MRP8/14 serum levels as diagnostic markers for systemic juvenile idiopathic arthritis in children with prolonged fever

Objectives Differential diagnosis in children with prolonged fever is challenging. In particular, differentiating systemic-onset juvenile idiopathic arthritis (SJIA) from infectious diseases is difficult. Biomarkers are needed supporting the diagnostic work-up. The aim of this study was to validate the usefulness of MRP8/14 measurements in the diagnostic wok-up of febrile children and transfer it to clinical practice. Methods Data of 1,110 paediatric patients were included and divided into two cohorts: (A) For validation of MRP8/14 test performance with 3 different testing systems: the experimental enzyme-linked immunosorbent sandwich assay (ELISA), commercial ELISA and an innovative (POCT) lateral flow immunoassay (LFIA); (B) to validate the diagnostic accuracy with the two latter assays. Results In cohort A (n = 940), MRP8/14 was elevated in SJIA (12110±2650 ng/ml mean ± 95% CI) compared to other diagnoses (including infections and autoinflammatory diseases; 2980±510 ng/ml) irrespective of fever and anti-inflammatory treatment (p < 0.001). In untreated patients with fever (n = 195) MRP8/14 levels in SJIA (19740±5080 ng/ml) were even higher compared to other diagnoses (4590±1160 ng/ml) (p < 0.001, sensitivity 73%, specificity 90%). In cohort B1, the performance of the tests was confirmed in untreated patients with fever (n = 170): commercial ELISA (sensitivity 79%, specificity 89%) and LFIA (sensitivity 84%, specificity 81%). Compared with ferritin, IL-18, ESR, sIL2-R, and procalcitonin, MRP8/14 showed the best accuracy. Conclusion MRP8/14 serum analyses have been validated as a helpful tool supporting the diagnosis of SJIA in febrile children. The results could be confirmed with commercial ELISA and LFIA enabling a rapid diagnostic point-of-care screening test.

Clinical and Genetic Characteristics, Target Therapy Results in Children with Traps Syndrome (on Clinical Surveillance Data)

The complexity of diagnosing and predicting the course of TNF-receptor-associated periodic syndrome TRAPS determines the importance of studying the dependence of clinical manifestations on the variant of genetic mutation and the presence of modifier genes. We observed 5 children with an identified diagnosis of TRAPS. It was established that the disease onset in most cases is defined as a juvenile arthritis with systemic onset. Genetic variants with the replacement of cysteine residues are associated with an early debut and an aggressive course, the c.362G> A p.R121Q mutation is associated with an erosive damage to the spine. The case of a favorable course of TRAPS in siblings with a newly detected mutation is described. The development of urgent complications of TRAPS was revealed when basic therapy with canakinumab was canceled.

Overlapping Features in Kawasaki Disease-Related Arthritis and Systemic-Onset Juvenile Idiopathic Arthritis: A Nationwide Study in Japan

Background: Arthritis may occur after the diagnosis of Kawasaki disease (KD). Most cases are self-limiting; however, some patients require prolonged treatment.Method: To characterize KD-related arthritis, 14 patients who required arthritis treatment within 30 days after the diagnosis of KD were recruited from the 23rd KD survey in Japan. Twenty-six additional patients were included from our tertiary center and literature review cohorts.Results: The estimated prevalence of KD-related arthritis in Japan was 48 per 100,000 KD patients. Patients with KD-related arthritis had an older age at onset (52 vs. 28 months, P = 0.002) and higher rate of intravenous immunoglobulin (IVIG) resistance in comparison to those without arthritis (86 vs. 17%, P < 0.001). Among 40 patients, 18 had arthritis in the acute phase KD (continued fever-onset type) and 22 did in the convalescent phase (interval fever-onset type). Both showed a similar rate of complete KD or IVIG response. Interval-type patients required biologics for arthritis control less frequently (5 vs. 39%, P = 0.02) and had a higher 2-year off-treatment rate (100 vs. 43%, P = 0.009) than continued-type ones. Interval-types showed lower serum ferritin and interleukin-18 levels than continued-types. When continued-types were grouped according to whether or not they required biologics (n = 7 and n = 11, respectively), the former subgroup had higher ferritin and interleukin-18 levels (P = 0.01 and 0.02, respectively). A canonical discriminant analysis differentiated interval-type from continued-type with the combination of age, time to arthritis, and the ferritin and matrix metalloproteinase-3 levels.Conclusion: Arthritis requiring treatment is a rare complication of KD. KD-associated arthritis includes interval-type (KD-reactive) and continued-type (true systemic-onset juvenile idiopathic arthritis [JIA] requiring biologics), and overlapping arthritis, suggesting the pathophysiological continuity of autoinflammation between KD and JIA.

The immunoregulatory function of peripheral blood CD71+ erythroid cells in systemic-onset juvenile idiopathic arthritis

CD71+ erythroid cells (CECs) are recognized to have an immunoregulatory function via direct cell–cell interaction and soluble mediators. Circulating CECs appear in newborns or patients with hemolytic and cardiopulmonary disorders. To assess the biological role of CECs in systemic inflammation, we studied the gene expression and function in systemic-onset juvenile idiopathic arthritis (SoJIA). Peripheral blood mononuclear cells of SoJIA patients expressed upregulated erythropoiesis-related genes. It represented the largest expansion of CECs during active phase SoJIA among other inflammatory diseases. Despite the opposing roles of erythropoietin and hepcidin in erythropoiesis, both serum levels were in concert with the amounts of SoJIA-driven CECs. Circulating CECs counts in inflammatory diseases were positively correlated with the levels of C-reactive protein, IL-6, IL-18, or soluble TNF receptors. Co-culture with active SoJIA-driven CECs suppressed secretions of IL-1β, IL-6, and IL-8 from healthy donor monocytes. The top upregulated gene in SoJIA-driven CECs was ARG2 compared with CECs from cord blood controls, although cytokine production from monocytes was suppressed by co-culture, even with an arginase inhibitor. CECs are driven to the periphery during the acute phase of SoJIA at higher levels than other inflammatory diseases. Circulating CECs may control excessive inflammation via the immunoregulatory pathways, partly involving arginase-2.

A Rare Case of a Severe Course of Systemic Onset of Juvenile Idiopathic Arthritis Associated with MEFV Gene Mutations in a 12-year-old Girl

Juvenile idiopathic arthritis (JIA) is a common rheumatic disease in children and adolescents. MEFV (Mediterranean fever, FMF) gene mutations are observed in systemic-onset JIA, that in addition to increasing the risk of JIA development, worsen the disease prognosis. We reported a rare case of a severe systemic-onset JIA associated with MEFV gene mutations in a 12-year-old girl. The patient had an aggressive disease course and resistance to conventional immunosuppressive agents. This case confirms the difficulties of diagnostic and treatment of systemic JIA (sJIA) associated with FMF. Currently, there are no established criteria for the definition or differential diagnosis of arthritis associated with FMF. The severe prognosis of JIA associated with FMF should motivate clinicians to initiate aggressive therapy early.

Relationship of genetic polymorphism of the acute phase marker of inflammation rs12218 of the SAA1 gene with clinical phenotypes of juvenile idiopathic arthritis

Objective: to test the hypothesis of a possible relationship between the rs12218 polymorphism of the SAA1 gene and a predisposition to different clinical phenotypes of juvenile idiopathic arthritis (JIA).Patients and methods. Genetic typing of rs12218 polymorphism was carried out in 142 children: 77 of them were diagnosed with JIA, including 30 patients with oligoarthritis (oJIA), 20 with polyarthritis (pJIA), and 27 with systemic onset (sJIA). Sixty five healthy volunteers were included in the control group. The rs12218 polymorphism of the SAA1 gene was investigated using real-time polymerase chain reaction.Results and discussion. A high risk of developing the clinical phenotype of oJIA in carriers of the C mutant allele of the rs12218 T/C polymorphism of the SAA1 gene was established. Statistically significant differences between the clinical phenotypes of oJIA and sJIA in the frequency distribution of genotypes and alleles of rs12218 T/C polymorphism of the SAA1 gene are shown.Conclusion. The results of the studies have confirmed the important role of the rs12218 T/C polymorphism of the SAA1 gene in the formation of susceptibility to clinical variants of JIA.

The Association of Serum IL-10 Levels with the Disease Activity in Systemic-Onset Juvenile Idiopathic Arthritis Patients

Objectives. Interleukin-10 (IL-10) has been suggested as a biomarker of disease activity in patients with adult-onset Still’s disease (AOSD). In this study, we evaluated the serum IL-10 levels and investigated its clinical relevance in systemic-onset juvenile idiopathic arthritis (SoJIA). Methods. IL-10 levels were determined in 21 patients diagnosed with SoJIA and 35 patients with fever diseases which were suspected as SoJIA, and IL-10 levels were compared between SoJIA patients with regard to disease activity, disease courses, and other biomarkers. Results. Patients with SoJIA had significantly higher levels of IL-10 compared to patients with other febrile diseases. The serum levels of IL-10 were significantly higher in active SoJIA compared to inactive and positively correlated with known disease activity markers such as erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), ferritin (FER), and IL-6 levels. Moreover, the levels of IL-10 at diagnosis were significantly higher in SoJIA patients with a nonmonocyclic pattern than in patients with a monocyclic pattern. Compared to CRP, ESR, FER, and IL-6, IL-10 levels were superior in predicting monocyclic patients from nonmonocyclic patients. Conclusion. Compared to other febrile diseases, SoJIA patients have markedly higher levels of IL-10 which may assist with diagnosis. And a clear association of serum IL-10 levels with disease activity and disease courses in SoJIA was found. These results suggest that serum IL-10 might be a reliable clinical marker in SoJIA.

Adult-Onset Still’s Disease: Clinical Aspects and Therapeutic Approach

Adult-onset Still’s disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still’s disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.