| 1. |
- af Klint, Erik, et al.
(författare)
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Evaluation of arthroscopy and macroscopic scoring.
- 2009
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Arthroscopy is a minimally invasive technique for retrieving synovial biopsies in rheumatology during the past 20 years. Vital for its use is continual evaluation of its safety and efficacy. Important for sampling is the fact of intraarticular variation for synovial markers. For microscopic measurements scoring systems have been developed and validated, but for macroscopic evaluations there is a need for further comprehensive description and validation of equivalent scoring systems.METHODS: We studied the complication rate and yield of arthroscopies performed at our clinic between 1998 and 2005. We also created and evaluated a macroscopic score set of instructions for synovitis.RESULTS: Of 408 procedures, we had two major and one minor complication; two haemarthrosis and one wound infection, respectively. Pain was most often not a problem, but 12 procedures had to be prematurely ended due to pain. Yield of biopsies adequate for histology were 83% over all, 94% for knee joints and 34% for smaller joints. Video printer photographs of synovium taken during arthroscopy were jointly and individually reviewed by seven raters in several settings, and intra and inter rater variation was calculated. A macroscopic synovial scoring system for arthroscopy was created (Macro-score), based upon hypertrophy, vascularity and global synovitis. These written instructions were evaluated by five control-raters, and when evaluated individual parameters were without greater intra or inter rater variability, indicating that the score is reliable and easy to use.CONCLUSIONS: In our hands rheumatologic arthroscopy is a safe method with very few complications. For knee joints it is a reliable method to retrieve representative tissue in clinical longitudinal studies. We also created an easy to use macroscopic score, that needs to be validated against other methodologies. We hope it will be of value in further developing international standards in this area.
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| 2. |
- Akselsson, Cecilia, et al.
(författare)
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Weathering rates in Swedish forest soils
- 2019
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 16:22, s. 4429-4450
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Forskningsöversikt (refereegranskat)abstract
- Soil and water acidification was internationally recognised as a severe environmental problem in the late 1960s. The interest in establishing “critical loads” led to a peak in weathering research in the 1980s and 1990s, since base cation weathering is the long-term counterbalance to acidification pressure. Assessments of weathering rates and associated uncertainties have recently become an area of renewed research interest, this time due to demand for forest residues to provide renewable bioenergy. Increased demand for forest fuels increases the risk of depleting the soils of base cations produced in situ by weathering. This is the background to the research programme Quantifying Weathering Rates for Sustainable Forestry (QWARTS), which ran from 2012 to 2019. The programme involved research groups working at different scales, from laboratory experiments to modelling. The aims of this study were to (1) investigate the variation in published weathering rates of base cations from different approaches in Sweden, with consideration of the key uncertainties for each method; (2) assess the robustness of the results in relation to sustainable forestry; and (3) discuss the results in relation to new insights from the QWARTS programme and propose ways to further reduce uncertainties. In the study we found that the variation in estimated weathering rates at single-site level was large, but still most sites could be placed reliably in broader classes of weathering rates. At the regional level, the results from the different approaches were in general agreement. Comparisons with base cation losses after stem-only and whole-tree harvesting showed sites where whole-tree harvesting was clearly not sustainable and other sites where variation in weathering rates from different approaches obscured the overall balance. Clear imbalances appeared mainly after whole-tree harvesting in spruce forests in southern and central Sweden. Based on the research findings in the QWARTS programme, it was concluded that the PROFILE/ForSAFE family of models provides the most important fundamental understanding of the contribution of weathering to long-term availability of base cations to support forest growth. However, these approaches should be continually assessed against other approaches. Uncertainties in the model approaches can be further reduced, mainly by finding ways to reduce uncertainties in input data on soil texture and associated hydrological parameters but also by developing the models, e.g. to better represent biological feedbacks under the influence of climate change.
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| 3. |
- Albrecht, Daniel S., et al.
(författare)
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Brain glial activation in fibromyalgia - A multi-site positron emission tomography investigation
- 2019
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Ingår i: Brain, behavior, and immunity. - : Elsevier BV. - 0889-1591 .- 1090-2139. ; 75, s. 72-83
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [C-11]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [C-11]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [C-11]PBR28 PET. 11 FM patients and 11 HC were scanned using [C-11]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V-T) were computed from the [C-11]PBR28 data. [C-11]-L-deprenyl-D2 was quantified using lambda k(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [C-11]PBR28 ITT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [C-11]-L-deprenyl-Ds signal, including those demonstrating elevated [C-11] PBR28 signal in patients (p's >= 0.53, uncorrected). The elevations in [C-11]PBR28 V-T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [C-11] PBR28 SUVR in the anterior and posterior middle cingulate cortices (p's < 0.03). SUVR was not significantly associated with any other clinical variable. Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [C-11]PBR28 signal were not also accompanied by increased [C-11]-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [C-11]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
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| 4. |
- Aldridge, Jonathan, et al.
(författare)
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Blood chemokine levels are markers of disease activity but not predictors of remission in early rheumatoid arthritis.
- 2022
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Ingår i: Clinical and experimental rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 40:7, s. 1393-1402
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Tidskriftsartikel (refereegranskat)abstract
- In early rheumatoid arthritis (eRA) plasma levels of specific chemokines have been shown to correlate with disease activity. However, it is unclear whether pre-treatment chemokine levels can predict disease remission at week 24, and it is not known how biological treatments with different modes of action affect plasma chemokine levels in patients with untreated eRA.This study included 347 Swedish patients with untreated eRA from the larger NORD-STAR randomised treatment trial. Here, eRA patients were treated with methotrexate combined with either prednisolone, anti-TNF (certolizumab-pegol), CTLA-4Ig (abatacept) or anti-IL6 receptor (tocilizumab). The primary clinical outcome was remission by clinical disease activity index (CDAI) defined as CDAI ≤ 2.8. Disease activity was assessed by CDAI, DAS28-ESR, DAS28-CRP, swollen joint counts, tender joint counts, ESR and CRP. The plasma concentrations of 14 chemokines were measured at baseline and after 24 weeks of treatment by bead-based immunoassay or ELISA.Baseline plasma concentrations of CXCL10, CXCL8, CXCL9, CXCL11, CXCL5 and CCL2 correlated with baseline disease activity measures. After 24 weeks of treatment, plasma levels of CXCL10, CXCL8, CXCL9, CXCL11 and CXCL13 decreased in all treatment groups except in patients treated with anti-IL6 receptor. In multivariate factor analysis, plasma chemokine levels at baseline could not differentiate patients who attained remission by week 24 from those who did not in any of the treatment groups.In patients with untreated eRA, plasma levels of several chemokines correlate with disease activity at baseline but cannot predict remission after 24 weeks of treatment with methotrexate combined with prednisolone, anti‑TNF, CTLA‑4Ig or anti‑IL6R.
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| 5. |
- Dubovyk, Violetta, et al.
(författare)
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Obesity is a risk factor for poor response to treatment in early rheumatoid arthritis: a NORD-STAR study
- 2024
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Ingår i: RMD Open. - : BMJ PUBLISHING GROUP. - 2056-5933. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA). Methods This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI >= 30 kg/m(2). All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI. Results Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms. Conclusion In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received.
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| 6. |
- Emami Khoonsari, Payam, et al.
(författare)
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The human CSF pain proteome
- 2019
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Ingår i: Journal of Proteomics. - : ELSEVIER SCIENCE BV. - 1874-3919 .- 1876-7737. ; 190, s. 67-76
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Tidskriftsartikel (refereegranskat)abstract
- Chronic pain represents one of the major medical challenges in the 21st century, affecting > 1.5 billion of the world population. Overlapping and heterogenous symptoms of various chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms. We have here investigated proteins found in human CSF with respect to known "pain" genes and in a cohort of patients with dysfunctional pain (fibromyalgia, FM), inflammatory pain (rheumatoid arthritis patients, RA) and non-pain controls utilized semi-quantitative proteomics using mass spectrometry (MS) to explore quantitative differences between these cohorts of patients. We found that "pain proteins" detected in CSF using MS are typically related to synaptic transmission, inflammatory responses, neuropeptide signaling- and hormonal activity. In addition, we found ten proteins potentially associated with chronic pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins might be of importance for understanding the mechanisms of dysfunctional/inflammatory chronic pain and also for use as potential biomarkers. Significance: Chronic pain is a common disease and it poses a large burden on worldwide health. Fibromyalgia (FM) is a heterogeneous disease of unknown etiology characterized by chronic widespread pain (CWP). The diagnosis and treatment of FM is based on the analysis of clinical assessments and no measurable biomarkers are available. Cerebrospinal fluid (CSF) has been historically considered as a rich source of biomarkers for diseases of nervous system including chronic pain. Here, we explore CSF proteome of FM patients utilizing mass spectrometry based quantitative proteomics method combined with multivariate data analysis in order to monitor the dynamics of the CSF proteome. Our findings in this exploratory study support notable presence of pain related proteins in CSF yet with specific domains including inflammatory responses, neuropeptide signaling- and hormonal activity. We have investigated molecular functions of significantly altered proteins and demonstrate presence of 176 known pain related proteins in CSF. In addition, we found ten proteins potentially associated with pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulindependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins are novel in the context of FM but are known to be involved in pain mechanisms including inflammatory response and signal transduction. These results should be of clear significance and interest for researchers and clinicians working in the field of pain utilizing human CSF and MS based proteomics.
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| 7. |
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| 8. |
- Fanton, Silvia, et al.
(författare)
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Multiple spatial scale mapping of time-resolved brain network reconfiguration during evoked pain in patients with rheumatoid arthritis
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Functional brain networks and the perception of pain can fluctuate over time. However, how the time-dependent reconfiguration of functional brain networks contributes to chronic pain remains largely unexplained. Here, we explored time-varying changes in brain network integration and segregation during pain over a disease-affected area (joint) compared to a neutral site (thumbnail) in 28 patients with rheumatoid arthritis (RA) in comparison with 22 healthy controls (HC). During functional magnetic resonance imaging, all subjects received individually calibrated pain pressures corresponding to visual analog scale 50 mm at joint and thumbnail. We implemented a novel approach to track changes of task-based network connectivity over time. Within this framework, we quantified measures of integration (participation coefficient, PC) and segregation (within-module degree z-score). Using these network measures at multiple spatial scales, both at the level of single nodes (brain regions) and communities (clusters of nodes), we found that PC at the community level was generally higher in RA patients compared to HC during and after painful pressure over the inflamed joint and corresponding site in HC. This shows that all brain communities integrate more in RA patients than in HC for time points following painful stimulation to a disease-relevant body site. However, the elevated community-related integration seen in patients appeared to not pertain uniquely to painful stimulation at the inflamed joint, but also at the neutral thumbnail, as integration and segregation at the community level did not differ across body sites in patients. Moreover, there was no specific nodal contribution to brain network integration or segregation. Altogether, our findings indicate widespread and persistent changes in network interaction in RA patients compared to HC in response to painful stimulation.
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| 9. |
- Flodin, Pär, et al.
(författare)
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Intrinsic Brain Connectivity in Chronic Pain : A Resting-State fMRI Study in Patients with Rheumatoid Arthritis.
- 2016
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Rheumatoid arthritis (RA) is commonly accompanied by pain that is discordant with the degree of peripheral pathology. Very little is known about the cerebral processes involved in pain processing in RA. Here we investigated resting-state brain connectivity associated with prolonged pain in RA.METHODS: 24 RA subjects and 19 matched controls were compared with regard to both behavioral measures of pain perception and resting-resting state fMRI data acquired subsequently to fMRI sessions involving pain stimuli. The resting-state fMRI brain connectivity was investigated using 159 seed regions located in cardinal pain processing brain regions. Additional principal component based multivariate pattern analysis of the whole brain connectivity pattern was carried out in a data driven analysis to localize group differences in functional connectivity.RESULTS: When RA patients were compared to controls, we observed significantly lower pain resilience for pressure on the affected finger joints (i.e., P50-joint) and an overall heightened level of perceived global pain in RA patients. Relative to controls, RA patients displayed increased brain connectivity predominately for the supplementary motor areas, mid-cingulate cortex, and the primary sensorimotor cortex. Additionally, we observed an increase in brain connectivity between the insula and prefrontal cortex as well as between anterior cingulate cortex and occipital areas for RA patients. None of the group differences in brain connectivity were significantly correlated with behavioral parameters.CONCLUSION: Our study provides experimental evidence of increased connectivity between frontal midline regions that are implicated in affective pain processing and bilateral sensorimotor regions in RA patients.
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| 10. |
- Kadetoff, Diana, et al.
(författare)
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Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels.
- 2012
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 242:1-2, s. 33-8
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Tidskriftsartikel (refereegranskat)abstract
- Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia. To our knowledge, this is the first study assessing intrathecal concentrations of pro-inflammatory substances in fibromyalgia. We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the hypothesis of glia cell activation in response to pain mechanisms.
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| 11. |
- Kanegawa, Naoki, et al.
(författare)
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In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects
- 2016
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 54, s. 149-157
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Tidskriftsartikel (refereegranskat)abstract
- Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [C-11]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [C-11]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation. (C) 2016 Elsevier Inc. All rights reserved.
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| 12. |
- Kastbom, Alf, et al.
(författare)
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Fcγ receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis
- 2007
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 56:2, s. 448-452
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fc receptor type IIIA (FcRIIIA) correlates with the response to treatment with tumor necrosis factor inhibitors in rheumatoid arthritis (RA). Methods: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcRIIIA genotypes. Results: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria. Conclusion: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.
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| 13. |
- Kosek, Eva, et al.
(författare)
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Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain--interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis.
- 2015
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 280, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1β inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).
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| 14. |
- Lampa, Jon, et al.
(författare)
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Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:31, s. 12728-33
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Tidskriftsartikel (refereegranskat)abstract
- During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
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| 15. |
- Lampa, Jon
(författare)
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Studies of pharmacological interventions and pathogenesis of rheumatoid arthritis
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is a systemic inflammatory disease primarily affecting the joints. The chronic inflammation frequently results in joint destruction and various forms of physical impairment. T cells are believed to be of importance for the propagation of many cases of RA due to the association with certain types of HLA class 11, whose function is to present antigen to the T cell receptor. There is, however, evidence that also macrophages and B cells may be of prime importance in driving the inflammatory process in RA In this thesis, an approach has been made to study immune functions in RA during treatment with two different anti-rheumatic drugs, intramuscular gold and tumour necrosis factor-(TNF)alpha-blockade with etanercept (a soluble TNFalpha-receptor), with the goal to learn more about RA pathogenesis. The mechanism of action of intramuscular gold treatment is not known but it has been suggested that gold may shift the immune system towards production of anti-inflammatory cytokines, rather than inducing a general immune suppression. We investigated the cytokine production in vitro in response to gold sodium thiomalate (GSTM), and found a stimulatory effect on monocyte dependent production of the and- inflammatory cytokine interleukin (IL)-10 along with a decrease of interferon-(IFN)gamma levels in corresponding supematants. In concordance with these results, there was an increased IL-10 production during GSTM treatment in RA patients. In addition, the in vitro effect of GSTM on IL-10 production from peripheral blood mononuclear cells (PBMC) predicted development of skin reactions during in vim treatment with GSTM, with low IL-10 production being associated with appearance of skin reactions. From these studies we conclude that intramuscular gold treatment has cytokine stimulating properties, and the stimulation of IL-1 0 production might have importance for the therapeutic effect of gold in RA- Moreover, the ability of RA patients to produce IL-1 0 in response to gold may influence the development of skin reactions. RA T cells are hyporesponsive when stimulated with microbial antigens in vitro compared to T cells from the blood of healthy subjects. Activated monocytes/macrophages suppress T cell functions, possibly mediated through pro-inflammatory cytokines such as TNFalpha We investigated peripheral T cell reactivity in RA patients during etanercept therapy and found an increased T cell reactivity against microbial antigens and collagen type 11, an autoantigen. These findings indicate that T cell hyporesponsiveness in RA is, at least partly, TNFalpha-mediated and that TNFalpha-blockade may not only suppress but also stimulate certain aspects of antimicrobial immune defence and autoimmunity. The findings thus warrant further consideration of development of autoimmune reactions during TNFalpha-blockade therapy. TNFalpha is also known to stimulate production of matrix metalloproteinases (MMPs), which are upregulated in the inflamed joint and highly associated with development of synovial degradation and joint erosions. During etanercept therapy, serum levels of both MMP-1 and MMP-3 were downregulated in parallel with the reduction of inflammatory parameters. Moreover, pre-treatment MMP-3 serum levels correlated with changes in disease activity during etanercept therapy. Cytokine promoter polymorphisms are known to be associated with different levels of production of the same cytokine. This observation indicates that also intervention with a cytokine may differ in efficacy depending on genetic variations. Although TNFalpha-blockade is very efficient in ameliorating diseases activity in most of the treated patients with RA, about one third of the patients do not respond appropriately to this therapy and there are as yet no prognostic markers for clinical response. We analysed whether promoter polymorphisms of pro- and anti-inflammatory cytokine genes correlated with clinical response to etanercept. A combination of alleles conferring a normal TNFalpha production (-308 T1/T1) and high IL-10 production (-1087 G/G) was associated with good clinical responsiveness to etanercept. Another combination conferring high inflammatory capacity (A2 allele in intron 2 of the IL1 RN gene and rare C allele in codon 25 of the TGF131 gene) was associated with nonresponsiveness. Thus, genetic polymorphisms that influence the balance of cytokines that are of relevance for the course of RA seem to be associated with clinical outcome of etanercept therapy. This finding may be of value for further studies possibly promoting the use of cytokine polymorphisms as predictors for response to various biological agents in the future.
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| 16. |
- Lend, Kristina, et al.
(författare)
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Methotrexate safety and efficacy in combination therapies in patients with early rheumatoid arthritis: a post-hoc analysis of a randomized controlled trial (NORD-STAR).
- 2024
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Ingår i: Arthritis & rheumatology (Hoboken, N.J.). - 2326-5205. ; 76:3, s. 363-376
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Tidskriftsartikel (refereegranskat)abstract
- To investigate methotrexate safety and influence of dose on efficacy outcomes in combination with three different biological treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA).This post-hoc analysis included 812 treatment-naïve early RA patients who were randomized (1:1:1:1) in the NORD-STAR trial (NCT01491815) to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24weeks of treatment.Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (HR 1.48 [95% CI 1.20 to 1.84]), but not with certolizumab-pegol (HR 0.99 [0.79 to 1.23]) or with abatacept (HR 0.93 [0.75 to 1.16]). With ACT as the reference, methotrexate dose was significantly lower when used in combination with tocilizumab (β -4.65 [95% CI -5.83 to -3.46], p<0.001), with abatacept (β -1.15 [-2.27 to -0.03], p=0.04), and numerically lower in combination with certolizumab-pegol (β -1.07 [-2.21 to 0.07], p=0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations.Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/week, and these were more frequent in combination with tocilizumab versus active conventional treatment. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24weeks.
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| 17. |
- Liu, Jianyang, et al.
(författare)
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Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis
- 2024
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Ingår i: ARTHRITIS RESEARCH & THERAPY. - 1478-6354 .- 1478-6362. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy. Methods: This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-alpha blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B-2 (TXBM), 2,3-dinor-6-keto prostaglandin F-1a (PGIM), leukotriene E-4 (LTE4) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes. Results: Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24. Conclusions: Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.
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| 18. |
- Lourdudoss, Cecilia, et al.
(författare)
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Dietary Intake of Polyunsaturated Fatty Acids and Pain in Spite of Inflammatory Control Among Methotrexate-Treated Early Rheumatoid Arthritis Patients.
- 2018
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Ingår i: Arthritis care & research. - : Wiley. - 2151-464X .- 2151-4658. ; 70:2, s. 205-212
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate potential associations between dietary intake of polyunsaturated fatty acids (FAs) and pain patterns in early rheumatoid arthritis (RA) patients after 3 months of methotrexate (MTX) treatment.METHODS: We included 591 early RA patients with MTX monotherapy from a population-based prospective case-control study, the Epidemiological Investigation of Rheumatoid Arthritis. Dietary data on polyunsaturated FAs (food frequency questionnaires) were linked with data on unacceptable pain (visual analog scale [VAS] >40 mm), noninflammatory/refractory pain (VAS >40 mm and C-reactive protein [CRP] level <10 mg/liter), and inflammatory pain (VAS >40 mm and CRP level >10 mg/liter) after 3 months. Statistical analysis included logistic regression.RESULTS: After 3 months of MTX treatment, 125 patients (21.2%) had unacceptable pain, of which 92 patients had refractory pain, and 33 patients had inflammatory pain. Omega-3 FA intake was inversely associated with unacceptable pain and refractory pain (odds ratio [OR] 0.57 [95% confidence interval (95% CI) 0.35-0.95] and OR 0.47 [95% CI 0.26-0.84], respectively). The omega-6:omega-3 FA ratio, but not omega-6 FA alone, was directly associated with unacceptable pain and refractory pain (OR 1.70 [95% CI 1.03-2.82] and OR 2.33 [95% CI 1.28-4.24], respectively). Furthermore, polyunsaturated FAs were not associated with either inflammatory pain or CRP level and erythrocyte sedimentation rate at followup. Omega-3 FA supplementation was not associated with any pain patterns.CONCLUSION: Omega-3 FA was inversely associated with, and the omega-6:omega-3 FA ratio was directly associated with, unacceptable and refractory pain, but not with inflammatory pain or systemic inflammation. The inverse association between omega-3 FA and refractory pain may have a role in pain suppression in RA.
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| 19. |
- Lund, Harald, et al.
(författare)
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CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier
- 2024
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 221:2
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Tidskriftsartikel (refereegranskat)abstract
- In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163(+) macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.
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| 20. |
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| 21. |
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| 22. |
- Mullazehi, Mohammed, et al.
(författare)
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High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset
- 2007
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 66:4, s. 537-541
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate whether the cytokine-inducing properties of surface-bound collagen type II (Cll)-containing immune complexes (IC), which were reported earlier, have any clinical impact. Methods: Anti-CII serology was analysed in 274 patients with early rheumatoid arthritis (RA). Patients with increased levels of anti-CII were followed serially for 1-5 years with regard to anti-CII IC-induced levels of tumour necrosis factor (TNF)a, interleukin (IL)1β and IL8. Levels of antibodies and IC-induced cytokines were compared with clinical indices over 5 years of follow-up. Results: 5/100 healthy controls and 24/274 (8.8%) patients with RA exhibited increased levels (>29 arbitrary units (AU)/ ml) of anti-native Cll antibodies, a non-significant difference. 9/274 (3.3%) patients with RA and no controls comprised a discrete group with high anti-CII levels >450 AU/ml. These high anti-CII level sera were associated with induction of proinflammatory cytokines by anti-CII-containing IC formed in vitro. 8/9 patients with high baseline anti-CII levels exhibited a parallel decline in antibody levels, IC-induced cytokines, C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Anti-CII-positive patients had significantly increased levels of CRP and ESR at baseline, but not later during the follow-up. Conclusions: Anti-native Cll-positive patients with RA have a distinct clinical phenotype characterised by an early acute phase response that might be driven by anti-CII-containing IC in joint cartilage.
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| 23. |
- Mullazehi, Mohammed, et al.
(författare)
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Surface-bound anti-type II collagen-containing immune complexes induce production of tumor necrosis factor α, interleukin-1β, and interleukin-8 from peripheral blood mononuclear cells via FcγRIIa : A potential pathophysiologic mechanism for humoral anti-type II collagen immunity in arthritis
- 2006
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:6, s. 1759-1771
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Type II collagen (CII) is a major component of hyaline cartilage, and antibodies against CII are found in a subgroup of patients with rheumatoid arthritis. We undertook this study to investigate whether and how antibodies directed against CII can form solid-phase immune complexes (ICs) with cytokine-inducing properties in a model theoretically resembling the situation in the inflamed joint, in which CII is exposed for interaction with anti-CII antibodies during periods of inflammation. METHODS: Sixty-five arthritis patients with varying levels of anti-native CII antibodies and 10 healthy controls were evaluated concerning anti-CII and cytokines induced in a solid-phase IC model. Monocytes were either depleted or enriched to define responder cells. Antibodies blocking Fc gamma receptors (Fc gammaR) were used to define the responsible T cell surface receptors. RESULTS: ICs containing anti-CII from arthritis patients induced the production of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-8. We found a close correlation between enzyme-linked immunosorbent assay optical density values and induction of TNFalpha (r = 0.862, P < 0.0001), IL-1beta (r = 0.839, P < 0.0001), and IL-8 (r = 0.547, P < 0.0001). The anti-CII-containing IC density threshold needed for cytokine induction differed among peripheral blood mononuclear cell donors. Anti-CII-containing IC-induced cytokine production was almost totally abolished (>99%) after monocyte depletion, and receptor blocking studies showed significant decreases in the production of TNFalpha, IL-1beta, and IL-8 after blocking Fc gammaRIIa, but not after blocking Fc gammaRIII. CONCLUSION: These findings represent a possible mechanism for perpetuation of joint inflammation in the subgroup of arthritis patients with high levels of anti-CII. Blockade of Fc gammaRIIa and suppression of synovial macrophages are conceivable treatment options in such patients.
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| 24. |
- Olofsson, Tor, et al.
(författare)
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Pain over 2 years after start of biological versus conventional combination treatment in early rheumatoid arthritis : results from the randomised controlled SWEFOT trial
- 2021
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Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 73:9, s. 1312-1321
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To compare the pain course between methotrexate (MTX)-refractory early rheumatoid arthritis (RA) patients randomised to infliximab (IFX) versus sulfasalazine+hydroxychloroquine (SSZ+HCQ).METHODS: The randomised, controlled, open-label SWEFOT (SWedish FarmacOTherapy) trial enrolled new-onset RA patients Oct 2002-Dec 2005. After 3 months on MTX, patients not reaching low disease activity (28-joint Disease Activity Score; DAS28≤3.2) were randomised to adding IFX (n=128) or SSZ+HCQ (n=130) and followed for 21 months. Here, outcomes included area-under-the-curve (AUC) for Visual Analogue Scale (VAS) of pain, unacceptable pain (VAS pain>40mm [0-100]); and unacceptable pain despite inflammation control (refractory pain; VAS pain>40+C-reactive protein<10mg/L). Between-group differences were analysed with multivariate regression models.RESULTS: Overall, 50% of randomised patients (n=258) in the crude setting, reported unacceptable pain at randomisation, declining to 29% at 21 months (p<0.001), when refractory pain constituted 82% of all unacceptable pain. Comparing randomised arms (intention-to-treat analysis), AUC for VAS pain was lower in the MTX+IFX-group (p=0.01), and at 21 months 32% with MTX+IFX and 45% with MTX+SSZ+HCQ had unacceptable pain (adjusted relative risk 0.68 [95%CI:0.51-0.90]; p=0.008). Regarding refractory pain, no between-group differences were observed.CONCLUSION: Despite active combination treatment, almost 1/3 of new-onset RA patients reported unacceptable pain after 21 months and refractory pain constituted more than 4/5 of this pain load. Adding IFX versus SSZ+HCQ to MTX reduced both cumulative pain and unacceptable pain at 21 months, suggesting less long-term pain for the biological therapy. These results display insufficient effects of current treatment strategies on inflammation-independent pain components, warranting alternative approaches in affected patients.
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| 25. |
- Ostergaard, Mikkel, et al.
(författare)
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Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis : 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial
- 2023
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ PUBLISHING GROUP. - 0003-4967 .- 1468-2060. ; 82:10, s. 1286-1295
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Tidskriftsartikel (refereegranskat)abstract
- Background The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. Methods Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naive early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI <= 2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). Results Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences. Conclusions Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments.
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