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Lack of funding
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| Name | Class |
|---|---|
| University of Leeds | OTHER |
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Giant Cell Arteritis (GCA) is the most common vasculitis and has significant morbidity in terms of blindness, stroke, and tissue necrosis. It requires protracted treatment with high-dose steroids, and despite this there is a risk of flare during the treatment. Little is known about the initial triggers for the inflammatory process, and there are no good markers of response or relapse. We will study patients referred with suspected GCA to identify important components of the immune response in GCA, and follow them over time to collect evidence of how best to monitor their condition.
Objectives and Study Plan:
Study Purpose:
The purpose of the study is to investigate the underlying immunological processes in GCA and to study the pattern of expression of immune response over time to give us information about how best to monitor GCA.
End Point:
The end point will be the final visit of the final patient.
Milestones:
The project is in 3 phases. In phase 1 (0-2 years) patients will be recruited to fulfil the specified primary and secondary objectives. In phase 2 (0-4 years), these patients will be followed up for a total of 2 years each, or until they are discharged from clinic. In phase 3 (1-5 years), further studies will be defined and tissue and data collected under amended ethics.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| GCA | Patients referred with suspected GCA, whose final diagnosis is GCA | ||
| Not GCA | Patients referred with suspected GCA, whose final diagnosis is another disorder |
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| Measure | Description | Time Frame |
|---|---|---|
| Phenotyping of innate lymphoid cells (ILC) in the arterial wall and blood of patients with GCA | Arterial biopsy tissue and peripheral blood will be collected from patients with suspected GCA. A proportion of these will be diagnosed with GCA and will be the "test" subjects, and a proportion will be diagnosed with other conditions that are not GCA and will be the "controls". We will use immunohistochemistry and immunofluorescence microscopy to locate and phenotype ILC in arterial biopsies. We will use semi-quantitative methods (ie cells per random high powered field) to compare prevalence of ILC in tests and controls. We will also isolate peripheral blood mononuclear cells (PBMCs) from fresh whole blood, and stain the cells to use flow cytometry to quantify and phenotype the ILC. Tests and Controls will be compared using Mann-Whitney statistical testing. | 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| CD70 in GCA | CD70 is a costimulatory molecule which is present for a short time on the surface of activated T cells. CD70 has been studied in other autoimmune conditions such as systemic lupus, where it is involved in generating the self-reactive factors responsible for the disease. It is therefore suggested that it might be involved in the development of another autoimmune vasculitis, GCA. We will quantify and phenotype CD70+ve cells in peripheral blood and biopsies of patients with GCA and in controls. We will also measure the levels of the soluble form of its receptor, CD27, in patients and controls. |
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Inclusion Criteria:
Exclusion Criteria:
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The proposed study will recruit a cohort of eligible patients (predominantly from primary care referrals) suspected by their referring doctor to have new onset of GCA.
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| Name | Affiliation | Role |
|---|---|---|
| Raashid A Luqmani, DM FRCP | University of Oxford | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24189842 | Result | Weyand CM, Goronzy JJ. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol. 2013 Dec;9(12):731-40. doi: 10.1038/nrrheum.2013.161. Epub 2013 Nov 5. | |
| 25592534 | Result | Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015 Jan 15;517(7534):293-301. doi: 10.1038/nature14189. |
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| ID | Term |
|---|---|
| D013700 | Giant Cell Arteritis |
| D014657 | Vasculitis |
| D001327 | Autoimmune Diseases |
| D003240 | Connective Tissue Diseases |
| D011111 | Polymyalgia Rheumatica |
| D009140 | Musculoskeletal Diseases |
| D007154 | Immune System Diseases |
| D012216 | Rheumatic Diseases |
| ID | Term |
|---|---|
| D020293 | Vasculitis, Central Nervous System |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D002561 | Cerebrovascular Disorders |
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Serum Plasma Peripheral Blood Mononuclear Cells Whole blood
| 12 months |
| IL-7 and sIL-7R in GCA | IL-7 is a key cytokine for development of all lymphoid cells, including ILC. Levels of sIL-7R have been linked to active renal disease in systemic lupus, and sIL-7R is suggested as a biomarker of lupus. We will collect serum at several time points from patients with GCA and controls (see primary outcome measures). The level of IL-7 and sIL-7R will be quanitified by Enzyme-linked Immunosorbent Assay (ELISA) and the results plotted as time series. We will analyse the trends of these series to see how useful IL-7 and sIL-7R may be in monitoring GCA. | 36 months |
| Vascular Endothelial Growth Factor (VEGF) levels over time | VEGF is a putative biomarker of GCA. We will collect serum at several time points from patients with GCA and controls (see primary outcome measures). The level of VEGF will be quanitified by Enzyme-linked Immunosorbent Assay (ELISA) and the results plotted as time series. We will analyse the trends of these series to see how useful VEGF may be in monitoring GCA. | 36 months |
| Pentraxin 3 levels over time | Pentraxin 3 is a second biomarker of interest in GCA, and we plan to analyse its expression in peripheral blood as for VEGF. | 36 months |
| Archiving of tissue for future studies | The cohort of patients recruited to this study represents a valuable resource for future ethically-approved studies of the aetiology of GCA. We believe that the majority of patients would like their donations to contribute to as much research as possible. Therefore we will archive tissue in the form of blood fractions and temporal artery biopsy specimens, as well as linking to anonymized clinical and imaging data. It is planned that the study ethics will be amended with novel substudies as they are designed. | 60 months+ |
| 25902790 | Result | Ciccia F, Guggino G, Rizzo A, Saieva L, Peralta S, Giardina A, Cannizzaro A, Sireci G, De Leo G, Alessandro R, Triolo G. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann Rheum Dis. 2015 Sep;74(9):1739-47. doi: 10.1136/annrheumdis-2014-206323. Epub 2015 Apr 22. |
| 19955046 | Result | Kozlowska A, Hrycaj P, Lacki JK, Jagodzinski PP. Fyn and CD70 expression in CD4+ T cells from patients with systemic lupus erythematosus. J Rheumatol. 2010 Jan;37(1):53-9. doi: 10.3899/jrheum.090424. Epub 2009 Dec 1. |
| 25396066 | Result | Lauwerys BR, Husson SN, Maudoux AL, Badot V, Houssiau FA. sIL7R concentrations in the serum reflect disease activity in the lupus kidney. Lupus Sci Med. 2014 Jul 17;1(1):e000036. doi: 10.1136/lupus-2014-000036. eCollection 2014. |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D001167 | Arteritis |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D009135 | Muscular Diseases |