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- Gerlag, Danielle M., et al.
(författare)
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EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis : report from the Study Group for Risk Factors for Rheumatoid Arthritis
- 2012
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 71:5, s. 638-641
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Tidskriftsartikel (refereegranskat)abstract
- The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix 'pre-RA with:' could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.
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| 2. |
- Hermansson, Monika, et al.
(författare)
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MS analysis of rheumatoid arthritic synovial tissue identifies specific citrullination sites on fibrinogen.
- 2010
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Ingår i: Proteomics - Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 4:5, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Citrullination is a post-translational modification of arginine residues to citrulline catalyzed by peptidyl arginine deiminases. Induced expression of citrullinated proteins are frequently detected in various inflammatory states including arthritis; however, direct detection of citrullination in arthritic samples has not been successfully performed in the past. Experimental design Citrullination of human fibrinogen, a candidate autoantigen in arthritis, was studied. Accurate identification of citrullinated fibrinogen peptides from rheumatoid arthritis synovial tissue specimens was performed using accurate mass and retention time analysis. Results A peptide with the sequence ESSSHHPGIAEFPSRGK corresponding to amino acids 559-575 of fibrinogen a-chain was identified to be citrullinated with an occupancy rate between 1.4 and 2.5%. Citrullination of the peptide KREEAPSLRPAPPPISGGGYRARPAK corresponding to amino acids 52-77 of the fibrinogen beta-chain was identified with an occupancy rate of 1.2%. Conclusions and clinical relevance We report a proof of principle study for the identification of citrullinated proteins and within them, identification of citrullination sites and quantification of their occupancies in synovial tissue from rheumatoid arthritis patients using high-resolution MS. Detailed studies on which molecules are citrullinated in arthritis can provide information about their role in immune regulation and serve as novel biomarkers and potentially even as therapeutic targets.
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| 6. |
- Laki, Judit, et al.
(författare)
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Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:7, s. 2078-2084
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Tidskriftsartikel (refereegranskat)abstract
- Objective Production of anticitrullinated protein antibodies (ACPAs) is an important biomarker for rheumatoid arthritis (RA). We undertook this study to determine whether genetic factors (HLADRB1 alleles) are associated with extreme ACPA levels in individuals with ACPA-positive RA, and to ascertain whether there are any phenotypic characteristics associated with these subgroups of RA. Methods HLADRB1 allelic groups were genotyped in 1,073 ACPA-positive RA patients from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. We found that 283 patients (26.4%) had high ACPA levels (defined as >1,500 units/ml using the Euro-Diagnostica anti-CCP2 test), while the rest of the patients had moderate ACPA levels and served as the comparison group. A replication group consisted of 235 RA patients. Results No significant differences in baseline disease activity were observed between patients with high and those with moderate ACPA levels. However, the HLADRB1*15 allele was associated with high ACPA levels (P = 0.0002). A similar trend was detected in HLADRB1*15positive patients in the replication cohort, with meta-analysis of the discovery and replication cohorts demonstrating an overall effect of HLADRB1*15 on development of high ACPA levels in both the discovery and replication cohorts (P < 0.0001 by Mantel-Haenszel test with a fixed-effects model). Conclusion Our data indicate that HLADRB1*15 may promote the production of high ACPA levels. Due to the high value of ACPA level scores in the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA, the presence of HLADRB1*15 may, at least in part, contribute to fulfilling the criteria for RA. This illustrates the complex nature of the genetic regulation of ACPA levels. Additional mechanistic studies of the regulation of ACPAs and ACPA-positive RA are pending.
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| 7. |
- Lindberg, Johan, et al.
(författare)
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The Gene Expression Profile in the Synovium as a Predictor of the Clinical Response to Infliximab Treatment in Rheumatoid Arthritis
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:6, s. e11310-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although the use of TNF inhibitors has fundamentally changed the way rheumatoid arthritis (RA) is treated, not all patients respond well. It is desirable to facilitate the identification of responding and non-responding patients prior to treatment, not only to avoid unnecessary treatment but also for financial reasons. In this work we have investigated the transcriptional profile of synovial tissue sampled from RA patients before anti-TNF treatment with the aim to identify biomarkers predictive of response. Methodology/Principal Findings: Synovial tissue samples were obtained by arthroscopy from 62 RA patients before the initiation of infliximab treatment. RNA was extracted and gene expression profiling was performed using an in-house spotted long oligonucleotide array covering 17972 unique genes. Tissue sections were also analyzed by immunohistochemistry to evaluate cell infiltrates. Response to infliximab treatment was assessed according to the EULAR response criteria. The presence of lymphocyte aggregates dominated the expression profiles and a significant overrepresentation of lymphocyte aggregates in good responding patients confounded the analyses. A statistical model was set up to control for the effect of aggregates, but no differences could be identified between responders and non-responders. Subsequently, the patients were split into lymphocyte aggregate positive-and negative patients. No statistically significant differences could be identified except for 38 transcripts associated with differences between good- and non-responders in aggregate positive patients. A profile was identified in these genes that indicated a higher level of metabolism in good responding patients, which indirectly can be connected to increased inflammation. Conclusions/Significance: It is pivotal to account for the presence of lymphoid aggregates when studying gene expression patterns in rheumatoid synovial tissue. In spite of our original hypothesis, the data do not support the notion that microarray analysis of whole synovial biopsy specimens can be used in the context of personalized medicine to identify non-responders to anti-TNF therapy before the initiation of treatment.
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| 8. |
- Neveen, Ahmed, et al.
(författare)
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Impact of Temporomandibular Joint Pain in Rheumatoid Arthritis
- 2013
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Ingår i: Mediators of Inflammation. - : Hindawi Publishing Corporation. - 0962-9351 .- 1466-1861. ; 2013
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the impact of temporomandibular joint (TMJ) pain on daily activities and quality of life in relation to systemic inflammatory activity in patients with rheumatoid arthritis (RA), thirty-three consecutive outpatients with RA were included. TMJ pain intensity at rest, on maximum mouth opening, and on chewing was assessed on a 0–10 numerical rating scale. TMJ palpatory tenderness, degree of anterior open bite, the impact of TMJ pain on daily activities and quality of life were also assessed. The systemic inflammatory activity was estimated by the disease activity score 28 (DAS28), blood levels of inflammatory markers and number of painful musculoskeletal regions. TMJ pain at rest, on maximum mouth opening, and on chewing as well as DAS28 was correlated with the impact of the TMJ pain on daily activities and quality of life. Partial correlations showed a significant interaction between TMJ pain on movement and DAS28 that explained the TMJ pain impact on daily activities and quality of life to a significant degree. This study indicates that both current TMJ pain intensity and systemic inflammatory activity play roles in the impact of TMJ pain on daily living and quality of life in RA.
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| 9. |
- Ossipova, Elena, et al.
(författare)
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Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint
- 2014
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Ingår i: Arthritis Research & Therapy. - London : BioMed Central (BMC). - 1478-6362 .- 1478-6354. ; 16:4
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A major subset of patients with rheumatoid arthritis (RA) is characterized by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPAs). These autoantibodies, which are commonly detected by using an enzyme-linked immunosorbent assay (ELISA) based on synthetic cyclic citrullinated peptides (CCPs), predict clinical onset and a destructive disease course. In the present study, we have used plasma and synovial fluids from patients with RA, for the affinity purification and characterization of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be used in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPAs that bind to autoantigens expressed in vivo in the major inflammatory lesions of RA (that is, in the rheumatoid joint). METHODS: Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels of above 300 AU/mL. Total IgG was isolated on Protein G columns and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analyzed for reactivity and specificity by using the CCPlus(R) ELISA, in-house peptide ELISAs, Western blot, and immunohisto-/immunocytochemistry. RESULTS: Approximately 2% of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from alpha-enolase, vimentin, fibrinogen, and collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but, more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from patients with RA. CONCLUSIONS: We have isolated ACPAs from plasma and synovial fluid and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISAs, de facto act as surrogate antigens for at least four different, well-characterized, largely non-cross-reactive, ACPA fine specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPAs can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs. © 2014 Ossipova et al.; licensee BioMed Central Ltd.
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| 10. |
- Raza, Karim, et al.
(författare)
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Delays in assessment of patients with rheumatoid arthritis: variations across Europe
- 2011
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ. - 1468-2060 .- 0003-4967. ; 70:10, s. 1822-1825
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Tidskriftsartikel (refereegranskat)abstract
- Objective The first 3 months after symptom onset represent an important therapeutic window for rheumatoid arthritis (RA). This study investigates the extent and causes of delay in assessment of patients with RA in eight European countries. Method Data on the following levels of delay were collected from 10 centres (Berlin, Birmingham, Heraklion, Lund, Prague, Stockholm, Umea, Vienna, Warsaw and Zurich): (1) from onset of RA symptoms to request to see healthcare professional (HCP); (2) from request to see HCP to assessment by that HCP; (3) from initial assessment by HCP to referral to rheumatologist; and (4) from referral to rheumatologist to assessment by that rheumatologist. Results Data were collected from 482 patients with RA. The median delay across the 10 centres from symptom onset to assessment by the rheumatologist was 24 weeks, with the percentage of patients seen within 12 weeks of symptom onset ranging from 8% to 42%. There were important differences in the levels underlying the total delays at individual centres. Conclusions This research highlights the contribution of patients, professionals and health systems to treatment delay for patients with RA in Europe. Although some centres have strengths in minimising certain types of delay, interventions are required in all centres to ensure timely treatment for patients.
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