Keywords
anti-TNFα therapy
Biomarkers
How to Cite
Abstract
The way rheumatoid arthritis (RA) is treated has changed dramatically in the last decade, with the use of molecular targeted therapies. These durgs act in pathways associated with the inflammatory process, improving disease control with less development of adverse effects. However, there are a percentage of patients in whom these therapies are not effective. So far, no validated biomarkers that can be used as a predictor of response in clinical practice has ben detected. Being able to predict which patients will respond to a certain treatment will optimize treatment with these expensive drugs. Objectives: To identify biomarkers for anti-TNF therapy remission in patients with rheumatoid arthritis in a large cohort of patients. Materials and Methods: A total of 628 RA patients that have received theire first anti-TNFα therapy (n = 159 adalimumab, etanercept and infliximab n = 251 n = 218) were included in the present study. All patients were collected as part of the IMID consortium. A number of epidemiological variables (ie origin, toxic habits, physical activity, level of education, etc.) and a large number of variables related to the AR itself (ie age of onset, presence of autoantibodies, previous treatments, etc) were collected. Clinical remission was defined as a value of DAS28 <2.6. To identify differences between the three treatment groups ANOVA statistical test was used. For association analysis univariate and multivariate logistic regression it was used. Results: Of the 628 patients, 127 (20%) achieved clinical remission, and 501 patients (80%) did not achieved it. Among patients who achieved remission, 67 patients (53%) were treated with ET A, 37 patients (29%) with ADA and 23 patients (18%) with IFX, showing a predominance of patients in remission treated with ET A (P = 3.5E-03). In the univariated analysis, it was found tha the educational level (P = 1,7E-02, OR (95% CI ) = 0.61 (0,40-0,92)), male gender (P = 4,6E -02, OR (95%) = 0.61 (0,38-0,99)) and smoking status (P = 1,5E-02, OR (95%) = 1.65 (1,10 to 2,48)) were significantly associated with clinical remission. No association was found in the multivariable anlaysis. With respect to clinical variables, a significant association with DAS28 at baseline was found in both, univariate and multivariate analysis. Discussion: In the present study, it was found a significant association in both, uni and multivariated analysis, between DAS28 at baseline and clinical remission at 12 weeks.References
(1) Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Pract Res ClinRheumatol. 2010; 24(6): 733-45.
(2) Kvien TK, Uhlig T, Ødegård S, Heiberg MS. Epidemiological aspects of rheumatoid arthritis: the sex ratio. Ann N Y Acad Sci. 2006; 1069: 212-22.
(3) Zhang J, Zhang Y, Jin J, Li M, Xie K, Wen C, et al. Cytokine The 1082A / G polymorphism in the Interleukin-10 gene and the risk of rheumatoid arthritis: A meta-analysis. Cytokine. 2011; 56(2): 351-5.
(4) Bijlsma JWJ, Weinblatt ME. Optimal use of methotrexate: the advantages of tight control. AnnRheum Dis. 2007; 66(11): 1409-10.
(5) Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007; 370(9602): 1861-74.
(6) Sanmartí R, García-Rodríguez S, Álvaro-Gracia JM, Andreu JL, Balsa A, Cáliz R, et al. 2014 update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological therapies in rheumatoid arthritis. Reumatol Clin. 2015. pii: S1699-258X (15)00075-3.
(7) Kievit W, Adang EM, Fransen J, Kuper HH, van de Laar M a FJ, Jansen TL, et al. The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data. Ann Rheum Dis. 2008; 67(9): 1229-34.
(8) Busquets N, Carmona L, Surís X. Systematic review: safety andefficacy of anti-TNF in elderly patients. Reumatol Clin. 2011; 7(2): 104-12.
(9) Greenberg JD, Reed G, Decktor D, Harrold L, Furst D, Gibofsky A, et al A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically naive and switched rheumatoid arthritis patients: results from the US CORRONA registry. Ann Rheum Dis. 2012; 71(7): 1134-42.
(10) Marenco de la Fuente JL, Solís Díaz R. [Anti-TNF drugs: New results on efficacy]. Reumatol Clin.2009; 5S1: 71-6. Tugwell P, Boers M, Baker P, Wells G SJ. Endpoints in rheumatoid
(11) Tugwell P, Boers M, Baker P, Wells G SJ. Endpoints in rheumatoid arthritis. J Rheumatol.1994;21(42): 2-8.
(12) Burmester GR, Ferraccioli G, Flipo R-M, Monteagudo-Sáez I, Unnebrink K, Kary S, et al. Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. Arthritis Rheum. 2008; 59(1): 32-41.
(13) Cui J, Saevarsdottir S, Thomson B, Padyukov L, Mil AHMVDH-van, Nititham J, et al. Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti – Tumor Necrosis Factor α Therapy. Arthritis Rheum. 2010; 62(7): 1849-61.
(14) Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31(3): 315-24.
(15) Smolen JS, Han C, van der Heijde DMFM, Emery P, Bathon JM, Keystone E, et al. Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade. Ann Rheum Dis. 2009; 68(6): 823-7.
(16) Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004; 363(9410):675-81.
(17) Smolen JS, Kay J, Doyle MK, Landewé R, Matteson EL, Wollenhaupt J, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009; 374(9685): 210-21.
(18) Fleischmann R, Vencovsky J, van Vollenhoven RF, Borenstein D, Box J, Coteur G, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST- 4WARD study. Ann Rheum Dis.2009; 68(6): 805-11.
(19) Sociedad Española de Reumatología. Guía de Práctica Clínica en España. Madrid; 2011. http://www.ser.es
(20) Singh J a, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64(5): 625-39.
(21) Deighton C. The updated BSR guidelines for anti-TNF in adults with RA: what has changed and why? Musculoskeletal Care. 2005; 3(3): 122-30.
(22) Felson D. Defining remission in rheumatoid arthritis. Ann Rheum Dis. 2012; 71 Suppl 2: i86-8.
(23) Listing J, Strangfeld A, Rau R, Kekow J, Gromnica-Ihle E, Klopsch T, et al. Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low results from RABBIT, the German biologics register. Arthritis Res Ther. 2006; 8(3): R66.
(24) Hyrich KL, Watson KD, Silman a J, Symmons DPM. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). 2006; 45(12): 1558-65.
(25) Mancarella L, Bobbio-Pallavicini F, Ceccarelli F, Falappone PC, Ferrante A, Malesci D, et al. Good clinical response, remission, and predictors of remission in rheumatoid arthritis patients treated with tumor necrosis factor-alpha blockers: the GISEA study. J Rheumatol. 2007; 34(8): 1670-3.
(26) Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen IT, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish. Arthritis Rheum. 2010; 62(1): 22-32.
(27) Forslind K, Hafström I, Ahlmén M, Svensson B. Sex: a major predictor of remission in early rheumatoid arthritis? Ann Rheum Dis. 2007; 66(1): 46-52.
(28) Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum. 2007;56(10): 3226-35.
(29) Keystone E, Freundlich B, Schiff M, Li J, Hooper M. Patients with moderate rheumatoid arthritis (RA) achieve better disease activity states with etanercept treatment than patients with severe RA. J Rheumatol. 2009; 36(3): 522-31.
(30) Atzeni F, Antivalle M, Pallavicini FB, Caporali R, Bazzani C, Gorla R, et al. Predicting response to anti-TNF treatment in rheumatoid arthritis patients. Autoimmun Rev. 2009; 8(5): 431-7.