Publications by authors named "Inger Gjertsson"

50 Publications

Intermediate monocytes correlate with CXCR3+ Th17 cells but not with bone characteristics in untreated early rheumatoid arthritis.

PLoS One 2021 26;16(3):e0249205. Epub 2021 Mar 26.

Centre for Bone and Arthritis Research, Institute of Medicine, Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients.

Methods: 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4+ helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT.

Results: Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3+ Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3+ Th17 cells were associated with bone density or bone microarchitecture measurements.

Conclusions: Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3+ Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249205PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996983PMC
March 2021

Adipocytokines in Untreated Newly Diagnosed Rheumatoid Arthritis: Association with Circulating Chemokines and Markers of Inflammation.

Biomolecules 2021 Feb 21;11(2). Epub 2021 Feb 21.

Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 46 Gothenburg, Sweden.

Adiponectin, leptin, and resistin are adipocytokines whose levels are elevated in blood and synovial fluid from patients with rheumatoid arthritis (RA). However, their role in RA pathogenesis is unclear. Here, we examined whether adipocytokines are associated with circulating chemokines, markers of inflammation and RA disease activity in patients with untreated newly diagnosed RA. Plasma levels of 15 chemokines, adiponectin, leptin, and resistin were measured using flow cytometry bead-based immunoassay or enzyme-linked immunosorbent assay (ELISA) in a cohort of 70 patients with untreated newly diagnosed RA. Markers of inflammation and disease activity were also assessed in all patients. Positive association was found between total adiponectin and CXCL10 (β = 0.344, = 0.021), CCL2 (β = 0.342, = 0.012), and CXCL9 (β = 0.308, = 0.044), whereas high-molecular weight (HMW) adiponectin associated only with CXCL9 (β = 0.308, = 0.033). Furthermore, both total and HMW adiponectin were associated with C-reactive protein (β = 0.485, = 0.001; β = 0.463, = 0.001) and erythrocyte sedimentation rate (β = 0.442, = 0.001; β = 0.507, < 0.001). Leptin and resistin were not associated with plasma chemokines, markers of inflammation, or disease activity scores. Our study shows an association between circulating adiponectin and pro-inflammatory chemokines involved in RA pathogenesis as well as markers of inflammation in a well-characterized cohort of patients with untreated newly diagnosed RA.
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http://dx.doi.org/10.3390/biom11020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924659PMC
February 2021

Physical activity with person-centred guidance supported by a digital platform for persons with chronic widespread pain: A randomized controlled trial.

J Rehabil Med 2021 Apr 1;53(4):jrm00175. Epub 2021 Apr 1.

Physiotherapy, Institute of Neuroscience and Physiology, Section of Health and Rehabilitation, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. E-mail:

Objective: To determine the effectiveness of a person-centred intervention, including advice on physical activity, for improving pain intensity, physical activity, and other health-related outcomes in persons with chronic widespread pain , when delivered with digital eHealth support compared with standard telephone follow-up.

Design: Randomized controlled trial.

Subjects: Individuals with chronic widespread pain (n = 139), aged 20-65 years, who had previously participated in a pain educational programme at primary healthcare units, were contacted during the period 2018-19 and randomized to an intervention group (n = 69) or an active control group (n = 70).

Methods: Together with a physiotherapist, participants in both groups developed person-centred health plans for physical activity. The intervention group was supported via a digital platform for 6 months. The active control group received support via one follow-up phone call. Primary outcome was pain intensity. Secondary outcomes were physical activity and other health-related outcomes.

Results: No significant differences were found between the groups after 6 months, except for a significant decrease in global fatigue in the active control group compared with the intervention group.

Conclusion: Future development of interventions supporting persons with chronic pain to maintain regular exercise is warranted.
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http://dx.doi.org/10.2340/16501977-2796DOI Listing
April 2021

Endophilin A2 deficiency protects rodents from autoimmune arthritis by modulating T cell activation.

Nat Commun 2021 01 27;12(1):610. Epub 2021 Jan 27.

Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.

The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.
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http://dx.doi.org/10.1038/s41467-020-20586-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840939PMC
January 2021

Diet intervention improves cardiovascular profile in patients with rheumatoid arthritis: results from the randomized controlled cross-over trial ADIRA.

Nutr J 2021 01 23;20(1). Epub 2021 Jan 23.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, PO Box 459, SE-405 30, Gothenburg, Sweden.

Background: The chronic inflammation in patients with rheumatoid arthritis (RA) increases the risk for cardiovascular diseases (CVD). The contribution of diet as a risk factor for CVD among these patients is however not fully understood. The aim of this study is to investigate if a proposed anti-inflammatory diet improves cardiovascular profile in weight stable patients with RA.

Methods: Patients (n = 50) with RA were included in a cross-over trial. They were randomized to either a diet rich in whole grain, fatty fish, nuts, vegetables and fruit and supplemented with probiotics, or a control diet resembling average nutritional intake in Sweden, for ten weeks. After a 4-month washout they switched diet. Participants received food bags and dietary guidelines. Primary outcome was triglyceride (TG) concentration. Secondary outcomes were total-, high density lipoprotein- (HDL) and low density lipoprotein- (LDL) cholesterol, Apolipoprotein-B100 and -A1, lipoprotein composition, plasma phospholipid fatty acids and blood pressure.

Results: Forty-seven patients completed at least one period and they remained weight stable. There was a significant between-dietary treatment effect in TG and HDL-cholesterol concentration in favor of intervention (p = 0.007 and p = 0.049, respectively). Likewise, Apolipoprotein-B100/A1 ratio shifted toward a less atherogenic profile in favor of the intervention (p = 0.007). Plasma fatty acids increased in polyunsaturated- and decreased in monounsaturated- and saturated fatty acids between diet periods in favor of the intervention period.

Conclusion: Blood lipid profile improved indicating cardioprotective effects from an anti-inflammatory dietary intervention in patients with RA.

Trial Registration: This trial is registered at ClinicalTrials.gov as NCT02941055 .
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http://dx.doi.org/10.1186/s12937-021-00663-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827982PMC
January 2021

T helper cells in synovial fluid of patients with rheumatoid arthritis primarily have a Th1 and a CXCR3Th2 phenotype.

Arthritis Res Ther 2020 10 16;22(1):245. Epub 2020 Oct 16.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30, Gothenburg, Sweden.

Background: The majority of CD4 T helper (Th) cells found in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) express CXCR3, a receptor associated with Th1 cells. In blood, subsets of Th2 and Th17 cells also express CXCR3, but it is unknown if these cells are present in RA SF or how cytokines from these subsets affect cytokine/chemokine secretion by fibroblast-like synoviocytes (FLS) from patients with RA.

Methods: We examined the proportions of Th1, Th2, CXCR3Th2, Th17, CXCR3Th17, Th1Th17, peripheral T helper (TPh) and T follicular helper (TFh) cells in paired SF and blood, as well as the phenotype of TPh and TFh cells in RA SF (n = 8), by the use of flow cytometry. We also examined the cytokine/chemokine profile in paired SF and plasma (n = 8) and in culture supernatants of FLS from patients with chronic RA (n = 7) stimulated with Th-associated cytokines, by the use of cytometric bead arrays and ELISA. Cytokine receptor expression in FLS (n = 3) were assessed by the use of RNA sequencing and qPCR.

Results: The proportions of Th1 and CXCR3Th2 cells were higher in SF than in blood (P < 0.05). TPh and PD-1TFh in RA SF were primarily of a Th1 and a CXCR3Th2 phenotype. Moreover, the levels of CXCL9, CXCL10, CCL20, CCL2, CXCL8, IL-6 and IL-10 were higher in SF than in plasma (P < 0.05). Lastly, IL-4, IL-13 and IL-17A induced RA FLS to secrete proinflammatory IL-6, CCL2, CXCL1 and CXCL8, while IFNγ mainly induced CXCL10.

Conclusion: These findings indicate that not only Th1 but also CXCR3Th2 cells may have a pathogenic role in RA synovial inflammation.
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http://dx.doi.org/10.1186/s13075-020-02349-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566124PMC
October 2020

Do Interventions with Diet or Dietary Supplements Reduce the Disease Activity Score in Rheumatoid Arthritis? A Systematic Review of Randomized Controlled Trials.

Nutrients 2020 Sep 29;12(10). Epub 2020 Sep 29.

Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, 40530 Gothenburg, Sweden.

The aim was to compile the evidence from Randomized Controlled Trials (RCTs) of diet or dietary supplements used to reduce disease activity in adults with Rheumatoid Arthritis (RA). Searches were performed in the databases PubMed, Scopus and Cochrane. Only RCT studies of diets, foods or dietary supplements, looking at effects on the Disease Activity Score in 28 joints (DAS28) among adults with RA, published in peer-reviewed journals, were included. A total of 27 articles were included-three of whole diets (Mediterranean diet, raw food and anti-inflammatory diet), five of food items, five of n-3 fatty acids, five of single micronutrient supplements, four of single antioxidant supplements and five of pre-, pro- or synbiotics. Studies that showed moderate strength evidence for positive effects on disease activity in RA included interventions with a Mediterranean diet, spices (ginger powder, cinnamon powder, saffron), antioxidants (quercetin and ubiquinone), and probiotics containing Lactobacillus Casei. Other diets or supplements had either no effects or low to very low strength of evidence. In conclusion, RCT studies on diet or dietary supplements are limited in patients with RA, but based on the results in this review there is evidence that some interventions might have positive effects on DAS28.
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http://dx.doi.org/10.3390/nu12102991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600426PMC
September 2020

Synthesis of an Array of Triple-Helical Peptides from Type II Collagen for Multiplex Analysis of Autoantibodies in Rheumatoid Arthritis.

ACS Chem Biol 2020 09 10;15(9):2605-2615. Epub 2020 Sep 10.

Department of Chemistry-BMC, Uppsala University, SE-75123 Uppsala, Sweden.

Type II collagen (CII) is the most abundant protein in joint cartilage. Antibodies to CII appear around the clinical onset of the autoimmune disease rheumatoid arthritis (RA) in a subset of patients. They target specific epitopes on CII and can be pathogenic or protective. Assays for early detection of such autoantibodies may provide new opportunities for selecting effective treatment strategies of RA. We report the efficient and reproducible assembly of an array of covalently branched native and citrullinated triple helical peptides (THPs) from CII that contain defined autoantibody epitopes. Both monoclonal antibodies and sera from experimental mouse models show a unique reactivity toward the THPs, compared to cyclic peptides containing the epitopes, revealing the importance that the epitopes are displayed in a triple-helical conformation. Importantly, antibodies against three of the THPs that contain major CII epitopes were found to be increased in sera from patients with RA, compared to control persons. These results indicate that such synthetic THPs should be included in multiplex analysis of autoantibodies that are uniquely occurring in individuals with early RA, to provide valuable information on disease prognosis and on what type of therapy should be chosen for individual patients.
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http://dx.doi.org/10.1021/acschembio.0c00680DOI Listing
September 2020

Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier.

Front Immunol 2020 21;11:1365. Epub 2020 Jul 21.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases ( = 270) and a prospective cohort of rheumatoid arthritis (RA) patients ( = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 μg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 μg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 μg/mL. ADA were seldom detected in patients with >1 μg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.
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http://dx.doi.org/10.3389/fimmu.2020.01365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385065PMC
April 2021

Long-time follow up of physical activity level among older adults with rheumatoid arthritis.

Eur Rev Aging Phys Act 2020 18;17:10. Epub 2020 Jul 18.

Department of Health and Rehabilitation, Unit of Physiotherapy, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 455, 405 30 Göteborg, Sweden.

Background: Physical activity and exercise are acknowledged as important parts in the management of rheumatoid arthritis (RA). However, long-term maintenance of exercise is known to be difficult. The aim of this study was to evaluate change in physical activity and physical fitness after four years in older adults with RA who had previously participated in exercise with person-centred guidance compared to controls.

Method: A follow-up study was performed where older adults (> 65 years) who had participated in a randomized controlled trial where they were allocated to either exercise with person-centred guidance or home-based, light-intensity exercise (controls) were invited to one visit and assessed with performance-based test, blood-sampling and self-reported questionnaires. Forty-seven out of 70 older adults accepted participation, 24 from the exercise group and 23 from the control group. Comparisons of the result with baseline values were performed and explanatory factors for increase of physical activity were examined with logistic regression.

Results: The result show that there was no significant difference in weekly hours of physical activity when groups where compared. However, participants in the exercise group rated significantly increased weekly hours of physical activity after four years ( = 0.004) when compared to baseline. Higher levels of fatigue, BMI and physical activity, at baseline were negatively associated with increased physical activity after four years. There was no significant difference in change of physical fitness between the groups. Within group analysis showed that the control group reported increased pain ( = 0.035), fatigue ( = 0.023) increased number of tender joints ( = 0.028) higher disease activity ( = 0.007) and worsening of global health ( = 0.004) when compared to baseline while the exercise group remained at the same level as at baseline.

Conclusion: These results indicate that introducing moderate- to high intensity exercise with person-centred guidance might favor increased physical activity after four years in older adults with RA. Previous partaking in moderate- to high intensity exercise might also be protective against increased disease activity, pain and fatigue over time.
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http://dx.doi.org/10.1186/s11556-020-00242-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368988PMC
July 2020

Data describing expression of formyl peptide receptor 2 in human articular chondrocytes.

Data Brief 2020 Aug 16;31:105866. Epub 2020 Jun 16.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Göteborg, Sweden.

The formyl peptide receptor 2 (FPR2) belongs to the family of seven-transmembrane G protein-coupled receptors (GPCR) and are expressed by many different cells but mainly studied in immune cells. FPR2 is involved in host defense against bacterial infections and clearance of damaged cells through the oxidative burst and chemotaxis of neutrophils. In addition, FPR2 has also been implicated as an immunomodulator in sterile inflammations, e.g. inflammatory joint diseases. Here we present data regarding FPR2 expression in human articular chondrocytes, isolated from healthy individuals and osteoarthritic patients, on both mRNA and protein level using qPCR and Imagestream flow cytometry. We also present data after receptor stimulation and monitoring of production of nitric oxide, reactive oxygen species, IL-6, IL-8 and MMP-3. The presented data show that human articular chondrocytes from patients with osteoarthritis as well as from healthy individuals express FPR2 both at mRNA and protein level. The biological relevance of FPR2 expression in chondrocytes needs to be further investigated.
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http://dx.doi.org/10.1016/j.dib.2020.105866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326719PMC
August 2020

Moderate- to high intensity aerobic and resistance exercise reduces peripheral blood regulatory cell populations in older adults with rheumatoid arthritis.

Immun Ageing 2020 16;17:12. Epub 2020 May 16.

1Department of Rheumatology and Inflammation research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Box 480, 405 30 Göteborg, Sweden.

Objective: Exercise can improve immune health and is beneficial for physical function in patients with rheumatoid arthritis (RA), but the immunological mechanisms are largely unknown. We evaluated the effect of moderate- to high intensity exercise with person-centred guidance on cells of the immune system, with focus on regulatory cell populations, in older adults with RA.

Methods: Older adults (≥65 years) with RA were randomized to either 20-weeks of moderate - to high intensity aerobic and resistance exercise ( = 24) or to an active control group performing home-based exercise of light intensity ( = 25). Aerobic capacity, muscle strength, DAS28 and CRP were evaluated. Blood samples were collected at baseline and after 20 weeks. The frequency of immune cells defined as adaptive regulatory populations, CD4 + Foxp3 + CD25 + CD127- T regulatory cells (Tregs) and CD19 + CD24hiCD38hi B regulatory cells (Bregs) as well as HLA-DR-/lowCD33 + CD11b + myeloid derived suppressor cells (MDSCs), were assessed using flow cytometry.

Results: After 20 weeks of moderate- to high intensity exercise, aerobic capacity and muscle strength were significantly improved but there were no significant changes in Disease Activity Score 28 (DAS28) or CRP. The frequency of Tregs and Bregs decreased significantly in the intervention group, but not in the active control group. The exercise intervention had no effect on MDSCs. The reduction in regulatory T cells in the intervention group was most pronounced in the female patients.

Conclusion: Moderate- to high intensity exercise in older adults with RA led to a decreased proportion of Tregs and Bregs, but that was not associated with increased disease activity or increased inflammation.

Trial Registration: Improved Ability to Cope With Everyday Life Through a Person-centered Training Program in Elderly Patients With Rheumatoid Arthritis - PEP-walk Study, NCT02397798. Registered at ClinicalTrials.gov March 19, 2015.
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http://dx.doi.org/10.1186/s12979-020-00184-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229606PMC
May 2020

Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.

BMC Infect Dis 2020 Feb 28;20(1):185. Epub 2020 Feb 28.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden.

Background: Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.

Methods: C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.

Results: Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.

Conclusions: Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.
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http://dx.doi.org/10.1186/s12879-020-4880-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048135PMC
February 2020

Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA)-a randomized, controlled crossover trial indicating effects on disease activity.

Am J Clin Nutr 2020 06;111(6):1203-1213

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Many patients with rheumatoid arthritis (RA) report symptom relief from certain foods. Earlier research indicates positive effects of food and food components on clinical outcomes in RA, but insufficient evidence exists to provide specific dietary advice. Food components may interact but studies evaluating combined effects are lacking.

Objectives: We aimed to investigate if an anti-inflammatory diet reduces disease activity in patients with RA.

Methods: In this single-blinded crossover trial, 50 patients with RA were randomly assigned to an intervention diet containing a portfolio of suggested anti-inflammatory foods, or a control diet similar to the general dietary intake in Sweden, for 10 wk. After a 4-mo washout period the participants switched diet. Food equivalent to ∼50% of energy requirements was delivered weekly to their homes. For the remaining meals, they were encouraged to consume the same type of foods as the ones provided during each diet. Primary outcome was change in Disease Activity Score in 28 joints-Erythrocyte Sedimentation Rate (DAS28-ESR). Secondary outcomes were changes in the components of DAS28-ESR (tender and swollen joints, ESR, and visual analog scale for general health) and DAS28-C-reactive protein.

Results: In the main analysis, a linear mixed ANCOVA model including the 47 participants completing ≥1 diet period, there was no significant difference in DAS28-ESR between the intervention and control periods (P = 0.116). However, in unadjusted analyses, DAS28-ESR significantly decreased during the intervention period and was significantly lower after the intervention than after the control period in the participants who completed both periods (n = 44; median: 3.05; IQR: 2.41, 3.79 compared with median: 3.27; IQR: 2.69, 4.28; P = 0.04, Wilcoxon's Signed Rank test). No significant differences in the components were observed.

Conclusions: This trial indicates positive effects of a proposed anti-inflammatory diet on disease activity in patients with RA. Additional studies are required to determine if this diet can cause clinically relevant improvements.This trial was registered at clinicaltrials.gov as NCT02941055.
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http://dx.doi.org/10.1093/ajcn/nqaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266686PMC
June 2020

Influence of blue mussel (Mytilus edulis) intake on fatty acid composition in erythrocytes and plasma phospholipids and serum metabolites in women with rheumatoid arthritis.

Prostaglandins Leukot Essent Fatty Acids 2019 11 24;150:7-15. Epub 2019 Aug 24.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden. Electronic address:

Intake of blue mussels decreased disease activity in women with rheumatoid arthritis (RA) in the randomized cross-over MIRA (Mussels, inflammation and RA) trial. This study investigates potential causes of the decreased disease activity by analysing fatty acid composition in erythrocytes and plasma phospholipids and serum metabolites in samples from the participants of the MIRA trial. Twenty-three women completed the randomized 2 × 11-week cross-over dietary intervention, exchanging one cooked meal per day, 5 days a week, with a meal including 75 g blue mussels or 75 g meat. Fatty acid composition in erythrocytes and plasma and H Nuclear Magnetic Resonance (H NMR) metabolomics data were analysed with multivariate data analysis. Orthogonal Projections to Latent Structures with Discriminant Analysis (OPLS-DA) and OPLS with effect projections (OPLS-EP) were performed to compare the two diets. The fatty acid profile in erythrocytes was different after intake of blue mussels compared to the control diet, and all samples were correctly classified to either the blue mussel diet or control diet. Changes following blue mussel intake included significant increases in omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at the group level but not for all individuals. The fatty acid profile in plasma phospholipids and H NMR serum metabolites did not differ significantly between the diets. To conclude, modelling fatty acids in erythrocytes may be a better biomarker for seafood intake than only EPA and DHA content. The change in fatty acid pattern in erythrocytes could be related to reduction in disease activity, although it cannot be excluded that other factors than omega-3 fatty acids potentiate the effect.
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http://dx.doi.org/10.1016/j.plefa.2019.08.004DOI Listing
November 2019

Moderate-to-high intensity exercise with person-centered guidance influences fatigue in older adults with rheumatoid arthritis.

Rheumatol Int 2019 Sep 20;39(9):1585-1594. Epub 2019 Jul 20.

Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Fatigue is described as a dominant and disturbing symptom of rheumatoid arthritis (RA) regardless of the advances in pharmacological treatment. Fatigue is also found to correlate with depression. The objective was to evaluate the impact of moderate-to-high intensity, aerobic and resistance exercise with person-centered guidance on fatigue, anxiety and depression, in older adults with RA. Comparisons were made between older adults (> 65 years) with RA taking part in a 20-week moderate-to-high intensity exercise at a gym (n = 36) or in home-based exercise of light intensity (n = 38). Assessments were performed at baseline, at 20 weeks, and at 52 weeks. Outcomes were differences in Multidimensional Fatigue Inventory (MFI-20), Visual Analog Scale Fatigue (VAS fatigue), and Hospital Anxiety and Depression Scale (HADS). Analysis of metabolomics was also performed. The subscales "physical fatigue" and "mental fatigue" in MFI-20 and symptoms of depression using HADS depression scale improved significantly at week 20 in the exercise group compared with the control group. Exercise did not influence global fatigue rated by VAS or subscales "reduced motivation", "reduced activity" and "general fatigue" in MFI-20. No significant change was found on the anxiety index of HADS. The improvements in physical fatigue were associated with changes in the metabolism of lipids, bile acids, the urea cycle and several sugars. Moderate-to-high intensity exercise with person-centered guidance decreased fatigue and improved symptoms of depression and were accompanied by metabolic changes in older adults with RA.
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http://dx.doi.org/10.1007/s00296-019-04384-8DOI Listing
September 2019

CD21 B cells associate with joint damage in rheumatoid arthritis patients.

Scand J Immunol 2019 Aug 17;90(2):e12792. Epub 2019 Jun 17.

Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.

Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21 B cells). In this study, we sought to determine whether there was any correlation between CD21 B cells and clinical outcome in patients with established RA, either ACPA /RF (n = 27) or ACPA /RF (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21 CD27 IgD memory B cell subset in peripheral blood (PB) was significantly increased in ACPA /RF RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL-9 and CXCL-10 were higher in synovial fluid than in plasma, and PB CD21 cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21 , approximately 40% of that population was CD27 IgD , and a third of those expressed the pro-osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL-6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27 IgD subset of CD21 B cells may mediate joint destruction in patients with ACPA /RF RA.
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http://dx.doi.org/10.1111/sji.12792DOI Listing
August 2019

Aspects of exercise with person-centred guidance influencing the transition to independent exercise: a qualitative interview study among older adults with rheumatoid arthritis.

Eur Rev Aging Phys Act 2019 5;16. Epub 2019 Apr 5.

1Department of Health and Rehabilitation, Unit of Physiotherapy, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Box 455, 405 30 Göteborg, Gothenburg, Sweden.

Background: Besides being health enhancing and disease preventing, exercise is also an important part of the management of chronic conditions, including the inflammatory joint disease rheumatoid arthritis (RA). However, older adults with RA present a lower level of physical activity than healthy older adults. The aim of this qualitative study was to explore aspects of participation in moderate- to high-intensity exercise with person-centred guidance influencing the transition to independent exercise for older adults with RA.

Methods: A qualitative interview study was conducted. In-depth interviews with 16 adults with RA aged between 68 and 75 years, who had taken part in the intervention arm of a randomized controlled trial performing moderate- to- high-intensity exercise with person-centred guidance, were analysed using qualitative content analysis.

Results: The analysis resulted in six main categories: A feasible opportunity to adopt exercise, Experiencing positive effects of exercise, Contextual factors affect the experience of exercise, Developing knowledge and thinking, Finding one's way, and Managing barriers for exercise. The exercise with person-centred guidance was described as a feasible opportunity to start exercising as a basis for the transition to independent exercise. They described developing knowledge and thinking about exercise during the intervention enabling them to manage the transition to independent exercise. Finding one's own way for exercise became important for sustaining independent exercise. Lastly, barriers for exercise and strategies for overcoming these were described. Reduced physical health, both temporary and permanent, was described as a considerable barrier for exercise.

Conclusion: The participants described several aspects of participating in exercise that influenced and facilitated their transition to independent exercise. The exercise was experienced as manageable and positive, by a careful introduction and development of an individual exercise routine in partnership with a physiotherapist. This seems to have favored the development of self-efficacy, with importance for future independent exercise. Reduced physical health, both temporary and permanent, was described as a considerable barrier for exercise. The personal process of trying to make the exercise one's own, and developing knowledge about exercise and new thoughts about oneself, seemed to prepare the participants for managing independent exercise and overcoming barriers.
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http://dx.doi.org/10.1186/s11556-019-0211-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449916PMC
April 2019

Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.

Front Immunol 2019 21;10:534. Epub 2019 Mar 21.

Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.

Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs. blockade of VLA-4 alone or in combination with LFA-1, but not LFA-1 alone, causes a release of MBCs from the spleen into the blood stream. In humans, we find that in peripheral blood, spleens, and tonsils from healthy donors the highest expression levels of the integrins LFA-1 and VLA-4 are also found on MBCs. Consistent with this, we found MBCs to have a higher capacity to adhere to ICAM-1 and VCAM-1 than naïve B cells. In patients with the autoimmune disease rheumatoid arthritis, it is the MBCs that have the highest levels of LFA-1 and VLA-4; moreover, compared with healthy donors, naïve B and MBCs of patients receiving anti-TNF medication have enhanced levels of the active form of LFA-1. Commensurate levels of the active αL subunit can be induced on B cells from healthy donors by exposure to the integrin ligands. Thus, our findings establish the selective use of the integrins LFA-1 and VLA-4 in the localization and adhesion of MBCs in both mice and humans.
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http://dx.doi.org/10.3389/fimmu.2019.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437070PMC
September 2020

Poor Dietary Quality Is Associated with Increased Inflammation in Swedish Patients with Rheumatoid Arthritis.

Nutrients 2018 Oct 18;10(10). Epub 2018 Oct 18.

Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Box 459, 40530 Gothenburg, Sweden.

The aim was to study whether dietary quality was associated with disease activity and inflammation among patients with rheumatoid arthritis (RA). This cross-sectional analysis included 66 Swedish participants, who each completed a food frequency questionnaire (FFQ) at screening. Food intake was scored by a dietary quality index created by the Swedish National Food Agency. Disease activity was measured as Disease Activity Score 28 (DAS28), based on erythrocyte sedimentation rate (ESR), a patient administered visual analogue scale of perceived global health and the number of tender and swollen joints out of 28 examined. Inflammation was measured as ESR and C-reactive protein (hs-CRP). Associations between dietary quality, disease activity and inflammation were evaluated using multivariable linear regression analysis. High dietary quality (high intake of fish, shellfish, whole grain, fruit and vegetables and low intake of sausages and sweets) was not related to DAS28 (B = -0.02, = 0.787). However, dietary quality was significantly negatively associated with hs-CRP (B = -0.6, = 0.044) and ESR (B = -2.4, = 0.002) after adjusting for body mass index, age, education, smoking and gender. Both hs-CRP and ESR decreased with increasing dietary quality. In conclusion, among patients with RA, high dietary quality was associated with reduced inflammation but not with disease activity.
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http://dx.doi.org/10.3390/nu10101535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213361PMC
October 2018

Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T-lymphocyte antigen-4.

Immunology 2018 12 31;155(4):446-457. Epub 2018 Jul 31.

Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.

CD4  Foxp3 regulatory T (Treg) cells can control both cellular and humoral immune responses; however, when and how Treg cells play a predominant role in regulating autoimmune disease remains elusive. To deplete Treg cells in vivo at given time-points, we used a mouse strain, susceptible to glucose-6-phosphate isomerase peptide-induced arthritis (GIA), in which the deletion of Treg cells can be controlled by diphtheria toxin treatment. By depleting Treg cells in the GIA mouse model, we found that a temporary lack of Treg cells at both priming and onset exaggerated disease development. Ablation of Treg cells led to the expansion of antigen-specific CD4 T cells including granulocyte-macrophage colony-stimulating factor, interferon-γ and interleukin-17-producing T cells, and promoted both T-cell and B-cell epitope spreading, which perpetuated arthritis. Interestingly, specific depletion of cytotoxic T-lymphocyte antigen-4 (CTLA-4) on Treg cells only, was sufficient to protect mice from GIA, due to the expansion of CTLA-4 Treg cells expressing alternative suppressive molecules. Collectively, our findings suggest that Treg cells, independently of CTLA-4, act as the key driving force in controlling autoimmune arthritis development.
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http://dx.doi.org/10.1111/imm.12983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231009PMC
December 2018

A Shared Epitope of Collagen Type XI and Type II Is Recognized by Pathogenic Antibodies in Mice and Humans with Arthritis.

Front Immunol 2018 12;9:451. Epub 2018 Apr 12.

Department of Medical Biochemistry and Biophysics, Section for Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.

Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the α3(XI) chain is identical to the α1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures.

Methods: Mice expressing the susceptible immune response gene were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments.

Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of α3(XI) or α1(II) chain. The L10D9 antibody binds cartilage and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis.

Conclusion: CXI is immunologically not exposed in healthy cartilage but contains T and B cell epitopes cross-reactive with CII, which could be activated in both mouse and human arthritis and could evoke an arthritogenic response.
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http://dx.doi.org/10.3389/fimmu.2018.00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906551PMC
June 2019

Effects of Aerobic and Resistance Exercise in Older Adults With Rheumatoid Arthritis: A Randomized Controlled Trial.

Arthritis Care Res (Hoboken) 2019 01;71(1):61-70

University of Gothenburg, Gothenburg, Sweden.

Objective: To evaluate the effect of a moderate-to-high-intensity, aerobic and resistance exercise with person-centered guidance in older adults with rheumatoid arthritis (RA), through a randomized controlled multicenter trial.

Methods: Older adults (ages 65-75 years) with RA (n = 74) were randomized to either a 20-week exercise intervention at a gym (n = 36) or to home-based exercise of light intensity (n = 38). Assessments were performed at baseline, at 20 weeks, and at 12 months. The primary outcome was the difference in the Health Assessment Questionnaire disability index (HAQ DI) score, and the secondary outcomes were the differences in physical fitness assessed by a cardiopulmonary exercise test, an endurance test, the timed up and go test, the sit to stand test, and an isometric elbow flexion force measurement.

Results: No significant differences between the groups were found for the primary outcome, HAQ DI score. Within the intervention group there was a significant improvement in the HAQ DI score when compared to baseline (P = 0.022). Aerobic capacity (P < 0.001) and 3 of 4 additional performance-based tests of endurance and strength significantly improved (P < 0.05) in the intervention group when compared to the control group. In the intervention group, 71% of patients rated their health as much or very much improved compared to 24% of patients in the control group (P < 0.001). At the 12-month follow-up, there were no significant differences in change between the 2 groups on the HAQ DI score. A significant between-group difference was found for change in an endurance test (P = 0.022).

Conclusion: Aerobic and resistance exercise with person-centered guidance improved physical fitness in terms of aerobic capacity, endurance, and strength in older adults with RA.
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http://dx.doi.org/10.1002/acr.23589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590333PMC
January 2019

A randomized controlled cross-over trial investigating the effect of anti-inflammatory diet on disease activity and quality of life in rheumatoid arthritis: the Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA) study protocol.

Nutr J 2018 04 20;17(1):44. Epub 2018 Apr 20.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Box 459, S-405 30, Gothenburg, Sweden.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 0.5-1.0% of the population, and where many patients in spite of modern pharmacological treatment fail to reach remission. This affects physical as well as mental wellbeing and leads to severely reduced quality of life and reduced work capacity, thus yielding high individual as well as societal costs. As a complement to modern pharmacological treatment, lifestyle intervention should be evaluated as a treatment option. Scientific evidence exists for anti-inflammatory effects by single foods on RA, but no study exists where these foods have been combined to obtain maximum effect and thus offer a substantial improvement in patient life quality. The main goal of the randomized cross-over trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis) is to test the hypothesis that an anti-inflammatory diet intervention, compared to a regular diet, will decrease disease activity and improve quality of life in patients with stable established RA.

Methods: In total, 50 RA patients with moderate disease activity are randomized to receive initially either a portfolio diet based on several food items with suggested anti-inflammatory effects or a control diet during 2 × 10 weeks with 3 months wash-out between diets. Food bags are delivered weekly by a home food delivery chain and referred to as the fiber bag and the protein bag, respectively, to partially blind participants. Both groups continue with regular pharmacological treatment. Known food biomarkers will be analyzed to measure intervention compliance. Impact on disease severity (measured by DAS28, a composite score which predicts disability and progression of RA), risk markers for cardiovascular disease and quality of life are evaluated after each diet regimen. Metabolomics will be used to evaluate the potential to predict responders to dietary treatment. A health economic evaluation is also included.

Discussion: The nutritional status of patients with RA often is poor and many ask their physician for diet advice. No evidence-based dietary guidelines for patients with RA exist because of the paucity of well-conducted sufficiently large diet intervention trials. ADIRA is an efficacy study and will provide evidence as to whether dietary treatment of RA can reduce disease activity and improve quality of life as well as reduce individual and societal costs.

Trial Registration: ClinicalTrials.gov Registration Number: NCT02941055 .
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http://dx.doi.org/10.1186/s12937-018-0354-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909253PMC
April 2018

Influence of Blue Mussel () Intake on Disease Activity in Female Patients with Rheumatoid Arthritis: The MIRA Randomized Cross-Over Dietary Intervention.

Nutrients 2018 Apr 13;10(4). Epub 2018 Apr 13.

Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease. This study evaluates the effect of blue mussel intake on disease activity and quality of life in women with RA. Thirty-nine women with established RA and a disease activity score 28 (DAS28) >3.0 were recruited to a randomized 2 × 11-week cross-over dietary intervention. The participants continued with their medication and habitual diet and exchanged one cooked meal a day, five days a week, with a meal including 75 g blue mussels or 75 g meat. Diets were switched after an eight week washout period. Data regarding quality of life (SF-36), blood lipids, erythrocyte sediment rate (ESR), C-reactive protein (CRP) and tender and swollen joints were examined at the start and end of each dietary period. Thirty women completed one period, and twenty-three completed both. Intake of the blue mussel diet led to a significant reduction of DAS28-CRP ( = 0.048), but not DAS28. The number of EULAR (European League Against Rheumatism) criteria moderate and good responders were higher when consuming blue mussel diet ( = 0.036). Blood lipids did not change. To conclude, blue mussel intake reduced disease symptoms in women with RA and improved perceived health. The reported effects need to be confirmed by non-patient reported outcomes, such as inflammation markers.
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http://dx.doi.org/10.3390/nu10040481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946266PMC
April 2018

Antibiotics with Interleukin-15 Inhibition Reduce Joint Inflammation and Bone Erosions but Not Cartilage Destruction in Staphylococcus aureus-Induced Arthritis.

Infect Immun 2018 05 23;86(5). Epub 2018 Apr 23.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden

-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that interleukin-15 (IL-15) inhibition without antibiotics is beneficial in -induced arthritis. We therefore hypothesized that the inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would reduce inflammation and joint destruction but preserve the host's ability to clear the infection. Female wild-type C57BL/6 mice were intravenously inoculated with the toxic shock syndrome toxin 1 (TSST-1)-producing LS-1 strain of with 0.8 × 10 CFU LS-1/mouse. Three days later, treatment consisting of cloxacillin, followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies, was started. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. The addition of aIL-15ab to antibiotics in -induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of induced arthritis, such as survival or weight change, or compromise the host's ability to clear the infection. Since the clinical outcome of induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL-15ab and antibiotics is a beneficial, but not optimal, treatment of -induced arthritis since it reduces synovitis and bone erosions but has a limited effect on cartilage destruction.
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http://dx.doi.org/10.1128/IAI.00960-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913847PMC
May 2018

Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis.

Arthritis Res Ther 2016 06 14;18(1):140. Epub 2016 Jun 14.

Department of Rheumatology and Inflammation Research, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Box 480, SE 405 30, Gothenburg, Sweden.

Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance.

Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used.

Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naïve mice ameliorated the development of CII-induced arthritis.

Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.
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http://dx.doi.org/10.1186/s13075-016-1037-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908726PMC
June 2016

Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis.

PLoS One 2016 9;11(5):e0154630. Epub 2016 May 9.

Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden.

Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naïve mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154630PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861286PMC
July 2017

The Bone-Inflammation-Cartilage (BIC) Stain: A Novel Staining Method Combining Safranin O and Van Gieson's Stains.

J Histochem Cytochem 2015 09 28;63(9):737-40. Epub 2015 May 28.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden (IG, BB)

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http://dx.doi.org/10.1369/0022155415591599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804731PMC
September 2015