Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

TNF Receptor: Fc Fusion Protein Downregulates RANKL/OPG Ratio by Inhibiting CXCL16/CXCR6 in Active Ankylosing Spondylitis

Author(s): Peiyi Zhang, Shufen Zhou, Zhe Chen, Ye Tian, Qianqian Wang, Hui Li, Tiantian Zhang, Qin Guo, Meiying Wang and Chengshan Guo*

Volume 22 , Issue 2 , 2021

Published on: 02 March, 2020

Page: [305 - 316] Pages: 12

DOI: 10.2174/1389201021666200302104418

Price: $65

Abstract

Background: Clinical studies indicate that recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) quickly alleviates symptoms and physical signs of active Ankylosing Spondylitis (AS), improving the manifestation of spinal inflammation on radiological imaging. However, the regulatory mechanism of rhTNFR:Fc in the chemokine pathway is unclear. Thus we study the mechanism of phlogogenic activity of CXCL16/CXCR6 in AS and the related mechanism of rhTNFR: Fc treatment.

Methods: Thirty-two cases of active AS were treated with rhTNFR:Fc for 3 consecutive months. Clinical response was evaluated at baseline and after treatment. CXCL16/CXCR6 expression as well as Receptor Activator Of Nuclear Factor-Κb Ligand (RANKL)/Osteoprotegerin (OPG), essential molecules for osteoclast differentiation, were studied in AS before and after treatment. Further, the proliferation of lymphocytes and the RANKL level stimulated by recombinant human CXCL16 (rhCXCL16) were measured in vitro.

Results: Thirty cases responded to rhTNFR:Fc treatment. The RANKL level, RANKL/OPG ratio, CXCLl6 level in serum, and CXCLl6 and CXCR6 mRNA levels in active AS were higher than those in controls and treated patients (P<0.001). rhCXCL16 treatment increased lymphocyte proliferation and RANKL level in active AS (P<0.001), but not in controls or treated patients (P>0.05). A positive linear correlation was noted between CXCL16 serum levels and RANKL/OPG ratio and between CXCL16 levels and C-reactive protein results (P<0.001).

Conclusions: Our findings suggest that rhTNFR:Fc suppresses inflammation and bone destruction of AS by reducing the RANKL/OPG ratio through inhibition of the CXCL16/CXCR6 pathway.

Keywords: Ankylosing spondylitis, tumor necrosis factor, recombinant tumor necrosis factor receptor, Fc fusion protein, CXCL16/CXCR6, RANKL/OPG.

Graphical Abstract
[1]
Walker, J. Ankylosing spondylitis. Nurs. Stand., 2006, 20(46), 48-52.
[http://dx.doi.org/10.7748/ns.20.46.48.s56] [PMID: 16898197]
[2]
van den Berg, R.; Lenczner, G.; Thévenin, F.; Claudepierre, P.; Feydy, A.; Reijnierse, M.; Saraux, A.; Rahmouni, A.; Dougados, M.; van der Heijde, D. Classification of axial SpA based on positive imaging (radiographs and/or MRI of the sacroiliac joints) by local rheumatologists or radiologists versus central trained readers in the DESIR cohort. Ann. Rheum. Dis., 2015, 74(11), 2016-2021.
[http://dx.doi.org/10.1136/annrheumdis-2014-205432] [PMID: 24962871]
[3]
Venkatesh, P.; Gogia, V.; Shah, B.; Gupta, S.; Sagar, P.; Garg, S. Patterns of uveitis at the apex institute for eye care in India: Results from a prospectively enrolled patient data base (2011-2013). Int. Ophthalmol., 2016, 36(3), 365-372.
[http://dx.doi.org/10.1007/s10792-015-0128-9] [PMID: 26408195]
[4]
Dougall, W.C.; Glaccum, M.; Charrier, K.; Rohrbach, K.; Brasel, K.; De Smedt, T.; Daro, E.; Smith, J.; Tometsko, M.E.; Maliszewski, C.R.; Armstrong, A.; Shen, V.; Bain, S.; Cosman, D.; Anderson, D.; Morrissey, P.J.; Peschon, J.J.; Schuh, J. RANK is essential for osteoclast and lymph node development. Genes Dev., 1999, 13(18), 2412-2424.
[http://dx.doi.org/10.1101/gad.13.18.2412] [PMID: 10500098]
[5]
Yasuda, H.; Shima, N.; Nakagawa, N.; Yamaguchi, K.; Kinosaki, M.; Mochizuki, S.; Tomoyasu, A.; Yano, K.; Goto, M.; Murakami, A.; Tsuda, E.; Morinaga, T.; Higashio, K.; Udagawa, N.; Takahashi, N.; Suda, T. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA, 1998, 95(7), 3597-3602.
[http://dx.doi.org/10.1073/pnas.95.7.3597] [PMID: 9520411]
[6]
Nakashima, T.; Hayashi, M.; Fukunaga, T.; Kurata, K.; Oh-Hora, M.; Feng, J.Q.; Bonewald, L.F.; Kodama, T.; Wutz, A.; Wagner, E.F.; Penninger, J.M.; Takayanagi, H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med., 2011, 17(10), 1231-1234.
[http://dx.doi.org/10.1038/nm.2452] [PMID: 21909105]
[7]
Theill, L.E.; Boyle, W.J.; Penninger, J.M. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol., 2002, 20, 795-823.
[http://dx.doi.org/10.1146/annurev.immunol.20.100301.064753] [PMID: 11861618]
[8]
Nakashima, T.; Takayanagi, H. RANKL signal and osteoimmunology. Clin. Calcium, 2011, 21(8), 1131-1140.
[PMID: 21814017]
[9]
Furuya, T.; Hakoda, M.; Ichikawa, N.; Higami, K.; Nanke, Y.; Yago, T.; Kamatani, N.; Kotake, S. Associations between HLA-DRB1, RANK, RANKL, OPG, and IL-17 genotypes and disease severity phenotypes in Japanese patients with early rheumatoid arthritis. Clin. Rheumatol., 2007, 26(12), 2137-2141.
[http://dx.doi.org/10.1007/s10067-007-0745-4] [PMID: 17876645]
[10]
Yang, H.; Liu, W.; Zhou, X.; Rui, H.; Zhang, H.; Liu, R. The association between RANK, RANKL and OPG gene polymorphisms and the risk of rheumatoid arthritis: A case-controlled study and meta-analysis. Biosci. Rep., 2019, 39(6)BSR20182356
[http://dx.doi.org/10.1042/BSR20182356] [PMID: 31209146]
[11]
Lee, S.K.; Park, K.K.; Kim, K.R.; Kim, H.J.; Chung, W.Y. isoliquiritigenin inhibits metastatic breast cancer cell-induced receptor activator of nuclear factor Kappa-B ligand/osteoprotegerin ratio in human osteoblastic cells. J. Cancer Prev., 2015, 20(4), 281-286.
[http://dx.doi.org/10.15430/JCP.2015.20.4.281] [PMID: 26734591]
[12]
Li, C.H.; Xu, L.L.; Zhao, J.X.; Sun, L.; Yao, Z.Q.; Deng, X.L.; Liu, R.; Yang, L.; Xing, R.; Liu, X.Y. CXCL16 upregulates RANKL expression in rheumatoid arthritis synovial fibroblasts through the JAK2/STAT3 and p38/MAPK signaling pathway. Inflamm. Res., 2016, 65(3), 193-202.
[http://dx.doi.org/10.1007/s00011-015-0905-y] [PMID: 26621504]
[13]
Yilmaz, S.; Cinar, M.; Pekel, A.; Simsek, I.; Musabak, U.; Erdem, H.; Pay, S. The expression of transmembrane and soluble CXCL16 and the relation with interferon-alpha secretion in patients with Behçet’s disease. Clin. Exp. Rheumatol., 2013, 31(3)(Suppl. 77), 84-87.
[PMID: 24064021]
[14]
van Lieshout, A.W.; van der Voort, R.; Toonen, L.W.; van Helden, S.F.; Figdor, C.G.; van Riel, P.L.; Radstake, T.R.; Adema, G.J. Regulation of CXCL16 expression and secretion by myeloid cells is not altered in rheumatoid arthritis. Ann. Rheum. Dis., 2009, 68(6), 1036-1043.
[http://dx.doi.org/10.1136/ard.2007.086611] [PMID: 18628285]
[15]
Adamski, V.; Mentlein, R.; Lucius, R.; Synowitz, M.; Held-Feindt, J.; Hattermann, K. The chemokine receptor CXCR6 evokes reverse signaling via the transmembrane chemokine CXCL16. Int. J. Mol. Sci., 2017, 18(7)E1468
[http://dx.doi.org/10.3390/ijms18071468] [PMID: 28698473]
[16]
Tabata, S.; Kadowaki, N.; Kitawaki, T.; Shimaoka, T.; Yonehara, S.; Yoshie, O.; Uchiyama, T. Distribution and kinetics of SR-PSOX/CXCL16 and CXCR6 expression on human dendritic cell subsets and CD4+ T cells. J. Leukoc. Biol., 2005, 77(5), 777-786.
[http://dx.doi.org/10.1189/jlb.1204733] [PMID: 15703197]
[17]
Aust, G.; Kamprad, M.; Lamesch, P.; Schmücking, E. CXCR6 within T-helper (Th) and T-cytotoxic (Tc) type 1 lymphocytes in Graves’ Disease (GD). Eur. J. Endocrinol., 2005, 152(4), 635-643.
[http://dx.doi.org/10.1530/eje.1.01892] [PMID: 15817921]
[18]
Stegmann, K.A.; Robertson, F.; Hansi, N.; Gill, U.; Pallant, C.; Christophides, T.; Pallett, L.J.; Peppa, D.; Dunn, C.; Fusai, G.; Male, V.; Davidson, B.R.; Kennedy, P.; Maini, M.K. CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver. Sci. Rep., 2016, 6, 26157.
[http://dx.doi.org/10.1038/srep26157] [PMID: 27210614]
[19]
Ruth, J.H.; Haas, C.S.; Park, C.C.; Amin, M.A.; Martinez, R.J.; Haines, G.K., III; Shahrara, S.; Campbell, P.L.; Koch, A.E. CXCL16-mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway. Arthritis Rheum., 2006, 54(3), 765-778.
[http://dx.doi.org/10.1002/art.21662] [PMID: 16508941]
[20]
Tran, P.T.; Park, D.H.; Kim, O.; Kwon, S.H.; Min, B.S.; Lee, J.H. Desoxyrhapontigenin inhibits RANKL induced osteoclast formation and prevents inflammation mediated bone loss. Int. J. Mol. Med., 2018, 42(1), 569-578.
[http://dx.doi.org/10.3892/ijmm.2018.3627] [PMID: 29693149]
[21]
François, R.J.; Neure, L.; Sieper, J.; Braun, J. Immunohistological examination of open sacroiliac biopsies of patients with ankylosing spondylitis: Detection of tumour necrosis factor alpha in two patients with early disease and transforming growth factor beta in three more advanced cases. Ann. Rheum. Dis., 2006, 65(6), 713-720.
[http://dx.doi.org/10.1136/ard.2005.037465] [PMID: 16249231]
[22]
Schulz, M.; Dotzlaw, H.; Neeck, G. Ankylosing spondylitis and rheumatoid arthritis: Serum levels of TNF-α and its soluble receptors during the course of therapy with etanercept and infliximab. BioMed Res. Int., 2014.2014675108
[http://dx.doi.org/10.1155/2014/675108] [PMID: 24783218]
[23]
Davis, J.C., Jr; Van Der Heijde, D.; Braun, J.; Dougados, M.; Cush, J.; Clegg, D.O.; Kivitz, A.; Fleischmann, R.; Inman, R.; Tsuji, W. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: A randomized, controlled trial. Arthritis Rheum., 2003, 48(11), 3230-3236.
[http://dx.doi.org/10.1002/art.11325] [PMID: 14613288]
[24]
van der Heijde, D.; Kivitz, A.; Schiff, M.H.; Sieper, J.; Dijkmans, B.A.; Braun, J.; Dougados, M.; Reveille, J.D.; Wong, R.L.; Kupper, H.; Davis, J.C., Jr Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum., 2006, 54(7), 2136-2146.
[http://dx.doi.org/10.1002/art.21913] [PMID: 16802350]
[25]
Braun, J.; Landewé, R.; Hermann, K.G.; Han, J.; Yan, S.; Williamson, P.; van der Heijde, D. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: Results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum., 2006, 54(5), 1646-1652.
[http://dx.doi.org/10.1002/art.21790] [PMID: 16646033]
[26]
Tracey, D.; Klareskog, L.; Sasso, E.H.; Salfeld, J.G.; Tak, P.P. Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacol. Ther., 2008, 117(2), 244-279.
[http://dx.doi.org/10.1016/j.pharmthera.2007.10.001] [PMID: 18155297]
[27]
Burns, P.B.; Rohrich, R.J.; Chung, K.C. The levels of evidence and their role in evidence-based medicine. Plast. Reconstr. Surg., 2011, 128(1), 305-310.
[http://dx.doi.org/10.1097/PRS.0b013e318219c171] [PMID: 21701348]
[28]
Garrett, S.; Jenkinson, T.; Kennedy, L.G.; Whitelock, H.; Gaisford, P.; Calin, A. A new approach to defining disease status in ankylosing spondylitis: The bath ankylosing spondylitis disease activity index. J. Rheumatol., 1994, 21(12), 2286-2291.
[PMID: 7699630]
[29]
Sieper, J.; Rudwaleit, M.; Baraliakos, X.; Brandt, J.; Braun, J.; Burgos-Vargas, R.; Dougados, M.; Hermann, K.G.; Landewé, R.; Maksymowych, W.; van der Heijde, D. The Assessment of Spondylo arthritis international Society (ASAS) handbook: A guide to assess spondyloarthritis. Ann. Rheum. Dis., 2009, 68(Suppl. 2), ii1-ii44.
[http://dx.doi.org/10.1136/ard.2008.104018] [PMID: 19433414]
[30]
Rudwaleit, M.; van der Heijde, D.; Landewé, R.; Akkoc, N.; Brandt, J.; Chou, C.T.; Dougados, M.; Huang, F.; Gu, J.; Kirazli, Y.; Van den Bosch, F.; Olivieri, I.; Roussou, E.; Scarpato, S.; Sørensen, I.J.; Valle-Oñate, R.; Weber, U.; Wei, J.; Sieper, J. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis., 2011, 70(1), 25-31.
[http://dx.doi.org/10.1136/ard.2010.133645] [PMID: 21109520]
[31]
Zochling, J.; van der Heijde, D.; Burgos-Vargas, R.; Collantes, E.; Davis, J.C., Jr; Dijkmans, B.; Dougados, M.; Géher, P.; Inman, R.D.; Khan, M.A.; Kvien, T.K.; Leirisalo-Repo, M.; Olivieri, I.; Pavelka, K.; Sieper, J.; Stucki, G.; Sturrock, R.D.; van der Linden, S.; Wendling, D.; Böhm, H.; van Royen, B.J.; Braun, J. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann. Rheum. Dis., 2006, 65(4), 442-452.
[http://dx.doi.org/10.1136/ard.2005.041137] [PMID: 16126791]
[32]
Martins, N.A.; Furtado, G.E.; Campos, M.J.; Leitão, J.C.; Filaire, E.; Ferreira, J.P. Exercise and ankylosing spondylitis with New York modified criteria: A systematic review of controlled trials with meta-analysis. Acta Reumatol. Port., 2014, 39(4), 298-308.
[PMID: 25351868]
[33]
Zhao, W.; Huang, F. The role of RANKL in the pathogenesis of peripheral joint bone destruction in ankylosing spondylitis. The People’s Liberat. Army Med. J. China, 2004, 29(6), 482-485.
[34]
Vandooren, B.; Cantaert, T.; Noordenbos, T.; Tak, P.P.; Baeten, D. The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation. Arthritis Rheum., 2008, 58(3), 718-729.
[http://dx.doi.org/10.1002/art.23290] [PMID: 18311801]
[35]
Czaja, A.J. Review article: Chemokines as orchestrators of autoimmune hepatitis and potential therapeutic targets. Aliment. Pharmacol. Ther., 2014, 40(3), 261-279.
[http://dx.doi.org/10.1111/apt.12825] [PMID: 24890045]
[36]
Kawai, T. Matsuyama, T.; Hosokawa, Y.; Makihira, S.; Seki, M.; Karimbux, N.Y.; Goncalves, R.B.; Valverde, P.; Dibart, S.; Li, Y.P.; Miranda, L.A.; Ernst, C.W.; Izumi, Y.; Taubman, M.A. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am. J. Pathol., 2006, 169(3), 987-998.
[http://dx.doi.org/10.2353/ajpath.2006.060180] [PMID: 16936272]
[37]
Kong, Y.Y.; Feige, U.; Sarosi, I.; Bolon, B.; Tafuri, A.; Morony, S.; Capparelli, C.; Li, J.; Elliott, R.; McCabe, S.; Wong, T.; Campagnuolo, G.; Moran, E.; Bogoch, E.R.; Van, G.; Nguyen, L.T.; Ohashi, P.S.; Lacey, D.L.; Fish, E.; Boyle, W.J.; Penninger, J.M. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature, 1999, 402(6759), 304-309.
[http://dx.doi.org/10.1038/46303] [PMID: 10580503]
[38]
Bultink, I.E.; Vis, M.; van der Horst-Bruinsma, I.E.; Lems, W.F. Inflammatory rheumatic disorders and bone. Curr. Rheumatol. Rep., 2012, 14(3), 224-230.
[http://dx.doi.org/10.1007/s11926-012-0252-8] [PMID: 22477520]
[39]
McInnes, I.B.; Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol., 2007, 7(6), 429-442.
[http://dx.doi.org/10.1038/nri2094] [PMID: 17525752]
[40]
Boyce, B.F.; Li, P.; Yao, Z.; Zhang, Q.; Badell, I.R.; Schwarz, E.M.; O’Keefe, R.J.; Xing, L. TNF-alpha and pathologic bone resorption. Keio J. Med., 2005, 54(3), 127-131.
[http://dx.doi.org/10.2302/kjm.54.127] [PMID: 16237274]
[41]
Peng, M.; Wang, Y.; Qiang, L.; Xu, Y.; Li, C.; Li, T.; Zhou, X.; Xiao, M.; Wang, J. Interleukin-35 inhibits TNF-α-induced osteoclastogenesis and promotes apoptosis via shifting the activation from TNF Receptor-Associated Death Domain (TRADD)-TRAF2 to TRADD-Fas-associated death domain by JAK1/STAT1. Front. Immunol., 2018, 9, 1417.
[http://dx.doi.org/10.3389/fimmu.2018.01417] [PMID: 30061878]
[42]
Kim, H.R.; Lee, S.H.; Kim, H.Y. Elevated serum levels of soluble receptor activator of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients with Ankylosing Spondylitis (AS). Rheumatology (Oxford), 2006, 45(10), 1197-1200.
[http://dx.doi.org/10.1093/rheumatology/kel072] [PMID: 16567356]
[43]
Abel, S.; Hundhausen, C.; Mentlein, R.; Schulte, A.; Berkhout, T.A.; Broadway, N.; Hartmann, D.; Sedlacek, R.; Dietrich, S.; Muetze, B.; Schuster, B.; Kallen, K.J.; Saftig, P.; Rose-John, S.; Ludwig, A. The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J. Immunol., 2004, 172(10), 6362-6372.
[http://dx.doi.org/10.4049/jimmunol.172.10.6362] [PMID: 15128827]
[44]
Xing, J.; Liu, Y.; Chen, T. Correlations of chemokine CXCL16 and TNF-α with coronary atherosclerotic heart disease. Exp. Ther. Med., 2018, 15(1), 773-776.
[PMID: 29399085]
[45]
Yang, H.; Qiu, B.; Chen, S.; Xun, Y.; Pan, Y.; Chen, M.; Li, W.X.; Liao, W.; El-Ashram, S.; Yang, A.; Liu, F. Soluble CXCL16 promotes TNF-α-induced apoptosis in DLBCL via the AMAD10-NF-κB regulatory feedback loop. Cell Biol. Int., 2019, 43(8), 863-874.
[http://dx.doi.org/10.1002/cbin.11154] [PMID: 31033093]
[46]
Guellec, D.; Nocturne, G.; Tatar, Z.; Pham, T.; Sellam, J.; Cantagrel, A.; Saraux, A. Should non-steroidal anti-inflammatory drugs be used continuously in ankylosing spondylitis? Joint Bone Spine, 2014, 81(4), 308-312.
[http://dx.doi.org/10.1016/j.jbspin.2014.01.003] [PMID: 24589253]
[47]
Baeten, D.; Baraliakos, X.; Braun, J.; Sieper, J.; Emery, P.; van der Heijde, D.; McInnes, I.; van Laar, J.M.; Landewé, R.; Wordsworth, P.; Wollenhaupt, J.; Kellner, H.; Paramarta, J.; Wei, J.; Brachat, A.; Bek, S.; Laurent, D.; Li, Y.; Wang, Y.A.; Bertolino, A.P.; Gsteiger, S.; Wright, A.M.; Hueber, W. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: A randomised, double-blind, placebo-controlled trial. Lancet, 2013, 382(9906), 1705-1713.
[http://dx.doi.org/10.1016/S0140-6736(13)61134-4] [PMID: 24035250]
[48]
Tong, Q.; Cai, Q.; de Mooij, T.; Xu, X.; Dai, S.; Qu, W.; Zhao, D. Adverse events of anti-tumor necrosis factor α therapy in ankylosing spondylitis. PLoS One, 2015, 10(3)e0119897
[http://dx.doi.org/10.1371/journal.pone.0119897] [PMID: 25764452]
[49]
Braun, J.; McHugh, N.; Singh, A.; Wajdula, J.S.; Sato, R. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology (Oxford), 2007, 46(6), 999-1004.
[http://dx.doi.org/10.1093/rheumatology/kem069] [PMID: 17389658]
[50]
Lee, J.; Noh, J.W.; Hwang, J.W.; Oh, J.M.; Kim, H.; Ahn, J.K.; Lee, Y.S.; Cha, H.S.; Koh, E.M. Extended dosing of etanercept 25 mg can be effective in patients with ankylosing spondylitis: A retrospective analysis. Clin. Rheumatol., 2010, 29(10), 1149-1154.
[http://dx.doi.org/10.1007/s10067-010-1542-z] [PMID: 20683738]
[51]
Li, H.; Li, Q.; Chen, X.; Ji, C.; Gu, J. Anti-tumor necrosis factor therapy increased spine and femoral neck bone mineral density of patients with active ankylosing spondylitis with low bone mineral density. J. Rheumatol., 2015, 42(8), 1413-1417.
[http://dx.doi.org/10.3899/jrheum.150019] [PMID: 26077412]
[52]
Dougados, M.; van der Heijde, D.; Sieper, J.; Braun, J.; Citera, G.; Lenaerts, J.; van den Bosch, F.; Wei, J.C.; Pedersen, R.; Bonin, R.; Jones, H.; Marshall, L.; Logeart, I.; Vlahos, B.; Bukowski, J.F.; Maksymowych, W.P. Effects of long-term etanercept treatment on clinical outcomes and objective signs of inflammation in early nonradiographic axial spondyloarthritis: 104-Week results from a randomized, placebo-controlled study. Arthritis Care Res. (Hoboken), 2017, 69(10), 1590-1598.
[http://dx.doi.org/10.1002/acr.23276] [PMID: 28482137]
[53]
Molnar, C.; Scherer, A.; Baraliakos, X.; de Hooge, M.; Micheroli, R.; Exer, P.; Kissling, R.O.; Tamborrini, G.; Wildi, L.M.; Nissen, M.J.; Zufferey, P.; Bernhard, J.; Weber, U.; Landewé, R.B.M.; van der Heijde, D.; Ciurea, A. TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: Results from the Swiss Clinical Quality Management cohort. Ann. Rheum. Dis., 2018, 77(1), 63-69.
[http://dx.doi.org/10.1136/annrheumdis-2017-211544] [PMID: 28939631]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy