Objectives To investigate metabolic features that may predispose to GCA in a nested case–control study. Methods Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Preventive Medicine Project; N = 33 346) were identified and validated through a structured review of medical records. Four controls for every validated case were selected from the database. Results A total of 76 cases with a confirmed incident diagnosis of GCA (61% female, 65% biopsy positive, mean age at diagnosis 70 years) were identified. The median time from screening to diagnosis was 20.7 years (range 3.0–32.1). Cases had significantly lower fasting blood glucose (FBG) at baseline screening compared with controls [mean 4.7 vs 5.1 mmol/l (s.d. overall 1.5), odds ratio (OR) 0.35 per mmol/l (95% CI 0.17, 0.71)] and the association remained significant when adjusted for smoking [OR 0.33 per mmol/l (95% CI 0.16, 0.68)]. Current smokers had a reduced risk of GCA [OR 0.35 (95% CI 0.18, 0.70)]. Both cholesterol [mean 5.6 vs 6.0 mmol/l (s.d. overall 1.0)] and triglyceride levels [median 1.0 vs 1.2 mmol/l (s.d. overall 0.8)] were lower among the cases at baseline screening, with significant negative associations with subsequent GCA in crude and smoking-adjusted models [OR 0.62 per mmol/l (95% CI 0.43, 0.90) for cholesterol; 0.46 per mmol/l (95% CI 0.27, 0.81) for triglycerides]. Conclusion Development of GCA was associated with lower FBG and lower cholesterol and triglyceride levels at baseline, all adjusted for current smoking, suggesting that metabolic features predispose to GCA.
Objective To investigate the relation between biomarkers of inflammation and subsequent development of giant cell arteritis (GCA). Method Participants in the population-based Malmö Diet Cancer Study (MDCS; N = 30447), established 1991–1996, who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth, and year of screening were selected from the study cohort. Baseline plasma samples were analyzed using the antibody-based OLINK proteomics inflammation panel (92 inflammatory proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on Eigenvalues, proteins with a factor loading of > 0.50 were investigated. Results 94 cases with a confirmed incident diagnosis of GCA (median 11.9 years after inclusion) were identified. Among biomarkers with a priori hypotheses, IFN-γ was positively associated with GCA (odds ratio (OR) per SD 1.52; 95% CI 1.00–2.30). Eight biomarkers in the hypothesis-generating analyses were significantly associated with development of GCA. Among these, higher levels of IFN-γ (OR 2.37; 95% CI 1.14–4.92) and MCP3 (OR 4.27; 95% CI 1.26–14.53) were particularly associated with increased risk of GCA in the subset sampled <8.5 years before diagnosis. Several other proteins known to be important for T cell function were also associated with GCA in these analyses, e.g. CXCL9, IL-2, CD40 and CCL25. Conclusion Elevated IFN-γ levels were found years prior to diagnosis of GCA. T cell activation may precede the clinical onset of GCA.
ObjectiveTo assess the frequency of comorbidities and metabolic risk factors at and prior to GCA diagnosis.MethodsRetrospective case-control study of patients with incident GCA between 1/1/2000 and 12/31/2019 in Olmsted County, MN. Two age- and sex-matched controls were identified, and each assigned an index date corresponding to an incidence date of GCA. Medical records were manually abstracted for comorbidities and laboratory data at incidence date, 5-years, and 10-years prior to incidence date. Twenty-five chronic conditions using ICD-9 diagnosis codes were also studied at incidence date and 5 years prior to incidence date.Results129 patients with GCA (74% female) and 253 controls were identified. At incidence date, the prevalence of diabetes mellitus (DM) was lower among GCA patients (5% vs 17%; p=0.001). At 5 years prior to incidence date, patients were less likely to have DM (2% vs 13%; p<0.001) and hypertension (27% vs 45%; p=0.002) and had a lower mean number (SD) of comorbidities [0.7 (1.0) vs [1.3 (1.4)] (p<0.001)] compared to controls. Moreover, patients had significantly lower median fasting blood glucose (FBG) (96 vs 104 mg/dL; p <0.001) and body mass index (BMI) (25.8 vs 27.7 kg/m2p=0.018) compared to controls. Multivariable logistic regression analysis revealed negative associations for FBG with GCA at 5 and 10 years prior to diagnosis/index date.ConclusionDM prevalence and median FBG and BMI were lower in patients with GCA up to 5 years prior to diagnosis, suggesting that metabolic factors influence the risk of GCA.
BackgroundIncident cases of of giant cell arteritis (GCA) have a significantly reduced prevalence of diabetes at time of diagnosis (1) and lower fasting blood glucose, lipid levels and body mass index compared to controls have been found years before clinical diagnosis [2,3]. This implicates metabolic pathways in the development of GCA.ObjectivesTo investigate the relation between plasma proteins associated with metabolism and subsequent development of GCA.MethodsParticipants in a population-based survey (N=30447), who were subsequently diagnosed with GCA, were identified in a structured process. GCA-free controls, matched for sex, year of birth, and year of screening were selected from the study cohort. Baseline plasma samples were analyzed using the antibody-based OLINK proteomics metabolism panel (92 proteins). Analyses were pre-designated as hypothesis-driven or hypothesis-generating. In the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome.ResultsThere were 95 cases with a confirmed incident diagnosis of GCA (median 11.4 years after inclusion). Among biomarkers with a priori hypotheses, Adhesion G protein-coupled receptor E2 (ADGRE2) was positively associated and Fructose-1,6-bisphosphatase 1 (FBP1) negatively associated with subsequent GCA (Table 1). In particular, ADGRE2 levels were elevated compared to controls in the subset sampled <8.5 years before diagnosis (Table 1). For meteorin-like protein (Metrnl), the highest impact on the risk of GCA was observed in those sampled closest to diagnosis, with a decreasing trend with longer time to GCA (p=0.03). In the hypothesis generating analyses, elevated levels of receptor tyrosine-like orphan receptor 1 (ROR1) were associated with subsequent GCA.ConclusionOur results indicate that changes in levels of plasma proteins that have regulatory effects on the immune system might precede clinical onset of GCA by many years. Among the biomarkers found to be predictive of subsequent GCA, both Metrnl and ADGRE2 are associated with macrophage activation. ROR1 mediated activation of NFkB may be relevant in this context. The negative association with FBP1, which is a rate-controlling enzyme in the gluconeogenic pathway, is compatible with a protective role for glucose metabolites.References[1]Ungpresart P et al. Mod Rheumatol. 2016;26(3):410-4[2]Wadström K et al. Rheumatology (Oxford) 2020;59(11):3229-36[3]Jakobsson K et al. Rheumatology (Oxford) 2015;54(3):433-40Table 1.Potential biomarkers of subsequent giant cell arteritis, from a priori hypotheses. Overall and stratified for time from screening to diagnosis.AllQuartile 1(0.3-8.5 years)(N*=45)Quartile 2(8.50-12.0 years) (N*=49)Quartile 3(12.0-15.5 years) (N*=46)Quartile 4(15.5-19.1 years) (N*=48)OR (CI)OR (CI)OR (CI)OR (CI)OR (CI)P for trendMETRNL1.42 (0.90-2.23)2.40 (0.98-5.85)3.13 (0.92-10.63)0.90 (0.38-2.15)0.74 (0.29-1.89)0.03FBP10.59 (0.35-0.99)0.29 (0.06-1.39)0.84 (0.43-1.65)1.13 (0.38-3.30)0.09 (0.02-0.48)0.24GAL0.98 (0.66-1.45)2.32 (0.83-6.51)0.65 (0.29-1.49)0.38 (0.15-0.97)2.17 (0.92-5.13)0.98GHRL0.83 (0.55-1.25)1.20 (0.52-2.78)1.38 (0.66-2.88)0.39 (0.16-0.96)0.55 (0.20-1.48)0.06ADGRE21.67 (1.08-2.57)3.91 (1.45-10.60)1.17 (0.52-2.64)0.94 (0.44-2.00)2.90 (0.83-10.16)0.26NECTIN21.33 (0.88-2.01)1.47 (0.66-3.32)1.64 (0.71-3.82)1.40 (0.63-3.11)0.84 (0.34-2.09)0.38*Total of cases and controlsConditional logistic regression analysis of biomarkers with a priori hypothesis. Odds ratios (OR) per standard deviation with 95 % confidence intervals (CI).Acknowledgements:NIL.Disclosure of InterestsKarin Wadström: None declared, Lennart T.H. Jacobsson Consultant of: personal fees from from Novartis, Eli-Lily and Janssen, Aladdin J Mohammad: None declared, Kenneth J Warrington Consultant of: personal fees from Chemocentryx, Grant/research support from: Support from Eli-Lilly, GSK and Kiniksa to the Mayo Clinic for clinical trials, Eric Matteson Consultant of: UpToDate, Magnus Jakobsson: None declared, Carl Turesson Speakers bureau: AbbVie, BMS, Nordic Drugs, Pfizer och Roche, Consultant of: Roche, Grant/research support from: research grant paid to Lund University from Bristol Myers-Squibb.
Background: Giant cell arteritis (GCA) is a systemic disease with extensive vascular involvement. There is limited and conflicting information on the relation between patient characteristics at diagnosis and future disease phenotypes. We aimed to investigate predictors of time dependent large vessel involvement (LVI) in a population-based cohort of patients with GCA. Methods: GCA patients with positive temporal artery biopsies (TAB) between 1997and 2010 were identified through a regional pathology register. A structured review of histopathology reports and relevant imaging studies was performed. Cases with LVI through July 2016 were identified. Patients were followed to first LVI, death, migration from the area or July 29, 2016. Event free survival by clinical and histopathologic features was estimated using the Kaplan-Meier method. Potential predictors of LVI were examined using Cox regression models.Results: A total of 274 patients were included. The mean age at GCA diagnosis was 75.7 years. Fifty-one patients (19 %) had documented LVI during the follow-up, corresponding to an incidence rate of 2.4/100 person-years. The median time from GCA diagnosis to the diagnosis of LVI was 4.5 years (interquartile range 0.6-7.4). Thirty-four patients had aortic involvement (67% of those with LVI; 12% of all GCA cases). Survival free of LVI was longer in patients with giant cells in the TAB (75th percentile 14.0 vs 6.7 years; p=0.014). In age-adjusted analysis, the presence of giant cells in the TAB was associated with reduced risk of LVI (hazard ratio 0.48; 95 % confidence interval 0.27-0.86). Conclusions: The negative association with giant cells in the TAB suggests that patients with LVI constitute a subset of GCA with particular disease mechanisms. This underlines the heterogeneity of GCA, which should be further explored in prospective studies.
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