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Background:Takayasu arteritis (TA) is a rare, large vessel vasculitis affecting mainly the aorta and its major branches. Data on paediatric TA (pTA) is very scarce.Objectives:The aim of this study was to characterize clinical presentation, therapy and outcome of pTA in a global study population.Methods:We conducted an international multicentre retrospective observational study of children diagnosed with pTA. Inclusion criteria were an age of less than 18 years at initial presentation in the year 2000 or more recently. Clinical data were collected from patients’ charts by the treating paediatric rheumatologist or nephrologist; data were fully anonymised for analysis purposes. Follow-up data was collected up to 2 years after diagnosis.Results:198 patients from 20 countries were included (76% female). The median age at disease onset was 12 years. Arterial hypertension (67%), a difference in pulses between limbs (65%) and fatigue (66%) were the most common symptoms at presentation. The gastrointestinal system was the second most affected organ system. The median eGFR (estimated glomerular filtration rate) at baseline was 105 ml/min/1.73m2. Renal artery stenosis was documented in 58% of all patients and in 37% there was need for an invasive renovascular procedure. In 25 of 32 (78%) patients who had either a positron emission tomography–magnetic resonance imaging (PET-MRI) or PET-computed tomography (CT) there was evidence of active inflammation mainly of the aorta. 67% of all patients showed thickened wall abnormalities and 31% had arterial dilatations in a major vessel on any one or more anatomical imaging modality such as ultrasound, CT or MRI. Immunosuppressive treatment was primarily steroids, cyclophosphamide and methotrexate, 37% of all patients were treated with monoclonal antibodies of which 65% received an anti-tumor necrosis factor (TNF) antibody, 31% an anti-Interleukin 6 (IL-6) antibody and 4% an anti-B-cell antibody. Dialysis was necessary in 7% and one patient underwent kidney transplantation. Seven patient deaths (4%) were documented at the most recent follow-up.The renal function after two years was median eGFR 102 ml/min/1.73m2, with 67% showing normal function, 31% presenting with chronic kidney disease (CKD) stage 1, 1% with stage 2, 1% with stage 3 and no patients showed stages 4 and 5. A quarter of the patients (27%) were still symptomatic at the 2-year follow-up. The median systolic blood pressure was 117 (interquartile range 107 – 125) mmHg. 64% of all patients still had antihypertensive treatment, and 87% were still on immunosuppressive therapy.Conclusion:Our study represents the largest paediatric cohort of children diagnosed with Takayasu arteritis. Several organ systems were involved at onset and the clinical spectrum was highly variable. We will in our further analyses in more detail describe the outcome in relation to presenting symptoms and treatment.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundEnthesitis related arthritis (ERA) is the subtype of juvenile idiopathic arthritis most closely related to adult spondyloarthropathy (SpA). Macrophages, the IL23/IL17 pathway and dysregulation of IFNγ are strongly implicated in the pathogenesis of adult SpA but remain relatively unexplored in ERA.ObjectivesTo compare levels of IL23 and IFNγ produced by monocyte-derived macrophages (MDMs) in the presence of lipopolysaccharide (LPS) from patients with ERA compared to healthy controls. The effect of clinical features such as enthesitis, peripheral and axial arthritis on IL23 and IFNγ expression was also studied.MethodsPeripheral blood monocytes from 39 patients (68% HLA B27 positive, 84% male, median age 16 years 4 months, median disease duration 3 years 10 months) and 21 age and gender-matched healthy controls were differentiated in vitro with macrophage-colony stimulating factor in to macrophages. Differentiated cells were treated with IFNγ for 24 hours to upregulate HLA B after which the cells were washed and stimulated with LPS (50 ng/mL). IL23 and IFNγ expression from the cell culture supernatants were measured by ELISA and luminex assay respectively.ResultsIL23 expression was significantly higher in patients with ERA [median 53580 pg/mL (IQR 35735–83945 pg/mL) vs 32110 pg/mL (IQR 13745–48235 pg/mL), p=0.01], particularly in patients who were HLA B27 positive [median 64650 pg/mL (IQR 36400–99650 pg/mL), p=0.0067]. IL23 was not significantly different between patients with and without peripheral arthritis or axial arthritis. However, patients who had active enthesitis (assessed clinically or on scan within 6 months of the sample) had significantly higher IL23 expression compared to patients without enthesitis [median 75905 pg/mL (IQR 36728–99425 pg/mL vs 38485 pg/mL (IQR 29923–63725 pg/mL, p=0.014] and healthy controls [p=0.0017]. Interestingly, patients who had both HLA B27 and active enthesitis had even higher levels of IL23 [median 79380 pg/mL (IQR 36540–103200 pg/mL), p=0.0018]. Conversely, levels of IFNγ were found to be lower from MDMs of patients with ERA compared to healthy controls, at baseline [median 3985 pg/mL (IQR 2820–6849 pg/mL) vs 6305 pg/mL (IQR 3938–8744 pg/mL), p=0.0054] and after LPS stimulation [median 9146 pg/mL (IQR 7438–11255 pg/mL) vs 11693 pg/mL (IQR 9481–13435 pg/mL), p=0.013]. No difference was found between patients who were HLA B27 positive and negative, although there was a trend towards lower levels of IFNγ in patients with enthesitis, this was not statistically significant.ConclusionsIL23 expression is significantly higher from stimulated MDMs of patients with ERA compared to healthy controls, especially in HLA B27 positive patients with active enthesitis. This suggests a role for IL23 in the pathogenesis of ERA and supports the hypothesis that this sub-population of patients might benefit from IL23 blockade. Interestingly, IFNγ expression is lower in patients with ERA. Dysregulation of IFNγ has been shown to cause upregulation of the IL23/17 pathway in animal models1 and thus may also contribute to the pathogenesis of ERA.Reference[1] Chu CQ, Swart D, Alcorn D, Tocker J, Elkon KB. Interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17. Arthritis Rheum2007Apr;56(4):1145–51.Disclosure of InterestNone declared

BackgroundEnthesitis related arthritis (ERA) is a subtype of juvenile idiopathic arthritis exhibiting many similarities to the adult spondyloarthropathies (SpA). The innate immune system and intracellular stress responses, including the unfolded protein response (UPR), have been implicated in the pathogenesis of SpA. Granulocyte macrophage colony stimulating factor (GMCSF), as well as being a haemopoietic growth factor, plays a central role in regulating innate immunity and has recently been implicated in the pathogenesis of SpA1 but has not been studied in ERA.ObjectivesTo compare levels of GMCSF produced by monocyte-derived macrophages (MDMs) from patients with ERA and healthy controls and to observe the effect of inducing the UPR on those levels.MethodsPeripheral blood monocytes were isolated from 39 patients with ERA (68% HLA B27 positive, 84% male, median age 16 years 4 months, median disease duration 3 years 10 months) and 21 age and gender-matched healthy controls and differentiated in vitro with macrophage-colony stimulating factor. Cells were treated with interferon gamma for 24 hours to upregulate HLA B, washed and then stimulated with lipopolysaccharide (LPS) alone (50 ng/mL) or LPS and tunicamycin (TM) (5 µg/mL), an inducer of the unfolded protein response. GMCSF was measured from the cell culture supernatants after 24 hours culture by luminex assay.ResultsLevels of GMCSF at baseline were similar in patients and healthy controls [median 121.3 pg/mL (IQR 96.6–194.0 pg/mL) vs 157.1 pg/mL (124.2–203.3 pg/mL), p=0.1]. However, with LPS stimulation, MDMs from patients secreted significantly higher levels of GMCSF [median 1853 pg/mL (IQR 1206–3061 pg/mL) vs 1342 pg/mL (IQR 713.3–1797 pg/mL), p=0.0057]. On stimulation with TM in addition to LPS, GMCSF production was further enhanced in both patients and healthy controls [median 9027 pg/mL (IQR 4746–13961 pg/mL) vs 3834 pg/mL (IQR 1603–9158 pg/mL)] and remained significantly higher in patients (p=0.0096). To investigate the effect of the UPR, fold change in GMCSF was calculated for each sample between MDMs stimulated with LPS alone and MDMs stimulated with both LPS and TM. Median fold change in patients was 3.95 (IQR 1.54–5.47) and 2.36 (IQR 0.49–4.69) in healthy controls. Interestingly, MDMs from patients who were HLA B27 positive exhibited significantly higher median fold change in GMCSF with UPR induction compared to HLA B27 negative patients [4.14 (IQR 2.22–6.10) vs 1.33 (IQR 0.36–3.91), p=0.0098]. No associations were seen with different treatment regimes in the patient group.ConclusionsMDMs from patients with ERA produce significantly higher levels of GMCSF after stimulation compared to healthy controls and this is further enhanced by the UPR, especially in HLA B27 positive patients. These results potentially implicate GMCSF in the pathogenesis of ERA and thus further support the concept of GMCSF as a novel target for treatment in certain subgroups of patients.Reference[1] Al-Mossawi MH, Chen L, Fang H, Ridley A, de Wit J, Yager N, et al. Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nat Commun2017Nov 15;8(1):1510.Disclosure of InterestNone declared

MAS, a form of secondary hemophagocytic lymphohistiocytosis (sHLH), is a severe, life-threatening complication of rheumatic diseases that occurs most frequently in patients (pts) with sJIA and adult-onset Still's disease (AOSD). MAS is characterized by hyperinflammation and overproduction of interferon γ (IFNγ). Treatment with emapalumab, an anti-IFNγ monoclonal antibody, rapidly neutralized IFNγ and controlled MAS secondary to sJIA in pts with an inadequate response to high-dose glucocorticoids (GCs) in a phase 2 study (parent study).[1] To report outcomes and safety among pts with MAS treated with emapalumab after 12 months of follow-up. The parent study enrolled pts with sJIA or AOSD who failed high-dose GCs (≥2 mg/kg/day). Pts who received emapalumab in the parent study (6 mg/kg on day [D] 0, followed by 3 mg/kg every 3 days until D15 and twice weekly until D28) and completed short-term follow-up (≥4 weeks) after last drug administration were invited to participate in this long-term follow-up study. Pts were assessed at follow-up Week (W) 2, W3, D30, D100, Month (M) 6 and M12. Emapalumab was not administered during follow-up. Overall MAS activity was monitored using a visual analog scale, comprehensive clinical evaluation and observation of pts' overall status. Serum samples for pharmacokinetic and pharmacodynamic analysis were collected at each study visit while serum emapalumab remained detectable. Safety was monitored throughout. All 14 pts (sJIA onset at <16 yrs, n=13; 1 had onset at age 16 yrs, 7 months) in the parent study participated in this long-term follow-up study. 6 pts had a history of 19 MAS episodes prior to the parent study. All prior episodes were treated with high-dose GCs; pts were also treated with anakinra (n=7) and/or cyclosporine A (n=8). 13/14 patients achieved MAS remission by W8, with rapid IFNγ neutralization during the parent study, as shown by decreased CXCL9 levels versus baseline. GCs were rapidly tapered in all pts. 13/14 pts did not present with another MAS episode; 1 MAS episode was reported 11 months after the pt stopped emapalumab (serum emapalumab was undetectable). The terminal elimination phase for emapalumab was slow and linear during follow-up (median t½, 24 days). CXCL9 and soluble interleukin-2 receptor levels remained close to, or within, the normal range. GC tapering continued during follow-up: at M12, 5 pts were off GCs and 6 pts were receiving <0.3 mg/kg/day of prednisone. 4 sJIA flares (without MAS) occurred during follow-up. In total, 37 adverse events (AEs) were reported by 12 patients, including 3 serious AEs (SAEs), all unrelated to emapalumab: 1 MAS reactivation, 1 sJIA flare and 1 ankle edema. All SAEs resolved spontaneously or with standard treatment. 10 infectious AEs (9 of viral origin) were reported during follow-up; 4 occurred when serum emapalumab levels were measurable and 6 after emapalumab became undetectable (Table 1). No new safety signals were observed. All pts were alive at M12. Most pts with MAS who had failed high-dose GCs and responded to emapalumab remained in remission and continued GC tapering during 12 months of follow-up. Any viral infections during follow-up resolved spontaneously or with standard treatment, confirming the favorable safety profile of emapalumab. A pivotal clinical trial of emapalumab in patients with sHLH and underlying rheumatic disease is ongoing (EMERALD; NCT05001737). [1] De Benedetti F, et al. Ann Rheum Dis 2022;81(Suppl 1):128 (OP0193). Medical writing assistance was provided by Blair Hesp PhD CMPP of Kainic Medical Communications Ltd. (Dunedin, New Zealand), which was funded by Sobi AG (Basel, Switzerland). Fabrizio De Benedetti Consultant of: AbbVie, Sobi, Pfizer, Roche, Sanofi, Novartis, Novimmune, Grant/research support from: AbbVie, Sobi, Pfizer, Roche, Sanofi, Novartis, Novimmune, Alexei Grom Consultant of: Novartis, AB2 Bio, Novimmune, Sobi, Paul Brogan Consultant of: Sobi, Novartis, Roche, UCB, Claudia Bracaglia: None declared, Manuela Pardeo: None declared, Giulia Marucci: None declared, Despina Eleftheriou Speakers bureau: Sobi, Charalampia Papadopoulou Speakers bureau: Sobi, Grant Schulert Consultant of: Novartis, Sobi, Novimmune, AB2 Bio, Pierre Quartier Speakers bureau: AbbVie, Chugai-Roche, Lilly, Novartis, Pfizer, Sobi, Consultant of: AbbVie, Chugai-Roche, Lilly, Novartis, Pfizer, Sobi, Jordi Antón Consultant of: Sobi, Novartis, Roche, Pfizer, AbbVie, GSK, Christian Laveille Consultant of: Sobi, Rikke Frederiksen Employee of: Former employee of Sobi, Veronica Asnaghi Employee of: Former employee of Sobi, Maria Ballabio Employee of: Former employee of Sobi, Philippe Jacqmin Consultant of: Sobi, Cristina de Min Employee of: Former employee of Sobi. Table 1N=14Emapalumab levels ≥lower limit of quantification (LLOQ)Emapalumab levels

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