Hematological involvement in pediatric systemic lupus erythematosus: A multi-center study

Introduction: Systemic lupus erythematosus (SLE) may present with features of several systems, including hematological manifestations. In this study, we aimed to evaluate the characteristics of hematological involvement and assess possible associations and correlations in pediatric SLE patients. Method: This is a retrospective multi-center study. The medical records of pediatric SLE patients followed between January 2000 and June 2020 were analyzed. All children fulfilled the criteria of the Systemic Lupus International Collaborating Clinics. Results: The study included 215 children with SLE, 118 of whom had hematological manifestations. Concomitant renal involvement and low C3 levels were significantly more frequent in patients with hematological involvement ( p = 0.04, p = 0.008, respectively). Also, anti-cardiolipin, anti-beta-2-glycoprotein I (anti-β2 GP1), and anti-Sm antibody positivity, and the presence of lupus anticoagulant were more common in the group with hematological findings ( p = 0.001 for anti-cardiolipin antibody positivity and p < 0.001 for the positivity of anti-β2 GP1 antibody, anti-Sm antibody, and lupus anticoagulant). The most common hematologic abnormality was anemia (n = 88, 74.5%), with autoimmune hemolytic anemia constituting the majority (n = 40). Corticosteroids followed by IVIG were the mainstay of treatment. In patients resistant to corticosteroid and IVIG treatments, the most preferred drug was rituximab. Low levels of C3, high SLEDAI score, high incidence of renal involvement, and positive antiphospholipid antibodies were associated with hematological involvement in the univariate analysis. The presence of antiphospholipid antibodies and high SLEDAI score were independently associated with hematological involvement in multivariate analysis (OR: 4.021; 95% CI: 2.041–7.921; p < 0.001 and OR: 1.136; 95% CI: 1.065–1.212; p < 0.001). Conclusion: Hematological abnormalities are frequently encountered in pediatric SLE. Positive antiphospholipid antibodies and high SLEDAI scores were associated with hematological involvement.

Guillain Barré Syndrome as Primary Presentation of Systemic Lupus Erythematosus (SLE-GBS) in a Teenage Girl: A Case Report

Background: Peripheral nervous system (PNS) involvement, including Guillain Barré Syndrome (GBS), accounts for fewer than 10% of SLE cases with neuropsychiatric manifestations. GBS as the presenting, major manifestation of pediatric SLE is extremely rare, and the best treatment approach is unknown. Case presentation: A 14-year-old, previously healthy female Emirati teenager presented with a classic picture of GBS with ascending, progressive bilateral muscle weakness leading to respiratory insufficiency within five weeks of symptom onset, associated with typical protein-cell dissociation in cerebro-spinal fluid and nerve root enhancement demonstrated by spinal MRI. Subsequently, elevated anti-dsDNA and anti-Smith/RNP and anti-SS-A and -B antibody concentrations were detected in serum, suggestive of SLE. GBS treatment was initiated with IVIG and methylprednisolone pulses, with minimal improvement. The patient required endotracheal intubation and ventilation, followed by a second course of IVIG, rituximab, and eventually plasma exchange (PLEX) therapy. The diagnosis of lupus-associated GBS was corroborated by a kidney biopsy demonstrating lupus nephritis WHO class II with “full house” immunofluorescence pattern. After 14 PLEX sessions, her muscle strength and respiratory efforts had improved substantially. Treatment was completed with two more rituximab infusions, followed by mycophenolate mofetil, in addition to HCQ and tapering doses of oral prednisolone. Five weeks after the last PLEX treatment, she had regained her usual strength and achieved full, sustained recovery from GBS. While she continued to demonstrate moderate anti-dsDNA antibodies and high-level anti-Smith and Sjogren antibodies, C3, C4 and urine readings quickly normalized with no other manifestations of lupus or lupus nephritis 11 months after the initial assessment. At this time she was maintained with hydroxychloroquine, with ongoing depletion of circulating B cells. To our knowledge, this is only the third pediatric patient reported with SLE-GBS.Conclusions: We report severe GBS as the first, dominant manifestation of pediatric SLE. Our case and a review of the literature reveal that cconventional GBS therapy may not be adequate to treat this rare lupus presentation. SLE should be included in the differential diagnosis of GBS. Importantly, treatment experiences and outcomes of such cases need be reported to inform future treatment recommendations.

Clinical Manifestation and Hematologic Interpretation of Pediatric Systematic Lupus Erythematosus at Initial Presentation: 2-Years Observation

Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by a spectrum of clinical manifestations, immunological abnormalities, and varied laboratories results. In children, SLE manifestation is particularly more severe, involving more organs. Hematological manifestation has been known as the most common manifestation. The purpose of this study was to describe the clinical manifestations and hematologic interpretation of pediatric SLE at initial presentation.Methods: This retrospective data collection study was conducted at the Department of Child Health Dr. Hasan Sadikin General Hospital Bandung on medical records from a two-year period of 2017–2018. The clinical manifestations were categorized into malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, renal disorders, and neurological disorders. The hematologic interpretations were categorized into anemia, leukopenia, neutropenia, lymphopenia, and thrombocytopenia. Clinical manifestations and hematological interpretations were presented as occurrence percentages and stratified into three age-group of pre-pubertal, peri-pubertal, and post-pubertal.Results: Among 79 pediatric SLE patients (median age 14 years old; IQR 11–16), female gender was predominant. Abnormalities hematologic interpretation occurs in more than half of the patients (83.5%). Malar rash and anemia were the commonest findings among all age groups. Increased occurrence of neuropsychiatric and renal disorders were observed in all age-groups.Conclusions: Malar rash and anemia are important findings among pediatric SLE patients. Furthermore, the occurrences of the neuropsychiatric and renal disorders are also important.

Hematological involvement in pediatric systemic lupus erythematosus: A multi-center study

Introduction Systemic lupus erythematosus (SLE) may present with features of several systems, including hematological manifestations. In this study, we aimed to evaluate the characteristics of hematological involvement and assess possible associations and correlations in pediatric SLE patients. Method This is a retrospective multi-center study. The medical records of pediatric SLE patients followed between January 2000 and June 2020 were analyzed. All children fulfilled the criteria of the Systemic Lupus International Collaborating Clinics. Results The study included 215 children with SLE, 118 of whom had hematological manifestations. Concomitant renal involvement and low C3 levels were significantly more frequent in patients with hematological involvement ( p = 0.04, p = 0.008, respectively). Also, anti-cardiolipin, anti-beta-2-glycoprotein I (anti-β2 GP1), and anti-Smith (anti-Sm) antibody positivity, and the presence of lupus anticoagulant were more common in the group with hematological findings ( p = 0.001 for anti-cardiolipin antibody positivity and p < 0.001 for the positivity of anti-β2 GP1 antibody, anti-Sm antibody, and lupus anticoagulant). The most common hematologic abnormality was anemia ( n = 88, 74.5%), with autoimmune hemolytic anemia constituting the majority ( n = 40). Corticosteroids followed by IVIG were the mainstay of treatment. In patients resistant to corticosteroid and IVIG treatments, the most preferred drug was rituximab. The presence of antiphospholipid antibodies and high SLEDAI score were independently associated with hematological involvement in multivariate analysis (OR: 0.249; 95%CI: 0.126–0.490; p < 0.001 and OR: 1.136; 95%CI: 1.065–1.212; p < 0.001). Conclusion Hematological abnormalities are frequently encountered in pediatric SLE. Positive antiphospholipid antibodies and high SLEDAI scores were associated with hematological involvement.

Differential parameters between activity flare and acute infection in pediatric patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) patients are vulnerable to infections. We aim to explore the approach to differentiate active infection from disease activity in pediatric SLE patients. Fifty pediatric SLE patients presenting with 185 clinical visits were collected. The associations between both clinical and laboratory parameters and the outcome groups were analyzed using generalized estimating equations (GEEs). These 185 visits were divided into 4 outcome groups: infected-active (n = 102), infected-inactive (n = 11), noninfected-active (n = 59), and noninfected-inactive (n = 13) visits. Multivariate GEE (generalized estimating equation) analysis showed that SDI, SLEDAI-2K, neutrophil‐to‐lymphocyte ratio (NLR), hemoglobin, platelet, RDW-to-platelet ratio (RPR), and C3 are predictive of flare (combined calculated AUC of 0.8964 and with sensitivity of 82.2% and specificity of 90.9%). Multivariate GEE analysis showed that SDI, fever temperature, CRP, procalcitonin (PCT), lymphocyte percentage, NLR, hemoglobin, and renal score in SLEDAI-2k are predictive of infection (combined calculated AUC of 0.7886 and with sensitivity of 63.5% and specificity of 89.2%). We can simultaneously predict 4 different outcome with accuracy of 70.13% for infected-active group, 10% for infected-inactive group, 59.57% for noninfected-active group, and 84.62% for noninfected-inactive group, respectively. Combination of parameters from four different domains simultaneously, including inflammation (CRP, ESR, PCT), hematology (Lymphocyte percentage, NLR, PLR), complement (C3, C4), and clinical status (SLEDAI, SDI) is objective and effective to differentiate flares from infections in pediatric SLE patients.

The performances of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 classification criteria in pediatric systemic lupus erythematosus

Objective Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The ACR (American College of Rheumatology) 1997, SLICC (Systemic Lupus International Collaborating Clinics) 2012, and EULAR (European League Against Rheumatism)/ACR 2019 SLE classification criteria are formed based on data mainly from adult patients. We aimed to test the performances of the SLE classification criteria among pediatric SLE patients. Methods Pediatric SLE patients (n=262; 80.9% female) were included from three different centers in Turkey. As controls, 174 children (60.9% female) with other diseases who had ANA (antinuclear antibody) test results were included. The gold standard for SLE diagnosis was expert opinion. Results The sensitivities of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 criteria were 68.7%, 95.4%, and 91.6%, respectively. The specificities of the ACR 1997, SLICC 2012, and EULAR/ACR 2019 criteria were 94.8%, 89.7%, and 88.5%, respectively. 18 SLE patients met the SLICC 2012 but not the EULAR/ACR 2019 criteria. Among these, hematologic involvement was prominent (13/18; 72.2%). Eight SLE patients fulfilled the EULAR/ACR 2019 but not the SLICC 2012 criteria. Among these, joint involvement was prominent (6/8; 75%). Conclusion This is the largest cohort study of pediatric SLE testing the performances of all three classification criteria. The SLICC 2012 criteria yielded the best sensitivity, while the ACR 1997 criteria had the best specificity. SLICC 2012 criteria performed better than EULAR/ACR 2019 criteria. Separation of different hematological manifestations in the SLICC 2012 criteria might have contributed to the higher performance of this criteria set.

SLICC-based Phenotype of Juvenile Systemic Lupus Erythematosus in the Philippines

Objective. To describe the clinical profile of Filipino pediatric SLE patients as determined using the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. Methods. We checked which among the SLICC criteria were fulfilled by Filipino pediatric SLE patients when weexamined them and their case records, as part of a nationwide genetic study on SLE conducted from October2015 to March 2017. Results. Ninety-seven (out of 321) who were diagnosed to have SLE before 19 years of age were evaluated.The mean age of the population at the time of evaluation was 19.8 ± 6.9 years. Females comprised 94% of ourpopulation. Mean age of onset was 14.4 ± 2.7 years, while the mean age of diagnosis was at 14.5 ± 2.6 years. Acute cutaneous rash was found in 87%; oral ulcers 65%; renal disorder 63%; non-scarring alopecia 61%; arthritis 58%; chronic cutaneous rash 36%; leukopenia 35%; hemolytic anemia 34%; serositis 25%; thrombocytopenia 23%, and neurologic disorder 8%. Anti-nuclear antibody was present in 85%; low complement 32%; anti-dsDNA 28%; direct Coombs’ 16%; antiphospholipid antibody 3%; and anti-Smith antibody 1%. Kidney biopsy was performed in only 14% (14/97) of patients, of whom 27% had class III histopathologic characteristic. Conclusions. Filipino pediatric SLE patients typically present with mucocutaneous, renal, and musculoskeletalinvolvement. Cardiopulmonary and neurologic manifestations are found to be less common among them. Finally, renal biopsy is not commonly performed among these patients.

AB0974 ANALYSIS OF DYSLIPIDEMIA IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Systemic lupus erythematosus (SLE) is an autoimmune disease and is characterized by multiple autoantibodies associated with a multisystem illness. However, studies of dyslipidemia in pediatric SLE patients are limited.Objectives:The aim of our study is to describe the lipid profiles associated with disease activity and organ damage and their correlation with laboratory parameters in pediatric SLE patients.Methods:We retrospectively reviewed medical records from a single tertiary hospital in Taipei, Taiwan from 2002 to 2018. One hundred and twenty-four patients diagnosed with SLE were included. Dyslipidemia is defined as elevations in total cholesterol (TC), low-density lipoprotein (LDL), and triglyceride (TG) levels, and a reduction in high-density lipoprotein (HDL) levels. We gathered all of the lipid profiles, clinical characteristics, and laboratory parameters from each patient. Pediatric SLE patients participated in this study, based on their lipid profile, were classified as dyslipidemic or not. The mean values of each evaluated parameters were calculated and analyzed with generalized estimating equation (GEE) method.Results:Total thirty-one SLE patients were enrolled; twenty-four (77%) patients had dyslipidemia. The levels of total cholesterol, TG, and LDL in the dyslipidemic group are significantly higher than those of non-dyslipidemia (214.0 mg/dLvs145.0 mg/dL, 130.1 mg/dLvs76.4 mg/dL, 138.7 mg/dLvs82.0 mg/dL; respectively). The mean values of white blood cell count (6726/µL) in dyslipidemia group are significantly higher than non-dyslipidemia group (4521/µL;p=0.0157). In contrast, the level of high-sensitivity CRP in the non-dyslipidemia group (0.2 mg/dL) are significantly lower than those of patients with dyslipidemia (0.49 mg/dL;p=0.0486).Conclusion:It has been well known that CRP could suppress HDL and increase TG and that elevation of CRP might indicate increased cardiovascular risk. Our results demonstrated that elevated high sensitivity CRP levels were noted in SLE patients with dyslipidemia. It is suggested that routine monitoring of cardiovascular risk factors, such as dyslipidemia, should be recommended for pediatric SLE patients.References:[1]Szabó, M.Z., Szodoray, P. & Kiss, E. Immunol Res (2017) 65: 543.[2]Atta, A.M., Silva, J.P.C.G., Santiago, M.B. et al. Clin Rheumatol (2018) 37: 1539.[3]Yu, H.H., Chen, P.C., Yang, Y.H. Atherosclerosis. 2015; 243(1): 11–18.Acknowledgments:The authors acknowledge statistical assistance provided by the Center of Statistical Consultation and Research in the Department of Medical Research, National Taiwan University HospitalDisclosure of Interests:None declared

FRI0469 TO DISTINGUISH BETWEEN DISEASE FLARE AND ACTIVE INFECTION IN PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Background:SLE is the autoimmune disease involving multiple systems. Infections might mimic SLE flare, leading to confusion over the diagnosis and appropriate treatment. To distinguishing acute infection from active flare always remains a clinical challenge.Objectives:We aim to explore the potential parameters in identifying active infection and disease activity in pediatric SLE.Methods:We reviewed the medical charts of the pediatric SLE patient in National Taiwan University Hospital from August 2015 to September 2019, and 50 SLE patients presented 185 episodes of suspicious activity or infection and received CRP, ESR, and Procalcitonin measurement were included. Time matched other laboratory parameters and clinical assessments were also collected. Episodes were divided into 4 groups: infected-active, infected-inactive, noninfected-active, and noninfected-inactive. Association of parameters with outcomes were predicted by generalized estimating equation. The receiver operating curve and the area under the curve were used to evaluate the diagnostic performance. We also used multinomial logistic regression model for nominal outcome, by setting noninfected-inactive group as the reference category.Results:There were 7 males (14%) and 43 females (86%), with the mean ages 13.9 ± 4.4 years old. Most of the patients had renal (72%) or mucocutaneous (72%) involvement. The most common infection site was respiratory system (56%). Multivariate GEE analysis showed Damage index(DI), SLEDAI-2k, neutrophil-to-lymphocyte ratio (NLR), hemoglobin, platelet, RDW-to-platelet ratio (RPR), and C3 are independent parameters for predicting SLE activity flare. Combination of these seven parameters resulted in a model with calculated AUC of 0.8964 and with sensitivity of 82.2 % and specificity of 90.9%. Multivariate GEE analysis showed DI, fever, CRP, Procalcitonin, lymphocyte percentage, NLR, hemoglobin, and renal score in SLEDAI-2k are independent parameters for predicting acute infection. These eight parameters resulted in a model with calculated AUC of 0.7886 and with sensitivity of 63.5% and specificity of 89.2%. We select a total of 10 variables (DI, SLEDAI-2k, Fever, Procalcitonin, lymphocyte percentage, NLR, hemoglobin, platelet, RPR, C3) to establish multinomial logistic regression, then predict four groups with accuracy of 70.13% for infected-active, 10% for infected-inactive, 59.57% for noninfected-active, and 84.62% for noninfected-inactive.Conclusion:The proposed predictive calculator could be a useful tool for differentiation between activity flares and acute infections in pediatric SLE. Obtaining and combination of several parameters is effective and helpful to make appropriate judgement and treatment decisions for SLE patients.References:[1]Ceccarelli, F., et al., Assessment of disease activity in Systemic Lupus Erythematosus: Lights and shadows. Autoimmun Rev, 2015.14(7): p. 601-8.[2]Jung, J.Y. and C.H. Suh, Infection in systemic lupus erythematosus, similarities, and differences with lupus flare. Korean J Intern Med, 2017.32(3): p. 429-438.[3]Gensous, N., et al., Predictive biological markers of systemic lupus erythematosus flares: a systematic literature review. Arthritis Res Ther, 2017.19(1): p. 238.[4]Beca, S., et al., Development and validation of a risk calculator to differentiate flares from infections in systemic lupus erythematosus patients with fever. Autoimmun Rev, 2015.14(7): p. 586-93.[5]Sciascia, S., et al., Systemic lupus erythematosus and infections: clinical importance of conventional and upcoming biomarkers. Autoimmun Rev, 2012.12(2): p. 157-63.[6]Ospina, F.E., et al., Distinguishing infections vs flares in patients with systemic lupus erythematosus. Rheumatology (Oxford), 2017.56(suppl_1): p. i46-i54.[7]Ballinger, G.A.,Using Generalized Estimating Equations for Longitudinal Data Analysis.Organizational Research Methods, 2004.7(2): p. 127-150.Disclosure of Interests:None declared

SAT0234 SERUM AXL, FERRITIN, IGFBP4 AND STNFR2 AS BIOMARKERS OF PEDIATRIC SLE

Background:Proteomic screening is an efficient approach for identifying protein biomarkers in various inflammatory diseases. Our preliminary proteomic analysis revealed elevated levels of serum Axl, Ferritin, IGFBP4 and sTNFR2 in adult patients with active lupus nephritis (LN) (1). However, the role of these serum biomarkers in pediatric systemic lupus erythematosus (SLE) patients has not been examined.Objectives:To evaluate the performance of 4 serum protein markers for detecting disease activity in pediatric patients with SLE.Methods:83 pediatric patients who fulfilled ≥4 ACR criteria for SLE and 25 healthy controls were recruited for serological testing of 4 protein markers identified by antibody-coated microarray screen, namely Axl, ferritin, IGFBP4 and sTNFR2. SLE disease activity was assessed using the SLEDAI-2k score, renal disease activity was assessed by the renal SLEDAI (range 0-16; 0= inactive LN, ≥ 8= active renal). 57 patients had clinically active SLE (SLEDAI score ≥ 4 or having a flare) (28 active renal and 29 active non-renal SLE patients). In active renal patients, concurrent renal biopsy was performed, unless contraindicated. The ISN/RPS criteria were used to assess the histopathologic features of LN. Those Patients were further subcategorized into 2 groups; active proliferative (ISN/RPS classes III/IV) and non-proliferative (classes I/II/V).Results:The serum concentrations of Axl and ferritin were significantly higher in patients with active SLE than inactive SLE (3765±235 vs. 2513±130 pg/ml,P= 0.001) and (111±26 vs. 18±4 ng/ml,P =0.0001) respectively. Serum Axl levels were significantly higher in active renal versus active non-renal SLE patients (3765±235.3 vs. 2825±200.7 pg/ml,P= 0.04). In the active renal patients with paired kidney tissue and blood samples, none of the biomarkers tested discriminated classes of LN, although serum Axl, ferritin and IGBPB4 levels were higher in the proliferative subgroup. The levels of Axl, ferritin and IGFBP4 correlated significantly with SLEDAI scores (Axl, r= 0.58,P<0.0001; ferritin, r= 0.53,P<0.0001; IGFBP4, r= 0.229,P= 0.03). However, only serum Axl levels correlated significantly with the renal SLEDAI (r= 0.46,P= 0.01). The levels of Axl, IFGBP4 and sTNFR2 correlated with decreased C3 levels (r= - 0.54,P<0.0001; r= - 0.29,P= 0.007; r= - 0.29,P= 0.007) respectively. Only serum Axl and ferritin correlated with urinary PCR (r= 0.42,P<0.0001; r= 0.22,P=0.04) respectively. These markers were more specific, but less sensitive, in detecting concurrent SLE activity than elevated anti-dsDNA or decreased C3. The specificity values of serum ferritin and IGFBP4 for concurrent active lupus nephritis were higher than anti-dsDNA or C3. Serum ferritin was the best predictor of global SLE activity (AUC 0.81,P<0.0001), followed by C3 (AUC 0.79,P<0.0001) then Axl (AUC 0.71,P= 0.002), while both Axl and C3 were the best predictors of lupus nephritis activity (AUC 0.72, both).Conclusion:In pediatric SLE patients, serum ferritin and Axl perform better than traditional yardsticks in identifying disease activity, either global or renal. The performance of these serum markers should be explored further in a longitudinal cohort of pediatric SLE patients.References:[1]Wu T, Ding H, Han J, et al. Antibody-Array-Based Proteomic Screening of Serum Markers in Systemic Lupus Erythematosus: A Discovery Study. J Proteome Res. 2016 Jul 1;15 (7): 2102-14.Disclosure of Interests:None declared