20 Paediatric SLE

Case 1: 9-year-old female with rash and oral ulcer Alexandre Belot Alisson is 9 years old and came to the outpatient unit with a rash and oral ulcer. Her past medical history highlighted two invasive infections (meningitidis and pneumonia). She had no muscular weakness, no lymphoproliferative disease and no fever. Her laboratory exams revealed: WBC: 2.5 G/L, with PNM=1.2G/L, Hb = 10 g/dl, Platelet = 135G/L, CRP = 10 mg/L. CPK and aldolase were within normal values. Serology for Epstein-Barr Virus, parvovirus B19 and measles were negative. Autoimmune check-up showed: ANA+ 1/1280, C3 and C4 normal, anti-dsDNA negative, anti SSA+ >8. The dosage of immunoglobulins was normal (including subclasses). She further developed severe systemic disease with lupus nephritis, white matter lesions at the cerebral MRI. Complement CH50 was dramatically decreased and her C1q level was undetectable. Discussion Points Explore complement deficiency in juvenile systemic lupus erythematosus (SLE) Discuss monogenic SLE Case 2: 13-year-old female with skin rash and chilblain Alexandre Belot Jade is 13 years old and has been recently diagnosed with juvenile SLE. Her past medical history revealed a pervasive developmental disorder with features of autism and mental delay. Her parents are first cousins. Her first symptoms were skin rash, chilblain. Following first-line therapy with hydroxychloroquine and topical steroids, she developed a polyarthritis with hepatitis and leukopenia. Abdominal sonography was normal. Autoantibodies for autoimmune liver disease (dot hepatitis) were negative. Treatment with steroids and methotrexate was introduced and effective on the joints. Further genetic exploration revealed a biallelic mutation of TREX1. Later on, she was treated with a JAK inhibitor in addition to methotrexate resulting in a positive outcome. Discussion Points Type I interferon in juvenile SLE Interferonopathies Case 3: 14-year-old male with haematuria and renal colic Alexandre Belot Michael presented a macroscopic hematuria with renal colic at the age of 14 years old. Sonography revealed a left nephromegaly without evidence of urinary tract obstruction. A CT scan showed a left renal venous thrombosis. Initial work-up identified a triple positivity for lupus anticoagulant, anti-B2 Gp-I and anti-cardiolipin antibodies. Anticoagulant therapy was initiated. dsDNA and ANA were negative and complement was normal. Six months later, the hematuria had completely disappeared, according to a urine dipstick test, but proteinuria was still present with a protein:creatinine ratio of 120 mg/mmol in the urine. A new doppler sonography and CT scan showed the absence of perfusion in the left kidney. Considering the proteinuria, a percutaneous biopsy was performed on the contralateral kidney and histology revealed Class V lupus nephritis. Notably, autoantibodies and complement were still normal. Rituximab and ACE inhibitors were introduced, and proteinuria rapidly disappeared. Discussion Points How to explore APS in children Management of thrombosis in pediatric autoimmune diseases Case 4: Anti-histone antibodies: does it always mean drug-induced lupus erythematosus? Rolando Cimaz A South-American 14-year-old girl presented with arthralgia, weakness and alopecia. As she was under antiepileptic treatment since she was 5 years old, on suspicion of drug-induced lupus erythematosus (DILE) anti-histone antibodies were dosed and showed positive results. She presented with mild anemia, leukopenia, hypocomplementemia, ANA, anti-dsDNA and LAC positivity. The antiepileptic therapy was initially modified and then, as no more crises were present, interrupted. However, anemia, leukopenia, hypocomplementemia, ANA and anti-dsDNA persisted, and the diagnosis of idiopathic systemic lupus erythematosus (SLE) was made. After treatment with hydroxychloroquine and low dose prednisone the girl clinically improved and her laboratory results normalized. This case report is suggestive of the complexity in differentiating SLE and DILE and underlines the importance of a long and careful follow-up. Discussion Points Medications that can trigger lupus symptomatology Triggers of lupus or of lupus-like disease (autoimmunity in general) with TNF inhibitors used for arthritis Risks of prescribing such medications (i.e. anti-TNF) in patients with inflammatory arthritis and pre-existing autoantibodies or a family history of autoimmune disease Case 5: Bleeding and thrombosis in juvenile systemic lupus erythematosus Rolando Cimaz A young girl with immune thrombocytopenic purpura was also found to have antiphospholipid antibody syndrome. This case describes the complexity of therapeutic management linked to the risk of bleeding and thrombosis. Irene is 15-year-old. In recent hours she has experienced intermittent claudication and lower right limb pain. Her physical exam reveals swelling and tenderness of right calf, pain to compression and mobilization of right foot. Laboratory tests reveal WBC 21.610 (N 77%); Hb 13.1 g/dl; PLT 91000/mmc; aPTT 48.4 sec, PT 99%; fibrinogen 236 mg/dl; D-Dimer 0.59 mg/L. Ultrasound revealed thrombosis. Past medical history showed that 8 months before she had suffered from severe metrorrhagia. Laboratory tests had shown: PLT 7000, Hb 10.2 g/dl, Coombs direct test +, PT 1.18, aPTT 76 sec; IgM e IgG anticardiolipin +. Therapy consisted in intravenous immunoglobulin (two infusions) and then oral steroids. Five relapses occurred, and laboratory showed: ANA+ (1:160), ENA -, anticardiolipin -, C3 85, C4 7.5, LAC +. Repeat laboratory test showed ANA+, ENA-, anticardiolipin +, anti-b2 glycoprotein -, LAC +. Discussion Points For thrombosis Heparin 6000U/x2/day. For how long? And for thrombocytopenia? Oral steroids (2 mg/kg/day); Mycophenolate mofetil (750 mg/m2 x 2/day). But despite this therapy, she relapsed. So > rituximab 750 mg/m2/2 weeks. For SLE hydroxychloroquine was given. Learning Objectives Distinguish between idiopathic and drug-induced SLE Describe the treatment of APS in children Discuss treatment options for hematologic SL

Pseudohypoaldosteronisms, report on a 10-patient series

Background. Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. Methods. Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. Results. Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. Conclusions. PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronis

Elevated monocyte HLA-DR in pediatric secondary hemophagocytic lymphohistiocytosis: a retrospective study

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, and its diagnosis may be challenging. In particular, some cases show close similarities to sepsis (fever, organ failure, and high ferritin), but their treatment, while urgent, differ: prompt broad-spectrum antibiotherapy for sepsis and immunosuppressive treatment for HLH. We questioned whether monocyte human leucocyte antigen (mHLA)–DR could be a diagnostic marker for secondary HLH (sHLH).MethodsWe retrospectively reviewed data from patients with a sHLH diagnosis and mHLA-DR quantification. mHLA-DR data from healthy children and children with septic shock, whose HLA-DR expression is reduced, from a previously published study were also included for comparison.ResultsSix patients with sHLH had mHLA-DR quantification. The median level of monocyte mHLA-DR expression in patients with sHLH [79,409 antibodies bound per cell (AB/C), interquartile range (IQR) (75,734–86,453)] was significantly higher than that in healthy children and those with septic shock (29,668 AB/C, IQR (24,335–39,199), and 7,493 AB/C, IQR (3,758–14,659), respectively). Each patient with sHLH had a mHLA-DR higher than our laboratory normal values. Four patients had a second mHLA-DR sampling 2 to 4 days after the initial analysis and treatment initiation with high-dose corticosteroids; for all patients, mHLA-DR decreased to within or close to the normal range. One patient with systemic juvenile idiopathic arthritis had repeated mHLA-DR measurements over a 200-day period during which she underwent four HLH episodes. mHLA-DR increased during relapses and normalized after treatment incrementation.ConclusionIn this small series, mHLA-DR was systematically elevated in patients with sHLH. Elevated mHLA-DR could contribute to sHLH diagnosis and help earlier distinction with septic shock

Subcutaneous anakinra in the management of refractory MIS-C in France

IntroductionMultisystemic inflammatory syndrome in children (MIS-C) is a therapeutic emergency and can lead to myocardial dysfunction (17%–75%) and heart failure (52%–53%). Intravenous immunoglobulins (IVIG) and corticosteroids (CST) have been validated for the management of this condition. Recent reports suggest that an interleukin-1 (IL-1) receptor antagonist, namely anakinra, may be a valuable add-on to the 2019 novel coronavirus disease (COVID-19) treatment for refractory patients. The purpose of this study was to describe the clinico-biological characteristics of patients treated with anakinra as well as the efficacy and safety of subcutaneous anakinra therapy in this condition.MethodsThe prospective multicentre study of children hospitalized for MIS-C between March 2020 and September 2022, including 23 international paediatric centres, followed for a mean duration of 3.072 ± 3.508 months. The patient data were extracted from the Juvenile Inflammatory Rheumatism (JIR) cohort. The clinico-pathological characteristics, cardiac ultrasound data, and adverse events were reported in patients receiving anakinra.ResultsOf the 470 children admitted with MIS-C, 18 French patients (50% girls) with a mean age of 10.06 ± 3.9 years were treated with subcutaneous anakinra. Anakinra was used in two situations, macrophage activation syndrome (MAS) (4 patients) and heart failure (14 patients) with a median left ventricular ejection fraction (LVEF) of 39.5% (30%–45%). The average dose of anakinra received was 2.53 ± 1.3 mg/kg/day for a median duration of 3 days. Prior to introduction, 78% (n = 14/18) of the patients had received CST and 56% (n = 10/18) had received IVIG. Only two patients received IVIG alone and six received CST alone plus anakinra. In 10% of cases, IVIG was poorly tolerated from a cardiovascular point of view and was discontinued. Transient elevations in serum transaminases were noted in four patients on anakinra without the need for treatment or dose modification. In all patients, rapid (48 h) improvement in myocardial function was observed (LVEF > 55%) with a concomitant significant decrease in myocardial enzymes (p < 0.05). All patients survived with complete recovery of cardiac function without sequelae.ConclusionsSubcutaneous anakinra appears to be a safe and effective treatment for the management of heart failure or MAS in MIS-C patients. The value of IVIG in these two situations remains to be reviewed

Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis

BACKGROUND: Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. METHODOLOGY: Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-). PRINCIPAL FINDINGS: In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice. CONCLUSION/SIGNIFICANCE: These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorder

Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching

INTRODUCTION: Accurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs. METHODS: We collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient. RESULTS: Our results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2. DISCUSSION: This study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs

Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children

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