Macrophage Activation Syndrome Research Articles

LUNG DAMAGE AS A COMPLICATION OF SYSTEMIC JUVENILE ARTHRITIS

According to modern science, systemic juvenile arthritis (sJA) is an autoinflammatory disease characterized by severe systemic manifestations and life-threatening complications. This article discusses the developmental predictors, clinical and radiological manifestations and pathogenetic features of the disease. Particular attention is paid to genetically engineered biological therapy.
 Numerous pulmonary complications are now known in sJA children, including interstitial lung disease (ILD), pulmonary alveolar proteinosis (PAP), pulmonary hypertension (PH), and lipoid pneumonia. Fatality rate in sJA patients increases against the macrophage activation syndrome (MAS) development and pulmonary hypertension, which occurs with proliferation of endothelial cells, muscle tissue and fibroblasts in the lungs vessels. A more severe disease progression is typical for children with genetic defects. SAM and PAP relapses are observed more often in such patients. Instrumental diagnostic methods helped to identify, 5 subtypes determining the lung tissue damage in sJA. Computer tomography (CT) revealed the main signs of lung damage in sJA patients: ground-glass opacity, crazy-paving sign, thickening of the bronchial wall, interlobar septum, pleura, peripheral consolidation, and lymphadenopathy. Due to the high level of sJA activity, children were prescribed genetically engineered biological drugs (GEBP). Timely therapeutic correction is necessary to exclude life-threatening adverse reactions. Under dynamic observation, it is possible to diagnose lung damage in children at the early stage and to control the pathology.
 The purpose of this review is to systematize the existing data on developmental predictors, pathogenetic features of the disease, sJA clinical and radiological manifestations, and genetically engineered biological therapy as a method of sJA treatment.

Disseminated Multifocal Tuberculosis: An Unusual Presentation with Macrophagic Activation Syndrome

Disseminated Multifocal Tuberculosis: An Unusual Presentation with Macrophagic Activation Syndrome

Ruxolitinib rescued the macrophage activation syndrome in adult-onset Still's disease with delayed hypersensitivity reaction to tocilizumab.

Ruxolitinib rescued the macrophage activation syndrome in adult-onset Still's disease with delayed hypersensitivity reaction to tocilizumab.

Relapses are common in severe hematologic systemic lupus erythematosus and may be prevented by early institution of immunosuppressive agents: Α real-life single-center study

Hematologic manifestations are common in systemic lupus erythematosus (SLE), either at initial presentation or during the course of the disease, but data regarding their natural history are scarce. To describe the characteristics, treatments, and outcomes of severe hematological manifestations in a large cohort of lupus patients. Retrospective cohort study of patients in the "Attikon" lupus cohort who had a history of a severe hematologic manifestation, defined as autoimmune hemolytic anemia (AIHA) with hemoglobin < 8g/dL, thrombocytopenia with platelet count < 30,000/mm3, Evans syndrome with hemoglobin < 8g/dL, and/or platelet count < 30,000/mm3, neutropenia with < 500 neutrophils/mm3, thrombotic microangiopathy (TMA)/thrombotic thrombocytopenic purpura (TTP)-like syndrome, or macrophage activation syndrome (MAS). Demographic and clinical characteristics, treatments, and outcomes were recorded. From over 300 patients with hematologic manifestations, 41 qualified as severe (70.7% women, mean [SD] age at SLE diagnosis 42.6 [18.0] years). Hematologic manifestations preceded SLE diagnosis in 13 patients (31.7%), was concomitant to SLE diagnosis in 16 patients (39%), and occurred during the course of the disease in 12 (29.3%) patients, with a mean (SD) disease duration of 8.7 (5.5) years. Thrombocytopenia was the most common severe hematological manifestation (56.1%), followed by AIHA (17.1%) and TTP-like syndrome (12.2%). For initial treatment, all patients were treated with glucocorticoids (GC), while rituximab and cyclophosphamide were the most frequently used immunosuppressive agents. Following initial treatment, relapse occurred in 22 patients (53.7%). Compared to patients that did not relapse, those that relapsed had less often received concomitant immunosuppressive agents following treatment of initial episode (n = 17/23, 73.9% vs 5/17, 29.4%, p = 0.005). Severe hematologic disease in SLE has a high risk of relapse, which may be mitigated by the early institution of GC-sparing agents.

Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review.

Systemic juvenile idiopathic arthritis associated with lung disorders (sJIA-LD) is a subtype of sJIA characterized by the presence of chronic life-threatening pulmonary disorders, such as pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, which were exceptionally rare before 2013. Clinically, these children show a striking dissociation between the relatively mild clinical manifestations (tachypnoea, clubbing and chronic cough) and the severity of the pulmonary inflammatory process. Our review describes sJIA-LD as having a reported prevalence of approximately 6.8%, with a mortality rate of between 37% and 68%. It is often associated with an early onset (&lt;2 years of age), macrophage activation syndrome and high interleukin (IL)-18 circulating levels. Other risk factors may be trisomy 21 and a predisposition to adverse reactions to biological drugs. The most popular hypothesis is that the increase in the number of sJIA-LD cases can be attributed to the increased use of IL-1 and IL-6 blockers. Two possible explanations have been proposed, named the "DRESS hypothesis" and the "cytokine plasticity hypothesis". Lung ultrasounds and the intercellular-adhesion-molecule-5 assay seem to be promising tools for the early diagnosis of sJIA-LD, although high resolution computed tomography remains the gold standard. In this review, we also summarize the treatment options for sJIA-LD, focusing on JAK inhibitors.

Macrophage Activation Syndrome in Adult Onset Still’s Disease: A Life Threatening Complication

Adult onset Still’s disease (AOSD), a multi-systemic inflammatory disorder, is a rare disorder but an important differential to be considered in patients of Pyrexia of Unknown Origin, especially if patient presents with polyarthritis. Macrophage activation syndrome (MAS), a subset of Secondary Hemophagocytic Lymphohistiocytosis (HLH), considered as the most life threatening complication of AOSD, mostly develops around the onset of disease. Hence, in a previously undiagnosed case of AOSD, recognizing MAS as a presenting feature complicating underlying AOSD is essential for increased patient survival, as in our case.&#x0D;  &#x0D;  &#x0D; A 39 year old diabetic female presented with high grade fever with chills and multiple joint pains symmetrically involving proximal shoulder, knees and distal joints (involving MCP, PIP and DIP joints of hand) associated with swelling and early morning stiffness, relieved on activity, since past 6 months. No history of oral ulcers, rash, jaundice, weight loss, loss of appetite, foreign travel or close animal contact.&#x0D;  &#x0D; On examination, Pallor was present, Blood Pressure was 120/70 mm Hg, pulse rate was 102/min and temperature was 100 F. On per abdomen, mild hepatomegaly was present and other system examination was unremarkable.&#x0D;  &#x0D; Routine laboratory findings on day of presentation have been summarised (Table 1.1). Ultrasound Abdomen revealed hepatomegaly and Chest X-ray showed signs of old infective foci. Peripheral smear for Malarial parasite, Ns1Ag and dengue serology, Widal test and Montoux test were negative. Blood cultures and urine cultures were sterile. X-Ray of joints were normal. USG of B/L Knee joints showed mild joint effusion bilaterally with no internal echoes (non tappable). Trans-thoracic echo and Trans-esophageal echo were normal. CT chest, neck and abdomen showed old tubercular changes in lung. Tests for atypical bacterial infections which was normal (RK 39, Chickungunya, Brucella, Leptospirosis  and Scrub typhus). Fever did not respond to Broad Spectrum Antibiotics, Antimalarials or Antitubercular therapy and patient continued to have persistent fever spikes.&#x0D;  &#x0D; Autoimmune profile showed ANA and RA Factor negative but markers of inflammation were raised: CRP- 521, ESR -148, IL-6 – 84.0, Procalcitonin-6.9 and S.Ferritin &gt;2000. During the work up for Anemia, Microcytic hypochromic anemia was found with Elevated NAP SCORE-165. Incidentally, her triglycerides were found to be elevated (356) and a reduced fibrinogen.  With these results, we planned for a bone marrow aspirate and biopsy which showed increased myeloid preponderance (32:1), increased histiocytes and evidence of hemophagocytosis.&#x0D;  &#x0D; The 2004 diagnostic criteria of HLH was fulfilled. After ruling out almost all infectious and malignant causes of secondary HLH, we searched for a rheumatologic cause. Thus diagnosis of AOSD (after fulfilling Yamaguchi’s criteria) with MAS (a subset of 2’ HLH) was made. Patient had dramatic improvement after receiving steroids with her fever episodes and joint pains settling completely thereafter.&#x0D;  &#x0D;  &#x0D; Prompt recognition of life threatening complications like MAS which pose diagnostic difficulty due to overlapping features in a patient of AOSD, should be done at the earliest to improve patient prognosis and survival. Serum Ferritin levels can be considered a useful marker to assess the disease activity and to predict MAS occurrence in such patients.

Adult-Onset Still's Disease With Macrophage Activation Syndrome During Pregnancy: A Unique Cause of Hepatic Dysfunction.

Adult-Onset Still's Disease With Macrophage Activation Syndrome During Pregnancy: A Unique Cause of Hepatic Dysfunction.

Targeting TLR-4 Signaling to Treat COVID-19-induced Acute Kidney Injury

The newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has turned into a potentially fatal pandemic illness. Numerous acute kidney injury (AKI) cases have been reported, although diffuse alveolar destruction and acute respiratory failure are the major symptoms of SARS-CoV-2 infection. The AKI, often known as a sudden loss of kidney function, carries a greater risk of mortality and morbidity. AKI was the second most frequent cause of death after acute respiratory distress syndrome (ARDS) in critically ill patients with coronavirus disease 2019 (COVID-19). While most patients with COVID-19 have moderate symptoms, some have severe symptoms, such as septic shock and ARDS. Also, it has been proven that some patients have severe symptoms, such as the failure of several organs. The kidneys are often affected either directly or indirectly. The major signs of kidney involvement are proteinuria and AKI. It is hypothesized that multiple mechanisms contribute to kidney injury in COVID-19. Direct infection of podocytes and proximal tubular cells in the kidneys may lead to acute tubular necrosis and collapsing glomerulopathy. SARS-CoV2 may also trigger a cascade of immunological responses that lead to AKI, including cytokine storm (CS), macrophage activation syndrome, and Toll-like receptor type-4 activation (TLR-4). Other proposed processes of AKI include interactions between organs, endothelial failure, hypercoagulability, rhabdomyolysis, and sepsis. Furthermore, ischemic damage to the kidney might result from the decreased oxygen supply. This article focuses on kidney injury’s epidemiology, etiology, and pathophysiological processes. Specifically, it focuses on the CS and the role of TLR-4 in this process. To effectively manage and treat acute kidney damage and AKI in COVID-19, it is crucial to understand the underlying molecular pathways and pathophysiology.

MTORC1 links pathology in experimental models of Still’s disease and macrophage activation syndrome

Still’s disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still’s disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still’s disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still’s disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still’s disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still’s disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still’s disease and macrophage activation syndrome.

A brand new medical condition - 6 years old patient with neurological symptoms diagnosed with PIMS-TS (Paediatric Inflammatory Multisystem Syndrome – Temporally Associated with SARS-CoV-2) - case report

Children's multi-system inflammatory syndrome PIMS-TS is a completely new challenge for pediatricians, which has established a separate branch of the fight against the still active COVID-19 pandemic. It turns out that even a pediatric patient who has not suffered symptomatic infection with the SARS-CoV-2 virus, as a result of contact with this pathogen, can develop a severe systemic inflammatory reaction rich in symptoms originating in almost every system of the human body. The first reports of the inflammatory syndrome that is the subject of this work come from May 2020. It is known that the symptoms of PIMS are caused by a multi-system inflammatory response in the body, potentially related to the immune system. The course of this disease may bring to mind other inflammatory diseases in children, such as Kawasaki disease, toxic shock syndrome and MAS macrophage activation syndrome.

Kikuchi-Fujimoto disease as the initial manifestation of systemic lupus erythematosus complicated with macrophage activation syndrome: two case reports and a review of literature

BackgroundKikuchi-Fujimoto disease (KFD) is a self-limiting and benign disease characterized by cervical lymphadenopathy and fever. Although KFD should be made differentially diagnosed from infectious, autoimmune, and malignant diseases, it sometimes occurs in patients with systemic lupus erythematosus (SLE) and can be complicated with macrophage activation syndrome (MAS). However, it is rare that KFD is the initial manifestation of SLE and to be complicated with MAS.Case presentationA 9.6-year-old girl presented with high-grade fever, double-side cervical lymphadenopathy with mild pain of one week, leukopenia, alopecia, and rash on the cheek. During hospitalization, laboratory investigations showed positive antinuclear antibody (ANA), low complement 3 (C3), and low complement 4 (C4). Imaging investigations showed pleural and pericardial effusion. A 10.3-year-old girl presented with intermittent high-grade fever, double-sided cervical lymphadenopathy with obvious pain of 1-month duration, and discoid lesion on the cheek. During hospitalization, laboratory investigations showed positive ANA, leukopenia, thrombocytopenia, anemia with positive Coombs’ test, low C3, and positive Smith antibodies. Both cases were diagnosed with KFD using lymph node biopsy, simultaneously fulfilling the diagnostic criteria of SLE. Subsequently, the two girls became complicated with MAS, followed by interstitial lung disease and neuropsychiatric lupus, respectively. Both patients benefited from high-dose methylprednisolone pulse therapy combined with intravenous cyclophosphamide.ConclusionsMore attention should be paid to differential diagnosis, especially SLE, in children diagnosed with KFD. In addition, children with SLE who presented with KFD as the initial manifestation seem to have a higher risk of developing MAS and experiencing organ involvement.

Adult-Onset Still’s Disease with an Atypical Cutaneous Manifestation

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder, characterized by daily fevers, arthralgias, and rash without evidence of infection. Recently there has been a growing number of cases reported with atypical cutaneous manifestations. We present a 37-year-old type VI Fitzpatrick skin type female who was seen in the hospital for a pruritic rash on her chest, back, and legs. Skin examination was significant for hyperpigmented papules coalescing into plaques on the chest, and hyperpigmented linear patches and excoriated plaques on the back and legs. Punch biopsy showed acanthosis and numerous apoptotic keratinocytes in the upper layers of the epidermis, which was characteristic of AOSD. As of recently, there is a growing body of evidence describing an atypical eruption of persistent, pruritic papules and plaques with typical histologic findings of AOSD. Further, these atypical features may be associated with more severe symptoms, higher incidence of macrophage activation syndrome, and possible delayed malignancy. Due to the scarcity of atypical cutaneous manifestations reported in the literature, these eruptions have not been included in the diagnostic criteria and can therefore be overlooked and misdiagnosed. Prompt recognition of these atypical eruptions is imperative to prevent a worsening prognosis and serious adverse effects.

Diagnostics of macrophage activation syndrome, depending on IL-6 initial level in patients with a novel coronavirus infection

Introduction. The novel coronavirus infection caused by the SARS-CoV-2 remains the main problem, which is being studied by all the efforts of the global scientific community. Large clinical recourse has been accumulated that allows to conduct more effective treatment of patients, but there are still unresolved issues on the pathogenesis for development and course of the disease.&#x0D; Materials and methods. The study included 163 patients admitted to the infectious diseases hospital diagnosed with Novel coronavirus infection caused by the SARS-CoV-2. Upon admission, all patient serum samples were quantified for IL-6 level that allowed to stratify patients into three groups: A 55 patients with IL-6 below 5.0 pg/ml. The mean age in the group was 57.314.9 years, body mass index (BMI) was 28.25.6 kg/m2; C 52 patients whose serum IL-6 level was in the range of 549 pg/ml. The average age in the group was 60.811.8 years, BMI 29.65.5 kg/m2; C 56 patients in whom the level of IL-6 in the blood serum ranged within 50300 pg/ml. The average age in the group was 62.515.6 years, BMI 28.85.6 kg/m2. Patients at admission were analysed for serum level of IL-6, IL-8, and C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) were also determined on day 3 and 7.&#x0D; Results. The minimum production of IL-6 within the range of 0.15 pg/ml, corresponds to the minimum changes in IL-8, CRP, and ferritin as well as LDH that was within the range of physiological values. Moderate cytokinemia, IL-6 is within the range of 549 pg/ml was associated with elevated ferritin and LDH not tending to decline by the end of treatment. Significant cytokinemia, the level of IL-6 within the range of 50300 pg/ml was associated with hyperferritinemia and increased LDH. The course of COVID-19 in such patients is characterized by increased ferritin by day 3 of treatment, consistently high level of LDH, without a significant trend towards a decline in the studied markers by the end of treatment.&#x0D; Conclusion. The risk of developing macrophage activation syndrome is not observed of the serum IL-6 level was below 5 pg/ml, whereas ferritin and LDH were within the range of physiological values, with no/degree I ARF. Moderate macrophage activation syndrome is characterized by increased serum IL-6 level within the range 549 pg/ml, a moderate increase in LDH and ferritin, as well as signs of ARF III degree. Severe signs are diagnosed in case of serum IL-6 level exceeded 50 pg/ml, along with significant increase in LDH and ferritin, as well as signs of IIIII degree ARF.

HLA-DR+ CD38high Expression in T Cells Is Excellent in Quantifying the Amplitude of T-Cell Activation in a Spectrum of Hyperinflammatory Disorders Including HLH

Introduction: T cell activation is the hallmark of several hyperinflammatory states such as HLH and immune dysregulation disorders like LRBA deficiency. Identifying T-cell activation and quantifying the amplitude of T-cell activation is critical for diagnosis, management, and monitoring treatment response in patients with hyperinflammatory and immune regulatory disorders. Soluble Interleukin 2 Receptor (sIL2R) is one of the established systemic T-cell activation markers for diagnosing and monitoring HLH and other hyperinflammatory disorders. However, the clinical availability of sIL2R testing is limited, and it may not be a reliable marker of T-cell activation in patients with eosinophilia and T-cell lymphoma. A recent study by Chaturvedi et.al has demonstrated the utility of flow-based T-cell activation assessment in differentiating HLH from sepsis. However, its utility in defining and quantifying T-cell activation across the hyperinflammatory spectrum and its correlation with sIL2R has not yet been established. Methods: A total of 125 samples were collected either at disease onset (n = 81) or at follow-up (n = 44) from 85 human subjects. Paired plasma sIL2R and T-cell activation markers were prospectively evaluated in patients with suspected HLH (n = 79) or immune dysregulation disorders (n = 46). Out of 85 patients, 21 patients were diagnosed with either primary HLH (p-HLH), Epstein-Barr virus infection-associated HLH (EBV-HLH), malignancy-associated HLH (m-HLH), or macrophage activation syndrome (MAS). The rest of the patients were diagnosed with either sepsis, multisystem inflammatory syndrome in children (MIS-C), hyperinflammatory conditions, hepatitis, or acute liver failure. Flow cytometry-based T-cell activation was evaluated in different T-cell sub-compartments by the co-expression of HLA-DR and CD38 surface markers. Plasma sIL2R levels and CXCL9 (a chemokine driven by IFN-g) were determined independently in CLIA certified clinical diagnostic laboratory. Research personnel who analyzed the flow cytometry data were blinded to the corresponding sIL2R test results and clinical diagnosis. Longitudinal follow-up was performed for a subset of patients with HLH or immune dysregulation with evidence of T-cell activation. We also evaluated T-cell activation in 30 healthy controls (HC) to establish a reference range. In addition, the correlation between T-cell activation markers with plasma levels of sIL2R and CXCL9 was also investigated. Results: Evaluation of T-cell activation measured by HLADR+CD38high in HCs and different hyperinflammatory/ immune regulatory disorders revealed that HCs have less than 8% of T-cell activation in CD8+ T effector memory (TEM) and less than 4% for activation in the CD4+ TEM compartments. In patients with suspected hyperinflammatory/ immune regulatory disorders, we identified significant correlation of direct T-cell activation with plasma sIL2R level in different T-cell subsets, CD3 (r = 0.44, p < 0.0001), CD4 (r = 0.41, p < 0.0001), CD8 (r = 0.45, p <0.001), CD4 TEM (T effector memory) (r =0.53, p < 0.001), and CD8 TEM (r =0.53, p < 0.0001). The strongest correlation between HLADR+CD38high with sIL2R level was noted in CD4+ TEM and CD8+ TEM compartments (Figure 1). The correlation is even more robust at disease onset (r = 0.69, p <0.0001 for CD4+ TEM and r = 0.64, p < 0.0001 for CD8+ TEM). However, at follow up, only activation in CD8+ TEM correlated with sIL2R levels (r = 0.4, p = 0.0069). Moreover, T-cell activation in CD8+ TEM correlated well with CXCL9 and ferritin levels. Among the cohort of patients with the confirmed final diagnosis, we found that both p-HLH and EBV-HLH have CD8+ TEM activation > 70%, whereas MAS and m-HLH have a median T cell activation of 37.8% (10.5-67) and 48.1% (4.9-80.6) respectively. Immune dysregulation patients had T-cell activation range from 8.0 to 46.0 % and sepsis group has 0% to 10.8% (Figure 2). A similar trend was also validated using corresponding plasma sIL2R levels in different hyperinflammatory states. Conclusions: Flow cytometry-based direct assessment of HLADR+CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulations disorders. If validated, this could be used as a real-time assessment of T-cell activation at disease onset and monitoring response to therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimizing the Supportive Care of Intensive Chemotherapy in AML : Impact of Vitamin C and D Supplementation in Patients with NPM1 Mutation. a Dataml Registry Study

Background Vitamin (vit) deficiencies are frequently observed in patients (pts) with newly diagnosed AML (ND-AML). A lower level of vit D is associated with a worse prognosis in pts treated with intensive chemotherapy (IC) (Lee HJ, Cancer 2014). Similarly, a pretransplant vit D deficiency is associated with a higher risk of relapse (Radujkovic JCO, 2017). Moreover, preclinical studies demonstrated the antileukemic activity of vit D through the modulation of cell cycle, differenciation and apoptosis even though the clinical translation has not been successful (Cao H, Exp Hematol 2017 ; Paubelle E, Cell Rep 2020). More recent data have highlighted the role of vit C in AML. Vit C is a cofactor and increases the activity of TET2 enzyme, inducing DNA demethylation, stem cell differentiation and antileukemic activity (Agathocleous M, Nature 2017; Cimmino L, Cell 2017). Cases of remission following vit C supplementation have been reported (Foster M, Antioxidants, 2018 ; Das A, Blood Cancer J, 2019) and a small study showed that the addition of vit C to decitabine/AraC/aclarubicin/G-CSF improved outcome compared to DCAG (Zhao H, Leuk Res 2018). Based on these data, we modified our practice by adding vit C and D to the supportive care (SC) of IC. Methods The study population included all pts with ND-AML treated by IC and registered in Toulouse DATAML from 01/2015 to 05/2020. As of March 2018, as part of the SC for AML pts treated by IC and in the absence of contra indication (renal lithiasis, renal insufficiency, G6PD deficiency, hypercalcemia), vit C (1g x 2/d, three times a week ; IV) and vit D (100,000 IU/week ; PO) have been administered from d10 until hematologic recovery of induction and consolidation. The principal objective of this retrospective study was to assess the impact of the vit supplementation on EFS. Secondary objectives were response to induction, early death, OS, RFS, incidence of relapse, vitamin levels during treatment and safety. Results 431 pts were included, 262 without (from 01/2015 to 02/2018 ; control group) and 169 with vit C/D supplementation (03/2018-05/2020 ; vitC/D group). Data were updated on 03/03/2022. The median FU was 45.6 months. Pt characteristics were well balanced except for age, PS and creatinine (Table 1). In the vitC/D group, the median plasma level of vit C was 3.20 mg/L (range, 0.47-15.42) at diagnosis and 4.62 mg/L (range, 0.18-18.1) at time of hematologic recovery from induction (P=0.18). The level of vit D at diagnosis was 16 ng/mL (range, 4-56) and 18 ng/mL (range, 4-42) in the control and vitC/D groups, respectively. Upon recovery from induction, vit D levels significantly increased compared to diagnosis in the vitC/D group (median, 39 ng/ml, range, 5-93 ; P<0.0001). CR/CRi rate was 84.4% (control) and 84% (vitC/D) (P=0.93). Day-30 death rate was 4.2% (control) and 2.4% (vitC/D) (P=0.31). During induction, the rates of grade 3-4 bacterial infections (vitC/D, 27.2% vs control, 35.1%, P=0.086), fungal infections (10.1 vs 18.3%, P=0.019), hemorrhages (1.8 vs 5.7%, P=0.045) or macrophage activation syndrome (1.8 vs 8.8%, P=0.002) were lower in the vitC/D group. Median level of day-21 calcemia was higher in the vitC/D group (2.48 mmol/L vs 2.44, P=0.003). Grade 2 hypercalcemia was observed in only 1 patient of the control group. Allo-SCT was performed in 37 (26.1%) and 75 (33.9%) pts of the vitC/D and control groups, respectively. Median pretransplant vit D levels were significantly higher in the vitC/D group (33 vs 19 ng/mL, P<0.0001). There was no significant difference in EFS (vitC/D, median 13.9 vs 17.4 months, P=0.26), RFS (15.5 vs 23.5, P=0.24) and OS (30.8 vs 34.5, P=0.80) between both groups. However, multivariate analysis for OS showed a significant interaction between vitC/D and NPM1 mutation meaning that vitC/D supplementation was significantly and independently associated with better OS in pts with NPM1 mutations (HR, 0.52 ; 95%CI: 0.30-0.90, P=0.019) but not in NPM1 wildtype pts (HR, 1.01 ; 95%CI: 0.68-1.51, P=0.95). MV analysis for EFS, RFS and CIR did not find any significant interactions. Conclusion Vit C and D supplementation is feasible and safe in AML pts during IC. Normal Vit D levels can be restored before transplant, which may be important. The potential impact of vit C/D supplementation in AML with NPM1 mutations needs further studies and pave the way for exploratory analyses to explain how the VDR pathway and/or vit C activity may interact with the biology of NPM1 mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Case of Macrophage Activation Syndrome (MAS) and Atypical HUS in Newely Diagnosed SLE

A Case of Macrophage Activation Syndrome (MAS) and Atypical HUS in Newely Diagnosed SLE

The Spectrum of Still's Disease: A Comparative Analysis of Phenotypic Forms in a Cohort of 238 Patients.

Still's disease (SD) is a heterogeneous autoinflammatory disorder for which several phenotypes have been described. We conducted a retrospective study to re-evaluate the dichotomous view of the disease, to compare the juvenile and adult forms, and to look for prognostic factors. We collected data from ten French centers, seeking patients with a diagnosis of adult-onset SD (AOSD) or systemic juvenile idiopathic arthritis (sJIA). We identified 238 patients, 152 (64%) of whom had AOSD while 86 (36%) had sJIA. The median age at SD onset was 26.6 years. In patients with identifiable patterns, the course of SD was systemic in 159 patients (74%), chronic in 55 (26%). Sore throat and myalgia were more frequent in patients with AOSD. Abnormal liver tests, serum ferritin and C-reactive protein levels were higher in AOSD group. Fever and skin rash were predictive of complete remission or recovery and high lactate dehydrogenase level was a poor prognosis factor. Symptoms such as splenomegaly, skin rash, high polymorphonuclear neutrophils count and macrophage activation syndrome were predictive of a systemic phenotype. Overall, there were no major differences between sJIA and AOSD. Our results are consistent with the "biphasic" model of an autoinflammatory disease that can progress to chronic arthritis if not treated early.

A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis.

To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH). A literature search was conducted using the search terms "hemophagocytic lymphohistiocytosis," "hemophagocytic syndrome," "macrophage activation syndrome," and "treatment" on Ovid and PubMed from January 1, 2017, through September 28, 2022. Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH. Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH. The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician's armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab. Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.

Life threatening macrophage activation syndrome as the initial presentation of systemic lupus erythematosus: A case report and review of the literature

BackgroundMacrophage activation syndrome (MAS) is characterized by activation of hemophagocytic cells and is a very rare initial manifestation of systemic lupus erythematosus (SLE). Aim of the workTo describe the features of a challenging case of SLE initially presented with MAS. Case reportA previously healthy 20-year-old female was referred to the Rheumatology clinic with a 25-days’ history of persistent fever, general fatigue, and significant weight loss. Clinical examination revealed a high-grade fever (41 °C), significant hair loss and general malaise. Laboratory investigations revealed leucopenia (1.5 × 109/L), neutropenia (0.7 × 109/L), lymphopenia (0.6 × 109/L), normocytic normochromic anemia (9 g/dL), thrombocytopenia (95 × 109/L), elevated liver enzymes, hyperbilirubinemia (2.6 mg/dl); hypertriglyceridemia (306 mg/dL), hyperferritinemia (16000 ng/mL), elevated D-Dimer (4.7 mg/L), elevated lactate dehydrogenase (1379 U/L) and direct and indirect Coombs' tests were positive. Erythrocyte sedimentation rate was 28 mm/1st h. Immunological screening was positive for antinuclear antibody (ANA) and anti-double stranded deoxyribonucleic acid (anti-dsDNA). Serum C3 and C4 complement factors were low and C reactive protein was negative. Soluble CD25 was elevated (9800 pg/ml). Bone marrow biopsy showed hypocellular bone marrow with normal megakaryocytes and erythroid series with evidence of hemophagocytosis. A diagnosis of SLE initially presented with MAS was made. The patient received intravenous methylprednisolone for 5 consecutive days followed by prednisolone and cyclosporine A and intravenous immunoglobulin. The condition deteriorated with progressive coagulopathy, thrombocytopenia and hyperferritinemia. Subsequently, the conscious level of the patient deteriorated, multiorgan failure developed and the patient died. ConclusionMAS is a serious condition that may be the first presentation of SLE.

Possible Macrophage Activation Syndrome Caused by Endoscopic Retrograde Cholangiopancreatography for Bacteremia Due to Chronic Cholelithiasis

Hypoglycemia is caused by various clinical diseases. Among older patients, occult bacteremia may cause critical illness-related corticosteroid insufficiency (CIRCI), triggering hypoglycemia. Additionally, older patients have various chronic medical and homeostatic conditions. Interventions may be needed when chronic conditions cause clinical diseases and CIRCI. Herein, we report a case of possible macrophage activation syndrome (MAS) caused by endoscopic retrograde cholangiopancreatography for bacteremia due to chronic cholelithiasis in an 85-year-old man. Interventions for chronic conditions could impinge on homeostasis in older patients, causing acute conditions such as MAS. Among older frail patients with chronic conditions, interventions for chronic conditions should be discussed, including the triggering of other acute conditions, such as MAS.