Macrophage Activation Syndrome Research Articles

Anakinra and hepatotoxicity in pediatric rheumatology: a case series

BackgroundAnakinra is a recombinant interleukin-1 (IL-1) receptor antagonist used in systemic juvenile idiopathic arthritis (sJIA), refractory Kawasaki disease (KD) and cryopyrin-associated autoinflammatory syndrome (CAPS). Anakinra associated hepatotoxicity, while rare, has been described in several cases in daily practice. ​In this case series the authors describe three pediatric patients with this side effect in the setting of severe macrophage activation syndrome (MAS) in KD and sJIA.Case presentationThe first patient was a 12-year-old boy who presented with fever, maculo-papular exanthema and polyarthralgia. Tonsillitis, distal limb induration and tender cervical lymph nodes were observed. Erythrocyte-sedimentation rate (ESR), C-reactive protein (CRP), ferritin (11,975 ng/mL), D-dimers (5,98 mg/L FEU) and soluble CD25 (3645 pg/mL) levels were elevated. Exclusion of sepsis / toxic shock syndrome warranted introduction of IV methylprednisolone and immunoglobulin (IG IV), with partial response. A MAS secondary to KD was assumed, and anakinra 2 mg/kg/day was introduced. Twenty days later he developed new-onset nausea and severe cyto-cholestasis, normalizing after 2 months of drug discontinuation. Posterior onset of polyarthritis and evanescent lead to a final diagnosis of sJIA. The second patient was a 2-year-old boy with a 10-day history of fevers, generalized rash, hepatosplenomegaly and strawberry tongue. Leucocytosis with neutrophilia and elevated CRP were observed. Initial treatment with IVIG in the setting of incomplete KD was ineffective. Mild anaemia, leukopenia and very high serum ferritin (maximum 26,128 ng/mL) ensued. Presumptive sJIA associated MAS was treated with IV methylprednisolone and anakinra 2 mg/kg/day, with prompt response. Four weeks later transaminitis was detected, and temporary anakinra suspension led to normalisation of laboratorial values. The third case related to a 4-year-old boy presenting with fever, maculopapular rash and cervical lymphadenopathy. CRP and ESR were elevated, and KD was diagnosed. IVIG and methylprednisolone were initiated with clinical worsening, warranting for anakinra introduction at 2 mg/kg/day. After three weeks, liver enzymes progressively elevated, resolving on 2 weeks of anakinra discontinuation.ConclusionsTo the best of our knowledge, this is the first case series describing anakinra associated hepatotoxicity in pediatric patients with rheumatic diseases other than sJIA, bringing additional insight to therapeutic monitoring in patients undergoing this treatment.

Successful use of extracorporeal membrane oxygenation for life‐threatening macrophage activation syndrome after treatment with tocilizumab in an systemic juvenile idiopathic arthritis patient

AbstractMacrophage activation syndrome (MAS) is a rare, potentially life‐threatening condition in rheumatic diseases. The primary treatments consist of high‐dose corticosteroids and immunosuppressive drugs, although more recently, cytokine inhibitors like anakinra or tocilizumab (TCZ) have been reported. We present a case of a child with systemic juvenile idiopathic arthritis (sJIA). After receiving a single infusion of TCZ, the child developed progressive hypoxia and was subsequently transferred to the pediatric intensive care unit (PICU) after 4 days. An immediate postintubation chest X‐ray revealed a diffuse exudative lesion. Despite continuous efforts to provide mechanical ventilation and respiratory support, the patient's oxygen saturation continued to decline. Moreover, the patient developed hemodynamic compromise, necessitating the administration of norepinephrine. Eventually, vasopressin and dopamine were added to maintain stable hemodynamics. After an intensive but ineffective treatment, extracorporeal membrane oxygenation (ECMO) was initiated in the PICU after 16 h. The patient successfully recovered and was weaned off ECMO support after 60 h. Following discharge from the PICU, given the severe refractory clinical features, we made an attempt to readminister TCZ treatment. However, within half an hour of TCZ infusion, the patient experienced anaphylaxis characterized by palpitations and chest tightness, leading to the discontinuation of TCZ. TCZ, as a biological agent, is commonly used in the treatment of sJIA. Nonetheless, the occurrence of MAS and anaphylaxis following TCZ administration for sJIA may be more prevalent than previously recognized. Pediatric rheumatologists should exercise caution when initiating TCZ for active sJIA. Furthermore, we want to underscore the importance of life‐saving techniques such as ECMO for sJIA patients in emergency situations.

The Role of the IL-33/ST2 Axis in CpG-Induced Macrophage Activation Syndrome.

Macrophage activation syndrome (MAS) is a fatal inflammatory condition, which is often associated with the elevation of multiple proinflammatory cytokines and multiple organ dysfunction. Previous studies have shown that ST2 contributes to T cell overactivation and plays a detrimental role in mouse models of primary hemophagocytic lymphohistiocytosis. The purpose of this study was to investigate the role of the IL-33/ST2 axis in a mouse model of MAS induced by repeated injections of cytosine-phosphate-guanine (CpG). Serum cytokines were determined using the cytometric bead array by flow cytometry. IL-33 and ST2 were detected by immunohistochemistry and real-time quantitative PCR in the liver and spleen of mice. CD3 and F4/80 in the liver were detected by immunohistochemistry. Inflammatory macrophages and effector memory T lymphocytes were detected by flow cytometry. The CpG-induced MAS model was successfully induced after repeated CpG injections, presenting with hypercytokinemia and hepatosplenomegaly. The numbers of IL-33 positive cells in the liver and spleen decreased significantly, while the expression of ST2 in the liver tended to increase in the mice with MAS. IL-33 and St2 knockout mice showed similar levels of hepatosplenomegaly, peripheral blood count, and cytokine storm when compared with wild-type (WT) mice after induction of MAS. There were also no significant differences in liver pathology (including inflammatory cell infiltration of CD3 and F4/80) and levels of splenic inflammatory macrophages and effector memory T cells between the WT and knockout mice. These results suggested that IL-33 decreased in the liver and spleen tissues of MAS mice. Further results suggest that IL-33 and St2 knockout mice have no treatment potential in CpG-induced MAS. Thus, the IL-33/ST2 axis has little effect on the prognosis of CpG-induced MAS.

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.

S2057 Systemic Lupus Erythematous in Disguise: Acute Pancreatitis and Macrophage Activation Syndrome as Initial Presentation

S2057 Systemic Lupus Erythematous in Disguise: Acute Pancreatitis and Macrophage Activation Syndrome as Initial Presentation

Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogenous disorders characterized by childhood-onset chronic joint inflammation. It is the most common rheumatologic disease in the pediatric population and an important cause of chronic illness in children. Early recognition and treatment are vital to prevent sequelae of uncontrolled inflammation on the developing skeleton. JIA can have significant complications that general pediatricians should be aware of, especially uveitis, which can be insidious and asymptomatic in very young children, and macrophage activation syndrome, which can be life-threatening if not recognized and appropriately treated. Although advances have been made in the past few decades, the etiology of JIA remains incompletely understood. Efforts are underway to refine the classification of JIA. The currently accepted classification scheme identifies subsets of JIA that are important clinically in terms of prognosis and tailoring treatment approaches. However, it is limited in identifying homogenous groups of children with early childhood onset and antinuclear antibody positivity, which may have different pathogenic mechanisms that could be important in developing more targeted and effective treatment approaches in the future. Treatment strategies for JIA have changed significantly in recent years with the availability of multiple newer targeted therapies, often modeled after medications used in adult-onset forms of arthritis. These treatments, and likely many others to come, have markedly improved symptom control and reduced complications in patients with JIA.

Adult-onset Still's disease with Acute Kidney Injury Requiring Hemodialysis: A Case Report and Literature Review.

Adult-onset Still's disease (AOSD) is characterized by high spiking fever, evanescent rash, and arthritis. However, AOSD rarely presents with severe acute kidney injury (AKI). We herein present the case of a 56-year-old woman with new-onset AOSD who rapidly developed AKI. A physical examination and laboratory data revealed spiking fever, evanescent rash, thrombocytopenia, hyperferritinemia, and azotemia. The patient was diagnosed with AOSD complicated by AKI and macrophage activation syndrome. Treatment with high-dose steroids, hemodialysis, and plasma exchange successfully resolved her AKI. In this report, we review previously published reports on AOSD accompanied by AKI and discuss this rare complication in AOSD.

Macrophage activation syndrome induced by Staphylococcus Epidermidis in a pediatric patient with cystic fibrosis and familial Mediterranean fever.

Staphylococcus epidermidis (S. epidermidis) is the most frequently isolated member of the coagulase-negative staphylococci, which colonizes the skin and mucous membranes of the human body. Despite being a component of the normal flora, S. epidermidis can act as an opportunistic pathogen and is frequently implicated in both bacterial and nosocomial infections. Macrophage activation syndrome (MAS) is a rare but potentially fatal disease that occurs as a result of increased activation and proliferation of T lymphocytes and macrophages in response to infections and immune mediated diseases. It is very rare in patients with cystic fibrosis. Here we report a case of an 8-year-old girl with cystic fibrosis and familial Mediterranean fever who developed MAS after contracting a S. epidermidis infection.

Kawasaki Disease Complicated with Macrophage Activation Syndrome: The Importance of Prompt Diagnosis and Treatment–Three Case Reports

Kawasaki disease (KD) is an acute vasculitis that mainly affects children under 5 years of age, leading to coronary artery alterations (CAAs) in 25% of untreated patients. Macrophage activation syndrome (MAS) is a secondary hemophagocytic lymphohistiocytosis (HLH) that can complicate the acute, subacute, and chronic phases of KD. We retrospectively reviewed three cases of children affected by KD complicated with MAS hospitalized in two pediatric units in Emilia Romagna, a northern region of Italy. Case 1: a previously healthy 23-month-old female with full clinical criteria of KD and a hemorrhagic rash due to MAS during the acute phase of the illness. This patient responded promptly to a high dose of intravenous immune globulin (IVIG) and three pulses of high doses of methylprednisolone (MPD) with improvement in clinical signs and laboratory tests without the development of CAA at any phase of illness. Case 2: a previously healthy 10-month-old female with incomplete KD with persistent fever and maculopapular rash. This patient did not respond to IVIG and developed MAS during the subacute phase, characterized by persistent fever, hypertransaminasemia, hyperferritinemia, and hypofibrinogenemia after two high doses of IVIG and boluses of MPD. The patient responded to the addition of IL-1 blocker and anakinra and did not present CAA alterations during any phase of the illness. Case 3: a previously healthy 26-month-old male with incomplete KD with fever, maculopapular rash, cheilitis, and hyperemic conjunctivitis. This patient developed gallbladder hydrops and CAA in the acute phase and did not respond to two high doses of IVIG and a high dose of MPD. In the subacute phase, this patient was complicated with MAS and responded to intravenous anakinra. During the subacute phase, the patient developed transient aneurysms that regressed during the chronic phase. These cases reiterate that prompt diagnosis and aggressive immunomodulatory treatment can limit the most severe complications of MAS complicating KD. High doses of IVIG and MPD may result in a favorable outcome or more aggressive adjunctive treatment may be needed. Anakinra, cyclosporine, monoclonal antibodies, and plasmapheresis can be used as adjunctive treatment in the case of unresponsive MAS in KD. Notably, MAS, present during the subacute phase in cases 2 and 3, promptly responded to anakinra, an IL-1 blocker, without the use of cyclosporine. Our experience confirms that the IL-1 blocker can be considered an optimal choice after non-response to IVIG and MPD in KD complicating with MAS, avoiding over-treatment with cytotoxic drugs.

Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation

AbstractHemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes. Familial HLH is caused by genetic impairment of granule-mediated cytotoxicity (eg, perforin deficiency). MAS is linked to excess activity of the inflammasome-activated cytokine interleukin-18 (IL-18). Though individually tolerated, mice with dual susceptibility (Prf1⁻/⁻Il18tg; DS) succumb to spontaneous, lethal hyperinflammation. We hypothesized that understanding how these susceptibility factors synergize would uncover key pathomechanisms in the activation, function, and persistence of hyperactivated CD8 T cells. In IL-18 transgenic (Il18tg) mice, IL-18 effects on CD8 T cells drove MAS after a viral (lymphocytic choriomeningitis virus), but not innate (toll like receptor 9), trigger. In vitro, CD8 T cells also required T-cell receptor (TCR) stimulation to fully respond to IL-18. IL-18 induced but perforin deficiency impaired immunoregulatory restimulation-induced cell death (RICD). Paralleling hyperinflammation, DS mice displayed massive postthymic oligoclonal CD8 T-cell hyperactivation in their spleens, livers, and bone marrow as early as 3 weeks. These cells increased proliferation and interferon gamma production, which contrasted with increased expression of receptors and transcription factors associated with exhaustion. Broad-spectrum antibiotics and antiretrovirals failed to ameliorate the disease. Attempting to genetically “fix” TCR antigen-specificity instead demonstrated the persistence of spontaneous HLH and hyperactivation, chiefly on T cells that had evaded TCR fixation. Thus, drivers of HLH may preferentially act on CD8 T cells: IL-18 amplifies activation and demand for RICD, whereas perforin supplies critical immunoregulation. Together, these factors promote a terminal CD8 T-cell activation state, combining features of exhaustion and effector function. Therefore, susceptibility to hyperinflammation may converge on a unique, unrelenting, and antigen-dependent state of CD8 T-cell hyperactivation.

Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005-2021).

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005-October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6-14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.

Development of a Screening Algorithm for Lung Disease in Systemic Juvenile Idiopathic Arthritis.

Lung disease (LD) is an increasingly recognized complication of systemic juvenile idiopathic arthritis (sJIA). As there are no currently available guidelines for pulmonary screening in sJIA, we sought to develop such an algorithm at our institution. A multidisciplinary workgroup was convened, including members representing rheumatology, pulmonary, stem cell transplantation, and patient families. The workgroup leaders drafted an initial algorithm based on published literature and experience at our center. A modified Delphi approach was used to achieve agreement through three rounds of anonymous, asynchronous voting and a consensus meeting. Statements approved by the workgroup were rated as appropriate with moderate or high levels of consensus. These statements were organized into the final approved screening algorithm for LD in sJIA. The workgroup ultimately rated 20 statements as appropriate with a moderate or high level of consensus. The approved algorithm recommends pulmonary screening for newly diagnosed patients with sJIA with clinical features that the workgroup agreed may confer increased risk for LD. These "red flag features" include baseline characteristics (young age of sJIA onset, human leukocyte antigen type, trisomy 21), high disease activity (macrophage activation syndrome [MAS], sJIA-related ICU admission, elevated MAS biomarkers), respiratory symptoms or abnormal pulmonary examination findings, and features of drug hypersensitivity-like reactions (eosinophilia, atypical rash, anaphylaxis). The workgroup achieved consensus on the recommended pulmonary work-up and monitoring guidelines. We developed a pulmonary screening algorithm for sJIA-LD through a multidisciplinary consensus-building process, which will be revised as our understanding of sJIA-LD continues to evolve.

Vitamin C and D supplementation in acute myeloid leukemia

AbstractRecent studies have highlighted the role of vitamin C and D in acute myeloid leukemia (AML). In 2018, we changed our practices to add both vitamins to the supportive care for all consecutive patients with AML undergoing intensive chemotherapy. In this study, we compared the outcomes of patients treated before and after this change in practice. From 2015 to 2020, 431 patients were included, 262 of whom received no supplementation and 169 of whom received vitamin supplementation. Vitamin C and vitamin D was administered from day 10 of chemotherapy until hematologic recovery from induction and consolidation. Most patients presented at diagnosis with low levels of vitamin C and D. Upon recovery from induction, vitamin D levels among the vitamin C/D group significantly increased compared with those at diagnosis, and pretransplant levels were significantly higher in the vitamin C/D group compared with the control group (median of 33 vs 19 ng/mL; P < .0001). During induction, the rates of bacterial or fungal infection, hemorrhage, or macrophage activation syndrome were lower in the vitamin C/D group, whereas there was no difference in response rate, relapse incidence, and overall survival (OS). However, the multivariate analysis for OS showed a significant interaction between vitamin C/D and NPM1 mutation, meaning that vitamin C/D supplementation was significantly and independently associated with better OS in patients with NPM1 mutations (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.30-0.90; P = .019) compared with patients with wild-type NPM1 (HR, 1.01; 95% CI, 0.68-1.51; P = .95). In conclusion, vitamin C/D supplementation is safe and could influence the outcomes of patients with AML undergoing intensive chemotherapy.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis

BackgroundOne of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network’s objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis.MethodsWe assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed.ResultsMortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55–9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia.ConclusionsThese findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Refractory macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis treated with canakinumab

Refractory macrophage activation syndrome in children with systemic onset juvenile idiopathic arthritis treated with canakinumab

A Case of Adult-onset Still’s Disease Complicated with Macrophage Activation Syndrome and Diffuse Alveolar Hemorrhage

Adult-onset Still’s Disease (AOSD) is a rare inflammatory disease of unknown etiology characterized by high fever, skin rash, arthritis, elevated ferritin and organ involvement. Macrophage Activation Syndrome (MAS) can be seen as a rare, potentially fatal complication in AOSD. Here, we presented a case who was diagnosed with MAS due to general condition disorder, increased ferritin and cytopenia while being followed up with the diagnosis of chronic articular form ESH, and then developed diffuse alveolar hemorrhage (DAH) after a short time. We aimed to draw attention to rare complications after AOSD with this case report that showed a dramatic response to corticosteroid and tocilizumab treatment.

Clinical features of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with macrophage activation syndrome.

This study aimed to describe the clinical features of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM) who had macrophage activation syndrome (MAS). We retrospectively examined 44 patients with anti-MDA5-positive DM and compared the clinical features between patients with MAS (n = 11) and those without (n=33). Patients without MAS were selected randomly in the same year as those with MAS at a ratio of 3:1. Among patients with MAS, we compared the features between non-survivors and survivors. We used Fisher's exact test, Student's t test, the Mann-Whitney U test and the log-rank test for statistical analysis. Patients complicated with MAS had a significantly higher incidence of infection, heliotrope sign, Gottron's papule, V-neck sign, and higher serum levels of ferritin, aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and creatine kinase (CK) than those without MAS (p<0.05). Among the 11 patients with MAS, 4 (36.4%) died after intensive treatment. Deceased patients were older, given more combination therapy with tofacitinib (TOF) and had a higher incidence of rapid progressive interstitial lung disease, infection, heart failure and renal impairment than those who survived (p<0.05). Among anti-MDA5-positive DM, Infection, DM typical rashes, and higher serum levels of ferritin, AST, LDH, and CK were more common in patients complicated with MAS. The mortality of patients with MAS was high, particularly among patients who were older, given more combination therapy with TOF, and had RP-ILD, infection, heart failure and renal impairment.

Macrophage activation syndrome in systemic lupus erythematosus - a case report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition that results from the immune system hyperactivation. The primary form of HLH appears mainly in children and is caused by a genetically determined failure of NK and T cells. Secondary (acquired) HLH usually occurs due to insufficiency of these cells caused by other disease entities or drugs. Potential factors that may be responsible for the appearance of this rare condition include: malignancies (especially lymphomas), infections (EBV, CMV, HIV), autoimmune diseases (SLE, Still’s disease). The clinical appearance of hemophagocytic lymphohistiocytosis is dominated by persistent fever, hepatomegaly, splenomegaly, pallor of the skin, signs of hemorrhagic diathesis, lymph node enlargement. Characteristic abnormalities in laboratory tests include: hypertriglyceridemia, cytopenia, hyperferritinemia, hyperfibrinogenemia and hypertransaminasemia. One subtype of the secondary form of hemophagocytic lymphohistiocytosis, which is associated with rheumatic diseases, is called the macrophage activation syndrome (MAS). The following describes a case of a 26-year-old woman with exacerbated systemic lupus erythematosus, who was admitted to a Rheumatology Unit in severe general condition. Clinical presentation of the patient included primarily: long-lasting fever, hepatomegaly and splenomegaly. Various test were performed during her hospitalization, including laboratory test and a bone marrow biopsy. Finally, the woman was diagnosed with the macrophage activation syndrome. She was successfully treated with ciclosporin and methylprednisolone.

E51 Guillain-Barre syndrome revealing systemic lupus erythematosus: a case report

Abstract Introduction Neuropsychiatric systemic lupus erythematosus (NPSLE) as described by the American College of Rheumatology (ACR) research committee includes 19 neuropsychiatric syndromes divided into neurologic syndromes of the central, peripheral, and autonomic nervous system and the psychiatric syndromes observed in patients with SLE in which other causes have been excluded. These symptoms may precede the onset of SLE or can occur at any time during the course of SLE. Guillain-Barré syndrome which is classified under the peripheral involvement has been rarely associated with SLE. Objective Guillain-Barré syndrome as an initial presentation of SLE has been reported in only a few cases. The isolated presentation of GBS may delay the diagnosis of SLE and its management. Methods We report a case of Guillain-Barré syndrome presenting as an initial manifestation of SLE, followed later by a succession of revelations of multi-visceral involvement. Case Report Z a 13-year-old girl, with no medical history, who presented to the emergency department with worsening muscle weakness in the lower limbs that appeared 15 days ago with an inability to walk for 3 days. The parents reported two episodes of fever, mouth ulcers, arthralgia accompanied by profound asthenia and behavioral disorder with visual hallucinations and nightmares preceding this episode. On initial physical examination revealed a generalized weakness of the lower exttremities. Sensory loss was variable in both her leg and feet. The deep tendon reflexes of her lower limbs were absent. A general physical examination revealed no other neurological, or organic findings. Respiratory and cardiac functions were within normal limits. A diagnosis of post-infectious Guillain-Barré syndrome was made, especially since she had an upper respiratory infection and viral serologies were initiated. Seven days after admission, the patient’s condition and neurological status worsened; She had a persistent fever with a maximum temperature at 40 °C, resistant to antipyretics. She had oedema of the lower limbs, hepatomegaly and splenomegaly. The hematological assessment revealed normocytic anaemia at 8.5 g/l, leukopenia with lymphopenia (500 cells/mm2) and thrombocytopenia (50 000 cells/mm2) with acute renal failure. Proteinuria &amp;gt;3 g/24h. A chest X-ray revealed moderate bibasilar pleural effusion and moderate pericardial effusion. Brain magnetic resonance imaging revealed no abnormalities. We suspected a macrophage activation syndrome (MAS) secondary to SLE. The inflammatory and autoimmune assessment were contributory with: antinuclear antibodies 1/1000 homogeneous fluorescence, positive anti-ribosome antibodies, reduced complement C3 and C4 fraction, serum ferritin &amp;gt; 3000 ng/ml, hypofibrinogenemia 1.3 g/l and D-dimer 3500 ng/ml. Patient fulfilling the ACR SLE criteria, with a severe multivisceral form: mucocutaneous, articular, neurological, renal, cardiac, hematological associated with MAS. Despite immunoglobulin and high-dose methylprednisolone, our patient died before the first session of plasmapheresis and first dose of cyclophosphamide. Discussion Neurolupus is a severe form of SLE with very high disease activity. Inaugural clinical presentation was not typical (SGB), but diagnosis was early after acute and severe revelation of other organic damage. Our patient presented with MAS as severe SLE whose short-term prognosis was compromised. Conclusion Pediatric neurolupus would be very heterogeneous and more severe than that of adults according to the few published pediatric series. Guillain-Barré syndrome revealing SLE is uncommon. In addition to this disorder, there are psychotic crises which are rarely mentioned during the initial clinical manifestations and which are a source of diagnostic difficulties, especially if they are isolated.

E08 Single center study of Systemic Juvenile Idiopathic Arthritis in Moroccan patients

Abstract Introduction Juvenile idiopathic arthritis (JIA) is the most common rheumatological disorder in childhood. About 10% to 20% of children with JIA have a rare and serious subtype called systemic juvenile idiopathic arthritis (SJIA). SJIA differs from other subtypes in that it’s the only one considered an autoinflammatory rather than autoimmune disease because of the association with systemic features and is therefore treated differently with anti-IL1 and anti-IL6. Objectives To describe epidemiological data of SJIA in Moroccan patients taking into account environmental conditions. To compare existing criteria (ILAR, Fautrel, Yamaguchi) to the new Pediatric Rheumatology International Trials Organization (PRINTO) classification currently in the process of validation. Patient and methods Retrospective prospective study conducted between January 2019 and December 2022. SJIA was diagnosed based on one of the four classification criteria ILAR, Fautrel, Yamaguchi or PRINTO Classification after ruling out infectious disease, immunodeficiency and malignancy whenever necessary. Complete remission was defined as the absence of clinical signs and inflammatory syndrome. Partial remission was defined as the absence of active clinical signs with persistence of inflammatory syndrome. Results Nine SIJA (44% male) patients were enrolled. The mean age at diagnosis was 4 years 8 months, the mean time to diagnosis was 4.8 months (range 1 – 24 months), the average follow up period was 16.4 months. At the time of diagnosis, the most common findings were typical fever (100%), arthritis (66%), skin rash (55%), 2 patients had pericarditis and one had macrophage activation syndrome (MAS), there was no renal or pulmonary involvement. Laboratory data showed in all patients, high level of C-reactive protein at mean value of 183 mg/l, increased erythrocyte sedimentation rate at mean of 88 mm first h, hyperleukocytosis at mean of 17 000 WBC/mm3 with high neutrophil counts at a mean of 12 297/mm3 and thrombocytosis at a mean of 625 000/mm3. To rule out other diagnosis, para clinical evaluation showed a positive antinuclear antibody in one patient without pathogenic significance, a bone marrow count performed in 3 patients, showed normal count in 2 patients and hemophagocytosis in one patient and immunoglobulins assay performed in 3 patients was normal. Of the 9 patients, 4 met all the criteria, 2 were diagnosed based on Yamaguchi criteria and one on Fautrel criteria, one fulfilled all criteria except ILAR and the last fulfilled only ILAR and new PRINTO classification. One patient was treated with corticosteroid pulse therapy for MAS and then oral corticosteroids with complete remission. Another received corticosteroids and biotherapy [tocilizumab (TCZ)] upfront due to late consultation and severe form with complete remission. Seven patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) of which one achieved partial remission with a delay of 2 months of follow up and 6 required adjunctions of another medication: corticosteroids (4), MTX (2), biotherapy (5) [anakinra (5), Switch TCZ (2)] with complete remission. The last patient reached complete remission under corticosteroids, Triamcinolone Hexacetonide knee infiltration and methotrexate. Anakinra was the most common first-line biologic treatment choice (n = 5), and 2 of them need switch to Tocilizumab to achieve remission. One of the 2 patients with pericarditis needed a rescue drainage. Outcome was favorable in all patients except one who had a relapse with final remission, and articular sequel in 3 patients. Discussion and conclusion SJIA is a rare but serious condition with high risk of morbidity related to arthritis and mortality from MAS and pericarditis. The latter features turn into a good prognosis with early diagnosis and treatment, as we have done. It can occur any time during childhood, but it most commonly starts at around the age of two years, unlike our patients who were older. No predominance ratio is reported as we have noted. SJIA is referred to as Still disease by some authors justifying the new PRINTO classification and the specific treatment. In our study, Yamaguchi criteria seem to be the most sensitive (7/9 fulfilled) followed by New PRINTO classification and Fautrel criteria (6/9 fulfilled), ILAR criteria are the less sensitive (5/9 fulfilled) what can delay diagnosis and treatment. Our study showed the benefit of biological agent, 66% of patients achieved remission with at least one biological agent and we concluded that Anti-IL1 drugs are mostly preferred for ongoing systemic inflammation. However Anti-IL-6 agents are very efficient in patients with a polyarticular course.