| 1. |
- Arve-Butler, Sabine, et al.
(författare)
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Identification of novel autoantigens as potential biomarkers in juvenile idiopathic arthritis associated uveitis
- 2023
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Ingår i: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 10, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many children with juvenile idiopathic arthritis (JIA) have autoantibodies, targeting nuclear components (anti-nuclear antibodies, ANA). ANA in JIA is associated with uveitis, an eye inflammation which may cause permanent vision impairment if not detected and treated. However, ANA-testing is neither specific nor sensitive enough to be a clinically reliable predictor of uveitis risk, and the precise autoantigens targeted by ANA in JIA are largely unknown. If identified, specific autoantibodies highly associated with uveitis could be used as biomarkers to facilitate identification of JIA patients at risk.METHODS: Antibodies from six ANA-positive, oligoarticular JIA patients, with and without uveitis, were explored by two large-scale methods: (1) screening against 42,100 peptides on an autoimmunity profiling planar array, and (2) immunoprecipitations from cell lysates with antigen identification by mass spectrometry. Three hundred thirty-five peptide antigens, selected from proteins identified in the large-scale methods and the scientific literature were investigated using a bead-based array in a cohort of 56 patients with oligoarticular- or RF-negative polyarticular JIA, eight of which were having current or previous uveitis.RESULTS: In the planar array, reactivity was detected against 332 peptide antigens. The immunoprecipitations identified reactivity towards 131 proteins. Only two proteins were identified by both methods. In the bead-based array of selected peptide antigens, patients with uveitis had a generally higher autoreactivity, seen as higher median fluorescence intensity (MFI) across all antigens, compared to patients without uveitis. Reactivity towards 17 specific antigens was significantly higher in patients with uveitis compared to patients without uveitis. Hierarchical clustering revealed that patients with uveitis clustered together.CONCLUSION: This study investigated autoantigens in JIA and uveitis, by combining two exploratory methods and confirmation in a targeted array. JIA patients with current or a history of uveitis had significantly higher reactivity towards 17 autoantigens and a generally higher autoreactivity compared to JIA patients without uveitis. Hierarchical clustering suggests that a combination of certain autoantibodies, rather than reactivity towards one specific antigen, is associated with uveitis. Our analysis of autoantibodies associated with uveitis in JIA could be a starting point for identification of prognostic biomarkers useful in JIA clinical care.
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| 2. |
- Arve-Butler, Sabine, et al.
(författare)
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Neutrophils Lose the Capacity to Suppress T Cell Proliferation Upon Migration Towards Inflamed Joints in Juvenile Idiopathic Arthritis
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4+ T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in an in vitro transmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4+ T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint.
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| 3. |
- Arve-Butler, Sabine, et al.
(författare)
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Synovial fluid neutrophils in oligoarticular juvenile idiopathic arthritis have an altered phenotype and impaired effector functions
- 2021
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neutrophils are the most prevalent immune cells in the synovial fluid in inflamed joints of children with oligoarticular juvenile idiopathic arthritis (JIA). Despite this, little is known about neutrophil function at the site of inflammation in JIA and how local neutrophils contribute to disease pathogenesis. This study aimed to characterize the phenotype and function of synovial fluid neutrophils in oligoarticular JIA. Methods: Neutrophils obtained from paired blood and synovial fluid from patients with active oligoarticular JIA were investigated phenotypically (n = 17) and functionally (phagocytosis and oxidative burst, n = 13) by flow cytometry. In a subset of patients (n = 6), blood samples were also obtained during inactive disease at a follow-up visit. The presence of CD206-expressing neutrophils was investigated in synovial biopsies from four patients by immunofluorescence. Results: Neutrophils in synovial fluid had an activated phenotype, characterized by increased CD66b and CD11b levels, and most neutrophils had a CD16hi CD62Llowaged phenotype. A large proportion of the synovial fluid neutrophils expressed CD206, a mannose receptor not commonly expressed by neutrophils but by monocytes, macrophages, and dendritic cells. CD206-expressing neutrophils were also found in synovial tissue biopsies. The synovial fluid neutrophil phenotype was not dependent on transmigration alone. Functionally, synovial fluid neutrophils had reduced phagocytic capacity and a trend towards impaired oxidative burst compared to blood neutrophils. In addition, the effector functions of the synovial fluid neutrophils correlated negatively with the proportion of CD206+ neutrophils. Conclusions: Neutrophils in the inflamed joint in oligoarticular JIA were altered, both regarding phenotype and function. Neutrophils in the synovial fluid were activated, had an aged phenotype, had gained monocyte-like features, and had impaired phagocytic capacity. The impairment in phagocytosis and oxidative burst was associated with the phenotype shift. We speculate that these neutrophil alterations might play a role in the sustained joint inflammation seen in JIA.
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| 4. |
- Berthold, Elisabet, et al.
(författare)
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Continuation of TNF blockade in patients with inflammatory rheumatic disease. An observational study on surgical site infections in 1,596 elective orthopedic and hand surgery procedures
- 2013
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 84:5, s. 495-501
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Increased infection risk in inflammatory rheumatic diseases may be due to inflammation or immunosuppressive treatment. The influence of tumor necrosis factor (TNF) inhibitors on the risk of developing surgical site infections (SSIs) is not fully known. We compared the incidence of SSI after elective orthopedic surgery or hand surgery in patients with a rheumatic disease when TNF inhibitors were continued or discontinued perioperatively.PATIENTS AND METHODS: We included 1,551 patients admitted for elective orthopedic surgery or hand surgery between January 1, 2003 and September 30, 2009. Patient demographic data, previous and current treatment, and factors related to disease severity were collected. Surgical procedures were grouped as hand surgery, foot surgery, implant-related surgery, and other surgery. Infections were recorded and defined according to the 1992 Centers for Disease Control definitions for SSI. In 2003-2005, TNF inhibitors were discontinued perioperatively (group A) but not during 2006-2009 (group B).RESULTS: In group A, there were 28 cases of infection in 870 procedures (3.2%) and in group B, there were 35 infections in 681 procedures (5.1%) (p = < 0.05). Only foot surgery had significantly more SSIs in group B, with very low rates in group A. In multivariable analysis with groups A and B merged, only age was predictive of SSI in a statistically significant manner.INTERPRETATION: Overall, the SSI rates were higher after abolishing the discontinuation of anti-TNF perioperatively, possibly due to unusually low rates in the comparator group. None of the medical treatments analyzed, e.g. methotrexate or TNF inhibitors, were significant risk factors for SSI. Continuation of TNF blockade perioperatively remains a routine at our center.
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| 5. |
- Berthold, Elisabet
(författare)
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Juvenile idiopathic arthritis - from macrophage to mortality
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Studies of the immunopathogenesis in JIA has mainly focused on the adaptive immune system, while less is known of the role of the monocytes. JIA is considered a chronic disease, although only about 50% of participants in long-term follow-up studies have active disease as adults. The treatment arsenal for JIA has expanded during the last three decades, but if this has improved the long-term outcome is not known.When a diagnosis of JIA is confirmed almost all children and parents ask the same important questions: “Why did I/my child get this disease?”, “What will happen to me now?” and “Will I ever get well?”. The overall aim of this thesis has been to study different aspects of these questions – from the pathophysiological role of monocytes and their function in blood and the synovial environment, to incidence, outcome measures with short- and long-term perspectives, risk of depression and anxiety, and mortality.Children with active oligoarticular JIA display monocytes of a mixed pro- and anti-inflammatory polarization pattern in the synovial environment, with reduced capacity to phagocytize, unique for this JIA subtype. This supports the hypothesis that oligoarticular JIA should not be considered as a pediatric version of adult rheumatic arthritides.The mean annual incidence rate in Skåne (the southernmost region of Sweden) 1980 – 2010 was 9.9/100,000 children < 16 years, with significantly increasing numbers during the period. The mortality was interpreted as low, fewer patients were diagnosed with JIA-associated uveitis and the need of joint corrective surgery was decreased compared to previously published data. However, children with JIA diagnosed since the introduction of biologic immunomodulatory treatment still experienced disease activity more than 50% of the follow-up years. No increased risk for diagnosis with depression or anxiety was found in JIA patients and they were also not diagnosed at an earlier age than age- and sex-matched controls.In conclusion, the long-term outcome of JIA has improved and the risk for depression and anxiety is not found to be increased in JIA. There are however still challenges with active disease more than half of the time in spite of state-of-the-art treatment. Follow-up in adulthood is needed to answer the question of how many JIA patients that still needs healthcare as adults.
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| 6. |
- Berthold, Elisabet, et al.
(författare)
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Outcome in Juvenile Idiopathic arthritis : a population-based study from Sweden
- 2019
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 21, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: As the treatment arsenal for children with juvenile idiopathic arthritis (JIA) has expanded during the last decades, follow-up studies are needed on children diagnosed in the era of biological treatment to evaluate if this has improved the outcome. Our aim was to study the epidemiology and outcome of JIA in southern Sweden using a population-based cohort of children with a validated diagnosis of JIA collected over 9 years. Methods: Potential cases of JIA between 2002 and 2010 were collected after a database search, using the ICD codes M08-M09. The study area was Skåne, the southernmost county of Sweden (population 1.24 million; 17.6% aged < 16 years). The JIA diagnosis was validated and subcategorized through medical record review based on the criteria defined by the International League of Associations for Rheumatism (ILAR). Parameters on disease activity and pharmacologic treatment were recorded annually until the end of the study period (December 31, 2015). Results: In total, 251 cases of JIA were confirmed. The mean annual incidence rate for JIA was estimated to be 12.8/100,000 children < 16 years, with the highest age-specific annual incidence at the age of 2 years (36/100,000). Oligoarthritis was the largest subgroup (44.7%), and systemic JIA was the smallest subgroup (2.8%). Methotrexate was the most common disease-modifying anti-rheumatic drug prescribed (60.6%). Tumor necrosis factor alpha inhibitors were used as treatment for 23.9% of the children. Only 40.0% of the follow-up years, with a median follow-up time of 8 years, were free of arthritis or uveitis. Uveitis occurred in 10.8% of the children (8.0% chronic uveitis), and the need for joint corrective orthopedic surgery was 9.2%. Conclusions: The incidence of JIA in this well-defined, population-based cohort is slightly lower than in previously published studies from Scandinavia. The need for orthopedic surgery and the presence of uveitis are diminished compared to studies with patients diagnosed more than 20 years ago. Children with JIA however still experience disease activity more than 50% of the time. In conclusion, we still have long-term challenges in the care for children with JIA, in spite of state-of-the-art treatment.
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| 7. |
- Berthold, Elisabet, et al.
(författare)
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The risk of depression and anxiety is not increased in individuals with juvenile idiopathic arthritis - results from the south-Swedish juvenile idiopathic arthritis cohort
- 2022
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Ingår i: Pediatric Rheumatology. - : Springer Science and Business Media LLC. - 1546-0096. ; 20:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildren with chronic diseases are reported to have increased risk of psychiatric comorbidity. Few studies have investigated this risk in juvenile idiopathic arthritis (JIA), with conflicting results. We performed a population-based, longitudinal cohort study of the risk of depression and anxiety in south-Swedish patients with juvenile arthritis.MethodsThe south-Swedish JIA cohort (n = 640), a population-based cohort with validated JIA diagnosis 1980 – 2010 and comparators, a reference group of 3200 individuals free from JIA, matched for sex, year of birth and residential region, was used. Data on comorbid diagnosis with depression or anxiety were obtained from the Skåne Healthcare Register, containing all healthcare contacts in the region, from 1998 to 2019. We used Cox proportional models for the calculation of hazard ratios.ResultsDuring the study period, 1998 to 2019, 93 (14.5%) of the individuals in the JIA group were diagnosed with depression, and 111 (17.3%) with anxiety. Corresponding numbers among the references was 474 (14.8%) with depression and 557 (17.4%) with anxiety. Hazard ratio for depression was 1.1 (95% CI 0.9 – 1.5) in females and 0.8 (95% CI 0.5 – 1.4) in males, and for anxiety 1.2 (95% CI 0.9 – 1.5) in females and 0.6 (95% CI 0.4 – 1.1) in males. There were no statistically significant hazard ratios when analyzing subgroups of JIA patients with long disease duration or treatment with disease-modifying antirheumatic drugs.ConclusionsIndividuals with JIA do not have any statistically increased risk of being diagnosed with depression or anxiety compared to matched references.
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| 8. |
- Kahn, Robin, et al.
(författare)
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Capillary leak syndrome was associated with more severe multisystem inflammatory syndrome in children during the COVID-19 pandemic
- 2024
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Ingår i: Acta Paediatrica, International Journal of Paediatrics. - 0803-5253.
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This population-based study investigated the occurrence of capillary leak syndrome (CLS) in children with multisystem inflammatory syndrome in children (MIS-C), associated with COVID-19. We also examined associations between CLS and MIS-C disease severity. Methods: All eligible individuals aged 0–18 years, who were diagnosed with MIS-C in Skåne, southern Sweden, from 1 April 2020 to 31 July 2021, were studied. They were all included in the Pediatric Rheumatology Quality Register and clinical and laboratory data were compared between patients with and without CLS. Results: We included 31 patients (61% male) with MIS-C in the study. The median age at diagnosis was 10.6 years (range 1.99–17.15) and 45% developed CLS. All six patients who required intensive care had CLS. Patients with CLS also had a higher incidence of reduced cardiac function, measured as low ejection fraction. The CLS group exhibited significantly higher C-reactive protein values (p < 0.001) and N-terminal pro-B-type natriuretic peptide levels (p < 0.001), as well as lower platelet counts (p = 0.03), during the first week of treatment. Individuals with CLS also received more intense immunosuppression. Conclusion: CLS was a common complication of MIS-C in our study and these patients had a more severe disease course that required more intensive treatment.
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| 9. |
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| 10. |
- Kahn, Robin, et al.
(författare)
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Population-based study of multisystem inflammatory syndrome associated with COVID-19 found that 36% of children had persistent symptoms
- 2022
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Ingår i: Acta Paediatrica, International Journal of Paediatrics. - : Wiley. - 0803-5253 .- 1651-2227. ; 111:2, s. 354-62
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Our aim was to describe the outcomes of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Methods: This national, population-based, longitudinal, multicentre study used Swedish data that were prospectively collected between 1 December 2020 and 31 May 2021. All patients met the World Health Organization criteria for MIS-C. The outcomes 2 and 8weeks after diagnosis are presented, and follow-up protocols are suggested. Results: We identified 152 cases, and 133 (87%) participated. When followed up 2weeks after MIS-C was diagnosed, 43% of the 119 patients had abnormal results, including complete blood cell counts, platelet counts, albumin levels, electrocardiograms and echocardiograms. After 8weeks, 36% of 89 had an abnormal patient history, but clinical findings were uncommon. Echocardiogram results were abnormal in 5% of 67, and the most common complaint was fatigue. Older children and those who received intensive care were more likely to report symptoms and have abnormal cardiac results. Conclusion: More than a third (36%) of the patients had persistent symptoms 8weeks after MIS-C, and 5% had abnormal echocardiograms. Older age and higher levels of initial care appeared to be risk factors. Structured follow-up visits are important after MIS-C.
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