Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and ...adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial–entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.
Objective
Glycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly ...with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.
Methods
Using ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).
Results
Multiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).
Conclusion
The IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.
Enthesitis related arthritis (ERA) is a specific subtype of juvenile idiopathic arthritis (JIA), often regarded as an undifferentiated form of juvenile spondyloarthritis (jSpA). While gut is ...increasingly recognized as origin and/or target of inflammation in adult onset spondyloarthritis (SpA), the incidence of gut involvement in ERA patients is largely unknown. The aim of this study was to measure the concentration of fecal calprotectin (fCAL), a surrogate marker of gut inflammation, in patients with different subtypes of JIA, as well as to correlate the results with various demographic, clinical, laboratory, imaging, and treatment characteristics. The cross-sectional exploratory study involving 71 patients with ERA, other forms of JIA and children complaining musculoskeletal symptoms was therefore conducted. Along with fCAL assessment, a detailed clinical and laboratory examination was performed, including the calculation of a composite disease activity scores. Moreover, MRI of the sacroiliac joints was performed in all ERA and other patients complaining of low back pain. The median concentration of fCAL was highest in ERA patients (33.2 mg/kg,
= 0.02), with a significant difference between those with inactive and active disease (20.0 vs. 57.4,
= 0.01), as well as those with and without MRI signs of sacroiliitis (22.6 vs. 54.3,
= 0.04). The fCAL did not differ depending on the NSAID use (23 vs. 20,
= 0.18), although weak correlation was observed with the treatment duration (
= 0.25,
= 0.03). In conclusion, our findings indicate that a parallel inflammation in musculoskeletal system and gut can occur not just in adults with SpA, but in children with ERA as well.
The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and ...therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.
We report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.
This case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.
Thymic stromal lymphopoietin (TSLP), an epithelium-derived pro-inflammatory cytokine, activates distinct immune and non-immune cells. It has been shown to be a master regulator of type 2 immune ...responses. Limited information is available on TSLP in childhood asthma. The aim of the present study was to find out whether there is association between TSLP concentrations and asthma phenotypes or disease activity.
A total of 207 children with asthma and 100 healthy children aged 1–13 years were enrolled. This study examined serum TSLP concentrations using ELISA Kit in asthma patients and controls, analyzed its correlation with asthma phenotypes and pulmonary function. We also examined TSLP concentrations in 23 patients during stable asthma and in acute asthma exacerbation.
The serum concentrations of TSLP were significantly elevated in asthma patients compared with healthy controls (p < 0.05), but there was no significant difference (p > 0.05) in TSLP concentrations between three different asthma phenotypes (allergic asthma, virus induced asthma and nonallergic asthma). There was no significant correlation between TSLP concentrations and FEV1pred% (r = 0.01, p > 0.05).
In the acute asthma exacerbation TSLP concentrations were not significantly different than in stable phase of disease (p > 0.05).
Children with asthma have higher serum TSLP concentrations when compared to healthy controls. TSLP does not seem to be a biomarker of disease exacerbation in children. Different asthma phenotypes have similar TSLP concentration profile in peripheral blood and TSLP does not seem to be useful biomarker in asthma phenotyping in children.
•The thymic stromal lymphopoietin is a master regulator of type 2 immune responses.•Serum TSLP concentrations are higher in children with asthma.•TSLP role in identifying children with different asthma phenotypes is limited.•Serum TSLP does not seem to be a biomarker of asthma exacerbation.
Febrile illnesses in young children can be a major diagnostic challenge, despite the routine use of various laboratory markers. Recent advancements in the understanding of inflammatory processes have ...highlighted the role of calprotectin, a heterodimer consisting of S100A8 and S100A9 proteins, with many studies suggesting its clinical value as a biomarker of inflammation. This research aimed to evaluate the usefulness of serum calprotectin (sCal) as a biomarker of urinary tract infection (UTI), which was due to its high pooled prevalence and feasibility of urine culture as a diagnostic reference standard selected for a model of bacterial infection in children.
Febrile children aged 0-36 months with suspected UTI based on positive urinalysis or viral respiratory tract infection were included. Children with significant bacteriuria in urine culture were labeled as cases (
= 58), while those with confirmed viral infection (
= 51), as well as those with suspected UTI but sterile urine culture who went on to develop symptoms consistent with viral respiratory infection (
= 7), were labeled as controls. sCal levels were determined by a commercial immunoassay. Conventional inflammation markers (C-reactive protein, procalcitonin, white blood cell count, absolute neutrophil count, and neutrophil percentage) were measured on the day of the clinical examination. Differences in measured inflammatory markers between cases and controls were analyzed with Mann-Whitney
-test. ROC analysis reported cut-off values with the best sensitivity and specificity to distinguish bacterial UTI from viral respiratory infection.
All analyzed inflammatory biomarkers, including sCal, were significantly higher in cases than in controls. Median concentration of sCal was 4.97 μg/mL (IQR 3.43-6.42) and 2.45 μg/mL (IQR 1.63-3.85) for cases and controls, respectively (
< 0.001). For identifying bacterial UTI, sensitivity and specificity of sCal were 77.6 and 69.0%, respectively, at an adjusted cut-off point of >3.24 μg/mL (AUC 80.2%).
sCal could have substantial added value in the management of a child with fever and positive urinalysis and is a promising biomarker in distinction between bacterial UTI and viral respiratory causes of febrile illness in children under the age of 3 years.
Osteoid osteoma is a painful benign skeletal tumour of unknown aetiology. Most often it occurs in the long bones of extremities and responds well to nonsteroidal anti-inflammatory medications. ...However, unusual localization and atypical presentation of this tumour might present a diagnostic challenge, especially if symptoms mimic that indicative of juvenile spondyloarthritis.
A misdiagnosed ten-and-a-half-year-old girl with osteoid osteoma involving the distal phalanx of a little finger is presented. Her initial symptoms were pain and swelling of the little finger resembling dactylitis, while various imaging modalities showed signs of tenosynovitis, indicating a possible development of juvenile spondyloarthritis. Several trials of different non-steroid anti-inflammatory drugs gave no satisfactory results and ultrasound guided triamcinolone-hexacetonide injection provided only a short relief. Finally, almost three years after initial presentation, persistent clinical symptoms warranted repeated imaging that raised suspicion of an osteoid osteoma. Directed treatment with surgical intervention led to almost immediate and complete resolution of her symptoms.
Osteoid osteoma should be suspected in case of a tender swelling of a digit in children and adolescents, regardless of initial imaging findings and clinical presentation. Early diagnosis and treatment of this benign condition can have a substantial impact on quality of life of patients and their families and protect them from many unnecessary diagnostic procedures and treatment.
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