Application of Interferon-γ Release Assay in the Assessment of T-Cell Immunity to SARS-CoV-2 Antigens in the Cohort of Pediatric Patients with Juvenile Idiopathic Arthritis.

Background: an accurate assessment of the immunity against SARS-CoV-2 can facilitate a better understanding and management of not only the recent coronavirus but similar pathogens as well. Objective: the aim of this study was to evaluate T-cell immunity with reference to antibody titers in a group of pediatric patients with autoimmune arthritides utilizing the widely known Interferon-γ Release Assay (IGRA). Materials and Methods: This study was conducted in the cohort of 55 children suffering from Juvenile Idiopathic Arthritis (JIA). This research analyzed the SARS-CoV-2 T-cell response measured by a specific quantitative IGRA, followed by a serological ELISA test measuring the presence and quantity of IgG, IgM, and IgA antibodies in serum. Results: The cellular response to SARS-CoV-2 measured by the IGRA test significantly correlated with the antibody titers, IgA (p < 0.00003, R = 0.537), IgG (p < 0.0001, R = 0.668), and IgG nucleocapsid protein (NCP) (p < 0.003, R = 0.0399), with no correlation with IgM levels. The antibody levels in patients receiving biological agents were significantly lower compared to the rest of the cohort (p = 0.0369), while traditional disease-modifying antirheumatic drugs had no such effect. Limitations: the main limitation of the research is the small sample size, mostly due to the specific cohort of patients and the lack of a healthy control. Conclusions: IGRA appears to be a viable tool in the accurate evaluation of T-cell responses to SARS-CoV-2, and serodiagnostics alone is not always sufficient in the assessment of immune responses.

Interferon-γ Release Assay in the Assessment of Cellular Immunity-A Single-Centre Experience with mRNA SARS-CoV-2 Vaccine in Patients with Juvenile Idiopathic Arthritis.

Background: As the SARS-CoV-2 virus remains one of the main causes of severe respiratory system infections, the Food and Drug Administration strongly advises the continuation of current vaccination programs, including the distribution of updated boosters, especially in high-risk groups of patients. Therefore, there is an unceasing need for further research on the safety and, no less importantly, the clinical effectivity of the vaccines, with an extra focus on cohorts of patients with underlying health problems. This study aimed to assess the efficacy of the SARS-CoV-2 vaccine in possibly immunocompromised children with rheumatic disease while utilizing the interferon-gamma release assay (IGRA) as a marker for COVID-19 immunity in the study follow-up. Methods: This prospective study was performed in a group of 55 pediatric patients diagnosed with juvenile idiopathic arthritis. Eight participants were immunized with the Comirnaty mRNA vaccine before the research commenced, while the rest of the group (n = 47) had not been vaccinated against SARS-CoV-2. At the study baseline, the cellular response to the virus antigen was measured using a specific quantitative IGRA in whole blood; subsequently, the anti-SARS-CoV-2 test was performed, marking the antibodies' levels in serum. Around four months after the enrollment of the last patient in the study, a follow-up survey regarding the events of COVID-19 infection within the cohort was conducted. Results: The study confirmed that all the vaccinated children developed specific T-cell (p = 0.0016) and humoral (p = 0.001 for IgA antibodies, p = 0.008 for IgG antibodies) responses to the inoculation, including those receiving biological treatment and those on conventional disease-modifying anti-rheumatic drugs. The study also showed the different patterns of immunity elicited both after infection and post-vaccination, with higher levels of antibodies and T-cell response after inoculation than after natural exposure to the pathogen. According to the follow-up survey, six children developed PCR-confirmed SARS-CoV-2 infection, whereas the additional 10 patients admitted to having COVID-like symptoms with no laboratory verification. Conclusions: SARS-CoV-2 vaccinations elicit valid immune responses in pediatric rheumatic patients. Including the assessment of T-cell immunity in the evaluation of inoculation-induced immunization can enhance the accuracy of sole humoral response assays.

Why and How Should We Assess the Cardiovascular Risk in Patients with Juvenile Idiopathic Arthritis? A Single-Centre Experience with Carotid Intima-Media Measurements.

BACKGROUND: Children diagnosed with juvenile idiopathic arthritis (JIA) are thought to be more likely to develop cardiovascular disease in adulthood. The factors modulating the cardiovascular risk, involving exposure to secondhand smoking, sedentary lifestyle and abnormal body mass index, might have had a stronger impact during the COVID-19 pandemic. The lack of reliable prognostic markers for a higher probability of cardiovascular events might be solved by carotid intima-media thickness (cIMT) measurement. The paramount goal of the study was to assess its usefulness in JIA patients. MATERIALS AND METHODS: The results of cIMT measured by a single physician in 45 children diagnosed with JIA were compared to 37 age- and sex-matched healthy counterparts. The analysis also involved anthropometric parameters, laboratory tests, and a survey regarding lifestyle-related factors. RESULTS: Four JIA patients appeared to have cIMT above the 94th percentile. A positive correlation between erythrocytes sedimentation rate (ESR) and right carotid artery percentiles was found. Passive smoking increased the cardiovascular risk regardless of JIA. Doubling the daily screen time during the pandemic led to a significant reduction in children's physical activity. However, the number of enrolled subjects was not enough to make significant recommendations. CONCLUSIONS: cIMT measurements remain an interesting perspective for future cardiovascular screening of children with JIA. It has yet to be determined whether it should be considered in all JIA patients on a reliable basis.

Immunity in SARS-CoV-2 Infection: Clarity or Mystery? A Broader Perspective in the Third Year of a Worldwide Pandemic.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its mechanisms have been thoroughly studied by researchers all over the world with the hope of finding answers that may aid the discovery of new treatment options or effective means of prevention. Still, over 2 years into the pandemic that is an immense burden on health care and economic systems, there seem to be more questions than answers. The character and multitude of immune responses elicited in coronavirus disease 2019 (COVID-19) vary from uncontrollable activation of the inflammatory system, causing extensive tissue damage and consequently leading to severe or even fatal disease, to mild or asymptomatic infections in the majority of patients, resulting in the unpredictability of the current pandemic. The aim of the study was to systematize the available data regarding the immune response to SARS-CoV-2, to provide some clarification among the abundance of the knowledge available. The review contains concise and current information on the most significant immune reactions to COVID-19, including components of both innate and adaptive immunity, with an additional focus on utilizing humoral and cellular responses as effective diagnostic tools. Moreover, the authors discussed the present state of knowledge on SARS-CoV-2 vaccines and their efficacy in cases of immunodeficiency.

The effect of vitamin D3 and thyroid hormones on the capillaroscopy-confirmed microangiopathy in pediatric patients with a suspicion of systemic connective tissue disease-a single-center experience with Raynaud phenomenon.

Raynaud phenomenon (RP) may be the first manifestation of a systemic connective tissue disease (SCTD). Early detection of dysfunction of small vessels called microangiopathy is essential for the diagnostic process. The focus of this single-center, retrospective study was to investigate the potential dependencies between microvascular image and laboratory markers measured in children with RP. The study analyzed the nail-fold video-capillaroscopy (NVC) findings and laboratory results of 81 children between the ages 6 and 17 who were referred to pediatric rheumatologist with a suspicion of SCTD. Out of 52 patients presenting with RP at the time of evaluation, abnormalities in capillary microscopic imaging were found in 34. NVC findings were then compared to levels of specific biomarkers in serum. Vitamin D3 serum levels have been significantly decreased in patients with RP (23.4 ng/mL ± 8.76 vs. 30.0 ng/mL ± 12.66, P = 0.0148). There were positive significant correlations between levels of vitamin D3 and acute-phase reactants in serum, such as C-reactive protein (P = 0.0292). Furthermore, free thyroxine levels (fT4) in patients with both RP (P = 0.0126) and micro-angiopathy (P = 0.05496) persisted in the lower range of the normal limit (< 1.0 ng/dL). Regular oral supplementation of vitamin D3 should be always considered in children with RP if deficiency is found. Additionally, low fT4 level (< 1.0 ng/dL) should be considered as an indication to perform NVC in patients suspected of SCTD even when they do not present RP.

The Potential Importance of MicroRNAs as Novel Indicators How to Manage Patients with Juvenile Idiopathic Arthritis More Effectively.

Small, noncoding sequences of ribonucleic acid called microRNAs (miRNAs, miR) are functioning as posttranscriptional regulators of gene expression. As they draw increasing attention of rheumatologists, there is a growing body of evidence concerning specific molecules that may affect the long-term care of patients with inflammatory arthritides. Findings involving children with juvenile idiopathic arthritis (JIA) are still limited though. The aim of the study was to browse the available data on microRNAs which may be utilized as potential biomarkers helpful in diagnosing and monitoring JIA patients. The review contains a brief summary on the most studied sequences: miR-16, miR-125a-5p, miR-146a, miR-155, and miR-223. It is complemented with other miRNAs possibly relevant for JIA (miR-145, miR-23b, miR-27a, and miR-204) and discussion on challenges for using miRNAs in pediatric rheumatology (particularly, issues regarding specificity of biomarkers and measurements involving synovial fluid).

How Does Endothelial Permeability Affect the Development of Juvenile Idiopathic Arthritis? Vascular Endothelial Cadherin as a Promising New Tool Helpful in the Diagnostic Process.

INTRODUCTION: Vascular endothelial cadherin (VE-cadherin) is a calcium-dependent protein essential for stabilization of the adherens junctions of the endothelial cells. Through vasculogenic mimicry, VE-cadherin may influence angiogenesis in synovial fibroblast-like cells. The soluble extracellular domain of VE-cadherin may be considered an indicator of endothelial dysfunction. Its potential as a diagnostic biomarker in rheumatic diseases, including juvenile idiopathic arthritis (JIA), needs to be investigated. MATERIALS AND METHODS: The study group included 80 patients diagnosed with JIA. In 53 individuals, blood samples were obtained twice with an average interval of 102.4 ± 4.6 days. Results from the study group were compared to 29 age- and sex-matched healthy children. RESULTS: Serum levels of VE-cadherin were significantly higher in JIA patients than in healthy controls. In such comparison, VE-cadherin had 87.5% sensitivity and 69.0% specificity for the cutoff level 4.36 ng/ml (Youden index 0.56, area under the curve 0.724). VE-cadherin concentrations negatively correlated with the disease activity score. However, such finding may be a false result because of the downregulation of VE-cadherin induced by glucocorticosteroids. CONCLUSIONS: VE-cadherin may become a promising diagnostic biomarker of early stages of JIA. Its predictive significance may be decreased by utilization of glucocorticosteroids. A multicentre study including patients with other arthritides is recommended for further evaluation of this protein.

Tocilizumab in the treatment of systemic-onset juvenile idiopathic arthritis - single-centre experience.

OBJECTIVES: The aim of the study was to evaluate the efficacy and long-term safety of tocilizumab treatment in children with systemic-onset juvenile idiopathic arthritis in a single centre. MATERIAL AND METHODS: The study was based on a retrospective analysis of a cohort of 10 patients with systemic-onset juvenile idiopathic arthritis who were treated with tocilizumab in the period September 2011-July 2017. Their medical records were analysed taking into consideration the effectiveness of tocilizumab treatment and frequency of side effects. RESULTS: Before the initiation of treatment, 9/10 patients from the study group complained of fever and had significantly increased values of inflammatory markers, with the median CRP concentration 41.1 mg/l (norm < 5 mg/l) and ESR 37 mm/h (norm < 12 mg/l). The period of the initial 12 weeks of treatment was a quantum leap in the course of the disease: all children were afebrile, and inflammatory markers values decreased by 99.4% in the case of CRP and 91.9% in ESR. All patients fulfilled ACR Pedi 50 criteria, and 3 of them achieved ACR Pedi 70. In the next stages of treatment the response to tocilizumab was sustained, reaching 10 children achieving ACR Pedi 70 and 5 ACR Pedi 90 after one year of therapy. Tocilizumab appeared to be relatively safe in the study group. Although elevation of transaminases and neutropenia were observed in 5/10 patients, they were usually mild and transitional in their course. CONCLUSIONS: Tocilizumab is both effective and has a relatively good safety profile in children with severe systemic-onset juvenile idiopathic arthritis. It should be considered in the recommendations as a first-line treatment of this disease.

A Granulocyte-Specific Protein S100A12 as a Potential Prognostic Factor Affecting Aggressiveness of Therapy in Patients with Juvenile Idiopathic Arthritis.

BACKGROUND: Defining new prognostic biomarkers has become one of the most promising perspectives for the long-term care of patients with juvenile idiopathic arthritis (JIA). The new efficient indicators of disease activity and potential response to treatment are crucial in establishing new therapeutic plans in accordance with the "treat to target" strategy. One of the most studied proteins is called S100A12, which is an alarmin specific for granulocytes, considered as a marker of their activity. MATERIALS AND METHODS: Study involved 80 patients diagnosed with JIA. Children with systemic subtype were not included in the study. In 53 cases, blood samples were obtained in two time points. Results from the study group were compared to 29 age- and sex-matched healthy individuals. RESULTS: Serum S100A12 levels were higher in JIA than in healthy controls at the study baseline (11.67 ± 6.59 vs. 6.01 ± 2.33 ng/ml). There were no significant differences in S100A12 values between assessed subtypes of JIA. The highest concentrations were observed in patients within a disease flare. S100A12 levels were not dependent from using glucocorticosteroids. The studied protein appeared to be an efficient biomarker for JIA patients: 100% specificity as a diagnostic marker (cut-off level: 10.73 ng/ml) and 100% sensitivity as an indicator of exacerbations within a 3-month observation (cut-off level: 5.48 ng/ml). CONCLUSIONS: S100A12 may become an important factor influencing decisions on aggressiveness of JIA therapy. Further elaboration on the clinical algorithm is necessary for that protein to be included in everyday practice.

Is it possible to predict a risk of osteoporosis in patients with juvenile idiopathic arthritis? A study of serum levels of bone turnover markers.

BACKGROUND: Low bone mineral density is a common finding in children with systemic connective tissue diseases, including juvenile idiopathic arthritis (JIA). The influence of the ongoing process of bone remodeling on the disease course merits further investigation. The aim of this study was to assess the clinical relevance of markers of bone turnover and their potential role as predictors of higher fracture risk and, by extension, risk of osteoporosis. MATERIALS AND METHODS: Blood samples were collected from 59 patients diagnosed with JIA in order to determine serum levels of the following markers of bone turnover: Beta-Crosslaps, osteocalcin, bone alkaline phosphatase, osteoprotegerin and receptor activator for nuclear factor kappa-B ligand. The values were analyzed with laboratory parameters and results of dual X-ray absorptiometry (DXA). RESULTS: Osteoprotegerin and bone alkaline phosphatase levels were age-dependent. Beta-Crosslaps values were significantly higher in patients with positive JADAS27 score (p=0.0410). Osteoprotegerin levels were higher in patients treated with biological agents than only with disease-modifying anti-rheumatic drugs (p=0.0273). There was no relation between markers of bone turnover and sex, DXA results, dosage of glucocorticosteroids and disease duration. CONCLUSIONS: The authors postulate performing DXA measurements every 6 months in patients with higher disease activity. The potential lower fracture risk in children with JIA within biological treatment needs further assessment. Age- and sex-adjusted reference rates of bone turnover markers need to be developed for Central European patients in order to assess individual values properly.

Are We Right to Consider Mesenchymal Stem Cells to Be a New Perspective for Patients with Juvenile Idiopathic Arthritis?

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood. Up to 50% of patients are resistant to standard therapy, which includes non-steroid anti-inflammatory drugs, corticosteroids, disease-modifying anti-rheumatic drugs and biologic therapies. Intra-articular injection of mesenchymal stem cells (MSCs) is proposed as a new approach to JIA treatment. MSCs can modulate inflammation via mechanisms of both adaptive and innate immune response. They are able to inhibit T and B cell proliferation, promote regulatory T cells, suppress the maturation of dendritic cells, stimulate macrophage differentiation into M2 phenotype and reduce effectiveness of natural killer cells. They also secrete plethora of soluble factors which influence joint inflammation. Recent clinical studies reviewed in the article provide promising results which may suggest including intra-articular injection of MSCs in therapy of patients with oligoarticular JIA.

Protective and Predisposing Morphological Factors in Suprascapular Nerve Entrapment Syndrome: A Fundamental Review Based on Recent Observations.

Suprascapular nerve entrapment syndrome (SNES) is a neuropathy caused by compression of the nerve along its course. The most common compression sites include the suprascapular notch and the spinoglenoid notch. The aim of this article was to review the anatomical factors influencing the occurrence of SNES in the light of the newest reports. Potential predisposing morphological factors include a V-shaped, narrow, or "deep" suprascapular notch; a band-shaped, bifurcated, or completely ossified superior transverse scapular ligament (STSL); particular arrangements of the suprascapular nerve and vessels at the suprascapular notch. A very recent report indicates structures at the suprascapular notch region that may protect from SNES, such as the suprascapular notch veins (SNV). The role of the anterior coracoscapular ligament (ACSL) is still not clear. While some studies indicate that it may predispose for SNES, the newest study proposes a protective function. Knowledge of these variations is essential for arthroscopic and other surgical procedures of this area in order to avoid iatrogenic injury of the suprascapular nerve or unexpected bleeding from the suprascapular vessels running alongside the STSL.

When a patient suspected with juvenile idiopathic arthritis turns out to be diagnosed with an infectious disease - a review of Lyme arthritis in children.

The Lyme arthritis is a common manifestation of infection with Borrelia burgdorferi spirochete. Despite its infectious background, the inflammation clinically and histopatologically resembles juvenile idiopathic arthritis. As it affects a considerable number of Lyme disease patients, it should be routinely considered in differential diagnosis. Development of arthritis is partially dependent on spirochetal factors, including the ribosomal spacer type and the sequence of outer surface protein C. Immunological background involves Th1-related response, but IL-17 provides an additional route of developing arthritis. Autoimmune mechanisms may lead to antibiotic-refractory arthritis. The current diagnostic standard is based on a 2-step testing: ELISA screening and immunoblot confirmation. Other suggested methods contain modified two-tier test with C6 ELISA instead of immunoblot. An initial 28-day course of oral antibiotics (doxycycline, cefuroxime axetil or amoxicillin) is a recommended treatment. Severe cases require further anti-inflammatory management. Precise investigation of new diagnostic and therapeutic approaches is advisable.

What Each Clinical Anatomist Has to Know about Left Renal Vein Entrapment Syndrome (Nutcracker Syndrome): A Review of the Most Important Findings.

Nutcracker syndrome (NCS) is the most common term for compression of the left renal vein between the superior mesenteric artery and the abdominal aorta. The development of NCS is associated with the formation of the left renal vein (LRV) from the aortic collar during the sixth to eighth week of gestation and abnormal angulation of the superior mesenteric artery from the aorta. Collateralization of venous circulation is the most significant effect of NCS. It includes mainly the left gonadal vein and the communicating lumbar vein. Undiagnosed NCS may affect retroperitoneal surgery and other radiological and vascular procedures. The clinical symptoms of NCS may generally be described as renal presentation when symptoms like haematuria, left flank pain, and proteinuria occur, but urologic presentation is also possible. Radiological methods of confirming NCS include Doppler ultrasonography as a primary test, retrograde venography, which can measure the renocaval pressure gradient, computed tomography angiography, which is faster and less traumatic, intravascular ultrasound, and magnetic resonance angiography. Treatment can be conservative or surgical, depending on the severity of symptoms and degree of LRV occlusion. Nutcracker syndrome is worth considering especially in differential diagnosis of haematuria of unknown origin.

Macrophages - silent enemies in juvenile idiopathic arthritis.

The inflammatory response by secretion of cytokines and other mediators is postulated as one of the most significant factors in the pathophysiology of juvenile idiopathic arthritis (JIA). The effect of macrophage action depends on the type of their activation. Classically activated macrophages (M1) are responsible for release of molecules crucial for joint inflammation. Alternatively activated macrophages (M2) may recognize self antigens by scavenger receptors and induce the immunological reaction leading to autoimmune diseases such as JIA. Molecules essential for JIA pathophysiology include: TNF-α, the production of which precedes synovial inflammation in rheumatoid arthritis; IL-1 as a key mediator of synovial damage; chemotactic factors for macrophages IL-8 and MCP-1; IL6, the level of which correlates with the radiological joint damage; MIF, promoting the secretion of TNF-α and IL-6; CCL20 and HIF, significant for the hypoxic synovial environment in JIA; GM-CSF, stimulating the production of macrophages; and IL-18, crucial for NK cell functions. Recognition of the role of macrophages creates the potential for a new therapeutic approach.