Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis.
Journal
Experimental & molecular medicine
ISSN: 2092-6413
Titre abrégé: Exp Mol Med
Pays: United States
ID NLM: 9607880
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
26
02
2020
accepted:
31
03
2020
revised:
29
03
2020
pubmed:
29
5
2020
medline:
31
7
2021
entrez:
29
5
2020
Statut:
ppublish
Résumé
Angiogenesis and synoviocyte hyperplasia, called 'pannus,' are pathologic hallmarks of rheumatoid arthritis (RA). To determine the clinical significance of angiogenic cytokines in RA, the levels of pro-angiogenic cytokines, including VEGF, placenta growth factor (PlGF), and IL-6, were measured in the synovial fluid (SF, n = 54) and sera of RA patients (n = 157) using ELISA. Patients (n = 103) with disease activity score 28 (DAS28) > 3.2, which indicates moderate to high RA activity, underwent follow-up blood sampling at 6 months after treatment with conventional disease-modifying anti-rheumatic drugs (c-DMARD) or biologic DMARD (b-DMARD) including an anti-TNFα antibody, an anti-IL-6 antibody, and abatacept. Ultrasonography (US) was performed on affected joints to define the synovitis severity at the time of sampling. Consequently, in the SF of RA patients, PlGF and IL-6 levels correlated well with synovitis severity determined by US. In RA sera, VEGF and IL-6 levels were elevated in proportion to synovitis severity, correlating with conventional markers for disease activity, including ESR, CRP, and DAS28. In c-DMARD users (n = 53), serially monitored levels of serum VEGF, IL-6, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) all decreased in good and moderate responders but not in nonresponders. In b-DMARD users (n = 49), only serum VEGF well represented the treatment response, while CRP nonspecifically decreased irrespective of the treatment outcome. By multivariable analysis, serum ΔVEGF, but not ΔESR or ΔCRP, was an independent factor associated with good and moderate responses to DMARD. In summary, the angiogenic cytokines PlGF and VEGF represent the synovitis severity of RA assessed by US. In patients receiving b-DMARD, serum VEGF may be more valuable than CRP in reflecting the treatment response.
Identifiants
pubmed: 32461558
doi: 10.1038/s12276-020-0443-8
pii: 10.1038/s12276-020-0443-8
pmc: PMC7272442
doi:
Substances chimiques
Antirheumatic Agents
0
Biological Products
0
Biomarkers
0
Cytokines
0
Inflammation Mediators
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
843-853Subventions
Organisme : National Research Foundation of Korea (NRF)
ID : 2015R1A3A2032927
Pays : International
Organisme : National Research Foundation of Korea (NRF)
ID : 2018R1D1A1B07045491
Pays : International
Références
You, S., Koh, J. H., Leng, L., Kim, W. U. & Bucala, R. The tumor-like phenotype of rheumatoid synovium: molecular profiling and prospects for precision medicine. Arthritis Rheumatol. 70, 637–652 (2018).
pubmed: 29287304
pmcid: 5920713
doi: 10.1002/art.40406
Marrelli, A. et al. Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation? Autoimmun. Rev. 10, 595–598 (2011).
pubmed: 21545851
doi: 10.1016/j.autrev.2011.04.020
Jackson, J. R., Minton, J. A., Ho, M. L., Wei, N. & Winkler, J. D. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J. Rheumatol. 24, 1253–1259 (1997).
pubmed: 9228120
Berse, B. et al. Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin. Exp. Immunol. 115, 176–182 (1999).
pubmed: 9933439
pmcid: 1905193
doi: 10.1046/j.1365-2249.1999.00775.x
Hitchon, C. et al. Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum. 46, 2587–2597 (2002).
pubmed: 12384916
doi: 10.1002/art.10520
Akhavani, M. A. et al. Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis. Arthritis Res. Ther. 11, R64 (2009).
pubmed: 19426483
pmcid: 2714109
doi: 10.1186/ar2689
Konisti, S., Kiriakidis, S. & Paleolog, E. M. Hypoxia–a key regulator of angiogenesis and inflammation in rheumatoid arthritis. Nat. Rev. Rheumatol. 8, 153–162 (2012).
pubmed: 22293762
doi: 10.1038/nrrheum.2011.205
de Bandt, M. et al. Suppression of arthritis and protection from bone destruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum. 43, 2056–2063 (2000).
pubmed: 11014357
doi: 10.1002/1529-0131(200009)43:9<2056::AID-ANR17>3.0.CO;2-2
Ferrara, N. & Davis-Smyth, T. The biology of vascular endothelial growth factor. Endocr. Rev. 18, 4–25 (1997).
pubmed: 9034784
doi: 10.1210/edrv.18.1.0287
Veikkola, T. & Alitalo, K. VEGFs, receptors and angiogenesis. Semin. Cancer Biol. 9, 211–220 (1999).
pubmed: 10343072
doi: 10.1006/scbi.1998.0091
Ikeda, M., Hosoda, Y., Hirose, S., Okada, Y. & Ikeda, E. Expression of vascular endothelial growth factor isoforms and their receptors Flt-1, KDR, and neuropilin-1 in synovial tissues of rheumatoid arthritis. J. Pathol. 191, 426–433 (2000).
pubmed: 10918218
doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH649>3.0.CO;2-E
Fava, R. A. et al. Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J. Exp. Med. 180, 341–346 (1994).
pubmed: 8006592
doi: 10.1084/jem.180.1.341
Koch, A. E. et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J. Immunol. 152, 4149–4156 (1994).
pubmed: 7511670
Paleolog, E. M. et al. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 41, 1258–1265 (1998).
pubmed: 9663484
doi: 10.1002/1529-0131(199807)41:7<1258::AID-ART17>3.0.CO;2-1
Harada, M. et al. Vascular endothelial growth factor in patients with rheumatoid arthritis. Scand. J. Rheumatol. 27, 377–380 (1998).
pubmed: 9808403
doi: 10.1080/03009749850154429
Lee, S. S. et al. Vascular endothelial growth factor levels in the serum and synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 19, 321–324 (2001).
pubmed: 11407088
Clavel, G. et al. Angiogenesis markers (VEGF, soluble receptor of VEGF and angiopoietin-1) in very early arthritis and their association with inflammation and joint destruction. Clin. Immunol. 124, 158–164 (2007).
pubmed: 17560831
doi: 10.1016/j.clim.2007.04.014
Kurosaka, D. et al. Clinical significance of serum levels of vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in patients with rheumatoid arthritis. J. Rheumatol. 37, 1121–1128 (2010).
pubmed: 20436077
doi: 10.3899/jrheum.090941
Kim, W. U. et al. Interaction of vascular endothelial growth factor 165 with neuropilin-1 protects rheumatoid synoviocytes from apoptotic death by regulating Bcl-2 expression and Bax translocation. J. Immunol. 177, 5727–5735 (2006).
pubmed: 17015762
doi: 10.4049/jimmunol.177.8.5727
Bottomley, M. J. et al. Placenta growth factor (PlGF) induces vascular endothelial growth factor (VEGF) secretion from mononuclear cells and is co-expressed with VEGF in synovial fluid. Clin. Exp. Immunol. 119, 182–188 (2000).
pubmed: 10606981
pmcid: 1905543
doi: 10.1046/j.1365-2249.2000.01097.x
Yoo, S. A. et al. Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: a link between angiogenesis and inflammation. Arthritis Rheum. 60, 345–354 (2009).
pubmed: 19180491
doi: 10.1002/art.24289
Yoo, S. A. et al. Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid synoviocytes. J. Immunol. 194, 2513–2521 (2015).
pubmed: 25694608
doi: 10.4049/jimmunol.1402900
Yoo, S. A. et al. Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity. Nat. Immunol. 20, 1348–1359 (2019).
pubmed: 31406382
doi: 10.1038/s41590-019-0456-4
Wang, J., Devenport, J., Low, J. M., Yu, D. & Hitraya, E. Relationship between baseline and early changes in C-reactive protein and interleukin-6 levels and clinical response to tocilizumab in rheumatoid arthritis. Arthritis Care. Res. 68, 882–885 (2016).
doi: 10.1002/acr.22765
Chiu, W. C. et al. Ultrasound is more reliable than inflammatory parameters to evaluate disease activity in patients with RA receiving tocilizumab therapy. J. Investig. Med. 66, 1015–1018 (2018).
pubmed: 29581384
pmcid: 6073910
doi: 10.1136/jim-2017-000705
Aletaha, D. et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 69, 1580–1588 (2010).
pubmed: 20699241
doi: 10.1136/ard.2010.138461
Gopinathan, G. et al. Interleukin-6 stimulates defective angiogenesis. Cancer Res. 75, 3098–3107 (2015).
pubmed: 26081809
pmcid: 4527186
doi: 10.1158/0008-5472.CAN-15-1227
Szkudlarek, M. et al. Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis Rheum. 48, 955–962 (2003).
pubmed: 12687537
doi: 10.1002/art.10877
D’Agostino, M. A. et al. Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR-OMERACT ultrasound taskforce-Part 1: definition and development of a standardised, consensus-based scoring system. RMD Open 3, e000428 (2017).
pubmed: 28948983
pmcid: 5597799
doi: 10.1136/rmdopen-2016-000428
van der Heijde, D. How to read radiographs according to the Sharp/van der Heijde method. J. Rheumatol. 27, 261–263 (2000).
pubmed: 10648051
Anderson, J. et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care. Res. 64, 640–647 (2012).
doi: 10.1002/acr.21649
Fransen, J. & van Riel, P. L. The disease activity score and the EULAR response criteria. Rheum. Dis. Clin. North. Am. 35, 745–757, vii-viii (2009).
pubmed: 19962619
doi: 10.1016/j.rdc.2009.10.001
Houssiau, F. A., Devogelaer, J. P., Van Damme, J., de Deuxchaisnes, C. N. & Van Snick, J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 31, 784–788 (1988).
pubmed: 3260102
doi: 10.1002/art.1780310614
Sone, H. et al. Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis correlation with disease activity. Life. Sci. 69, 1861–1869 (2001).
pubmed: 11693266
doi: 10.1016/S0024-3205(01)01264-4
Rajaei, E. et al. Evaluating the relationship between serum level of interleukin-6 and rheumatoid arthritis severity and disease activity. Curr. Rheumatol. Rev. https://doi.org/10.2174/1573397115666190206144223 (2019).
Andersen, M. et al. Ultrasound colour Doppler is associated with synovial pathology in biopsies from hand joints in rheumatoid arthritis patients: a cross-sectional study. Ann. Rheum. Dis. 73, 678–683 (2014).
pubmed: 23475981
doi: 10.1136/annrheumdis-2012-202669
Hau, M. et al. High resolution ultrasound detects a decrease in pannus vascularisation of small finger joints in patients with rheumatoid arthritis receiving treatment with soluble tumour necrosis factor alpha receptor (etanercept). Ann. Rheum. Dis. 61, 55–58 (2002).
pubmed: 11779760
pmcid: 1753871
doi: 10.1136/ard.61.1.55
Terslev, L. et al. Effects of treatment with etanercept (Enbrel, TNRF:Fc) on rheumatoid arthritis evaluated by Doppler ultrasonography. Ann. Rheum. Dis. 62, 178–181 (2003).
pubmed: 12525391
pmcid: 1754421
doi: 10.1136/ard.62.2.178
Naredo, E., Moller, I., Cruz, A., Carmona, L. & Garrido, J. Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Arthritis Rheum. 58, 2248–2256 (2008).
pubmed: 18668537
doi: 10.1002/art.23682
Foltz, V. et al. Power Doppler ultrasound, but not low-field magnetic resonance imaging, predicts relapse and radiographic disease progression in rheumatoid arthritis patients with low levels of disease activity. Arthritis Rheum. 64, 67–76 (2012).
pubmed: 21904998
doi: 10.1002/art.33312
Scire, C. A. et al. Ultrasonographic evaluation of joint involvement in early rheumatoid arthritis in clinical remission: power Doppler signal predicts short-term relapse. Rheumatology 48, 1092–1097 (2009).
pubmed: 19561156
doi: 10.1093/rheumatology/kep171
Saleem, B. et al. Can flare be predicted in DMARD treated RA patients in remission, and is it important? A cohort study. Ann. Rheum. Dis. 71, 1316–1321 (2012).
pubmed: 22294638
doi: 10.1136/annrheumdis-2011-200548
Kawashiri, S. Y. et al. The power Doppler ultrasonography score from 24 synovial sites or 6 simplified synovial sites, including the metacarpophalangeal joints, reflects the clinical disease activity and level of serum biomarkers in patients with rheumatoid arthritis. Rheumatology 50, 962–965 (2011).
pubmed: 21186172
doi: 10.1093/rheumatology/keq415
Kitchen, J. & Kane, D. Greyscale and power Doppler ultrasonographic evaluation of normal synovial joints: correlation with pro- and anti-inflammatory cytokines and angiogenic factors. Rheumatology 54, 458–462 (2015).
pubmed: 25193808
doi: 10.1093/rheumatology/keu354
Smolen, J. S. et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann. Rheum. Dis. 75, 3–15 (2016).
pubmed: 25969430
doi: 10.1136/annrheumdis-2015-207524
Wells, G., Li, T., Maxwell, L., Maclean, R. & Tugwell, P. Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis. Ann. Rheum. Dis. 67, 260–265 (2008).
pubmed: 17846044
doi: 10.1136/ard.2007.069690
Bottiger, L. E. & Svedberg, C. A. Normal erythrocyte sedimentation rate and age. Br. Med. J. 2, 85–87 (1967).
pubmed: 6020854
doi: 10.1136/bmj.2.5544.85
Kushner, I. C-reactive protein in rheumatology. Arthritis Rheum. 34, 1065–1068 (1991).
pubmed: 1859483
doi: 10.1002/art.1780340819
Pincus, T., Braun, J., Kavanaugh, A. & Smolen, J. S. Optimisation of assessment for rheumatic diseases in clinical trials, observational studies and routine clinical care. Clin. Exp. Rheumatol. 32, S–1 (2014).
pubmed: 25365080