Karim Raza

The Queen Elizabeth Hospital, Tarndarnya, South Australia, Australia

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Publications (148)913.21 Total impact

  • Rheumatology (Oxford, England) 07/2015; DOI:10.1093/rheumatology/kev261 · 4.44 Impact Factor
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    ABSTRACT: To investigate serum antibody reactivity against a panel of post-translationally modified vimentin peptides (PTMPs) in patients with early inflammatory arthritis. A panel of PTMPs was developed. Microtitre plates were coated with peptides derived from vimentin that were identical in length and composition except at one amino acid that was changed to introduce one of three post-translational modifications (PTMs)-either a citrullinated, carbamylated or acetylated residue. Sera of 268 treatment-naive patients with early inflammatory arthritis and symptoms ≤3 months' duration were tested. Patients were assigned to one of three outcome categories at 18-month follow-up (rheumatoid arthritis (RA), persistent non-RA arthritis and resolving arthritis). Antibodies against citrullinated, carbamylated and acetylated vimentin peptides were detected in the sera of patients with early inflammatory arthritis. The proportion of patients seropositive for all antibody types was significantly higher in the RA group than in the other groups. Anti cyclic citrullinated peptide (CCP)-positive patients with RA had higher numbers of peptides recognised and higher levels of antibodies against those peptides, representing a distinct profile compared with the other groups. We show for the first time that antibodies against acetylated vimentin are present in the sera of patients with early RA and confirm and extend previous observations regarding anticitrullinated and anticarbamylated antibodies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 07/2015; DOI:10.1136/annrheumdis-2014-206785 · 10.38 Impact Factor
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    ABSTRACT: Impairment in the ability of the inflamed synovium to generate cortisol has been proposed to be a factor in the persistence and severity of inflammatory arthritis. In the inflamed synovium, cortisol is generated from cortisone by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The objective of this study was to determine the role of endogenous glucocorticoid metabolism in the development of persistent inflammatory arthritis. Urine samples were collected from patients with early arthritis (symptoms ≤12 weeks duration) whose final diagnostic outcomes were established after clinical follow-up and from patients with established rheumatoid arthritis (RA). All patients were free of disease-modifying anti-rheumatic drugs at the time of sample collection. Systemic measures of glucocorticoid metabolism were assessed in the urine samples by gas chromatography/mass spectrometry. Clinical data including CRP and ESR were also collected at baseline. Systemic measures of 11β-HSD1 activity were significantly higher in patients with early arthritis whose disease went on to persist, and also in the subgroup of patients with persistent disease who developed RA, when compared with patients whose synovitis resolved over time. We observed a significant positive correlation between systemic 11β-HSD1 activity and ESR/CRP in patients with established RA but not in any of the early arthritis patients group. The present study demonstrates that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity when compared with patients whose synovitis developed into RA or other forms of persistent arthritis. Low absolute levels of 11β-HSD1 activity do not therefore appear to be a major contributor to the development of RA and it is possible that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution.
    Arthritis Research & Therapy 05/2015; 17(1). DOI:10.1186/s13075-015-0633-2 · 4.12 Impact Factor
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    ABSTRACT: During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.
    Nature medicine 04/2015; 21(5). DOI:10.1038/nm.3842 · 28.05 Impact Factor
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    ABSTRACT: Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response programme. We tested the hypothesis that a serum response programme can be used to classify diseased tissues, and investigated the serum response programme in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including rheumatoid arthritis (RA), osteoarthritis (OA) and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response programme discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through _3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts.
    PLoS ONE 03/2015; 10(3):e0120917. DOI:10.1371/journal.pone.0120917 · 3.53 Impact Factor
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    ABSTRACT: There is currently no biochemical test for detection of early-stage osteoarthritis (eOA). Tests for early-stage rheumatoid arthritis (eRA) such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies require refinement to improve clinical utility. We developed robust mass spectrometric methods to quantify citrullinated protein (CP) and free hydroxyproline in body fluids. We detected CP in the plasma of healthy subjects and surprisingly found that CP was increased in both patients with eOA and eRA whereas anti-CCP antibodies were predominantly present in eRA. A 4-class diagnostic algorithm combining plasma/serum CP, anti-CCP antibody and hydroxyproline applied to a cohort gave specific and sensitive detection and discrimination of eOA, eRA, other non-RA inflammatory joint diseases and good skeletal health. This provides a first-in-class plasma/serum-based biochemical assay for diagnosis and type discrimination of early-stage arthritis to facilitate improved treatment and patient outcomes, exploiting citrullinated protein and related differential autoimmunity.
    Scientific Reports 03/2015; 5:9259. DOI:10.1038/srep09259 · 5.58 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is a heterogeneous chronic immune-mediated inflammatory disease, associated with significant morbidity and reduced life expectancy. Here, we review recent discoveries; particularly those which have attempted to integrate genome-wide association studies (GWAS) with biological pathways and cell types known to play a role in disease pathology in order to expand our current understanding of the pathogenesis of RA. As the role of stromal cells in the pathogenesis of RA has been reviewed in detail in Current Opinions in Rheumatology, this area will not be covered in this review. Although our understandings of the pathogenic processes that drive disease in RA remain incomplete, remarkable advances over the past year can be highlighted. GWAS have raised awareness of important new risk loci with genes that either are the targets of approved therapies for RA, or involve pathways for drugs that could be repurposed from other disease indications such as cancer. Furthermore, promising strides have been made in predicting the likelihood of developing RA in those at risk using human leukocyte antigen (HLA), smoking, and autoantibody status prediction models. These findings give a fresh insight into RA pathogenesis and help identify new, or repurpose known therapeutic targets from other disease areas. The findings discussed in this review underscore the progress made to date and the need for future studies, investigating disease mechanisms in RA, with particular interest in at-risk RA gene loci, their function in immune and stromal cells within the synovium, and how they interact with environmental factors to initiate and perpetuate disease.
    Current Opinion in Rheumatology 03/2015; 27(3). DOI:10.1097/BOR.0000000000000174 · 5.07 Impact Factor
  • Karim Raza, Andrew Filer
    Annals of the Rheumatic Diseases 03/2015; 74(5). DOI:10.1136/annrheumdis-2014-206993 · 10.38 Impact Factor
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    ABSTRACT: For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis CONCLUSIONS: Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the Rheumatic Diseases 03/2015; DOI:10.1136/annrheumdis-2014-206921 · 10.38 Impact Factor
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    ABSTRACT: To explore how social interactions at the onset of rheumatoid arthritis (RA) influence help-seeking behaviour from the perspectives of those with RA and their significant others (family and friends). Nineteen semi-structured qualitative interviews were undertaken with people recently diagnosed with RA and their significant others. Interviews were audio-recorded, transcribed verbatim and analysed using thematic analysis. Significant others' initial appraisals of symptoms led them to provide practical support with daily activities rather than advice to seek help. People with RA described difficulties in communicating the severity of their symptoms and often attempted to hide their symptoms from others. Significant others also reacted negatively, expressing disbelief and dismissing symptoms. On occasion, early symptoms were even described as the catalyst for the breakdown of relationships. On reflection, significant others expressed guilt about their initial reactions and wished that they had recognized the need for intervention earlier. When symptoms had advanced and were more obvious, significant others often strongly advised that help should be sought and, in some cases, physically escorted the patient to their medical appointment. In many instances, people with RA described significant others as the catalyst for eventually seeking help. Significant others play an important role in influencing help-seeking behaviour; this has implications for theoretical models of help-seeking and the development of help-seeking interventions. A negative consequence of social interactions resulted from a lack of understanding and knowledge about RA among significant others, highlighting the need for greater public awareness about the early symptoms of RA. Statement of contribution What is already known on this subject? At the onset of rheumatoid arthritis (RA) people often delay in seeking help, leading to poor clinical outcomes. Previous research has highlighted the role of personal interpretations of symptoms in help seeking. However, little is known about the social context of help-seeking decisions and role of social networks in influencing help-seeking behaviour. What this study adds? This study highlights the importance of social interactions at the onset on RA from multiple perspectives (i.e., those with RA, their family and friends) Family and friends played a critical role at symptom onset, and help-seeking was found to be both facilitated and hindered by social networks. It is vital that help-seeking campaigns and theoretical models give more weight to the role of social interactions in encouraging help-seeking behaviour. © 2015 The British Psychological Society.
    British Journal of Health Psychology 02/2015; DOI:10.1111/bjhp.12134 · 2.70 Impact Factor
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    ABSTRACT: Background and objectives We have recently identified a subset of pro-inflammatory memory B cells in RA synovial fluid and tissue, characterised by the expression of Fc receptor-like 4 (FcRL4). These cells produce RANKL, and express high levels of TNFα mRNA, indicating a destructive, pro-inflammatory role. Their immunophenoptype suggest that they are activated B cells; however, they show no signs of differentiation towards plasmablasts, suggesting that their functional role does not involve antibody production. The aim of this project was to investigate the characteristics of their immunoglobulin genes and determine whether their B cell receptors recognise autoantigens.
    Annals of the Rheumatic Diseases 02/2015; 74(Suppl 1):A11-A11. DOI:10.1136/annrheumdis-2015-207259.26 · 10.38 Impact Factor
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    ABSTRACT: Objectives Fibroblasts have been shown to actively regulate the inflammatory infiltrate that accumulates within synovial joints. On way they achieve their effects in part by conversing with neighbouring vascular endothelial cells imparting a stromal “address code” that regulates leukocyte recruitment. Here we compared the ability of synovial fibroblasts from resolving arthritis and very early RA to communicate with vascular endothelial cells (EC).
    Annals of the Rheumatic Diseases 02/2015; 74(Suppl 1):A57-A57. DOI:10.1136/annrheumdis-2015-207259.132 · 10.38 Impact Factor
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    ABSTRACT: Treating patients with rheumatoid arthritis (RA) within 3 months of symptom onset leads to significantly improved clinical outcomes. However, many people with RA symptoms wait a long time before seeking medical attention. To develop effective health interventions to encourage people to seek help early, it is important to understand what the general public knows about RA, how they would react to the symptoms of RA, and what might delay help-seeking. Qualitative interviews were conducted with 38 members of the general public (32 women) without any form of inflammatory arthritis about their perceptions of RA symptoms and decisions to seek help were they to experience such symptoms. The interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis. A number of barriers and drivers to help-seeking were identified and grouped into 5 themes: perceived causes of symptoms; factors related to presentation, location, and experience of symptoms; perceived effect of symptoms on daily life; self-management of symptoms; and general practitioner-related drivers and barriers. To our knowledge, our study is the first to investigate barriers to and drivers of help-seeking in response to the onset of RA symptoms in individuals without a diagnosis of RA. It has revealed a number of additional factors (e.g., the importance of the location of the symptoms) besides those previously identified in retrospective studies of patients with RA. Together with the data from previous research, these findings will help inform future health interventions aimed at increasing knowledge of RA and encouraging help-seeking.
    The Journal of Rheumatology 02/2015; 42(4). DOI:10.3899/jrheum.140913 · 3.17 Impact Factor
  • Immunology 12/2014; 143:57-57. · 3.74 Impact Factor
  • Immunology 12/2014; 143:130-131. · 3.74 Impact Factor
  • Immunology 12/2014; 143:143-143. · 3.74 Impact Factor
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    ABSTRACT: The immune suppressive protein CTLA-4 is constitutively expressed by Tregs and induced in effector T cells upon activation. Its crucial role in adaptive immunity is apparent from the fatal autoimmune pathology seen in CTLA-4 knockout mice. However, little is known regarding factors that regulate CTLA-4 expression and their effect upon its function to remove CD80 and CD86 from antigen presenting cells by transendocytosis. Th17 cells are emerging as significant players in autoimmunity as well as other diseases. Therefore, in this study we have examined the effects of Th17 polarising conditions on CTLA-4 expression and function in human T cells and show that Th17 conditions can suppress the expression of CTLA-4 and its transendocytic function. In contrast to Th17 cells, vitamin D is inversely associated with autoimmune disease. We have previously shown a striking ability of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to enhance CTLA-4, however, its effects upon B7 transendocytosis and its activity in the context of inflammation remained unknown. Here we show that induction of CTLA-4 by 1,25(OH)2D3 can actually be enhanced in the presence of Th17 polarising cytokines. Furthermore, its transendocytic function was maintained such that T cells generated in the presence of Th17 conditions and 1,25(OH)2D3 were highly effective at capturing CTLA-4 ligands from antigen presenting cells and suppressing T cell division. Taken together, these data reveal an inhibitory effect of Th17 polarising conditions upon CTLA-4-mediated regulation and show that 1,25(OH)2D3 counteracts this effect. Given the importance of CTLA-4-mediated suppression in the control of autoimmune diseases, our novel data highlight the importance of vitamin D in inflammatory settings.
    Immunology 12/2014; 143(7):142-142. DOI:10.1371/journal.pone.0131539 · 3.74 Impact Factor
  • Karim Raza, Danielle M. Gerlag
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    ABSTRACT: Chronic inflammatory and autoimmune conditions result from an interplay between genetic and environmental factors culminating in the phenotypes of established disease. The transition from health to established disease is relatively well understood in rheumatoid arthritis (RA), which provides an exemplar for other diseases. This article addresses terminologies to describe the phases of disease leading to RA, disease initiation and the point from which disease duration should be timed, the future research agenda suggested by this approach to the definition of phases of disease, and the importance of capturing the patient perspective in research into the earliest phases of disease. Copyright © 2014 Elsevier Inc. All rights reserved.
    Rheumatic Disease Clinics of North America 11/2014; 40(4). DOI:10.1016/j.rdc.2014.07.001 · 1.74 Impact Factor
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    ABSTRACT: To examine the diagnostic outcomes associated with clinical ankle synovitis in an early inflammatory arthritis cohort.
    Clinical and experimental rheumatology 07/2014; · 2.97 Impact Factor
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):1191-1191. DOI:10.1136/annrheumdis-2014-eular.4424 · 10.38 Impact Factor

Publication Stats

3k Citations
913.21 Total Impact Points

Institutions

  • 2015
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia
  • 2008–2015
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 2006–2015
    • Sandwell and West Birmingham Hospitals NHS Trust
      Birmingham, England, United Kingdom
  • 2002–2015
    • University of Birmingham
      • • School of Immunity and Infection
      • • Institute for Biomedical Research
      • • MRC Centre for Immune Regulation
      Birmingham, England, United Kingdom
  • 2012
    • Keele University
      Newcastle-under-Lyme, England, United Kingdom
  • 1998
    • The Dudley Group NHS Foundation Trust
      Dudley, England, United Kingdom