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Objective A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1. Methods A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework. Results Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%). Conclusion Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.

The first objective was to assess the role of vascular inflammatory factors in the pathogenesis of deficiency of adenosine deaminase 2 (DADA2) and to compare these markers among DADA2 patients with different phenotypes. We also aimed to investigate differences between DADA2 patients with vasculitic features and classic polyarteritis nodosa (PAN) for the aforementioned markers.The study included eighteen DADA2 patients, ten PAN patients, and eight healthy controls. Plasma levels of sST2, sRAGE, Tie-2, sCD40L, Tie-1, sFlt-1, LIGHT, TNF-α, PlGF, IL-6, IL-18, IL-10, MCP-1 were studied by cytometric bead-based multiplex assay panel.Among the DADA2 patients, five had hematological manifestations, 13 had vasculitic findings, and accompanying immunological findings were present in seven patients. Nine patients had neurological findings, five of whom had neuropathy. Plasma levels of Tie-1 and sFlt-1 were higher in the overall DADA2 patients compared to healthy controls and PAN patients (p0.001 and p = 0.004, respectively). DADA2 patients with PAN-like features had higher sRAGE, Tie-2, and TNF-α levels compared to PAN patients (p = 0.013, p = 0.003, and p = 0.001, respectively). In DADA2 patients with hematological findings, plasma IL-18 levels were higher than those with PAN-like phenotype (p = 0.001). Finally, DADA2 patients with neuropathy had higher sRAGE concentrations than patients without neuropathy and healthy controls (p = 0.03 and p = 0.008, respectively).We suggest that the high plasma IL-18 levels observed in DADA2 patients with hematologic manifestations may be associated with an activated IFNγ pathway, and lack of response to anti-TNF treatment. We identified sRAGE as a potential biomarker of neuropathy in DADA2 patients. Higher concentrations of Tie-1, Tie-2, sFlt-1, sRAGE, and TNF-α distinguished DADA2 patients with PAN-like features from PAN patients.

Objectives The COVID-19 pandemic is a global health problem. We, as the EMERGE (EMErging RheumatoloGists and rEsearchers) group of PReS (Pediatric Rheumatology European Society) analyzed how the pandemic has affected pediatric rheumatology practice. Methods An online survey was developed to assess changes in pediatric rheumatology practice due to the pandemic. Results were analyzed using descriptive statistics. Results From 70 countries, 493 pediatric rheumatologists (80.3% in pediatric rheumatology practice for ≥5 years) responded to the survey. Around 70% disagreed that the pandemic led to reduced prescription of nonsteroidal anti-inflammatory drugs, conventional synthetic and biologic disease-modifying antirheumatic drugs. Almost half were more likely to taper corticosteroids faster. One-fifth hesitated to switch the major immunosuppressant during a flare. Patients encountering difficulties obtaining hydroxychloroquine and tocilizumab due to shortages were noted by 192 (38.9%) and 44 (8.9%), respectively. Twenty to 30% indicated that their patients had experienced a flare or delay in diagnosis/intervention due to postponed appointments.53% mentioned use of phone calls/smartphone applications while 47% shifted towards video consultations for patient care. Respondents indicated an increased number of patients with Kawasaki disease (30%), macrophage activation syndrome (15.6%), unusual vasculitic rashes (31.4%), and hyperinflammation (33.5%) during the pandemic. Conclusion This is the largest survey to date addressing changes in pediatric rheumatology practice due to the COVID-19 pandemic. Primary changes were due to delays in clinic appointments, increase in use of virtual technologies, and concerns about the use of immunosuppressive therapies. An increased number of patients with Kawasaki disease/hyperinflammation mentioned by the respondents is noteworthy., • COVID-19 pandemic threatens millions of lives worldwide. • As pediatric rheumatologists, we take care of a vulnerable population. • The main changes in pediatric rheumatology practice during the COVID-19 pandemic were due to delays in clinic appointments, increase in use of virtual technologies to decrease in-person visits, use of anti-rheumatic drugs treatment/prophylaxis, and concerns about using immunosuppressive therapies. • An increase in the number of patients with Kawasaki disease/hyperinflammation was also mentioned by the respondents of the survey. • Understanding the challenges imposed by the COVID-19 pandemic on the community of pediatric rheumatologists will help tailor future recommendations regarding the management of pediatric rheumatology patients during the pandemic according to the needs in daily clinical practice.

Behçet's disease (BD) is a variable vessel vasculitis which is rare in children.We aimed to compare the main characteristics of pediatric BD patients from Turkey versus Israel.Three centers from Turkey and two centers from Israel participated in this study. The BD diagnosis was before 16 years of age and based on expert opinion. Disease activity was assessed with BD current activity form (BDCAF).A total of 205 patients were included (165 from Turkey; 40 from Israel). HLA-B51 positivity (68.3% vs. 46.2%, p = 0.028), male gender (52% vs. 30%, p = 0.012), and skin involvement (55.2% vs. 22.5%, p0.001) were more frequent among patients from Turkey compared to patients from Israel. Tests of pathergy and HLA-B51 were more frequently performed in patients from Turkey than patients from Israel (93.3% vs. 32.5%, p0.001 and 97.6% vs. 65%, p0.001; respectively). For BD classification in the whole group, International Criteria for BD (ICBD) had the highest sensitivity (73.2%), followed by pediatric BD (PED-BD) (47.8%), and The International Study Group (ISG) (42%) criteria sets. The most commonly prescribed drug was colchicine in the whole group (96.6%). Significantly more patients were treated with corticosteroids (50% vs. 28.5%, p = 0.006), methotrexate (17.5% vs. 3%, p = 0.002), and nonsteroidal anti-inflammatory drugs (12.5% vs. 1.8%, p = 0.007) in Israel than in Turkey. The median BDCAF values were higher at the first visit for patients from Turkey compared to those in Israel (4 vs. 2, p0.001).This is the largest cohort of pediatric BD reported to date. The disease characteristics significantly differ among pediatric BD patients from Turkey and Israel, which may be due to different ethnicity and environmental factors.

Objective Recently a new set of criteria proposed for the classification of auto inflammatory recurrent fevers including familial Mediterranean Fever (FMF). We aimed to compare the sensitivity and specificity of the new Eurofever/PRINTO classification criteria with those of the Tel Hashomer and Yalcinkaya–Ozen criteria. Methods 151 consecutive FMF patients between February and May 2019 who were followed at Hacettepe University Department of Pediatric Rheumatology were included in this study. A group of 82 patients with periodic fever 66 periodic fever, aphthosis, pharyngitis and adenitis syndrome (PFAPA), nine cryopyrin-associated periodic syndrome (CAPS) and seven mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS) patients) served as controls. GraphPad 6.0 was used for statistical analysis. Results Three different classification criteria were analyzed in 151 FMF patients with a median age at diagnosis of 5 years and in 82 controls with a median age at diagnosis of 3 years. The sensitivity of the new Eurofever/PRINTO criteria (96%) was highest (Tel Hashomer criteria-88.4% and Yalcinkaya–Ozen criteria-93.4%). However, the specificity of these criteria (73.1%) was lowest (Tel Hashomer criteria-92.6% and Yalcinkaya–Ozen criteria-84.1%). The new Eurofever/PRINTO criteria achieved the highest sensitivity (100%) in biallelic exon 10 mutation patients (Tel Hashomer criteria-87.4% and Yalcinkaya–Ozen criteria-94.2%). However, the new set had the lowest sensitivity (88.2%) in heterozygote exon 10 mutation patients (Tel Hashomer criteria 94.1% and Yalcinkaya–Ozen criteria 94.1%). Conclusion In this Turkish cohort, the new Eurofever/PRINTO criteria have a better sensitivity but lower specificity with higher misclassifications than other two well-known criteria. The combination of clinical manifestations with genotype increased the sensitivity. The lower specificity may be due to the high carrier rate in our population. Although the ethnicity information lowers the specificity, ‘clinical-only’ criteria set may still guide the clinician to perform appropriate genetic testing in patients with recurrent fever.

The aim of our study is twofold: To evaluate the presentation, diagnosis, clinical course, and management of juvenile dermatomyositis (JDM) in children under three years of age, and to compare with older-onset patients.Nine patients with early-onset, and 63 patients with older-onset JDM followed between December 2010 and April 2022 are included. We also reviewed the literature on early-onset JDM from the inceptions of the PubMed/MEDLINE and Scopus databases up to April 1st, 2022.Early-onset JDM patients were characterized by longer median diagnostic delay (p = 0.005), calcinosis (p = 0.006), anti-NXP2 antibody (p = 0.049). Diagnostic pathway included muscle biopsy (77.7% versus 50.8%). Muscle biopsy findings were more severe in the early-onset group (p0.001). Although there was no difference in the partial and complete remission rates, the relapse rate was significantly higher in the early-onset group (p = 0.001), reflected to requirement of intravenous immunoglobulin (p = 0.001), cyclophosphamide (p = 0.011), and biological agents (p = 0.016). Literature search revealed 32 articles reporting 75 patients. The median diagnostic delay was 5 (1-30) months. Calcinosis was present in 29.5%. Twenty-three of the 44 patients (52.3%) had a muscle biopsy. Forty-one patients (64.1%) received second and third-line treatments. Complete remission was achieved in almost half of these patients (48.9%), but relapse was observed in 75%. The mortality rate was 10.2%.Diagnosis can be challenging and delayed in early-onset JDM patients. Compared to older-onset JDM patients, this group had higher relapse rate, more severe muscle biopsy findings, and received intensive immunosuppressive treatment.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, has opened a new era in the practice of pediatric rheumatology since it has been associated with inflammatory complications such as vasculitis and arthritis. In this review, we aimed to present a detailed analysis of COVID-19 associated pediatric vasculitis.A systematic review of the English literature was performed through Pubmed/MEDLINE and Scopus up to January 1st, 2022. Articles including data about the patients with 1) onset of vasculitis18 years of age, 2) evidence of SARS-CoV-2 exposure, 3) evidence of vasculitis diagnosis (imaging, histopathologic evidences or fulfilling the specific diagnostic/classification criteria) were included in the final analysis. Patients with Kawasaki disease-like vasculitis associated with multisystem inflammatory syndrome in children (MIS-C) were excluded.A total of 25 articles describing 36 patients with COVID-19 associated pediatric vasculitis (median age 13 years; M/F: 2.3) were included. The most frequent phenotype was IgA vasculitis (n=9) followed by chilblains (n=7) and ANCA associated vasculitis (AAV) (n=5). Skin (58.3%) and renal (30.5%) involvements were the most common manifestations of vasculitis. The majority of patients received corticosteroids (40%), while rituximab (14.2%) and cyclophosphamide (11.4%) were the most frequently used immunosuppressive drugs. Remission was achieved in 23 of 28 patients. Five patients (4 with central nervous system vasculitis; 1 with AAV) died.Although COVID-19 associated pediatric vasculitis is very rare, awareness of this rare entity is important to secure earlier diagnosis and treatment. The clinical features of COVID-19 associated pediatric vasculitis subtypes look similar to those in pediatric vasculitis not associated with COVID-19. Whether COVID-19 is the reason of the vasculitis or only the trigger remains unknown.

Background Diagnosis of childhood polyarteritis nodosa (PAN) has become challenging after the definition of deficiency of adenosine deaminase 2 (DADA2). We aimed to define the differential features of pediatric PAN and DADA2 patients in our center and in the literature. Methods The charts of pediatric PAN and DADA2 patients followed at the Pediatric Rheumatology Unit of Hacettepe University between 2010–2020 were analyzed. A systematic literature review was conducted for articles regarding pediatric PAN or DADA2. Results Thirty-four pediatric PAN and 18 pediatric DADA2 patients were included. The age at onset was younger, parental consanguinity, livedo reticularis, neurologic involvement (especially strokes), lymphopenia, and hypogammaglobulinemia were more frequent, while thrombocytosis and panniculitis were less frequent in DADA2 patients. The primary treatment was anti-tumor necrosis factor (anti-TNF) in DADA2. For induction treatment, all systemic PAN patients received corticosteroids, and cyclophosphamide (n=11) or mycophenolate mofetil (MMF) (n = 3). Cyclophosphamide was replaced with MMF in nine once remission was confirmed with PVAS. In the literature, 28 articles describing 613 pediatric PAN patients and 26 articles describing 207 pediatric DADA2 patients were identified. Neurologic, gastrointestinal, and cardiac involvements were more frequent in DADA2, while constitutional symptoms and testis involvement were more common in PAN. Conclusion In a child with PAN-like phenotype, DADA2 should be considered in the presence of young age at disease onset, parental consanguinity, strokes, lymphopenia, and lack of thrombocytosis during active disease. Anti-TNF treatment is indicated for vasculitic DADA2. Cyclophosphamide could be switched to MMF when remission is confirmed with PVAS in severe PAN.

Introduction Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy of childhood. Objective To analyze clinical features, paraclinical examinations, MSAs, treatment response and long-term outcome in a JDM cohort Methods 58 patients (35F, 23 M) from a tertiary referral center in the last two decades are included. Results Mean age at onset was 8.1 ± 4.3, with a mean follow-up period of 5.66±3.59 years. Dermatological manifestations (91%) and muscle weakness (76%) were the key diagnostic elements. Elevated serum creatine kinase levels (86%), electromyography (23/25), muscle MRI (12/15), and muscle biopsy (n = 35) were compatible with the diagnosis. Out of 46 patients tested, 34 (76%) had autoantibodies, with NXP2 (21.7%), followed by TIF1g (17.4%), MDA5 (8.7%), and Mi-2 (8.7%). Presence of TIF1g and NXP2 indicated a severe course; and Ku a much severe course compared to previous studies. Corticosteroids (100%) combined with methotrexate (93%) was the initial treatment. Biological disease modifying anti-rheumatic drugs (DMARDs) were used in 22% of the cohort. Calcinosis (36%) was the most common long-term complication, associated with disease onset ≤6 years, higher muscle biopsy scores and MDA5 positivity. Complete remission was achieved in 65.5% of the patients in a median 24 (IQR 11.8–42.5) months with a relapse rate of 26.3%. 43.9% of NXP2 and 33.3% of TIF-1 g positive patients had a relapse. Course was monophasic (31%), polyphasic (17.2%), chronic (51.8%) without mortality. Conclusion Integration of clinical features with laboratory and biopsy findings may help to predict prognosis and guide treatment in JDM. In our cohort calcinosis was associated with age, MDA5 autoantibodies, and muscle biopsy scores.

Background IgA vasculitis (IgAV) is the most common vasculitis of childhood. Renal involvement defines late morbidity of the disease. A better understanding of the pathophysiology of the progression to kidney disease and predictive biomarkers are required for better management of IgAV and its nephritis (IgAVN). Objectives An untargeted metabolomics approach was performed to reveal the underlying molecular mechanism of disease pathogenesis and to define potential biomarkers from plasma samples from IgAV and IgAVN patients. Methods Forty-five active IgAV patients (H) and six healthy controls (C) were enrolled in the study. Plasma samples were collected on the same day of diagnosis and before any immunosuppressive treatment was initiated. At the time of diagnosis and sample collection, none of the patients had renal involvement. We used Quadrupole Time of Flight Mass Spectrometry (Q-TOF LC/MS) to investigate the alterations in plasma metabolomic profiles. Three separate pools were created: healthy controls (group C), active IgAV patients who did not develop renal involvement (group H), and patients who developed IgAVN at follow up (group N). Peak picking, grouping, and comparison parts were performed via XCMS ( https://xcmsonline.scripps.edu/ ) software. Results At follow-up, IgAVN developed in 6 out of 45 IgAV patients. The median time of renal involvement development is 23 days (range 5–45 days). Of these, 3 had nephritic proteinuria, one had nephrotic proteinuria, and 2 had microscopic hematuria. There were no significant differences in gender, age, clinical manifestations, and laboratory findings between the six patients who developed renal involvement and those who did not. In multivariate analysis, there was no significant association between any of the defined demographic and clinical characteristics (male sex, gastrointestinal system involvement, joint involvement, CRP, WBC, PLT) and the occurrence of renal involvement. Totally 2618 peaks were detected for group H, N, and C. Among them, 355 peaks were found to be statistically significant and reliable (p 1.5) between the groups C and H, and 66 peaks were found to be changed (fold change >1.5) between the groups H and N. The number of the peaks on the intersection of the peaks found to be different between the groups (C and H) and (H and N) was 39. Based on putative identification results, 15 putatively identified metabolites matched with 11 peaks were presented as biomarker candidates after careful evaluation with a clinical perspective. Conclusion We suggest that DHAP (18:0), prostaglandin D2/I2, porphobilinogen, 5-methyltetrahydrofolic acid, and N-Acetyl-4-O-acetylneuraminic acid/N-Acetyl-7-O-acetylneuraminic acid may serve as biomarkers for predicting kidney disease. Future studies with larger groups of IgAV patients are needed to validate the identified metabolic profile.

Background Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory syndrome characterized by recurrent serositis or arthritis attacks and, in some patients, chronic subclinical inflammation that predisposes to secondary amyloidosis. Colchicine is the gold standard of treatment, which reduces attack frequency and amyloidosis risk. However, up to 5% of patients are considered resistant or inadequately respond to colchicine, and some others cannot tolerate the side effects of effective doses of colchicine (colchicine intolerant). Methods We examine how the definition of colchicine resistance has evolved along with various characteristics of colchicine that may help explain unresponsiveness to the drug. Results Key factors in assessing colchicine resistance include attack frequency and severity, levels of acute phase reactants, colchicine dosage and composition, and treatment compliance. Promising clinical results have been obtained with biologics targeting interleukin-1 in colchicine-resistant or -intolerant patients with FMF. Conclusions These results underscore the need to identify patients who are not optimally managed with colchicine and who might therefore benefit from additional biologic therapies.

Objective Our aim was to describe our experience with tocilizumab (interleukin 6 receptor antagonist) treatment in children with Takayasu arteritis and to review previous studies regarding tocilizumab use in Takayasu arteritis patients. Patients and methods We reviewed the charts of all pediatric Takayasu arteritis patients followed up between 2000 and 2015 in Department of Pediatric Rheumatology in Hacettepe University, Ankara, Turkey, and we present the patients who were treated with tocilizumab. We screened PubMed and MEDLINE for articles involving Takayasu arteritis patients treated with tocilizumab. Results We have followed four pediatric Takayasu arteritis patients who received tocilizumab. The median duration of immunosuppressive treatment before tocilizumab onset was 16 (1–60) months. The median duration of tocilizumab treatment was 9.5 (7–13) months. One of our patients received tocilizumab as a first line immunosuppressive treatment directly after methylprednisolone. Others were resistant to their initial immunosuppressive treatment (cyclophosphamide, methotrexate, or azathioprine). All achieved complete response to tocilizumab at the third month of treatment. None of the patients reported any adverse events during the follow-up. In literature review, we identified 19 articles describing 75 Takayasu arteritis patients treated with tocilizumab. Eight of these received tocilizumab before the age of 18 years. Tocilizumab was the first line immunosuppressive treatment in six patients (five adults and one child). Conclusion Our small series suggests that tocilizumab may be a promising alternative for Takayasu arteritis treatment. Long-term controlled studies are warranted to provide better evidence for tocilizumab treatment in childhood Takayasu arteritis.

Objective: To analyze cumulated data about renal involvement in Behcet's disease (BD) and to report on 6 patients with BD and renal problems. Methods: We found reports of 159 patients (including our patients) with BD and specific renal disease (amyloidosis 69, glomerulonephritis [GN] 51, renal vascular disease 35, and interstitial nephritis 4) in our survey. Results: The frequency of renal problems among BD patients has been reported to vary between 0% to 55%. Male gender is a risk factor for all types of renal BD. Nephrotic syndrome was present in 83% of patients with amyloidosis, and renal failure was common at the time of diagnosis. The mean interval between the initial manifestation of BD and diagnosis of amyloidosis was shorter in men than in women ( P =.02). AA-type amyloid fibrils were shown in all cases studied. Vascular involvement was common in the patients with amyloidosis (60%). The renal findings in GN show a wide spectrum, from asymptomatic hematuria and/or proteinuria to rapidly progressive GN. Several types of glomerular lesions ranging from minor glomerular changes to crescentic glomerulonephritis are observed in BD. The common types of glomerular lesions among the reported cases are crescentic GN, proliferative GN, and immunoglobulin A (IgA) nephritis. Aneurysms may be located throughout the renal artery, from the orifice of the main artery to intrarenal microaneurysms. Another type of renal disease (amyloidosis or GN) and other major vascular involvement were present in all cases with renal vein thrombosis. Hypertension is common among patients with renal artery aneurysm or stenosis. Microscopic vascular disease was described in 4 patients. Conclusions: Based on data in the literature, we suggest that renal involvement in BD is more frequent than has been recognized, although it is most often mild in nature. Amyloidosis is one of the prognostic factors affecting survival. Patients with vascular involvement carry high risk for amyloidosis, and administration of colchicine to these patients may be beneficial. More evidence is needed to accept interstitial nephritis as a manifestation of BD. In spite of some difficulties, hemodialysis and renal transplantation are safe treatment options in BD-related uremia. Semin Arthritis Rheum 31:317-337. Copyright 2002, Elsevier Science (USA). All rights reserved.

Background: Familial Mediterranean Fever (FMF) is caused by mutations in the gene encoding pyrin and is characterized by self-limited, recurrent attacks of fever and serositis. Vasculitis has been increasingly reported in FMF. A study evaluating the prognosis in FMF and polyarteritis nodosa (PAN) patients has not been reported previously. Objectives: To determine the special characteristics and the prognosis of PAN in FMF patients. Methods: A questionnaire was used for the present survey. The setting was 7 referral centers from Turkey and Israel. Seventeen patients who were diagnosed with FMF and who developed PAN were included. PAN was diagnosed in those who met the Chapel Hill consensus criteria for microscopic polyarteritis or classic PAN. The clinical features of these 17 patients and the outcomes of their vasculitis were analyzed. Results: The age at diagnosis of PAN in these FMF patients ranged from 3.5 to 37 years. All patients had constitutional symptoms, elevated acute phase reactants, and myalgia at the time PAN was diagnosed. The diagnosis of PAN was confirmed by renal angiography in 8 patients, by renal biopsy in 6 patients, and by muscle and/or nodule biopsies in 6 patients. A number of patients had definite features of both classic PAN and microscopic polyarteritis. Conclusions: When compared with other PAN patients, those with FMF tended to have a younger age at PAN onset, more frequent perirenal hematomas, and an overall better prognosis. The cases with overlapping features of microscopic and classic PAN pose a problem for the current classification of vasculitis. We suggest that the clinical representation of PAN in FMF patients has certain characteristics and may be a feature of FMF per se. Semin Arthritis Rheum 30:281-287. Copyright © 2001 by W.B. Saunders Company