranging from macrophage activation syndrome to lupus like disease. Evidence will be presented showing that the diseases in these mice result from autorecognition of nucleic acids and can be reversed by mutation of nucleic acid sensing pathways. PLD3 and PLD4 tend to limit TLR9 recognition but have a more complex effect on recognition by TLR7 and TLR8. Unc93b13d/3dPld3−/−Pld4−/− mice spontaneously signal through STING suggesting that PLD3 and PLD4 also may regulate cytoplasmic nucleic acid sensing. Supported by NIH grants R01 AI142945 and R56AG070775

Clinical characteristics and treatment of elderly onset adult-onset Still\u2019s disease

Adult-onset Still’s disease (AOSD)—a systemic inflammatory disease—often occurs at a young age. Recently, elderly onset patient proportion has been increasing; however, data are limited. To evaluate the characteristics of elderly patients with AOSD in a multicenter cohort, we retrospectively analyzed 62 patients with AOSD at five hospitals during April 2008–December 2020. Patients were divided into two groups according to age at disease onset: younger-onset (≤ 64 years) and elderly onset (≥ 65 years). Clinical symptoms, complications, laboratory findings, treatment, and outcomes were compared. Twenty-six (41.9%) patients developed AOSD at age ≥ 65 years. The elderly onset group had a lower frequency of sore throat (53.8% vs. 86.1%), higher frequency of pleuritis (46.2% vs. 16.7%), and higher complication rates of disseminated intravascular coagulation (30.8% vs. 8.3%) and macrophage activation syndrome (19.2% vs. 2.8%) than the younger onset group. Cytomegalovirus infections were frequent in elderly onset patients (38.5% vs. 13.9%) but decreased with early glucocorticoid dose reduction and increased immunosuppressant and tocilizumab use. Elderly AOSD is not uncommon; these patients have different characteristics than younger-onset patients. Devising a way to control disease activity quickly while managing infections may be an important goal in elderly AOSD.

P163 The cytokine horror: Kawasaki disease shock syndrome complicated with macrophage activation syndrome

Abstract Background/Aims Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown aetiology, affecting medium-sized vessels. It often occurs in children less than 5 years old. During the acute phase of the disease, less than 5% of children develop hypotension and shock. This severe form is called Kawasaki Disease Shock Syndrome (KDSS). Macrophage activation syndrome (MAS) is a heterogenous syndrome complex encompassing a broad spectrum of clinical features. MAS associated with KDSS is an extremely rare life threatening entity that warrants a high index of clinical suspicion, prompt and proper management. Methods We present our experience in the dilemmas and challenges faced in the diagnosis and management of KDSS complicated with MAS in a poor resource setting. It is our first experience of encountering MAS in KDSS. Results A 9-month-old baby with fever and a maculopapular rash involving palms and soles for 5 days duration was transferred from a peripheral hospital. A preliminary diagnosis of acute Kawasaki disease was made with the classical features that included the rash, cracked lips, pedal oedema, BCG scar inflammation, perianal excoriation and irritability. The fever did not settle following standard therapy that included three doses of intravenous immunoglobulins 2g/kg, aspirin and low dose dexamethasone. The child quickly began to decompensate. She developed cold clammy skin with hypotension on the 8th day of the illness. There was evidence of hepatosplenomegaly with transaminitis. 2D Echo revealed normal coronary vasculature without any dilatations or strictures. However, there was evidence of myocarditis supported by diffuse T inversions in the anterolateral leads and a highly positive troponin titre. Investigations revealed aa leucocytosis (22,100/dl), an abrupt drop in platelet count (350,000/dl to 80,000/dl), red blood cells, haemoglobin (11g/dl to 8g/dl) and erythrocyte sedimentation rate 95mm/hr to 50mm/hr. Hyperferritinemia, hypertriglyceridemia and hypofibrinogenemia supported the diagnosis of MAS. Blood culture was sterile. Initial bone marrow biopsy was inconclusive. High dose dexamethasone 10mg/m2/day and cyclosporine 2mg/kg/day was initiated. The circulatory collapse was managed with fluid boluses and a low dose adrenaline infusion. Subsequently there was dramatic clinical improvement and her cell counts and transaminases normalised on day 15. Conclusion We emphasise the importance of early recognition of refractory MAS in pediatric populations with rheumatic diseases and we suggest early initiation of cyclosporin as a rapid and effective treatment option in the poor resource settings where the ideal management with anakinra is beyond the realms of possibility. Disclosure L. Rajagopala: None. J. Jagoda: None. M.L. Gunatilaka: None.

P295 Establishing adenosine deaminase 2 activity in a cohort of patients with large vessel vasculitis

Abstract Background/Aims Deficiency of adenosine deaminase 2 (DADA2) leads to a broad phenotype; some patients develope vasculitis and strokes, and others have predominantly haematological manifestations. Small, medium and large vessel vasculitis has been described. In contrast, plasma ADA2 activity is elevated in inflammatory conditions including systemic lupus erythematosus and systemic juvenile idiopathic arthritis with macrophage activation syndrome. The role of ADA2 and how its deficiency associates with the vasculitides is not well understood. Using a well-characterised large vessel vasculitis cohort, we sought to establish the potential role of ADA2 activity. Methods ADA2 activity was measured in adults with Takayasu arteritis (TA), large vessel giant cell arteritis (LV-GCA), intracranial vasculitis (IV) and healthy control (HC) subjects using a coupled spectrophotometric assay. Plasma from 11 patients with genotyped DADA2 and 10 patients heterozygous for pathogenic variants in ADA2 were used to define thresholds for deficiency and carrier status respectively (DADA2 activity 0 - 0.90 U/L, ADA2 carrier activity 2.02 - 10.62 U/L). Activity levels above the upper limit of normal (ULN) were defined as &amp;gt; 99th percentile of the HC activity (30.3U/L). To assess potential associations with TA disease status, ADA2 was measured prospectively in matched active and remission samples. TA disease activity was determined as active, grumbling or stable using clinical and radiological features, physician impression, CRP, ESR and Indian Takayasu clinical Activity Score (ITAS). Results No patients had deficient ADA2 activity while 7 subjects had activity within the carrier range (1 HC [1.9%], 5 TA [3.7%], 1 LV-GCA [2.3%]). Compared to HC levels (17.43 [14.11 - 20.78] U/L), activity in the TA group was significantly increased (TA 19.68U/L, p = 0.0061), while LV-GCA and IV were not significantly different. In 20 cases, activity exceeded the ULN; 16 TA (11.9%, p = 0.044; 4 active, 2 grumbling, 10 stable) and 4 LV-GCA (9.1%, ns). In TA, there was a positive correlation between ADA2 activity and ESR (Spearman R = 0.2863, p = 0.0009) but not with CRP or ITAS score. Subgroup analysis revealed ADA2 activity was most prominently elevated in the stable group relative to HCs (TA stable 20.54 U/L [8.08 - 48.66], median +17.8%, p = 0.0006), but not with active or grumbling disease. Consistent with this, prospective analysis demonstrated a significant increase in ADA2 activity in remission vs active disease (p = 0.024), with activity increasing in 18 (62%) patients achieving remission. Conclusion There were no cases of ADA2 deficiency in this cohort. Consistent with other inflammatory conditions, ADA2 activity was elevated in TA compared to HC subjects. Surprisingly, increased ADA2 activity was linked to stable TA in both cross-sectional and prospective analyses. This may suggest a potential role of ADA2 enzyme activity in vascular repair and regrowth - possibly tying in with known elevated levels of ADA2 activity in growing children. Disclosure A. Porter: None. R. Maughan: None. C. Pericleous: None. A. Kiprianos: None. H. Jee: None. P. Lee: None. T. Youngstein: None. J. Mason: None.

Cytokine profile, ferritin and multi-visceral involvement characterize macrophage activation syndrome during adult-onset Still's disease.

To multidimensionally characterize macrophage activation syndrome (MAS) complicating adult-onset Still's disease (AOSD) considering cytokine profile, inflammatory markers and multi-visceral involvement of the disease. To perform a high-dimensional phenotypic analysis of circulating immune cells in AOSD patients with and without MAS. To assess interferon (IFN)-related pathways in AOSD synovial tissues by a bulky RNA sequencing. Clinical and biologic data were collected and compared in AOSD patients with and without MAS. Sera biomolecules were analysed by Luminex multiplexing technology. Mass cytometry (CyTOF) was used to characterize circulating immune cells. A bulky RNA sequencing was performed in AOSD synovial tissues. Forty consecutive AOSD patients were assessed, 14 complicated with MAS. Paralleling with increases of systemic score and ferritin, MAS patients showed higher levels of IL-1α, IL-1β, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-17A, IFN-γ, G-CSF, MCP-1, MIP-1α and SCF. Combining the discriminatory ability of these data in identifying MAS, the best model was composed by systemic score, ferritin, IFN-γ and IL-10. By CyTOF analysis, MAS patients showed an increase of circulating 'classical monocytes' and a reduction of total NK cells. Our assessment showed 3477 IFN-related genes (IRGs) were differently expressed in AOSD synovial tissues. A multidimensional characterization of AOSD patients suggested that IFN-γ, IL-10, ferritin and systemic score discriminated the occurrence of cytokine storm syndrome associated with MAS. The inflammatory milieu of AOSD and MAS may be related to a signature of circulating immune cells. Finally, our results about IRGs reinforced the role of IFN-γ in these patients.

New-onset Systemic Lupus Erythematosus presenting with Macrophage Activation Syndrome and Diffuse Alveolar Hemorrhage: a case-based review

Macrophage activation syndrome is a form of secondary hemophagocytic lymphohistiocytosis in the setting of autoimmune diseases. It’s a rare, hyperinflammatory complication requiring prompt institution of therapy to prevent organ dysfunction and death. We report a young female presenting with macrophage activation syndrome with multiorgan failure and diffuse alveolar hemorrhage in the setting of inaugural systemic lupus erythematosus. The patient was successfully treated with steroids, plasma exchange and cyclophosphamide.

Implications of SARS-CoV-2 Infection in Systemic Juvenile Idiopathic Arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is a serious multifactorial autoinflammatory disease with a significant mortality rate due to macrophage activation syndrome (MAS). Recent research has deepened the knowledge about the pathophysiological mechanisms of sJIA-MAS, facilitating new targeted treatments, and biological disease-modifying antirheumatic drugs (bDMARDs), which significantly changed the course of the disease and prognosis. This review highlights that children are less likely to suffer severe COVID-19 infection, but at approximately 2–4 weeks, some cases of multisystem inflammatory syndrome in children (MIS-C) have been reported, with a fulminant course. Previous established treatments for cytokine storm syndrome (CSS) have guided COVID-19 therapeutics. sJIA-MAS is different from severe cases of COVID-19, a unique immune process in which a huge release of cytokines will especially flood the lungs. In this context, MIS-C should be reinterpreted as a special MAS, and long-term protection against SARS-CoV-2 infection can only be provided by the vaccine, but we do not yet have sufficient data. COVID-19 does not appear to have a substantial impact on rheumatic and musculoskeletal diseases (RMDs) activity in children treated with bDMARDs, but the clinical features, severity and outcome in these patients under various drugs are not yet easy to predict. Multicenter randomized controlled trials are still needed to determine when and by what means immunoregulatory products should be administered to patients with sJIA-MAS with a negative corticosteroid response or contraindications, to optimize their health and safety in the COVID era.

Adult Onset Still’s Disease Presenting as Fever of Unknown Origin: A Case Report

26 years’ female patient attended triage with complaints of fever of almost 1-month duration. She was diagnosed as a case of Brucellosis outside. However, her fever persisted and she was finally diagnosed to have new onset adult-onset still’s disease (AOSD) with active macrophage activation syndrome (MAS) and multi organ failure. She met the diagnostic criteria for AOSD. She had high spiky fevers, hepatosplenomegaly, Lymphadenopathy, coagulopathy, anaemia with thrombocytopenia, hemophagocytosis, markedly elevated serum ferritin, low to absent natural killer (NK) cells, and remained unresponsive to steroids, intravenous immunoglobulin (IVIG) and hemophagocytic lymphohistiocytosis (HLH) protocol treatment. Interleukin-1 (IL1) inhibitors were not available. Interleukin-6 (IL6) blockers were not considered due to greater concerns about exacerbating bacterial infections with IL-6 blockade than with IL-1 blockade and much longer half-lives of the IL-6 inhibitors. We were also reluctant in using tocilizumab or sarilumab in new-onset disease where diagnostic uncertainty remains, as is often the case. She succumbed to her disease which had rapid fulminating course with multi organ failure. Her diagnostic and therapeutic challenges are discussed.