The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and i... more The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and is linked to disease severity and mortality. However, antibody and cytokine responses in the early disease stage and their association with disease course and outcome are still not completely understood. In this large, multi-centre cohort study, blood samples of 434 Belgian COVID-19 hospitalized patients with different disease severities (ranging from asymptomatic/mild to critically ill) from the first wave of the COVID-19 pandemic were obtained. Baseline antibody and cytokine responses were characterized and associations with several clinical outcome parameters were determined. Anti-spike immunoglobulin (Ig)G and IgM levels were elevated in patients with a more severe disease course. This increased baseline antibody response however was associated with decreased odds for hospital mortality. Levels of the pro-inflammatory cytokines IL-6, IP-10 and IL-8, the anti-inflammatory cytokine IL-1...
<0.05, q = 0.02), supporting the idea that they should be involved in the pathophysiology of the ... more <0.05, q = 0.02), supporting the idea that they should be involved in the pathophysiology of the disease. Conclusion: These preliminary data confirm that the innate immune cells could play an important role in AxSpA. MAIT cells are at the forefront of the expression of IL-17A before gd T, CD4+T and CD8+T. Neutrophils do not appear to participate in the production of IL-17A, but the high expression of AS linked genes in these cells suggests their involvement in AxSpA. REFERENCES: [1] Appel H, et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther. 2011 [2] Kenna TJ, et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive g/d T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 2012 [3] Gracey E, et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann Rheum Dis. 2016 [4] Taylor PR, et al. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORgt and dectin-2. Nat Immunol. 2014
If you would like to know when your article has been published online, take advantage of our free... more If you would like to know when your article has been published online, take advantage of our free alert service. For registration and further information, go to:. Due to the electronic nature of the procedure, the manuscript and the original figures will only be returned to you on special request. When you return your corrections, please inform us, if you would like to have these documents returned.
CD4+ CD25high regulatory T cells (Tregs) of patients with relapsing-remitting (RR) multiple scler... more CD4+ CD25high regulatory T cells (Tregs) of patients with relapsing-remitting (RR) multiple sclerosis (MS), in contrast to those of patients with secondary progressive (SP) MS, show a reduced suppressive function. In this study, we analysed forkhead box P3 (FOXP3) at the single-cell level in MS patients and controls (healthy individuals and patients with other neurological diseases) by means of intracellular flow cytometry. Our data revealed a reduced number of peripheral blood CD4+ CD25high FOXP3+ T cells and lower FOXP3 protein expression per cell in RR-MS patients than in SP-MS patients and control individuals, which was correlated with the suppressive capacity of Tregs in these patients. Interestingly, interferon (IFN)-β-treated RR-MS patients showed restored numbers of FOXP3+ Tregs. Furthermore, a higher percentage of CD4+ CD25high FOXP3+ Tregs in RR-MS patients, as compared with controls and SP-MS patients, expressed CD103 and CD49d, adhesion molecules involved in T-cell recruitment towards inflamed tissues. This was consistent with a significantly increased number of CD27+ CD25high CD4+ T cells in the cerebrospinal fluid (CSF), as compared with peripheral blood, in RR-MS patients. Taken together, these data show aberrant FOXP3 expression at the single-cell level correlated with Treg dysfunction in RR-MS patients. Our results also suggest that Tregs accumulate in the CSF of RR-MS patients, in an attempt to down-regulate local inflammation in the central nervous system.
BackgroundThere is an unmet need for biomarkers to identify patients with axial spondyloarthritis... more BackgroundThere is an unmet need for biomarkers to identify patients with axial spondyloarthritis (axSpA), as clinical manifestations often overlap with other disorders. Previously, we identified immunoglobulin G (IgG) antibodies to 3 Hasselt University (UH)-axSpA peptides which could provide a novel tool for diagnosis of a subset of axSpA patients [1].ObjectivesThe aim of this study was to identify novel IgA antibodies in early axSpA patients and to determine their diagnostic potential in combination with previously determined IgG antibodies against UH-axSpA-IgG antigens.MethodsAn axSpA cDNA phage display library constructed from axSpA hip synovium, was used to screen for novel IgA antibodies in plasma from early axSpA patients. The diagnostic value of these antibodies against novel UH-axSpA-IgA and previously identified UH-axSpA-IgG antigens was determined in two independent axSpA cohorts [UH cohort and the Leuven spondyloarthritis biologics cohort (BIOSPAR)], in healthy controls and in patients with chronic low back pain (CLBP) using ELISA.ResultsWe identified antibodies to 7 novel UH-axSpA-IgA antigens, of which 6 correspond to non-physiological peptides and 1 to the human histone deacetylase 3 (HDAC3) protein. IgA antibodies against 2 of these 7 novel UH-axSpA-IgA antigens and IgG antibodies against 2 of 3 the previously identified antigens were significantly more present in axSpA patients from the UH cohort (18/70, 25.7%) and the (Bio)SPAR cohort (26/164, 15.9%), compared to controls with CLBP (2/66, 3%). Antibodies to this panel of 4 antigens were present in 21.1 % (30/142) of patients with early axSpA from the UH and (Bio)SPAR cohorts. The positive likelihood ratio for confirming early axSpA using antibodies to these 4 UH-axSpA antigens was 7.0. So far, no clinical correlation between the novel identified IgA antibodies and inflammatory bowel disease could be identified.ConclusionScreening an axSpA cDNA phage display library for IgA reactivity resulted in the identification of 7 novel UH-axSpA-IgA antigens, of which 2 show promising biomarker potential for the diagnosis of a subset of axSpA patients, in combination with previously identified UH-axSpA-IgG antigens.Reference[1]Quaden D, Vandormael P, Ruytinx P, Geusens P, Corten K, Vanhoof J, et al. Antibodies Against Three Novel Peptides in Early Axial Spondyloarthritis Patients From Two Independent Cohorts. Arthritis Rheumatol. 2020;72(12):2094-105.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
Qualitative analysis mapped to previous themes will be summarised at the meeting. Conclusions: It... more Qualitative analysis mapped to previous themes will be summarised at the meeting. Conclusions: It is feasible and effective to see new patients in a group setting with an experienced team. New patients group clinics have a powerful effect in empowering patients and may become an important option for hard to manage patients especially where resources are limited. REFERENCES: 1. Ramdas K, Darzi A. Adopting innovations in care deliverythe case of shared medical appointments.
Objectives: To investigate the association between socioeconomic status (SES) on an individual le... more Objectives: To investigate the association between socioeconomic status (SES) on an individual level and incident RA Methods: EPIC is a multicentre, pan-European prospective cohort study of apparently healthy populations. We undertook a nested case-control study to investigate risk factors for RA, by identifying incident RA cases (pre-RA) and matched controls amongst subjects enrolled in four EPIC cohorts in Italy and Spain. The lifestyle, environmental exposure, anthropometric information and blood samples were collected at baseline. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. The exposure was SES as measured by level of educational attainment categorised as university (referent), secondary school/technical/professional school, primary school completed, and none. The primary outcome was incident RA. Conditional logistic regression (CLR) analysis was adjusted for ACPA seropositivity, smoking status, and presence of shared epitope (SE). A further model also adjusted for other potential confounders, including body mass index (BMI), waist circumference, physical activity, and alcohol intake. Results: The study sample included 398 individuals of which 99 individuals went on to subsequently develop RA. In this analysis, time to diagnosis (defined as time between date of blood sample and date of diagnosis), was 6.71 years (SD 3.43). A significant positive association was observed with level of educational attainment and RA incidence (secondary/technical vs university: OR 5.60, 95% CI 1.59-19.7, primary school vs university: OR 5.06, 95% CI 1.45-17.6, no education vs university: 7.11, 95% CI 1.37-36.8; p for trend 0.02) independent of ACPA seropositivity, SE and smoking). A significant positive association between level of educational attainment and RA incidence was confirmed in the fully adjusted model (secondary/technical vs university:
[3] Mei HE, et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in... more [3] Mei HE, et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood 2015;125(11):1739-1748. [4] Hoyer BF, et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.
Ankylosing spondylitis (AS) is a debilitating, chronic, rheumatic disease characterized by inflam... more Ankylosing spondylitis (AS) is a debilitating, chronic, rheumatic disease characterized by inflammation and new 18 bone formation resulting in fusion of the spine and sacroiliac joints. Since early treatment is impeded by a delayed 19 diagnosis, it is highly important to find new biomarkers that improve diagnosis and may also contribute to a bet-20 ter assessment of disease activity, prognosis and therapy response in AS. Because of the absence of rheumatoid 21 factor, AS was long assumed to have a seronegative character and antibodies are thus not considered a hallmark 22 of the disease. However, emerging evidence suggests plasma cells and autoantibodies to be involved in the 23 disease course. In this review, the role of B cells and antibodies in AS is discussed. Furthermore, an overview is 24 provided of antibodies identified in AS up till now, and their diagnostic potential. Many of these antibody re-25 sponses were based on small study populations and further validation is lacking. Moreover, most of them were 26 identified by an hypothesis-driven approach and thus limited to antibodies against targets that are already 27 known to be involved in AS pathogenesis. Hence, we consider an unbiased approach to identify novel diagnostic 28 antibodies. The already successfully applied technique cDNA phage display and serological antigen selection will 29 be used to identify antibodies against both known and new antigen targets in AS plasma. These newly identified 30 antibodies will enhance early diagnosis of AS and provide more insight into the underlying disease pathology, 31 resulting in a more effective treatment strategy and eventually an improved disease outcome.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease in which 30% of patients are sero... more Rheumatoid arthritis (RA) is an inflammatory autoimmune disease in which 30% of patients are seronegative for the two serological RA markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACCP). However, both markers also have lower sensitivities in early stages of the disease. The lack of effective biomarkers for this subpopulation of RA patients causes a delayed diagnosis. Therefore, discovery of novel circulating autoantibody biomarkers for these early RF-negative and ACCP-negative RA patients are advance planning of these subsets. 136 enriched antigenic markers were identified by high-throughput screening an RA library with autoantibodies in the sera of RA patients (positive selection) and healthy control (negative selection). Phage-ELISA-based re-screening determined 13 out of 136 enriched antigenic targets in which increased antibody levels rised up. Two of the 13 identified targets, namely special A-T rich DNA binding protein (SATB1) and EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1), which had highest increased antibody levels, were selected for further characterization. Reactivity of serum antibodies against these proteins was tested in a protein ELISA using the sera of 137 RA patients and 159 healthy controls. Autoantibodies against SATB1 were detected with 79% sensitivity and 82% specificity, while 87% sensitivity and 52% specificity were obatained for antibodies directed against EFEMP1. With regard to cytokine assay, interestingly, pro-inflammationary cytokines including TNF (tumour necrosis factor) increased over 1000 pg/ml or IL-4 (interleukin-4) or IL- 13 similarly increased up to 90 pg/ml and 102 pg/ml, respectively for co-culture with anti-SATB1 monoclonal antibody. Under treatment with EFEMP1 mAb resulting IL-1, TNF and IL-4 triggered up to 1300 pg/ml, 1250 pg/ml and 180 pg/ml, respectively. In T cell phenotype characterization, two subsets of CD4 + T cell and CD8 + cell were stimulated and differentiated from peripheral blood mononuclear cells (PBMCs) at 29.7% and 1.2% for anti-SATB mAb; 31.3% and 2.8% for anti-EFEMP1 mAb.
Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune... more Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia, and astrocytes switch their metabolism toward glycolysis, resulting in the formation of α-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound N δ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 ± 11 vs. 154 ± 21, p < 0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, α-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS.
The WHO defines different COVID-19 disease stages in which the pathophysiological mechanisms diff... more The WHO defines different COVID-19 disease stages in which the pathophysiological mechanisms differ. We evaluated the characteristics of these COVID-19 disease stages. Forty-four PCR-confirmed COVID-19 patients were included in a prospective minimal invasive autopsy cohort. Patients were classified into mild-moderate (n = 4), severe-critical (n = 32) and post-acute disease (n = 8) and clinical, radiological, histological, microbiological and immunological data were compared. Classified according to Thoracic Society of America, patients with mild-moderate disease had no typical COVID-19 images on CT-Thorax versus 71.9% with typical images in severe-critical disease and 87.5% in postacute disease (P < 0.001). Diffuse alveolar damage was absent in mild-moderate disease but present in 93.8% and 87.5% of patients with severe-critical and post-acute COVID-19 respectively (P = 0.002). Other organs with COVID-19 related histopathological changes were liver and heart. Interferon-γ levels were significantly higher in patients with severe-critical COVID-19 (P = 0.046). Anti-SARS CoV-2 IgG was positive in 66%, 40.6% and 87.5% of patients with mild-moderate, severe-critical and postacute COVID-19 respectively (n.s.). Significant differences in histopathological and immunological characteristics between patients with mild-moderate disease compared to patients with severecritical disease were found, whereas differences between patients with severe-critical disease and post-acute disease were limited. This emphasizes the need for tailored treatment of COVID-19 patients. Since the first report in December 2019 of patients infected with severe acute respiratory syndrome corona virus 2 (SARS CoV-2), this virus has travelled the globe. Coronavirus disease (COVID-19) has caused tremendous mortality and morbidity worldwide and continues to do so 1. SARS-CoV-2 infection is characterized by different disease stages. After primary infection, patients may either remain asymptomatic, or develop symptoms including fever, fatigue, cough, myalgia, loss of smell or gastro-intestinal complaints, so called mild disease.
Background: The patient global assessment (PtGA) is a core set variable to assess disease activit... more Background: The patient global assessment (PtGA) is a core set variable to assess disease activity in rheumatoid arthritis (RA). It is strongly linked to patient-reported pain and has shown to be a limiting factor for reaching remission in patients with remittent joint inflammation and normal acute phase response, particularly when the ACR/EULAR Boolean criteria are used. In these, the PtGA may not be greater than 10 on a 0-100 scale to reach remission. Objectives: To analyse the impact of higher cutoffs for or removal of the PtGA applied in the ACR/EULAR Boolean remission on the consistency with the SDAI remission definition, and with respect to long-term structural and functional outcomes. Methods: We retrieved data from six clinical trials testing the efficacy of tumor-necrosis factor inhibitors vs MTX or placebo/MTX. Three trials depicted early RA: ASPIRE (infliximab), Go Before (golimumab), PREMIER (adalimumab); and three late RA: ATTRACT (infliximab), DE019 (adalimumab) and Go Forward (golimumab). We increased the cutoff of the PtGA gradually by 5mm (mBoolean15-REM) up to 30mm, and also omitted the criterion completely (Boolean-NO REM, i.e. requiring only CRP, SJC, TJC£1). We assessed frequencies of remission by these definitions at 6 and 12 months and evaluated agreement with the Index based (SDAI) definition of remission (which does not include an inherent cutoff for PtGA). Further the impact on functional and structural outcomes after 1 year were explored based on achievement of each of these remission definitions at 6 months. Results: We included 3293 patients in our study, 2121 in early and 1172 in late RA (mean disease duration: 1.5±3.0 and 9.8±8.6 years, respectively). The rates of patients achieving Boolean remission increased with higher allowance for PtGA from 11.9% to 18.8% in early RA, and from 5.9% to 12.4% in late RA at 6 month, and from 19.7% to 29.9% and from 10.7% to 20.9%, respectively, at 1 year. Best agreement with SDAI occurred at a PtGA cutoff of 15mm and 20mm, while with higher allowances for PtGA the disconnect between Boolean and Index based remission increased again (Figure). Radiographic progression was very similar in the different Boolean groups (ranging from a mean of 0.27±4.7 to 0.41±5.1). As expected, removing the PtGA increased functional impairment in remission (% of patients scoring HAQ=0 in
Background The contribution of native or modified oligodendroglia-derived extracellular vesicles ... more Background The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death. Therefore, secretion of HSPB8 in OL-EVs could be beneficial for neurons during chronic inflammation. However, how secreted HSPB8 contribute to cellular proteostasis remains to be elucidated. Methods We produced oligodendroglia-derived EVs, either native (OL-EVs) or HSPB8 modified (OL-HSPB8-EVs), to investigate their effects in controlling chronic inflammation and cellular homeostasis. We analyzed the impact of both EV subsets on either a resting or activated microglial cell line and on primary mixed neural cell culture cells. Cells were activated by s...
The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and i... more The immune response in patients with Coronavirus Disease 2019 (COVID-19) is highly variable and is linked to disease severity and mortality. However, antibody and cytokine responses in the early disease stage and their association with disease course and outcome are still not completely understood. In this large, multi-centre cohort study, blood samples of 434 Belgian COVID-19 hospitalized patients with different disease severities (ranging from asymptomatic/mild to critically ill) from the first wave of the COVID-19 pandemic were obtained. Baseline antibody and cytokine responses were characterized and associations with several clinical outcome parameters were determined. Anti-spike immunoglobulin (Ig)G and IgM levels were elevated in patients with a more severe disease course. This increased baseline antibody response however was associated with decreased odds for hospital mortality. Levels of the pro-inflammatory cytokines IL-6, IP-10 and IL-8, the anti-inflammatory cytokine IL-1...
<0.05, q = 0.02), supporting the idea that they should be involved in the pathophysiology of the ... more <0.05, q = 0.02), supporting the idea that they should be involved in the pathophysiology of the disease. Conclusion: These preliminary data confirm that the innate immune cells could play an important role in AxSpA. MAIT cells are at the forefront of the expression of IL-17A before gd T, CD4+T and CD8+T. Neutrophils do not appear to participate in the production of IL-17A, but the high expression of AS linked genes in these cells suggests their involvement in AxSpA. REFERENCES: [1] Appel H, et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther. 2011 [2] Kenna TJ, et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive g/d T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 2012 [3] Gracey E, et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann Rheum Dis. 2016 [4] Taylor PR, et al. Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORgt and dectin-2. Nat Immunol. 2014
If you would like to know when your article has been published online, take advantage of our free... more If you would like to know when your article has been published online, take advantage of our free alert service. For registration and further information, go to:. Due to the electronic nature of the procedure, the manuscript and the original figures will only be returned to you on special request. When you return your corrections, please inform us, if you would like to have these documents returned.
CD4+ CD25high regulatory T cells (Tregs) of patients with relapsing-remitting (RR) multiple scler... more CD4+ CD25high regulatory T cells (Tregs) of patients with relapsing-remitting (RR) multiple sclerosis (MS), in contrast to those of patients with secondary progressive (SP) MS, show a reduced suppressive function. In this study, we analysed forkhead box P3 (FOXP3) at the single-cell level in MS patients and controls (healthy individuals and patients with other neurological diseases) by means of intracellular flow cytometry. Our data revealed a reduced number of peripheral blood CD4+ CD25high FOXP3+ T cells and lower FOXP3 protein expression per cell in RR-MS patients than in SP-MS patients and control individuals, which was correlated with the suppressive capacity of Tregs in these patients. Interestingly, interferon (IFN)-β-treated RR-MS patients showed restored numbers of FOXP3+ Tregs. Furthermore, a higher percentage of CD4+ CD25high FOXP3+ Tregs in RR-MS patients, as compared with controls and SP-MS patients, expressed CD103 and CD49d, adhesion molecules involved in T-cell recruitment towards inflamed tissues. This was consistent with a significantly increased number of CD27+ CD25high CD4+ T cells in the cerebrospinal fluid (CSF), as compared with peripheral blood, in RR-MS patients. Taken together, these data show aberrant FOXP3 expression at the single-cell level correlated with Treg dysfunction in RR-MS patients. Our results also suggest that Tregs accumulate in the CSF of RR-MS patients, in an attempt to down-regulate local inflammation in the central nervous system.
BackgroundThere is an unmet need for biomarkers to identify patients with axial spondyloarthritis... more BackgroundThere is an unmet need for biomarkers to identify patients with axial spondyloarthritis (axSpA), as clinical manifestations often overlap with other disorders. Previously, we identified immunoglobulin G (IgG) antibodies to 3 Hasselt University (UH)-axSpA peptides which could provide a novel tool for diagnosis of a subset of axSpA patients [1].ObjectivesThe aim of this study was to identify novel IgA antibodies in early axSpA patients and to determine their diagnostic potential in combination with previously determined IgG antibodies against UH-axSpA-IgG antigens.MethodsAn axSpA cDNA phage display library constructed from axSpA hip synovium, was used to screen for novel IgA antibodies in plasma from early axSpA patients. The diagnostic value of these antibodies against novel UH-axSpA-IgA and previously identified UH-axSpA-IgG antigens was determined in two independent axSpA cohorts [UH cohort and the Leuven spondyloarthritis biologics cohort (BIOSPAR)], in healthy controls and in patients with chronic low back pain (CLBP) using ELISA.ResultsWe identified antibodies to 7 novel UH-axSpA-IgA antigens, of which 6 correspond to non-physiological peptides and 1 to the human histone deacetylase 3 (HDAC3) protein. IgA antibodies against 2 of these 7 novel UH-axSpA-IgA antigens and IgG antibodies against 2 of 3 the previously identified antigens were significantly more present in axSpA patients from the UH cohort (18/70, 25.7%) and the (Bio)SPAR cohort (26/164, 15.9%), compared to controls with CLBP (2/66, 3%). Antibodies to this panel of 4 antigens were present in 21.1 % (30/142) of patients with early axSpA from the UH and (Bio)SPAR cohorts. The positive likelihood ratio for confirming early axSpA using antibodies to these 4 UH-axSpA antigens was 7.0. So far, no clinical correlation between the novel identified IgA antibodies and inflammatory bowel disease could be identified.ConclusionScreening an axSpA cDNA phage display library for IgA reactivity resulted in the identification of 7 novel UH-axSpA-IgA antigens, of which 2 show promising biomarker potential for the diagnosis of a subset of axSpA patients, in combination with previously identified UH-axSpA-IgG antigens.Reference[1]Quaden D, Vandormael P, Ruytinx P, Geusens P, Corten K, Vanhoof J, et al. Antibodies Against Three Novel Peptides in Early Axial Spondyloarthritis Patients From Two Independent Cohorts. Arthritis Rheumatol. 2020;72(12):2094-105.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
Qualitative analysis mapped to previous themes will be summarised at the meeting. Conclusions: It... more Qualitative analysis mapped to previous themes will be summarised at the meeting. Conclusions: It is feasible and effective to see new patients in a group setting with an experienced team. New patients group clinics have a powerful effect in empowering patients and may become an important option for hard to manage patients especially where resources are limited. REFERENCES: 1. Ramdas K, Darzi A. Adopting innovations in care deliverythe case of shared medical appointments.
Objectives: To investigate the association between socioeconomic status (SES) on an individual le... more Objectives: To investigate the association between socioeconomic status (SES) on an individual level and incident RA Methods: EPIC is a multicentre, pan-European prospective cohort study of apparently healthy populations. We undertook a nested case-control study to investigate risk factors for RA, by identifying incident RA cases (pre-RA) and matched controls amongst subjects enrolled in four EPIC cohorts in Italy and Spain. The lifestyle, environmental exposure, anthropometric information and blood samples were collected at baseline. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. The exposure was SES as measured by level of educational attainment categorised as university (referent), secondary school/technical/professional school, primary school completed, and none. The primary outcome was incident RA. Conditional logistic regression (CLR) analysis was adjusted for ACPA seropositivity, smoking status, and presence of shared epitope (SE). A further model also adjusted for other potential confounders, including body mass index (BMI), waist circumference, physical activity, and alcohol intake. Results: The study sample included 398 individuals of which 99 individuals went on to subsequently develop RA. In this analysis, time to diagnosis (defined as time between date of blood sample and date of diagnosis), was 6.71 years (SD 3.43). A significant positive association was observed with level of educational attainment and RA incidence (secondary/technical vs university: OR 5.60, 95% CI 1.59-19.7, primary school vs university: OR 5.06, 95% CI 1.45-17.6, no education vs university: 7.11, 95% CI 1.37-36.8; p for trend 0.02) independent of ACPA seropositivity, SE and smoking). A significant positive association between level of educational attainment and RA incidence was confirmed in the fully adjusted model (secondary/technical vs university:
[3] Mei HE, et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in... more [3] Mei HE, et al. A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood 2015;125(11):1739-1748. [4] Hoyer BF, et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice.
Ankylosing spondylitis (AS) is a debilitating, chronic, rheumatic disease characterized by inflam... more Ankylosing spondylitis (AS) is a debilitating, chronic, rheumatic disease characterized by inflammation and new 18 bone formation resulting in fusion of the spine and sacroiliac joints. Since early treatment is impeded by a delayed 19 diagnosis, it is highly important to find new biomarkers that improve diagnosis and may also contribute to a bet-20 ter assessment of disease activity, prognosis and therapy response in AS. Because of the absence of rheumatoid 21 factor, AS was long assumed to have a seronegative character and antibodies are thus not considered a hallmark 22 of the disease. However, emerging evidence suggests plasma cells and autoantibodies to be involved in the 23 disease course. In this review, the role of B cells and antibodies in AS is discussed. Furthermore, an overview is 24 provided of antibodies identified in AS up till now, and their diagnostic potential. Many of these antibody re-25 sponses were based on small study populations and further validation is lacking. Moreover, most of them were 26 identified by an hypothesis-driven approach and thus limited to antibodies against targets that are already 27 known to be involved in AS pathogenesis. Hence, we consider an unbiased approach to identify novel diagnostic 28 antibodies. The already successfully applied technique cDNA phage display and serological antigen selection will 29 be used to identify antibodies against both known and new antigen targets in AS plasma. These newly identified 30 antibodies will enhance early diagnosis of AS and provide more insight into the underlying disease pathology, 31 resulting in a more effective treatment strategy and eventually an improved disease outcome.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease in which 30% of patients are sero... more Rheumatoid arthritis (RA) is an inflammatory autoimmune disease in which 30% of patients are seronegative for the two serological RA markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACCP). However, both markers also have lower sensitivities in early stages of the disease. The lack of effective biomarkers for this subpopulation of RA patients causes a delayed diagnosis. Therefore, discovery of novel circulating autoantibody biomarkers for these early RF-negative and ACCP-negative RA patients are advance planning of these subsets. 136 enriched antigenic markers were identified by high-throughput screening an RA library with autoantibodies in the sera of RA patients (positive selection) and healthy control (negative selection). Phage-ELISA-based re-screening determined 13 out of 136 enriched antigenic targets in which increased antibody levels rised up. Two of the 13 identified targets, namely special A-T rich DNA binding protein (SATB1) and EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1), which had highest increased antibody levels, were selected for further characterization. Reactivity of serum antibodies against these proteins was tested in a protein ELISA using the sera of 137 RA patients and 159 healthy controls. Autoantibodies against SATB1 were detected with 79% sensitivity and 82% specificity, while 87% sensitivity and 52% specificity were obatained for antibodies directed against EFEMP1. With regard to cytokine assay, interestingly, pro-inflammationary cytokines including TNF (tumour necrosis factor) increased over 1000 pg/ml or IL-4 (interleukin-4) or IL- 13 similarly increased up to 90 pg/ml and 102 pg/ml, respectively for co-culture with anti-SATB1 monoclonal antibody. Under treatment with EFEMP1 mAb resulting IL-1, TNF and IL-4 triggered up to 1300 pg/ml, 1250 pg/ml and 180 pg/ml, respectively. In T cell phenotype characterization, two subsets of CD4 + T cell and CD8 + cell were stimulated and differentiated from peripheral blood mononuclear cells (PBMCs) at 29.7% and 1.2% for anti-SATB mAb; 31.3% and 2.8% for anti-EFEMP1 mAb.
Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune... more Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia, and astrocytes switch their metabolism toward glycolysis, resulting in the formation of α-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound N δ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 ± 11 vs. 154 ± 21, p < 0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, α-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS.
The WHO defines different COVID-19 disease stages in which the pathophysiological mechanisms diff... more The WHO defines different COVID-19 disease stages in which the pathophysiological mechanisms differ. We evaluated the characteristics of these COVID-19 disease stages. Forty-four PCR-confirmed COVID-19 patients were included in a prospective minimal invasive autopsy cohort. Patients were classified into mild-moderate (n = 4), severe-critical (n = 32) and post-acute disease (n = 8) and clinical, radiological, histological, microbiological and immunological data were compared. Classified according to Thoracic Society of America, patients with mild-moderate disease had no typical COVID-19 images on CT-Thorax versus 71.9% with typical images in severe-critical disease and 87.5% in postacute disease (P < 0.001). Diffuse alveolar damage was absent in mild-moderate disease but present in 93.8% and 87.5% of patients with severe-critical and post-acute COVID-19 respectively (P = 0.002). Other organs with COVID-19 related histopathological changes were liver and heart. Interferon-γ levels were significantly higher in patients with severe-critical COVID-19 (P = 0.046). Anti-SARS CoV-2 IgG was positive in 66%, 40.6% and 87.5% of patients with mild-moderate, severe-critical and postacute COVID-19 respectively (n.s.). Significant differences in histopathological and immunological characteristics between patients with mild-moderate disease compared to patients with severecritical disease were found, whereas differences between patients with severe-critical disease and post-acute disease were limited. This emphasizes the need for tailored treatment of COVID-19 patients. Since the first report in December 2019 of patients infected with severe acute respiratory syndrome corona virus 2 (SARS CoV-2), this virus has travelled the globe. Coronavirus disease (COVID-19) has caused tremendous mortality and morbidity worldwide and continues to do so 1. SARS-CoV-2 infection is characterized by different disease stages. After primary infection, patients may either remain asymptomatic, or develop symptoms including fever, fatigue, cough, myalgia, loss of smell or gastro-intestinal complaints, so called mild disease.
Background: The patient global assessment (PtGA) is a core set variable to assess disease activit... more Background: The patient global assessment (PtGA) is a core set variable to assess disease activity in rheumatoid arthritis (RA). It is strongly linked to patient-reported pain and has shown to be a limiting factor for reaching remission in patients with remittent joint inflammation and normal acute phase response, particularly when the ACR/EULAR Boolean criteria are used. In these, the PtGA may not be greater than 10 on a 0-100 scale to reach remission. Objectives: To analyse the impact of higher cutoffs for or removal of the PtGA applied in the ACR/EULAR Boolean remission on the consistency with the SDAI remission definition, and with respect to long-term structural and functional outcomes. Methods: We retrieved data from six clinical trials testing the efficacy of tumor-necrosis factor inhibitors vs MTX or placebo/MTX. Three trials depicted early RA: ASPIRE (infliximab), Go Before (golimumab), PREMIER (adalimumab); and three late RA: ATTRACT (infliximab), DE019 (adalimumab) and Go Forward (golimumab). We increased the cutoff of the PtGA gradually by 5mm (mBoolean15-REM) up to 30mm, and also omitted the criterion completely (Boolean-NO REM, i.e. requiring only CRP, SJC, TJC£1). We assessed frequencies of remission by these definitions at 6 and 12 months and evaluated agreement with the Index based (SDAI) definition of remission (which does not include an inherent cutoff for PtGA). Further the impact on functional and structural outcomes after 1 year were explored based on achievement of each of these remission definitions at 6 months. Results: We included 3293 patients in our study, 2121 in early and 1172 in late RA (mean disease duration: 1.5±3.0 and 9.8±8.6 years, respectively). The rates of patients achieving Boolean remission increased with higher allowance for PtGA from 11.9% to 18.8% in early RA, and from 5.9% to 12.4% in late RA at 6 month, and from 19.7% to 29.9% and from 10.7% to 20.9%, respectively, at 1 year. Best agreement with SDAI occurred at a PtGA cutoff of 15mm and 20mm, while with higher allowances for PtGA the disconnect between Boolean and Index based remission increased again (Figure). Radiographic progression was very similar in the different Boolean groups (ranging from a mean of 0.27±4.7 to 0.41±5.1). As expected, removing the PtGA increased functional impairment in remission (% of patients scoring HAQ=0 in
Background The contribution of native or modified oligodendroglia-derived extracellular vesicles ... more Background The contribution of native or modified oligodendroglia-derived extracellular vesicles (OL-EVs) in controlling chronic inflammation is poorly understood. In activated microglia, OL-EVs contribute to the removal of cytotoxic proteins following a proteotoxic stress. Intracellular small heat shock protein B8 (HSPB8) sustain this function by facilitating autophagy and protecting cells against oxidative stress mediated cell death. Therefore, secretion of HSPB8 in OL-EVs could be beneficial for neurons during chronic inflammation. However, how secreted HSPB8 contribute to cellular proteostasis remains to be elucidated. Methods We produced oligodendroglia-derived EVs, either native (OL-EVs) or HSPB8 modified (OL-HSPB8-EVs), to investigate their effects in controlling chronic inflammation and cellular homeostasis. We analyzed the impact of both EV subsets on either a resting or activated microglial cell line and on primary mixed neural cell culture cells. Cells were activated by s...
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Papers by Veerle Somers