Age plays a crucial role in crystal arthritis severity: a synovial fluid study
B. Ankli (1), Mb. Bigler (2), Ct. Berger (2,3), T. Daikeler (1)
Affiliation(s):
1. University Hospital Basel, Department of Rheumatology,
2. Department of Biomedicine, Translational immunology,
3 Medical Outpatient Clinic
Background: Incidence and severity of gout and calcium pyrophosphate deposition disease (CPPD)increase with age [1]. Aging is associated with immune senescence, leading to a deregulation of the innate immune system and hence inflammation [2]. MRI studies hinted on a significantly higher synovial inflammation in older compared to younger arthritis patients [3]. Whether inflammatory responses to synovial crystals are more pronounced in elderly patients or not is unknown.
Objectives: To test the hypothesis whether aging associates with a more pronounced synovial inflammation in response to urate and CPP crystals.
Methods: Gout or CPPD patients with a synovial fluid (SF) aspiration were included. Clinical, blood and synovial parameters were recorded. In the Cytokine study, SF was analyzed for interleukin (IL)-1-beta, IL-6, IL-8, IL-10, IL-12p70, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), IL-17, and transforming growth factor-beta (TGF-beta) by multiplexed cytokine analysis. In the Cell study, SF samples were immunophenotyped by flow cytometry, including surface markers CD4+ (CD3+), CD8+ (CD3+), and following stimulation for intracellular IFN-gamma and IL-17. The patients were divided into two groups by age median-split. Statistical analysis Categorical variables were reported as frequencies. Continuous variables were compared using Student’s t-test or in case of non-normal distribution Mann-Whitney U test.
Results: Cytokine study; Median C-reactive (CRP), SUA levels and synovial cell counts were higher in the older patient group. Serum creatinine levels were similar between the two groups. Synovial IL-1-beta, IL-8, and IL-17 levels were significantly higher in the older subjects. Age was correlated with SF IL-1-beta (r=0.62, p=0.02), IL-17 (r=0.63, p=0.04) and IL-8 (r=0.54, p=0.04) levels. Cell study; Median CRP was higher in older patients: 87 mg/l (IQR 65; 115) vs. 20 mg/l (IQR 7; 65, p=0.0129). Although not significant, a higher frequency of total Th17 (both CD4+IL17+ and CD8+IL17+) T-cells were seen in the SF of the older patient group. The remaining T-cell subsets were comparable between the two groups.
Conclusion: Gout and CPPD are paradigms for auto-inflammatory diseases. We here show an important autoinflammation enhancing cofactor: age. Inflammation measured as serum CRP, SF-IL-8, SF-IL-1-beta, and SF-IL-17 was pronounced in the older patients. Moreover, the adaptive immune system with a predominant Th-17 immune response was more prominent in the older patient group. High IL-17 concentrations may promote differentiation of T-cells in Th-17 cells and thus perpetuate inflammation in older patients with crystal arthritis [4].
References: 1. Kuo C-F, Grainge MJ, Zhang W, Doherty M. Global epidemiology of gout: prevalence, incidence and risk factors. Nat Rev Rheumatol 2015;11:649-62. 2. Goronzy JJ, Weyand CM. Immune aging and autoimmunity. Cell Mol Life Sci 2012;69:1615-23. 3. Nieuwenhuis WP, Mangnus L, van Steenbergen HW, Newsum EC, Huizinga TWJ, Reijnierse M, et al. Older age is associated with more MRI-detected inflammation in hand and foot joints. Rheumatology 2016;55:2212-9. 4. Eleftheriadis T, Pissas G, Sounidaki M, Antoniadi G, Tsialtas I, Liakopoulos V, et al. Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation. Biomed Rep 2017;7:365-9.
