Abstract
Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693 GG homozygotes actually had significantly worse BASDAI (mean 4.2, 95% CI: 4–4.5) than AA homozygotes (mean 3.8, 95% CI: 3.7–4) in both the unadjusted (difference = 0.4, p = 0.006) and adjusted analyses (difference = 0.2–0.5, p = 0.002–0.04 depending on the adjustment model). We found no evidence that rs1900693 predicted functional status (BASFI) or global disease scores (BAS-G), and it exerted no influence on either the intention to treat with or efficacy of anti-TNF treatment.
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References
Akkoc N, Khan MA. Overestimation of the prevalence of ankylosing spondylitis in the Berlin study: comment on the article by Braun et al. Arthritis Rheum. 2005;52:4048–9.
Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45:730–8.
Ellinghaus D, Jostins L, Spain SL, Cortes A, Bethune J, Han B, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48:510–8.
Castillo-Ortiz JD, Ramiro S, Landewé R, van der Heijde D, Dougados M, van den Bosch F, et al. Work outcome in patients with ankylosing spondylitis: results from a 12-year follow up of an international study. Arthritis Care Res. 2016;68:544–52.
Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis. 2011;70:1921–5.
Cortes A, Maksymowych WP, Wordsworth BP, Inman RD, Danoy P, Rahman P, et al. Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis. Ann Rheum Dis. 2015;74:1387–93.
Brown MA, Brophy S, Bradbury L, Hamersma J, Timms A, Laval S, et al. Identification of major loci controlling clinical manifestations of ankylosing spondylitis. Arthritis Rheum. 2003;48:2234–9.
Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev. 2015;4:cd005468.
Corbett M, Soares M, Jhuti G, Rice S, Spackman E, Sideris E, et al. Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health Technol Assess. 2016;20:1–334.
Zeng Z, Duan Z, Zhang T, Wang S, Li G, Gao J, et al. Association between tumor necrosis factor-alpha (TNF-alpha) promoter −308 G/A and response to TNF-alpha blockers in rheumatoid arthritis: a meta-analysis. Mod Rheumatol. 2013;23:489–95.
Chen W, Xu H, Wang X, Gu J, Xiong H, Shi Y. The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to anti-TNF therapy in patients with autoimmune disease: A meta-analysis. Int Immunopharmacol. 2015;28:146–53.
Idriss HT, Naismith JH. TNF-alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Technol. 2000;50:184–95.
Davidson SI, Liu Y, Danoy PA, Wu X, Thomas GP, Jiang L, et al. Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Ann Rheum Dis. 2011;70:289–92.
Karaderi T, Pointon JJ, Wordsworth TW, Harvey D, Appleton LH, Cohen CJ, et al. Evidence of genetic association between TNFRSF1A encoding the p55 tumour necrosis factor receptor, and ankylosing spondylitis in UK Caucasians. Clin Exp Rheumatol. 2012;30:110–3.
Gregory AP, Dendrou CA, Attfield KE, Haghikia A, Xifara DK, Butter F, et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature. 2012;488:508–11.
Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2012;476:214–9.
The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology. 1999;53:457–65.
Comabella M, Caminero AB, Malhotra S, Agullo L, Fernandez O, Reverter F, et al. TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis. Neurology. 2013;80:2010–6.
Ottoboni L, Frohlich IY, Lee M, Healy BC, Keenan BT, Xia Z, et al. Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. Neurology. 2013;81:1891–9.
Mowry EM, Carey RF, Blasco MR, Pelletier J, Duquette P, Villoslada P, et al. Multiple sclerosis susceptibility genes: associations with relapse severity and recovery. PLoS ONE. 2013;8:e75416.
Keat A, Barkham N, Bhalla A, Gaffney K, Marzo-Ortega H, Paul S, et al. BSR guidelines for prescribing TNF-alpha blockers in adults with ankylosing spondylitis. Report of a working party of the British Society for. Rheumatol Rheumatol. 2005;44:939–47.
Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27:361–8.
Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, et al. The development of assessment of spondyloarthritis International Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68:777–83.
Freeston J, Barkham N, Hensor E, Emery P, Fraser A. Ankylosing spondylitis, HLA-B27 positivity and the need for biologic therapies. J Bone Spine. 2007;74:140–3.
Roussou E, Sultana S. Spondyloarthritis in women: differences in disease onset, clinical presentation, and Bath Ankylosing Spondylitis disease activity and functional indices (BASDAI and BASFI) between men and women with spondyloarthritides. Clin Rheumatol. 2011;30:121–7.
Taylor AL, Balakrishnan C, Calin A. Reference centile charts for measures of disease activity, functional impairment, and metrology in ankylosing spondylitis. Arthritis Rheum. 1998;41:1119–25.
Acknowledgements
We wish to thank all the study participants who generously donated their DNA to this study. MV was funded by the NIHR Oxford Comprehensive Biomedical Research Centre (immunity and inflammation theme A93081) and Arthritis Research UK (grant 21428). ARR was funded by Arthritis Research UK (grant 20402). Additional funding was provided by Arthritis Research UK (18797, 19536, 20402, 20796), the NIHR Thames Valley collaborative research network and National Ankylosing Spondylitis Society (UK).
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Watts, L., Karaderi, T., Roberts, A. et al. The severity of ankylosing spondylitis and responses to anti-tumour necrosis factor biologics are not influenced by the tumour necrosis factor receptor polymorphism incriminated in multiple sclerosis. Genes Immun 20, 167–171 (2019). https://doi.org/10.1038/s41435-018-0017-0
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DOI: https://doi.org/10.1038/s41435-018-0017-0
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