Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis.

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.

Polyarticular juvenile idiopathic arthritis has a distinct co-inhibitor receptor profile.

OBJECTIVES: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood; the pathogenesis is associated with T cell activation. T cell activation can be counter-balanced by signals generated by inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG-3, and TIM-3. Here, we identify the role of IRs in the pathogenesis of different JIA subtypes. METHODS: In total, we included 67 oligoarticular JIA, 12 IgM-RF negative polyarticular JIA, 17 enthesitis related arthritis, 11 systemic JIA patients and 10 healthy controls. We collected plasma (and synovial fluid) samples from the patients either at the onset or during a flare of their disease. We measured the soluble levels of co-IRs (IL-2Rα, 4-1BB, CD86, TGF-ß1, CTLA-4, PD-L1, PD-1, TIM-3, LAG- 3, Galectin-9) by cytometric bead array kits and their cellular expression (PD-1, CTLA-4, TIM-3, LAG-3) by flow cytometry. We compared the plasma levels and cellular expressions of different co-IRs within different JIA subgroups. RESULTS: The polyarticular-JIA group was different from the three other examined JIA subgroups, having higher levels of plasma sCTLA-4(p< 0.001), sPD-1(p< 0.05), and s4-1BB(p< 0.05) when compared with the other JIA subgroups and healthy controls. We analyzed the cellular surface expression of different co-IRs on the PBMCs of different JIA subtypes. Similar to plasma levels, both the percentage(p< 0.05) and the MFI (mean fluorescence intensity) (p< 0.01) of CTLA4 expression were higher in the poly-JIA subgroup. CONCLUSION: This is the first report studying the expression profile of different co-IRs in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA.

Detection of genetic mutations underlying early-onset systemic lupus erythematosus.

OBJECTIVE: We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients. METHODS: Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing. RESULTS: The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [c.320+4_320+7del and G188 A (c.563 G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [G109 R (c.325 G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [L809 F (c.2425 C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147 W (c.441 C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy. CONCLUSION: Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations.

Evaluation of clinical outcomes in systemic juvenile idiopathic arthritis patients treated with biological agents in Turkey: the TURSIS study.

OBJECTIVES: Biological drugs are one of the most effective treatment methods for systemic juvenile idiopathic arthritis (SJIA) and can significantly prevent morbidity and mortality. This study aimed to evaluate the efficacy and safety of biologics in patients with SJIA and provide real-life data that might help improve the outcomes. METHODS: TURSIS was a retrospective multicentre study carried out in patients with SJIA for whom a biological treatment had been initiated between 1st March 2013 and 30th December 2018. Data include patients' characteristics, laboratory-clinical results, outcomes, and safety-related variables. The 24-month follow-up data of the patients and the efficacy and safety of biological drugs were evaluated. RESULTS: 147 patients were enrolled. The clinical course of the disease was as follows; it was monocyclic in 38.1%, polycyclic in 49%, and persistent in 12.9% of patients. First-choice biologics were interleukin (IL)-1 blockers in the majority of patients (56.5%), followed by the anti-IL-6 (25.2%) and anti-TNF-alpha drugs (18.4%). Anakinra was the most preferred biologic agent in patients with macrophage activation syndrome (MAS), and tocilizumab was used more frequently in patients with persistent type (p=0.000 and p=0.003). The most frequent switch rate was seen in patients receiving anakinra (n=40/68, 58.8%), and it was most frequently switched to canakinumab (n=32/40, 80%). Better physician's global assessment scores were achieved in patients treated with anakinra in Month 3, compared to other treatments (p=0.04). CONCLUSIONS: The results of our study support the efficacy of biological drugs in particular anti-IL-1 and anti-IL-6 drugs, in the treatment of SJIA. These treatments resulted in improvement in activity of disease and provide a considerable decrease in the frequency of MAS.

Changing Disease Course of Crimean-Congo Hemorrhagic Fever in Children, Turkey.

Crimean-Congo hemorrhagic fever (CCHF), endemic in certain regions of the world, is listed as a priority disease with pandemic potential. Since CCHF was first identified in Turkey, children have been known to experience milder disease than adults. However, during the COVID-19 pandemic, we observed an unusually severe disease course, including hemophagocytic lymphohistiocytosis (HLH). We examined cytokine/chemokine profiles of 9/12 case-patients compared with healthy controls at 3 time intervals. Interferon pathway-related cytokines/chemokines, including interleukin (IL) 18, macrophage inflammatory protein 3α, and IL-33, were elevated, but tumor necrosis factor-α, IL-6, CXCL8 (formerly IL-8), and cytokines acting through C-C chemokine receptor 2 and CCR5 were lower among case-patients than controls. Interferon pathway activation and cytokines/chemokines acting through CCR2 and CCR5 improved health results among children with severe CCHF. Children can experience severe CCHF, including HLH, and HLH secondary to CCHF can be successfully treated with intravenous immunoglobulin and steroid therapy.

The risk of cardiovascular comorbidity in children with Behçet's disease.

OBJECTIVE: Patients with Behcet disease (BD) may experience long term morbidity caused by different forms of cardiovascular diseases. This study aimed to assess the risk for cardiovascular comorbidity in pediatric BD patients with and without vascular involvement, independent of the contribution of traditional risk factors. METHODS: Pediatric patients classified as BD according to the 2015 International Pediatric BD criteria were included in the study. Twenty-four-h ambulatory blood pressure monitoring (ABPM), transthoracic echocardiography, and carotid intima media thickness (cIMT) measurements were performed. Patients with an active disease and have other known risk factors for cardiovascular disease were not included in the study. RESULTS: Thirty-one children and adolescents with pediatric BD (16 female, 51.6%; F/M: 1.06) were enrolled in the study. Among all BD patients 10 patients (34.4%) had abnormal ABPM. Carotid IMT values, mean arterial pressure, systolic and diastolic blood pressure by ABPM and the prevalence of abnormal ABPM, non-dipping, and ambulatory hypertension were similar between patients with and without vascular involvement. The echocardiography measurements showed that BD patients with vascular involvement had significantly higher velocity and velocity time integral of the left ventricle outflow tract which may point out increased stiffness of the aorta. CONCLUSION: Pediatric BD patients with vascular involvement may tend to have more cardiovascular risk factors. However, cardiovascular assessment should be considered in all BD patients regardless of the involved systems. We suggest that ABPM may accurately define hypertension and cardiovascular risk in BD.

A new tool supporting the diagnosis of childhood-onset Behçet's disease: venous wall thickness.

OBJECTIVES: The lower extremity venous wall thickness (VWT) of Behçet's disease (BD) patients was reported to be significantly increased in adults, suggesting its use for the support of BD diagnosis. This prospective study aimed to investigate the lower extremity VWT in childhood-onset definite and incomplete BD patients and compare it to healthy age-matched controls. METHODS: Paediatric patients classified with BD according to the 2015 international paediatric BD criteria in our centre were included in the study. Intima-media thickness of the lower extremity veins to evaluate VWT was measured by ultrasonography, including common femoral vein (CFV), femoral vein (FV), vena saphena magna, vena saphena parva and popliteal vein (PV). RESULTS: In this cross-sectional study, VWT was measured in 35 patients (63% male) and 27 healthy controls (55% male). Thirteen (37%) of 35 patients met the criteria for the diagnosis of BD. The remaining 22 (63%) had incomplete BD and met two criteria. The median VWT values of both definite and incomplete BD patients were significantly higher than the control group in all veins on both sides. Regarding the best cut-off values of VWT for all lower extremity veins, the sensitivity rates were between 63% and 86%, while specificity rates were between 71% and 100%. CONCLUSION: Increased VWT was present not only in BD patients with vascular involvement but also in those without. We suggest that VWT may be a new criterion in supporting the diagnosis of childhood BD both in definite and incomplete BD patients.

Pediatric mixed connective tissue disease versus other overlap syndromes: a retrospective multicenter cohort study.

Pediatric mixed connective tissue disease (MCTD) is a subgroup of overlap syndromes. We aimed to compare the characteristics and outcomes in children with MCTD and other overlap syndromes. All MCTD patients met either Kasukawa or Alarcon-Segovia and Villareal criteria. The patients with other overlap syndromes had the features of ≥ 2 autoimmune rheumatic diseases but did not meet MCTD diagnostic criteria. Thirty MCTD (F/M = 28/2) and thirty (F/M = 29/1) overlap patients were included (disease onset < 18 years). The most prominent phenotype at disease onset and the last visit was systemic lupus erythematosus (SLE) in the MCTD group; juvenile idiopathic arthritis and dermatomyositis/polymyositis, respectively, in the overlap group. At the last visit, systemic sclerosis (SSc) phenotype was more frequent among MCTD than overlap patients (60% vs. 33.3%; p = 0.038). The frequency of the predominant SLE phenotype had decreased (60% to 36.7%), while predominant SSc phenotype had increased (13.3% to 33.3%) during follow-up in MCTD patients. Weight loss (36.7% vs. 13.3%), digital ulcers (20% vs. 0), swollen hands (60% vs. 20%), Raynaud phenomenon (86.7% vs. 46.7%), hematologic involvement (70% vs. 26.7%), and anti-Sm positivity (29% vs. 3.3%) were more common, while Gottron papules (16.7% vs. 40%) were less frequent among MCTD than overlap patients (p < 0.05). A higher percentage of overlap patients achieved complete remission than MCTD patients (51.7% vs. 24.1%; p = 0.047). The disease phenotype and outcome differ between pediatric MCTD and other overlap syndromes where MCTD may be regarded as a more severe disease. Analyzing these patients could pave the way for early and effective treatment.

The difference of the inflammatory milieu in MIS-C and severe COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19) may have a severe course in children. Multisystem inflammatory syndrome in children (MIS-C) is the post-COVID complication characterized by an exaggerated inflammation, observed in children. However, data on the underlying pathophysiology are sparse. We therefore aimed to assess the cytokine and chemokine profiles of children with MIS-C and compare these to life-threatening severe SARS-CoV-2 and healthy controls (HCs) to shed light on disease pathophysiology. METHODS: Samples of 31 children with MIS-C, 10 with severe/critical COVID-19 and 11 HCs were included. Cytokine and chemokine profiles were studied and compared in between groups. RESULTS: Most cytokines and chemokines related to IL-1 family and IFN-γ pathway (including IL-18 and MIG/CXCL9) and IL-17A were significantly higher in the MIS-C group when compared to the severe/critical COVID-19 group and HCs. IP-10/CXCL10 and IL-10 were higher in both MIS-C patients and severe/critical COVID-19 compared to HCs. CONCLUSION: Our results suggest that IL-1 and IFN-γ pathways play an important role in the pathophysiology of MIS-C. IMPACT: This study defines a pattern of distinctive immune responses in children with MIS-C and in patients with severe/critical COVID-19. As the COVID-19 pandemic continues, biomarkers to identify MIS-C risk are needed to guide our management that study results may shed light on it.

Comparison of IVIG resistance predictive models in Kawasaki disease.

BACKGROUND: We aimed to compare the ten different scores (by Kobayashi, Egami, Harada, Formosa, Sano, Piram et al., Wu et al., Yang et al., Tan et al., and Kanai et al.) to assess their performance in predicting IVIG resistance in Turkish children. METHODS: Complete and incomplete KD patients diagnosed with KD at Hacettepe University between June 2007 and September 2019 were evaluated retrospectively. RESULTS: A total of 129 patients, 79 boys (61.2%), with a median age 36 (IQR 19.5-57.0) months were evaluated. Sixteen patients (12.4%) had IVIG resistance. Sensitivity was low for all the ten scores. Tan, Sano, and Egami predictive models had the highest specificity (97.3, 89.4, 86.7%, respectively). Almost all scoring systems distinguished the group of patients with low risk for IVIG resistance but could not differentiate IVIG-resistant patients. Multivariate analysis for the laboratory features showed that platelet count <300 × 109/L and GGT serum levels were independent risk factors for IVIG resistance (OR: 3.896; 95% CI: 1.054-14.404; p = 0.042 and OR: 1.008; 95% CI: 1.001-1.015; p = 0.050). CONCLUSIONS: The current scoring systems had a low sensitivity for predicting the risk for IVIG resistance in Turkish children. On the other hand, increased serum GGT levels and low platelet count were risk factors for predicting IVIG resistance. IMPACT: Intravenous immunoglobulin (IVIG) resistance may be observed in 10-20% of patients diagnosed with Kawasaki disease. Coronary artery involvement is more frequent in IVIG-resistant patients. It is important to predict the patients who might develop IVIG resistance to improve prognosis. The performance of the IVIG resistance predictive models in Kawasaki disease in our population is limited due to the low sensitivity.

The challenges in diagnosing pediatric primary antiphospholipid syndrome.

Pediatric primary antiphospholipid syndrome (APS) is a very rare disease with significant distinctions from the APS in adults. Herein, we present our experience in the diagnosis and treatment of six pediatric primary APS patients, who met the updated Sapporo criteria for the APS diagnosis. One of them was also diagnosed as having probable catastrophic APS (CAPS) due to the involvement of three different organ systems simultaneously. Besides vascular involvement, four patients had thrombocytopenia, one had psychiatric disorder, and one had chorea and valvular heart disease. All patients received immunosuppressive treatment along with long-term anticoagulation therapy. Specific neurologic and hematologic manifestations that are not part of the classification criteria can be seen in children with primary APS. Therefore, using the adult criteria for diagnosing pediatric APS may result in missed or delayed diagnoses in children.

Spinal involvement in juvenile idiopathic arthritis: what do we miss without imaging?

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. Enthesitis-related arthritis (ERA) has been one of the most controversial subtypes of JIA with a higher risk of axial involvement.  Our aim was to assess the frequency and spectrum of MRI findings of spine involvement in patients with JIA and determine if the axial involvement is always clinically symptomatic in patients with positive MRI findings. In this retrospective cross-sectional observational study we included known or suspected JIA patients who underwent spinal MRI examination between 2015 and 2017 and followed up in the Pediatric Rheumatology outpatient clinic. The demographic and clinical data were reviewed from the medical charts and electronic records. All patients were grouped as clinically symptomatic and asymptomatic for spinal involvement and MRI findings were re-evaluated for presence of inflammatory and erosive lesions. Of the 72 JIA patients, 57 (79.2%) were diagnosed with ERA, and 15 (20.8%) with non-ERA subtypes of JIA. Overall, 49 (68%) patients with JIA had positive spinal MRI findings (inflammatory and/or erosive lesions). Twenty-seven (47%) ERA patients were clinically symptomatic for spine involvement and among them, 19 (70.3%) had positive spinal MRI findings. Although 30 ERA (53%) patients were clinically asymptomatic, 23 of them (77%) had positive spinal MRI findings, as well. Eleven (73%) patients diagnosed with non-ERA JIA subtypes were clinically symptomatic for spine involvement at the time of MRI. Among them, four (36.3%) had inflammatory and/or erosive lesions on spine MRI. Four (26%) non-ERA patients were clinically asymptomatic for spine involvement, but three (75%) of them showed positive findings on spinal MRI. Inflammatory and/or erosive lesions of the thoracolumbar spine could exist in patients with JIA, regardless of the presence of symptoms. Not only because the significant proportion of ERA patients show asymptomatic axial involvement but also the presence of axial involvement in patients who were classified as non-ERA depending on current ILAR classification underlines the necessity of using MRI for accurate classification of patients with JIA.

Assessment of systemic and ocular inflammation in juvenile idiopathic arthritis via choroidal vascularity index.

We aimed to evaluate the retina and the choroid in children with juvenile idiopathic arthritis (JIA) employing optical coherence tomography (OCT). This cross-sectional study, carried out between June 2017-December 2019, included JIA patients with (JIAU; n = 28) and without (JIAN; n = 65) uveitis and age-matched healthy controls (HC) (n = 102). Laboratory and demographic information of the children were obtained from hospital records. Activity of the disease was evaluated by the Juvenile Arthritis Disease Activity Score-71 (JADAS-71). Choroidal scans were obtained with spectral domain-OCT in enhanced-depth imaging (EDI)-OCT mode to assess choroidal thickness (ChT) at five locations (under the fovea, at 750 and 1500 µm nasal and temporal sections), luminal area (LA), stromal area (SA), total subfoveal choroidal area (TCA) and CVI (choroidal vascularity index). Central foveal thickness (CFT) and 1-mm diameter foveal thickness (FT) were calculated automatically through macular volume scan analysis. The choroid was significantly thicker in JIAU and JIAN patients than in HC at the subfoveal and at the 750N, 750T, 1500T points (p < 0.001, p = 0.009, p < 0.001, and p < 0.001, respectively). The CVI was lower in JIAU patients than in JIAN patients and HC (p = 0.02). Conversely, CFT was greater in JIAU patients as compared to the JIAN patients and HC (p = 0.02). Changes in chorioretinal OCT parameters in the absence of uveitis in JIA patients may reflect subclinical choroidal inflammation in these patients. Ophthalmologic examination, including choroidal imaging in a larger cohort, may clarify this aspect.

Whole exome sequencing in unclassified autoinflammatory diseases: more monogenic diseases in the pipeline?

OBJECTIVE: Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES). METHODS: Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed. RESULTS: The median age at disease onset was 1.2 years (range 0.2-16) and at the time of study recruitment was 14 years (range 3.5-17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features. CONCLUSION: WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs.

Defining colchicine resistance/intolerance in patients with familial Mediterranean fever: a modified-Delphi consensus approach.

OBJECTIVES: Colchicine is the main treatment for FMF. Although a number of individuals with FMF are intolerant/resistant to colchicine, there is no standard definition of colchicine resistance/intolerance. We developed a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF that may serve as a guide for clinicians and health authorities. METHODS: A set of statements was identified using a modified-Delphi consensus-based approach. The process involved development of an initial colchicine resistance/intolerance-related questionnaire derived from a systematic literature review. The questionnaire, which was completed by an international panel of 11 adult and paediatric rheumatologists with expertise in FMF, was analysed anonymously. The results informed draft consensus statements that were discussed by a round-table expert panel, using a nominal group technique to agree on the selection and wording of the final statements. RESULTS: Consensus among the panel was achieved on eight core statements defining colchicine resistance/intolerance in patients with FMF. A definition of resistance was agreed upon that included recurrent clinical attacks (average one or more attacks per month over a 3-month period) or persistent laboratory inflammation in between attacks. Other core statements recognize the importance of assessing treatment adherence, and the impact of active disease and intolerance to colchicine on quality of life. CONCLUSION: Based on expert opinion, a set of evidence-based core statements defining colchicine resistance/intolerance in patients with FMF were identified to help guide clinicians and health authorities in the management of patients with FMF.

Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes.

BACKGROUND: We investigated the role of inhibitory receptors (IRs) and especially lymphocyte activation gene-3 (LAG-3) in the pathogenesis of oligoarticular juvenile idiopathic arthritis (o-JIA). METHODS: Paired samples of synovial fluid (SF) and plasma and peripheral blood (PBMCs) and synovial fluid mononuclear cells (SFMCs) were collected from o-JIA patients along with their clinical data (n = 24). Plasma from healthy controls (n = 14) and paired SF and plasma samples from five non-arthritic juvenile orthopedic patients (n = 5) served as controls. Spontaneously differentiated fibroblast-like synoviocytes (FLSs) from SFMCs were co-cultured with autologous PBMCs/SFMCs and used as ex vivo disease model. Soluble levels and cellular expressions of IRs together with their functional properties in the ex vivo model were analyzed. RESULTS: In patients with o-JIA, soluble levels of LAG-3 and expression of LAG-3 and T cell immunoglobulin mucin03 (TIM-3) on CD3+CD4+CD45RO+ T cells were increased, especially in SF. Major histocompatibility complex (MHC) class II expression was induced on FLSs when these were co-cultured with autologous PBMCs/SFMCs, together with an increased monocyte chemoattractant protein-1 (MCP-1) production. In PBMC and FLS + PBMC co-cultures, neutralizing antibodies to IRs were added. Only anti-LAG-3 antibodies significantly increased MCP-1 secretion. The addition of agonistic LAG-3 antibody resulted in decreased effector cytokine secretion. CONCLUSIONS: This is the first report comparing the effects of different IRs in o-JIA and suggests that LAG-3 might contribute to the pathogenesis of this disease. IMPACT: This is the first study addressing the role of different co-IRs in o-JIA. We showed that LAG-3 and TIM-3 seem more important in juvenile arthritis in contrast to adult rheumatoid arthritis, where cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death-1 were reported to be more important. We designed an ex vivo disease model for o-JIA, examined the effects of co-IRs in this model, and demonstrated that they might contribute to the pathogenesis of the disease. LAG-3 might play a role in o-JIA pathogenesis and might be a potential therapeutic option for o-JIA patients.

Plasma checkpoint protein levels and galectin-9 in juvenile systemic lupus erythematosus.

SLE is a disease of the adaptive immune system where T lymphocyte dysfunction has an important role as well. We assessed the plasma levels of checkpoint receptors expressed on T cells, along with Galectin-9 to reflect type-1 IFN activity and IL-2Rα in childhood SLE patients. Forty-nine children with SLE and15 healthy controls were included. SLEDAI scores were evaluated at the time of sampling. CD25 (IL-2Rα), 4-1BB, B7.2 (CD86), TGF-ß1, CTLA-4, PD-L1, PD-1, Tim-3, LAG- 3, Galectin-9 levels were studied by cytometric bead-based multiplex assay panel. Galectin-9 and PD-L1 were significantly higher in SLE patients. Other checkpoint proteins and IL-2Rα were also higher but did not reach statistical significance. There were significant correlations between SLEDAI and IL-2Rα, Galectin-9 and PDL1. There were three clinical clusters: Cluster 1 included patients with no major organ involvement, cluster 2 had predominantly haematological involvement(n=16) and cluster 3 (n=11) had predominantly renal involvement. Checkpoint proteins were not different among these three clusters. Our data supports that Galectin 9 and IL-2Rα are good markers for disease activity in childhood SLE. We need larger series to evaluate differences between disease clusters in SLE. We failed to show a significant correlation with checkpoint proteins and SLEDAI except for PDL1.

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-ß2 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-ß2 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.

Validation of the EULAR/ACR 2017 idiopathic inflammatory myopathy classification criteria in juvenile dermatomyositis patients.

OBJECTIVES: In 2017, a new set of criteria was proposed by EULAR/ACR to classify idiopathic inflammatory myopathies. Our aim was to validate the EULAR/ACR 2017 classification criteria in juvenile dermatomyositis (JDM) patients. METHODS: This study was carried out at Hacettepe University Children's Hospital Department of Paediatrics, Divisions of Rheumatology, Neurology and Paediatric Pathology Unit. Control patients included inborn errors of metabolism presenting with myopathy and/or rhabdomyolysis, idiopathic rhabdomyolysis, dystrophinopathies, neuromyotonia and systemic rheumatic disorders. Patients' data were collected retrospectively from patient files. RESULTS: Fifty-eight JDM patients (60.3% female) and 40 controls (32.5% female) were included in this study. When the probability cut-off was set at 55% as recommended, the sensitivity/specificity of the new criteria to diagnose JDM were 96.5%/85% in the total cohort, 95.8%/84.6% without the muscle biopsy data and 97%/85.7% with biopsy data. With the ROC curve analysis, the optimal probability cut-off for the whole cohort was found to be >62%; providing a sensitivity/specificity of 96.6% (95% CI: 88.1% to 99.6)/90% (95% CI: 76.3% to 97.2%), and >68.5% for the patients with muscle biopsy providing sensitivity/specificity of 97% (84.7-99.9%)/100% (76.8-100%), respectively. The new EULAR/ACR criteria were the most sensitive, however, the least specific compared to the Tanimoto criteria (sensitivity/specificity 64%/97.5%) and Bohan-Peter criteria (sensitivity/ specificity 74.1%/92.5%). CONCLUSIONS: The new EULAR/ACR criteria performed favourably in our JDM cohort especially with the probability cut-off of >62%.

Is Takayasu's arteritis more severe in children?

OBJECTIVES: Takayasu's arteritis (TAK) is a chronic vasculitis, affecting predominantly the aorta and/or its major branches. The aim of this study was to compare the differences between childhood and adult onset TAK. METHODS: We retrospectively evaluated 179 TAK patients followed between August 2005 and July 2019. Demographic characteristics, laboratory features, disease activity, echocardiographic data at diagnosis and treatment regimens in the disease course were compared between the paediatric and adult onset patients. RESULTS: Twenty-five paediatric-onset (<18 years of age at diagnosis) and 154 adult-onset patients (≥18 years of age at diagnosis) were enrolled. The mean age at diagnosis for children and adults were 13.6±4 and 35.6±13, respectively. Paediatric onset TAK patients had more intense inflammation at the time of diagnosis reflected in their clinical findings. Acute phase reactants were high in all paediatric patients and significantly higher in patients with paediatric-onset TAK (p=0.006 and p=0.005, respectively). Abdominal predominant disease was more common in the paediatric group, in contrast, focal disease and aortic arch predominant disease were more common in the adult group. Ascending aortic dilatation, left ventricular hypertrophy and moderate-severe aortic insufficiency were more frequent in echocardiography findings of paediatric onset TAK patients. In comorbidities, hypertension was more common in paediatric TAK patients during follow-up, whereas cerebrovascular disease was more common in adult patients. CONCLUSIONS: Our paediatric onset TAK patients presented with a more severe inflammation and more widespread vascular involvement. Multicentre studies from different geographic areas are needed to verify our observation and understand the underlying causes.