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      Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis—a prospective longitudinal study

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          Abstract

          Objective. To evaluate the association between inflammatory markers and relapse in GCA patients longitudinally assessed in a clinical trial of infliximab and glucocorticosteroids.

          Methods. Forty-four newly diagnosed GCA patients in glucocorticosteroid-induced remission were randomized to receive infliximab 5 mg/kg or placebo plus daily glucocorticosteroids, tapered using a standardized schedule. Sera were analysed for inflammatory markers at multiple, pre-defined time points. Temporal artery biopsies were performed in four patients before and after treatment to analyse changes in inflammatory and vascular remodelling marker expression.

          Results. Thirteen of 44 patients relapsed. Similar proportions of relapsed patients were present in both treatment arms. ESR, CRP, intercellular adhesion molecule (ICAM)-1, TNF-α, and IL-12p40 were significantly elevated near relapse. In post-treatment biopsies, mRNA expression of pro-inflammatory cytokines decreased, while vascular remodelling factors increased relative to baseline biopsies. Tissue IL-12p40 and IFN-γ mRNA remained elevated in relapsing vs remitting patients.

          Conclusion. Despite prior findings of high concentrations of TNF-α in temporal artery biopsies of GCA patients, infliximab plus glucocorticosteroids did not result in improved clinical outcomes. Increased measures of this biomarker did not provide useful insight into the relative importance of TNF-α in the pathogenesis of GCA. Gene expression analysis in paired temporal artery biopsies pre- and post-treatment revealed decreased inflammatory activity and active vascular remodelling following treatment. In relapsing patients, increased expression of IFN-γ and IL-12p40 in post-treatment biopsies suggests a role in sustaining disease and setting the stage for relapse during treatment withdrawal.

          Trial registration. ClinicalTrials.gov; http://www.clinicaltrials.gov; NCT00076726.

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          Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes.

          Anne Proven, Sherine E Gabriel, Carlos Orces … (2003)
          To evaluate the course of glucocorticoid (GC) therapy and associated adverse events in a population-based cohort of patients with giant cell arteritis (GCA). We identified 125 Olmsted County residents with GCA diagnosed between 1950 and 1991 and obtained followup information on the 120 patients who were diagnosed antemortem and agreed to participate in this study. Clinical variables, GC doses, and GC adverse events on each patient were recorded. The relationship between GC therapy and the development of adverse events was studied by the Cox and Anderson-Gill proportional hazards models. All patients were treated with GCs and responded rapidly (median initial dosage 60 mg prednisone/day). The dosage was later reduced according to the treating physicians' judgment. The median duration required to reach 7.5 mg/day was 6.5 months and the median duration required to reach 5 mg/day was 7.5 months. Relapses or recurrences occurred in 57 patients. For the 87 patients followed to discontinuation of GC therapy and permanent remission of GCA (median of 22 months), the total median dose of prednisone was 6.47 gm. Adverse events associated with GCs were recorded in 103 (86%) patients and 2 or more events occurred in 70 patients (58%). Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects. GCs are therapeutically effective in GCA and the prednisone dosage was reduced to physiologic levels in three-fourths of the patients within 1 year. However, most patients developed serious adverse side effects related to GCs, indicating that less toxic therapeutic measures are needed.
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            Tissue production of pro-inflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis.

            J. Hernandez-Rodriguez, M. Segarra, C Vilardell … (2004)
            To investigate proinflammatory cytokine expression in temporal arteries from patients with giant-cell arteritis (GCA) and to analyse its relationship with the intensity of the initial systemic inflammatory reaction and response to corticosteroid therapy. Quantification of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) mRNA by real-time quantitative PCR in temporal artery samples from 36 patients with biopsy-proven GCA and 11 controls. Immunohistochemical detection of IL-1beta, TNFalpha, and IL-6 in temporal artery sections from 74 patients with GCA and 15 controls. Clinical and biochemical parameters of inflammation as well as the time (weeks) required to reach a maintenance prednisone dose <10 mg/day were recorded. IL-1beta (13.8 +/- 2.5 vs 5.4 +/- 1.3 relative units, P = 0.012) and IL-6 transcripts (34 +/- 13.7 vs 7.8 +/- 4.5 relative units, P = 0.034) were significantly more abundant in patients with a strong systemic inflammatory response compared with those with no inflammatory parameters. Immunohistochemical scores for IL-1beta (2.7 +/- 0.3 vs 1.9 +/- 0.2, P = 0.018), TNFalpha (3.2 +/- 0.2 vs 2.4 +/- 0.3, P = 0.028) and IL-6 (3 +/- 0.2 vs 2.1 +/- 0.3, P = 0.023) were also significantly higher in patients with strong systemic inflammatory reaction. A significant correlation was found between the amount of tissue TNFalpha mRNA and the time required to reach a maintenance dose of prednisone <10 mg/day (r = 0.586, P = 0.001). GCA patients with a strong systemic inflammatory response, who have been previously shown to be more resistant to corticosteroid therapy, have elevated tissue expression of proinflammatory cytokines IL-1beta, TNFalpha and IL-6. High production of TNFalpha is associated with longer corticosteroid requirements.
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              Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis.

              J Goronzy, J Björnsson, Cornelia Weyand … (1998)
              To explore whether vasoocclusion in giant cell (temporal) arteritis (GCA) is related to intimal hyperplasia and in situ production of platelet-derived growth factor (PDGF). Temporal artery biopsy specimens from patients with GCA were analyzed for the presence of intimal hyperplasia. Expression of PDGF-A and PDGF-B was assessed by immunohistochemistry and digitized image analysis. PDGF-A and PDGF-B were widely expressed in inflamed arteries. CD68+ macrophages, smooth muscle cells, and multinucleated giant cells produced PDGF, whereas hyperplastic intimal tissue did not. Arteries with marked luminal narrowing and those with no or minimal luminal narrowing differed in the extent and distribution of PDGF expression. Concentric intimal hyperplasia was associated with the accumulation of PDGF-A- and PDGF-B-producing CD68+ macrophages at the media-intima junction. PDGF+,CD68+ macrophages in close proximity to the internal elastic lamina frequently coproduced matrix metalloproteinase 2. Intimal hyperplasia of the temporal artery correlated with ischemic complications of GCA, such as ocular involvement, jaw claudication, and aortic arch syndrome. Production of PDGF has a role in arterial occlusion in GCA. The excessive fibroproliferative response leading to luminal narrowing can be distinguished from the stenosing process in atherosclerosis and postangioplasty restenosis, suggesting that there are different response patterns to arterial injury. In GCA, macrophages at the media-intima border are the dominant source of PDGF. Since vasoocclusion is associated with a number of serious complications in GCA, inhibition of intimal proliferation should be a major goal of treatment.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Rheumatology (Oxford)
                Journal ID (publisher-id): brheum
                Journal ID (hwp): rheumatology
                Title: Rheumatology (Oxford, England)
                Publisher: Oxford University Press
                ISSN (Print): 1462-0324
                ISSN (Electronic): 1462-0332
                Publication date (Print): November 2011
                Publication date (Electronic): 25 August 2011
                Publication date PMC-release: 25 August 2011
                Volume: 50
                Issue: 11
                Pages: 2061-2070
                Affiliations
                1Centocor Research and Development, Malvern, 2School of Medicine, University of Pennsylvania, Philadelphia, PA, 3Cleveland Clinic, Lerner College of Medicine, Cleveland, OH, USA and 4Department of Systemic Autoimmue Diseases, Hospital Clínic, University of Barcelona, IDIBAPS, Barcelona, Spain.
                Author notes
                Correspondence to: Gary S. Hoffman, Harold C. Schott Professor of Rheumatic and Immunologic Diseases, Center for Vasculitis Care and Research, Cleveland Clinic, Lerner College of Medicine, A50, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Email: hoffmag@ 123456ccf.org

                Present addresses: Sudha Visvanathan, Hoffman-La Roche, Nutley, NJ, USA; Mahboob U. Rahman, Pfizer Inc., Collegeville, PA, USA.

                Article
                Publisher ID: ker163
                DOI: 10.1093/rheumatology/ker163
                PMC ID: 3198905
                PubMed ID: 21873264
                SO-VID: c3354c61-1f5e-4e4d-a306-ae87f4373548
                Copyright © © The Author(s) 2011. Published by Oxford University Press on behalf of The British Society for Rheumatology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 13 December 2010
                Date revision received : 21 March 2011
                Page count
                Pages: 10
                Categories
                Subject: Clinical Science

                ScienceOpen disciplines: Rheumatology
                Keywords: relapse,cytokines,remission,serum markers,giant cell arteritis
                Data availability:
                ScienceOpen disciplines: Rheumatology
                Keywords: relapse, cytokines, remission, serum markers, giant cell arteritis

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