Rheumatology Advance Access published March 31, 2015

RHEUMATOLOGY

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Letter to the Editor (other)

Good response to tumour necrosis factor alpha blockade results in an angiogenic T cell recovery in rheumatoid arthritis patients

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SIR, The increased cardiovascular (CV) morbidity of RA is associated with disease activity and the underlying inflammatory burden [1], although the actual mechanisms by which they play a role in CV susceptibility remain unclear. It has been proposed that angiogenic T cells (Tang), in cooperation with endothelial progenitor cells (EPCs), play a role in vascular repair. However, both populations are decreased in the circulation of RA patients, Tang being strongly related to disease activity [2]. Actually, disease activity may have a role in microparticle shedding from Tang, thereby suggesting a detrimental role for disease activity in this subset [3] that could potentially account for the decreased Tang levels in RA. Therefore, we aimed to analyse the effect of clinical response to TNFa-blockade on circulating Tang, EPCs and Tangderived microparticles (Tang-MPs). A total of 13 RA patients naive to TNFa blockers were longitudinally recruited [age: 48 (range 32–65) years, 1 man and 12 women, disease duration 1.50 (range 1.00–7.17) years, 5 RF+, 6 anti-CCP+, 3 active smokers], and a blood sample was taken immediately before as well as 3 months after anti-TNFa therapy (11 golimumab and 2 etanercept). All patients were on concomitant MTX, and 10 (76.9%) were also on low-dose glucocorticoid therapy. Clinical and immunological parameters and fasting lipid analysis were assessed at each patient visit. Clinical response was determined following the EULAR criteria [4]. EPCs (CD34+VEGFR2+CD133+), Tang (CD3+CD31+CXCR4+) and Tang-MPs were analysed by flow cytometry, as previously described [2, 3]. Serum TNFa, VEGF, IL-8, leptin and stromal cell-derived factor 1 (SDF-1a) levels were measured by immunoassays. A total of 33 healthy individuals [age: 49 (range 35–59) years, 11 men and 22 women] were used as healthy controls (HCs) (supplementary Table S1, available at Rheumatology Online). Differences were assessed by paired tests, and Hedges’ g statistic was calculated to measure size effect (g > 0.8 was considered as a large effect) [5]. Data were expressed as mean (interquartile range) or median (S.D.) as appropriate. Our study had a calculated power of 0.95 with a = 0.05. Approval from the local ethics committee (Comite´ de E´tica de Investigacio´n Clı´nica del Principado de Asturias) was obtained. Written informed consent was obtained from all participants. Both Tang [4.03 (5.22) vs 7.57 (8.85)  103 cells/ml, P = 0.002; g = 0.82] and EPC [0.007 (0.021) vs 0.034 (0.024)  103 cells/ml, P = 0.005; g = 1.72] populations increased after anti-TNFa therapy. However, whereas Tang reached levels similar to those found in HCs

[10.37 (7.14), P = 0.522], EPCs remained below normal levels [0.052 (0.039), P = 0.030]. The DAS28 score was significantly decreased after 3 months [4.05 (1.98) vs 5.15 (1.74), P < 0.001]. Moreover, the DAS28 score improvement paralleled Tang increase after treatment (r = 0.676, P = 0.011), but not that of EPC (r = 0.225, P = 0.449). Multivariate analysis adjusted by MTX and glucocorticoid dosages and smoking habit revealed that DAS28 improvement was the only predictor of Tang increase [b = 0.906 (95% CI 1.811, 0.001); P = 0.050], thereby highlighting the dependence of Tang on disease activity, and excluding the potential effects of concomitant DMARDs. Additionally, Tang frequency after treatment was related to traditional CV risk factors (total-cholesterol/ HDL ratio: r = 0.629, P = 0.028), as has been reported in HCs [3], but not at baseline (P = 0.236). Similar findings were observed with EPCs (baseline: r = 0.484, P = 0.131; after therapy: r = 0.741, P = 0.006), suggesting that disease activity control is a crucial step that should be targeted as aggressively as possible as part of the RA clinical routine. Further analysis of patients according to clinical response, showed a greater Tang increase after treatment in good responders (n = 5) compared with moderate/ non-responders (n = 8) [5.83 (5.32) vs 2.50 (2.42)  103 cells/ml, P = 0.030; g = 0.96]. In fact, whereas good responders reached Tang values similar to those of HCs [11.47 (11.98) vs 10.37 (7.14)  103 cells/ml, P = 0.598], a trend to a lower frequency was detected in moderate/ non-responders [6.24 (7.55), P = 0.115] (Fig. 1). Moreover, only good responders displayed a parallel increase in Tang and EPCs (correlation between the change in both populations: r = 0.900, P = 0.037), suggesting a more favourable pattern of vascular repair in these patients through cooperation between the two involved populations. Analysis of serum biomarkers revealed that TNFa blockade was associated with decreasing VEGF [122.84 (41.87) vs 105.76 (32.60) pg/ml, P = 0.002] leptin [16.07 (10.94) vs 13.58 (9.45) ng/ml, P = 0.014] and SDF1a levels [5.09 (5.33) vs 3.49 (4.67) ng/ml, P = 0.002] in the whole group, whereas IL-8 and TNFa were only reduced in good responders [TNFa: 451.05 ( 265.98) vs 150.14 (153.47) pg/ml, P = 0.045; IL-8: 43.41( 6.92) vs 33.84 (3.78) pg/ml, P = 0.040]. Interestingly, the decrease in TNFa levels paralleled EPC recovery (r = 0.900, P = 0.036), whereas that of leptin paralleled a decrease in EPCs (r = 0.850, P = 0.050) and Tang (r = 0.850, P = 0.050), thus suggesting that tighter control of inflammatory and vascular-related mediators is associated with better Tang and EPC recovery. Finally, Tang-MP shedding was decreased after TNFa blockade in all patients [3929.91 (9374.93) vs 7859.83 (9798.62) MP/ml, P = 0.021; g = 0.60], but to a greater

L ET T E R

doi:10.1093/rheumatology/kev025

Letter to the Editor

FIG. 1 Tang and EPC recovery after anti-TNFa therapy

extent in good responders [280.70 (1038.62) MP/ml, P = 0.006; g = 2.36), in line with the greater Tang-recovery in this group. In summary, our results confirm that disease activity control is responsible for the Tang recovery in RA patients undergoing TNFa blockade therapy. Additionally, lower Tang-MP shedding supports this hypothesis. This mechanism could underlie the clinical benefit of TNFa blockers on CV endpoints, which is dependent on clinical response [6, 7] and therefore on disease activity, a parameter closely related to the maintenance of this population [2]. Although total EPC recovery after anti-TNFa therapy has been reported [8], technical and clinical differences between the two studies should be noted. However, larger studies are needed to confirm these findings.

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Supplementary data Supplementary data are available at Rheumatology Online.

Javier Rodrı´guez-Carrio1, Mercedes Alperi-Lo´pez2, Patricia Lo´pez1, Francisco J. Ballina-Garcı´a2 and Ana Sua´rez1 1 Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo and 2Department of Rheumatology, Hospital Universitario Central de Asturias, Oviedo, Spain Revised version accepted 4 February 2015 Correspondence to: Ana Sua´rez, Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Campus El Cristo, C/ Julia´n Claverı´a s/n, 33006 Oviedo, Spain. E-mail: [email protected]

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References

Good response to TNFa-blockers leads to an angiogenic T-cell recovery in RA.

1 Innala L, Moller B, Ljung L et al. Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study. Arthritis Res Ther 2011;13:R131.

Acknowledgements J.R.-C. is a recipient of a FPU fellowship from the Ministerio de Educacio´n.

2 Rodriguez-Carrio J, Alperi-Lopez M, Lopez P et al. Angiogenic T cells are decreased in rheumatoid arthritis patients. Ann Rheum Dis 2014, doi: 10.1136/annrheumdis-2013-204250.

Funding: This work was supported by European Union FEDER funds and the Fondo de Investigacio´n Sanitaria (FIS, PI12/00523).

3 Rodriguez-Carrio J, Lo´pez P, Alperi-Lopez M et al. Angiogenic T cells and derived microparticles disturbances in rheumatoid arthritis patients. Ann Rheum Dis 2014;73:A33.

Disclosure statement: The authors have declared no conflicts of interest.

4 van Gestel AM, Anderson JJ, van Riel PL et al. ACR and EULAR improvement criteria have comparable validity in

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Patients were grouped by their clinical response according to EULAR criteria, and graphs indicate frequency before (t = 0) and 3 months after (t = 3) anti-TNFa therapy. Each dot represents one patient. Dotted line represents the HC median value (50th percentile). Differences were assessed by paired t-test. Tang: angiogenic T cells; EPCs: endothelial progenitor cells; HCs: healthy controls.

Letter to the Editor

rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology. J Rheumatol 1999;26:705–11. 5 Nakagawa S, Cuthill IC. Effect size, confidence interval and statistical significance: a practical guide for biologists. Biol Rev Camb Philos Soc 2007;82:591–605. 6 Barbhaiya M, Solomon DH. Rheumatoid arthritis and cardiovascular disease: an update on treatment issues. Curr Opin Rheumatol 2013;25:317–24.

7 Dixon WG, Watson KD, Lunt M et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007;56:2905–12. 8 Spinelli FR, Metere A, Barbati C et al. Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis. Mediators Inflamm 2013;2013:537539.

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Good response to tumour necrosis factor alpha blockade results in an angiogenic T cell recovery in rheumatoid arthritis patients.

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