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Our aim was to report our experiences of pediatric macrophage activation syndrome (MAS) patients treated with anakinra and to review previous studies reporting anakinra treatment in pediatric MAS patients associated with systemic juvenile idiopathic arthritis (sJIA) or autoinflammatory diseases (AIDs). The study group consisted of pediatric MAS patients due to sJIA or AIDs, followed up in the Pediatric Rheumatology Unit of Hacettepe University between January 2015 and January 2017 and treated with anakinra (anti-IL1). We conducted a systematic review of the published literature involving pediatric MAS patients associated with sJIA or AIDs, treated with anakinra. Thirteen sJIA patients and two AIDs patients were included the study. Nineteen MAS episodes were observed in 15 patients. Anakinra (2 mg/kg/day) was started in with a median 1 day after admission. Clinical symptoms resolved, and laboratory findings normalized within median (minimum–maximum) 2 (1–4) and 6 (4–9) days, respectively after the introduction of anakinra. Steroid treatment was stopped in a median of 10 (4–13) weeks after the initiation of anakinra treatment. Patients were followed up for a median of 13 (6–24) months. Two patients developed recurrent MAS episodes when the anakinra dose was reduced, while the other patients achieved remission. In the literature review, we identified nine articles, describing 35 pediatric MAS patients associated with sJIA or AIDs and treated with anakinra. Except for two, all the patients reached remission. Our study and systematic literature review may help to improve the knowledge on the role of anakinra treatment in the management of MAS.

Children with Coronavirus disease 2019 (COVID-19) are being reported to have manifestations of hyperinflammatory states and/or Kawasaki-like disease. In this study, we investigated children with typical and atypical Kawasaki disease (KD) likely to be associated with COVID-19. We have reported four children with Kawasaki-like disease probably associated with COVID-19. The clinical features were consistent with incomplete KD in three patients. SARS-CoV-2 RT-PCR was positive in one and the serology was positive in one patient with negative RT-PCR. Corticosteroids, anakinra, intravenous immunoglobulin (IVIG), and acetylsalicylic acid were used in the treatment. Three patients recovered after the treatment while one patient died. The literature review revealed 36 articles describing 320 children with Kawasaki-like disease associated with COVID-19. SARS-CoV-2 RT-PCR was negative in 120 (65.5%) of 183 patients while the serology was positive in 130 (83.8%) of 155 patients. The therapeutic options have included IVIG, acetylsalicylic acid, tocilizumab, anakinra, enoxaparin, and methylprednisolone. Pediatric COVID-19 cases may present with atypical/incomplete Kawasaki-like disease. Thus, pediatricians need to be aware of such atypical presentations resembling KD for early diagnosis of COVID-19.

BackgroundWe 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.MethodsComplete and incomplete KD patients diagnosed with KD at Hacettepe University between June 2007 and September 2019 were evaluated retrospectively.ResultsA 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).ConclusionsThe 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.ImpactIntravenous 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.

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.

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.

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.

Differentiating PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis) syndrome from familial Mediterranean fever (FMF) could be challenging in some cases. Galectin-3 is a lectin with regulatory functions in apoptosis and inflammation. We aimed to test whether galectin-3 could be a biomarker for differentiating PFAPA syndrome from FMF. Patients with PFAPA syndrome, FMF, cryopyrin-associated periodic syndrome (CAPS), and streptococcal pharyngitis, and healthy controls were included in this study. Serum galectin-3 levels were measured using enzyme-linked immunosorbent assay. Eighty-seven patients (36 with PFAPA, 39 with FMF, 8 with CAPS, 4 with streptococcal pharyngitis), and 17 healthy controls were included. Blood samples were drawn during attacks from 20 PFAPA and 7 FMF patients and attack-free periods from 22 PFAPA, 35 FMF, and 8 CAPS patients. The median serum galectin-3 level in the PFAPA-attack group (1.025 ng/ml) was significantly lower than the levels in healthy control (2.367 ng/ml), streptococcal pharyngitis (3.021 ng/ml), FMF attack (2.402 ng/ml), and FMF-attack-free groups (2.797 ng/ml) (p = 0.006, 0.03, 0.01, and < 0.001, respectively). PFAPA-attack-free group had lower galectin-3 levels than the FMF-attack-free group (1.794 vs. 2.797 ng/ml, respectively; p = 0.01). Galectin-3 levels did not differ significantly between CAPS and attack-free PFAPA patients (1.439 ng/ml vs. 1.794 ng/ml, respectively; p = 0.63). In our study, for the first time, we defined galectin-3 as a promising biomarker that differs between PFAPA and FMF patients during both disease flares and attack-free periods. Further studies with high number of patients could validate its role as a biomarker.

ObjectiveTo examine the performance in adults of the European Alliance of Associations for Rheumatology (EULAR)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 classification criteria for IgA vasculitis (IgAV).MethodsThe EULAR/PReS/Ankara 2008 classification criteria for IgAV were applied to patients enrolled in an international observational cohort which included patients with IgAV and comparators with other forms of small-vessel and medium-vessel vasculitis. After the initial assessment of the performance of the criteria, possible revisions to increase the performance were tested. The revised criteria were then assessed in an independent validation cohort within a multicentre Turkish vasculitis registry.ResultsThe dataset consisted of 178 IgAV cases and 1705 comparators. The Ankara 2008 criteria require skin involvement plus one of the following four criteria: abdominal pain, a biopsy showing IgA deposition, arthritis or arthralgia, or renal involvement (any haematuria and/or proteinuria). The specificity of the criteria improved when a positive test for anti-neutrophil cytoplasmic autoantibody or blood cryoglobulins was considered an exclusion criterion. The revised criteria had a sensitivity of 76.4% (95% CI 69.8% to 82.2%) and a specificity of 94.5% (95.0% CI 93.4% to 95.1%). In the validation set, the sensitivity and specificity of the revised criteria were 97.8% (95% CI 94.0% to 99.0%) and 85.0% (95.0% CI 78.0% to 90.0%), respectively.ConclusionThe revised EULAR/PReS-endorsed Ankara 2008 IgAV classification criteria perform well in adults with IgAV and are appropriate for use in clinical research.

Background Juvenile idiopathic arthritis (JIA), is the most common pediatric rheumatologic disorder with unknown etiology. Currently, no population-based data are available regarding the distribution of categories and frequency of uveitis in patients with JIA in Turkey. The purpose of this study was to evaluate the frequency of JIA-associated uveitis (JIAU) and distribution of JIA categories in a Turkish JIA cohort. Methods This was a retrospective study of 500 randomized patients in four pediatric rheumatology clinics in Turkey. Results Oligoarticular JIA (oJIA) was the most common JIA disease category in this study cohort (38.8%). The frequencies of the other categories were as follows: enthesitis-related arthritis (ERA), 23.2%; rheumatoid factor (RF)–negative polyarthritis, 15.6%; systemic arthritis, 12.2%; juvenile psoriatic arthritis, 5.2%; undifferentiated arthritis, 2.8%; and RF-positive polyarthritis, 2.2%. JIA-associated uveitis was observed in 6.8% of patients at a mean (Standard Deviation, SD) age of 9.1 (3.8) years over a mean JIA disease duration of 4 (1.9) years. Uveitis developed after joint disease, with a mean (SD) duration of 1.8 (1.9) years. Patients with oJIA had the highest rate of uveitis (12.9%) followed by patients with ERA (5.2%) and polyarticular RF-negative disease (3.8%). Compared with persistent oJIA, the extended oJIA category had a > 3-fold higher risk of uveitis (11.3% vs 27.7%; odds ratio, 3.38 [95% Confidence Interval, 1.09–10.4]). The most frequently administered drug after development of uveitis was tumor necrosis factor–alpha inhibitors (38.2%). Five patients (14.7%) had uveitis-related complications that required surgical intervention. Conclusions Turkish pediatric patients with JIA experience a lower frequency of oJIA and higher frequency of ERA than their white European counterparts; the occurrence of uveitis is also somewhat lower than expected. Geographic and ethnic factors may affect these differences and need further investigation.

Macrophage activation syndrome (MAS) is a devastating complication of systemic JIA (sJIA), seen in approximately 10–25% of the sJIA patients. A number of criteria have been proposed to differentiate between activation of sJIA and MAS, including HScore and the recently proposed MS-score. This is the first study comparing the performances of MS-score and HScore for the diagnosis of MAS in sJIA patients. Systemic JIA patients followed at Hacettepe University Pediatric Rheumatology Unit were included in the study. Clinical features and laboratory findings at the time when the disease was most active or patients were diagnosed with MAS were recorded retrospectively. HScore and MS-score were calculated and the diagnostic performance for MAS was compared by receiver operating characteristic (ROC) curve analysis. Seventy-one sJIA patients were included (23 MAS, 48 activation). There was no difference in age of onset (median 4.7 vs. 5.0 years) and gender (73.9% vs. 54.2%) between patients who had MAS and sJIA activation. Median MS-score and HScore were higher in the MAS group. ROC curve analysis revealed that the HScore performed slightly better in diagnosing MAS, compared with the MS-score (AUC = 0.965 and 0.901 for HScore and MS-score respectively, P < 0.001). In our cohort, the optimal cut-off for the MS score was ≥ − 1.64 (sensitivity: 91.3%; specificity: 83.8%) and for the HScore it was ≥ 162.5 (sensitivity: 91.3%; specificity: 90.2%). HScore performed slightly better than MS-score for the diagnosis of MAS in our cohort.