Please wait a minute...

Frontiers of Medicine

Front. Med.    2019, Vol. 13 Issue (4) : 411-419
Genetic and clinical markers for predicting treatment responsiveness in rheumatoid arthritis
Xin Wu1, Xiaobao Sheng2,3, Rong Sheng1, Hongjuan Lu1, Huji Xu1,4,5()
1. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, the Second Military Medical University, Shanghai 200003, China
2. School of Economics and Management, Tongji University, Shanghai 200092, China
3. The Third Research Institute of the Ministry of Public Security, Shanghai 200031, China
4. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 100084, China
5. Peking-Tsinghua Center for Life Sciences, Tsinghua University, Beijing 100084, China
Download: PDF(277 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA. We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.

Keywords rheumatoid arthritis      gene      clinical markers      therapy     
Corresponding Author(s): Huji Xu   
Just Accepted Date: 20 November 2018   Online First Date: 14 January 2019    Issue Date: 02 August 2019
 Cite this article:   
Xin Wu,Xiaobao Sheng,Rong Sheng, et al. Genetic and clinical markers for predicting treatment responsiveness in rheumatoid arthritis[J]. Front. Med., 2019, 13(4): 411-419.
E-mail this article
E-mail Alert
Articles by authors
Xin Wu
Xiaobao Sheng
Rong Sheng
Hongjuan Lu
Huji Xu
Fig.1  Overview of the MEDLINE/PubMed records related to RA (left panel) and the associated human genes (right panel), stratified by the year of publication. The left panel shows the number of related publications per year from the 1950s to 2013, whereas the right panel shows the total number of genes that are known to be associated with RA in a particular year and the years prior (cumulative sum). Related data are provided in Supplementary Table 1.
Interpro ID Annotation No. of genes
IPR007110 Immunoglobulin-like domain 68
IPR003599 Immunoglobulin subtype 51
IPR011009 Protein kinase-like domain 40
IPR000719 Protein kinase domain 37
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain 37
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain 37
IPR020635 Tyrosine-protein kinase, catalytic domain 37
IPR013106 Immunoglobulin V-set domain 34
IPR001811 Chemokine interleukin-8-like domain 30
IPR003598 Immunoglobulin subtype 2 25
Tab.1  Top 10 most frequently occurring protein families and functional domains (according to InterPro) in the 610 RA-associated genes
NCBI Entrez ID No. of PubMed abstracts HGNC gene symbol Note
7124 574 TNF Cytokine
3123 173 HLA-DRB1 Immunoglobulin
3569 157 IL6 Cytokine
3605 68 IL17A Cytokine
26191 64 PTPN22 Kinase
7422 61 VEGFA Cytokine
920 56 CD4 Immunoglobulin
4790 53 NFKB1 Transcription factor
8797 50 TNFRSF10A TNF receptor
3586 47 IL10 Cytokine
Tab.2  Top 10 most studied RA genes according to their associated MEDLINE/PubMed records
NCBI Entrez ID HGNC gene symbol Associated variations DMARD/TNF-blocking agent Note (reference and statistics)
1544 CYP1A2 SNP Leflunomide CYP1A2*1F allele is associated with leflunomide toxicity [17]; CC vs. A allele: OR= 9.7 (95% CI= 2.276–41.403), P = 0.002
s1557 CYP2C19 SNP Leflunomide CYP2C19*2 allele influences leflunomide metabolite concentrations that are associated with treatment responses but not with leflunomide-induced toxicity [18]; leflunomide metabolite concentration was ~71% higher in carriers in the CYP2C19*2 allele than in noncarriers
2212 FCGR2A Infliximab Infliximab treatment in patients with RA is influenced by the FCGR2A and FCGR3A genotypes; this effect is observed at different times during follow-up (6 and 30 weeks, respectively) [19]; in patients with low-affinity homozygotes, FCGR2A and FCGR3A alleles could achieve better responses to infliximab (P<0.05 for both cases)
2214 FCGR3A Infliximab Stated in the comment above and also in the reference [19]
SNP rs396991 Infliximab The wild-type allele is associated with better treatment responses, and the strength of the response depends on the type and stage of disease [20]; patients with homozygous V158F polymorphism achieved better response to infliximab (P<0.05)
3135 HLA-G Indel Methotrexate A –14bp deletion in the 3′-unstranslated region (3′ UTR) of HLA-G was clinically advantageous for methotrexate treatment; however, the results were controversial among studies [2123]; for example, one study showed that the –14/–14 bp deletion was enriched in the responder group (OR= 2.46 with 95% CI= 1.26–4.84, P = 0.009) [21], whereas another study reported the lack of significant results [23]
3569 IL6 SNP; −174 Rituximab −174 CC genotype is associated with a lack of response to rituximab [24] (OR= 2.83; 95% CI= 1.10–7.27; P = 0.031)
3586 IL10 Etanercept Promoter polymorphisms in IL10 are useful in predicting clinical response to etanercept treatment [25]
4524 MTHFR SNP; C677T and A1298C Methotrexate C667T polymorphism is associated with responses to methotrexate; however, controversial results were recorded among different populations [2629]
5243 ABCB1 SNP; C3435T Methotrexate More nonresponders to methotrexate were found in patients with the TT allele than the CC allele [30] (OR= 8.78, P = 0.038)
7124 TNF SNP; −308 Adalimumab Promoter SNP −308 is associated with treatment responses to adalimumab [31]; 88.2% of G/G versus 68.4% of G/A for the −308 polymorphism were responders (P = 0.05)
SNP; −308 Etanercept Promoter SNP −308 is not associated with treatment responses to etanercept [32]
SNP; −238 and+489 Methotrexate Promoter SNP −238 GG homozygosity is associated with severity and unresponsiveness, but the coding+489 polymorphism is not; the −238 AG genotype is absent in severe-unresponsive RA but present in mild-responsive RA subjects; thus, −238 GG homozygosity is associated with severity and unresponsiveness [33]
SNP; −308 and −238 Infliximab Promoter SNP −238 is associated with treatment responses to infliximab, but the −308 SNP is not; A allele carrier state was significantly lower among responders (OR 0.344, 95% CI= 0.152–0.779, P = 0.01) [34]
7133 TNFRSF1B SNP; M296R Infliximab The M196R SNP leads to lower responsiveness to infliximab [35]
7298 TYMS Indel Methotrexate 3′ UTR indel is associated with responses to methotrexate [27]; in patients with RA with the CC genotype, the OR (95% CI) for the risk of toxicity was 3.8 (2.29–6.33) for the CT genotype and 4.7 (2.40–9.04) for the TT genotype)
Tab.3  Gene polymorphisms and associations with response to DMARDs and drugs
1 RC Lawrence, DT Felson, CG Helmick, LM Arnold, H Choi, RA Deyo, S Gabriel, R Hirsch, MC Hochberg, GG Hunder, JM Jordan, JN Katz, HM Kremers, F Wolfe; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008; 58(1): 26–35 pmid: 18163497
2 CG Helmick, DT Felson, RC Lawrence, S Gabriel, R Hirsch, CK Kwoh, MH Liang, HM Kremers, MD Mayes, PA Merkel, SR Pillemer, JD Reveille, JH Stone; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008; 58(1): 15–25 pmid: 18163481
3 PC Taylor, M Feldmann. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 2009; 5(10): 578–582 pmid: 19798034
4 HE Seymour, A Worsley, JM Smith, SH Thomas. Anti-TNF agents for rheumatoid arthritis. Br J Clin Pharmacol 2001; 51(3): 201–208 pmid: 11298065
5 JO Costa, LL Lemos, MA Machado, AM Almeida, AM Kakehasi, VE Araújo, ML Cherchiglia, EI Andrade, FA Acurcio. Infliximab, methotrexate and their combination for the treatment of rheumatoid arthritis: a systematic review and meta-analysis. Rev Bras Reumatol 2015; 55(2): 146–158 pmid: 25593074
6 LJ Scott. Etanercept: a review of its use in autoimmune inflammatory diseases. Drugs 2014; 74(12): 1379–1410 pmid: 25034360
7 P Joshi, SS Dhaneshwar. An update on disease modifying antirheumatic drugs. Inflamm Allergy Drug Targets 2014; 13(4): 249–261 pmid: 25244345
8 A Mitchell, HY Chang, L Daugherty, M Fraser, S Hunter, R Lopez, C McAnulla, C McMenamin, G Nuka, S Pesseat, A Sangrador-Vegas, M Scheremetjew, C Rato, SY Yong, A Bateman, M Punta, TK Attwood, CJ Sigrist, N Redaschi, C Rivoire, I Xenarios, D Kahn, D Guyot, P Bork, I Letunic, J Gough, M Oates, D Haft, H Huang, DA Natale, CH Wu, C Orengo, I Sillitoe, H Mi, PD Thomas, RD Finn. The InterPro protein families database: the classification resource after 15 years. Nucleic Acids Res 2015; 43(Database issue): D213–D221 pmid: 25428371
9 RJ Kinsella, A Kahari, S Haider, J Zamora, G Proctor, G Spudich, J Almeida-King, D Staines, P Derwent, A Kerhornou, P Kersey, P Flicek. Ensembl BioMarts: a hub for data retrieval across taxonomic space. Database (Oxford) 2011; 2011: bar030
10 H Okamoto, A Kobayashi. Tyrosine kinases in rheumatoid arthritis. J Inflamm (Lond) 2011; 8(1): 21 pmid: 21861931
11 A Opar. Kinase inhibitors attract attention as oral rheumatoid arthritis drugs. Nat Rev Drug Discov 2010; 9(4): 257–258 pmid: 20357793
12 P Vasanthi, G Nalini, G Rajasekhar. Role of tumor necrosis factor-alpha in rheumatoid arthritis: a review. APLAR J Rheumatol 2007; 10(4): 270–274
13 EA Moelants, A Mortier, J Van Damme, P Proost. Regulation of TNF-a with a focus on rheumatoid arthritis. Immunol Cell Biol 2013; 91(6): 393–401 pmid: 23628802
14 D Plant, AG Wilson, A Barton. Genetic and epigenetic predictors of responsiveness to treatment in RA. Nat Rev Rheumatol 2014; 10(6): 329–337 pmid: 24535543
15 P Barrera, A van der Maas, AE van Ede, BA Kiemeney, RF Laan, LB van de Putte, PL van Riel. Drug survival, efficacy and toxicity of monotherapy with a fully human anti-tumour necrosis factor-a antibody compared with methotrexate in long-standing rheumatoid arthritis. Rheumatology (Oxford) 2002; 41(4): 430–439 pmid: 11961174
16 B Saleem, H Keen, V Goeb, R Parmar, S Nizam, EM Hensor, SM Churchman, M Quinn, R Wakefield, PG Conaghan, F Ponchel, P Emery. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 2010; 69(9): 1636–1642 pmid: 20421345
17 P Bohanec Grabar, B Rozman, M Tomsic, D Suput, D Logar, V Dolzan. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol 2008; 64(9): 871–876 pmid: 18496682
18 P Bohanec Grabar, I Grabnar, B Rozman, D Logar, M Tomsic, D Suput, T Trdan, L Peterlin Masic, A Mrhar, V Dolzan. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis. Drug Metab Dispos 2009; 37(10): 2061–2068 pmid: 19581389
19 JD Cañete, B Suárez, MV Hernández, R Sanmartí, I Rego, R Celis, C Moll, JA Pinto, FJ Blanco, F Lozano. Influence of variants of Fcγ receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor α therapy in rheumatoid arthritis. Ann Rheum Dis 2009; 68(10): 1547–1552 pmid: 18930989
20 MJ Morales-Lara, P Conesa-Zamora, MS García-Simón, F Pedrero, V Santaclara, M Perez-Guillermo, E Soriano-Navarro. Association between the FCGR3A V158F polymorphism and the clinical response to infliximab in rheumatoid arthritis and spondyloarthritis patients. Scand J Rheumatol 2010; 39(6): 518–520 pmid: 20560817
21 R Rizzo, M Rubini, M Govoni, M Padovan, L Melchiorri, M Stignani, S Carturan, S Ferretti, F Trotta, OR Baricordi. HLA-G 14-bp polymorphism regulates the methotrexate response in rheumatoid arthritis. Pharmacogenet Genomics 2006; 16(9): 615–623 pmid: 16906016
22 OR Baricordi, M Govoni, R Rizzo, F Trotta. In rheumatoid arthritis, a polymorphism in the HLA-G gene concurs in the clinical response to methotrexate treatment. Ann Rheum Dis 2007; 66(8): 1125–1126 pmid: 17626975
23 LK Stamp, JL O’Donnell, PT Chapman, ML Barclay, MA Kennedy, CM Frampton, RL Roberts. Lack of association between HLA-G 14 bp insertion/deletion polymorphism and response to long-term therapy with methotrexate response in rheumatoid arthritis. Ann Rheum Dis 2009; 68(1): 154–155 pmid: 19088262
24 M Fabris, L Quartuccio, S Lombardi, M Saracco, F Atzeni, A Carletto, M Cimmino, C Fabro, E Pontarini, R Pellerito, LM Bambara, P Sarzi-Puttini, M Cutolo, M Manfredi, M Benucci, P Morassi, F Fischetti, M Padovan, M Govoni, F Curcio, E Tonutti, S De Vita. The CC homozygosis of the −174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. Autoimmun Rev 2012; 11(5): 315–320 pmid: 20974296
25 H Schotte, B Schlüter, S Drynda, P Willeke, N Tidow, G Assmann, W Domschke, J Kekow, M Gaubitz. Interleukin 10 promoter microsatellite polymorphisms are associated with response to long term treatment with etanercept in patients with rheumatoid arthritis. Ann Rheum Dis 2005; 64(4): 575–581 pmid: 15345504
26 LB Hughes, TM Beasley, H Patel, HK Tiwari, SL Morgan, JE Baggott, KG Saag, J McNicholl, LW Moreland, GS Alarcón, SL Jr Bridges. Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 2006; 65(9): 1213–1218 pmid: 16439441
27 SK Kim, JB Jun, A El-Sohemy, SC Bae. Cost-effectiveness analysis of MTHFR polymorphism screening by polymerase chain reaction in Korean patients with rheumatoid arthritis receiving methotrexate. J Rheumatol 2006; 33(7): 1266–1274
pmid: 16758511
28 R Cáliz, J del Amo, A Balsa, F Blanco, L Silva, R Sanmarti, FG Martínez, MD Collado, MC Ramirez, D Tejedor, M Artieda, D Pascual-Salcedo, N Oreiro, JL Andreu, E Graell, L Simon, A Martínez, J Mulero. The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population. Scand J Rheumatol 2012; 41(1): 10–14 pmid: 22044028
29 S Inoue, M Hashiguchi, K Takagi, S Kawai, M Mochizuki. Preliminary study to identify the predictive factors for the response to methotrexate therapy in patients with rheumatoid arthritis. Yakugaku Zasshi 2009; 129(7): 843–849 pmid: 19571519
30 R Takatori, KA Takahashi, D Tokunaga, T Hojo, M Fujioka, T Asano, T Hirata, Y Kawahito, Y Satomi, H Nishino, T Tanaka, Y Hirota, T Kubo. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol 2006; 24(5): 546–554
pmid: 17181924
31 M Cuchacovich, L Soto, M Edwardes, M Gutierrez, C Llanos, D Pacheco, F Sabugo, M Alamo, C Fuentealba, L Villanueva, H Gatica, I Schiattino, L Salazaro, D Catalan, O Valenzuela, F Salazar-Onfray, JC Aguillón. Tumour necrosis factor (TNF)α –308 G/G promoter polymorphism and TNFα levels correlate with a better response to adalimumab in patients with rheumatoid arthritis. Scand J Rheumatol 2006; 35(6): 435–440 pmid: 17343250
32 S Stojanović, T Jevtović-Stoimenov, A Stanković, D Pavlović, J Neković, B Stamenković, A Dimić, M Marinković. Association of TNF-α polymorphism (−308 A/G) with high activity of rheumatoid arthritis and therapy response to Etanercept. Srp Arh Celok Lek 2011; 139(11-12): 784–789 (in Serbian) pmid: 22338476
33 M Fabris, E Di Poi, S Sacco, G Damante, L Sinigaglia, G Ferraccioli. TNF-α gene polymorphisms in rheumatoid arthritis patients treated with anti-TNF-α agents: preliminary results. Reumatismo 2002; 54(1): 19–26 (in Italian)
pmid: 12089610
34 YH Lee, JD Ji, SC Bae, GG Song. Associations between tumor necrosis factor-α (TNF-α) –308 and –238 G/A polymorphisms and shared epitope status and responsiveness to TNF-α blockers in rheumatoid arthritis: a metaanalysis update. J Rheumatol 2010; 37(4): 740–746 pmid: 20194454
35 C Rooryck, T Barnetche, C Richez, A Laleye, B Arveiler, T Schaeverbeke. Influence of FCGR3A-V212F and TNFRSF1B-M196R genotypes in patients with rheumatoid arthritis treated with infliximab therapy. Clin Exp Rheumatol 2008; 26(2): 340–342
pmid: 18565259
36 CM Ulrich, Y Yasui, R Storb, MM Schubert, JL Wagner, J Bigler, KS Ariail, CL Keener, S Li, H Liu, FM Farin, JD Potter. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 2001; 98(1): 231–234 pmid: 11418485
37 PB Grabar, B Rozman, D Logar, S Praprotnik, V Dolzan. Dihydroorotate dehydrogenase polymorphism influences the toxicity of leflunomide treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2009; 68(8): 1367–1368 pmid: 19605743
38 E Rath, J Zwerina, B Oppl, V Nell-Duxneuner. Efficacy and safety of rituximab in rheumatic diseases. Wien Med Wochenschr 2015; 165(1-2): 28–35 pmid: 25676699
39 PC Taylor, RO Williams. Combination cytokine blockade: the way forward in therapy for rheumatoid arthritis? Arthritis Rheumatol 2015; 67(1): 14–16 pmid: 25302944
40 LG van Baarsen, CA Wijbrandts, F Rustenburg, T Cantaert, TC van der Pouw Kraan, DL Baeten, BA Dijkmans, PP Tak, CL Verweij. Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther 2010; 12(1): R11 pmid: 20096109
41 TD de Jong, S Vosslamber, M Blits, G Wolbink, MT Nurmohamed, CJ van der Laken, G Jansen, AE Voskuyl, CL Verweij. Effect of prednisone on type I interferon signature in rheumatoid arthritis: consequences for response prediction to rituximab. Arthritis Res Ther 2015; 17(1): 78 pmid: 25889713
42 J Rodríguez-Carrio, P López, A Suárez. Type I IFNs as biomarkers in rheumatoid arthritis: towards disease profiling and personalized medicine. Clin Sci (Lond) 2015; 128(8): 449–464 pmid: 25630235
43 M Jani, H Chinoy, RB Warren. Em Griffiths C, Plant D, Fu B, Morgan AW, Wilson AG, Isaacs JD, Hyrich KL, Barton A; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate Collaborators. Clinical utility of random anti-TNF drug level testing and measurement of anti-drug antibodies on long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol 2015; 385(8): S48
44 T Takeuchi, K Yamamoto, H Yamanaka, N Ishiguro, Y Tanaka, K Eguchi, A Watanabe, H Origasa, T Shoji, N Miyasaka, T Koike. Early response to certolizumab pegol predicts long-term outcomes in patients with active rheumatoid arthritis: results from the Japanese studies. Mod Rheumatol 2015; 25(1): 11–20 pmid: 24842476
45 S Blaschke, K Rinke, M Maring, T Flad, S Patschan, O Jahn, CA Mueller, GA Mueller, H Dihazi. Haptoglobin-a1, -a2, vitamin D-binding protein and apolipoprotein C-III as predictors of etanercept drug response in rheumatoid arthritis. Arthritis Res Ther 2015; 17(1): 45 pmid: 25884688
46 F Atzeni, S Bongiovanni, A Marchesoni, M Filippini, R Caporali, R Gorla, L Cavagna, EG Favalli, F Saccardo, P Sarzi-Puttini. Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores. Joint Bone Spine 2014; 81(1): 37–40 pmid: 23731638
47 C Barnabe, J Homik, SG Barr, L Martin, WP Maksymowych. The effect of different remission definitions on identification of predictors of both point and sustained remission in rheumatoid arthritis treated with anti-TNF therapy. J Rheumatol 2014; 41(8): 1607–1613 pmid: 25028371
48 LE Kristensen, MC Kapetanovic, A Gülfe, M Söderlin, T Saxne, P Geborek. Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford) 2008; 47(4): 495–499 pmid: 18316338
49 S Luban, ZG Li. Citrullinated peptide and its relevance to rheumatoid arthritis: an update. Int J Rheum Dis 2010; 13(4): 284–287 pmid: 21199462
50 D Pietrapertosa, B Tolusso, E Gremese, MC Papalia, SL Bosello, G Peluso, L Petricca, A Michelutti, F Faustini, AL Fedele, G Ferraccioli. Diagnostic performance of anti-citrullinated peptide antibodies for the diagnosis of rheumatoid arthritis: the relevance of likelihood ratios. Clin Chem Lab Med 2010; 48(6): 829–834 pmid: 20298138
51 J Narváez, C Díaz-Torné, JM Ruiz, MV Hernandez, V Torrente-Segarra, S Ros, A Rodriguez de la Serna, C Díaz-López, R Sanmartí, JM Nolla. Predictors of response to rituximab in patients with active rheumatoid arthritis and inadequate response to anti-TNF agents or traditional DMARDs. Clin Exp Rheumatol 2011; 29(6): 991–997
pmid: 22133052
52 L Chara, A Sánchez-Atrio, A Pérez, E Cuende, F Albarrán, A Turrión, J Chevarria, AA del Barco, MA Sánchez, J Monserrat, A Prieto, A de la Hera, I Sanz, D Diaz, M Alvarez-Mon. The number of circulating monocytes as biomarkers of the clinical response to methotrexate in untreated patients with rheumatoid arthritis. J Transl Med 2015; 13(1): 2 pmid: 25592233
53 G Jutley, K Raza, CD Buckley. New pathogenic insights into rheumatoid arthritis. Curr Opin Rheumatol 2015; 27(3): 249–255 pmid: 25775189
54 A Johannsen, C Susin, A Gustafsson. Smoking and inflammation: evidence for a synergistic role in chronic disease. Periodontol 2000 2014; 64(1): 111–126 pmid: 24320959
55 IC Scott, R Tan, D Stahl, S Steer, CM Lewis, AP Cope. The protective effect of alcohol on developing rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford) 2013; 52(5): 856–867 pmid: 23287363
56 KL Hyrich, KD Watson, AJ Silman, DP Symmons; British Society for Rheumatology Biologics Register. Predictors of response to anti-TNFα therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford) 2006; 45(12): 1558–1565 pmid: 16705046
57 C Lin, EW Karlson, H Canhao, TA Miller, D Dligach, PJ Chen, RN Perez, Y Shen, ME Weinblatt, NA Shadick, RM Plenge, GK Savova. Automatic prediction of rheumatoid arthritis disease activity from the electronic medical records. PLoS One 2013; 8(8): e69932 pmid: 23976944
58 SK Sieberts, F Zhu, J García-García, E Stahl, A Pratap, G Pandey, D Pappas, D Aguilar, B Anton, J Bonet, R Eksi, O Fornés, E Guney, H Li, MA Marín, B Panwar, J Planas-Iglesias, D Poglayen, J Cui, AO Falcao, C Suver, B Hoff, VS Balagurusamy, D Dillenberger, EC Neto, T Norman, T Aittokallio, M Ammad-Ud-Din, CA Azencott, V Bellón, V Boeva, K Bunte, H Chheda, L Cheng, J Corander, M Dumontier, A Goldenberg, P Gopalacharyulu, M Hajiloo, D Hidru, A Jaiswal, S Kaski, B Khalfaoui, SA Khan, ER Kramer, P Marttinen, AM Mezlini, B Molparia, M Pirinen, J Saarela, M Samwald, V Stoven, H Tang, J Tang, A Torkamani, JP Vert, B Wang, T Wang, K Wennerberg, NE Wineinger, G Xiao, Y Xie, R Yeung, X Zhan, C; Members of the Rheumatoid Arthritis Challenge Consortium, Greenberg J Zhao, J Greenberg, J Kremer, K Michaud, A Barton, M Coenen, X Mariette, C Miceli, N Shadick, M Weinblatt, N de Vries, PP Tak, D Gerlag, TW Huizinga, F Kurreeman, CF Allaart, S Louis Bridges Jr, L Criswell, L Moreland, L Klareskog, S Saevarsdottir, L Padyukov, PK Gregersen, S Friend, R Plenge, G Stolovitzky, B Oliva, Y Guan, LM Mangravite, SL Bridges, L Criswell, L Moreland, L Klareskog, S Saevarsdottir, L Padyukov, PK Gregersen, S Friend, R Plenge, G Stolovitzky, B Oliva, Y Guan, LM Mangravite. Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis. Nat Commun 2016; 7: 12460 pmid: 27549343
59 S Viatte, D Plant, B Han, B Fu, A Yarwood, W Thomson, DP Symmons, J Worthington, A Young, KL Hyrich, AW Morgan, AG Wilson, JD Isaacs, S Raychaudhuri, A Barton. Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA 2015; 313(16): 1645–1656 pmid: 25919528
60 T Takeuchi, N Miyasaka, Y Tatsuki, T Yano, T Yoshinari, T Abe, T Koike. Inhibition of plasma IL-6 in addition to maintenance of an efficacious trough level of infliximab associated with clinical remission in patients with rheumatoid arthritis: analysis of the RISING Study. Ann Rheum Dis 2012; 71(9): 1583–1585 pmid: 22562980
Related articles from Frontiers Journals
[1] Ke Sheng. Artificial intelligence in radiotherapy: a technological review[J]. Front. Med., 2020, 14(4): 431-449.
[2] Xiaojing Jiao, Dong Zhang, Quan Hong, Lei Yan, Qiuxia Han, Fengmin Shao, Guangyan Cai, Xiangmei Chen, Hanyu Zhu. Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease[J]. Front. Med., 2020, 14(3): 293-304.
[3] Amy Lee, Fa-Chyi Lee. Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check[J]. Front. Med., 2020, 14(3): 273-283.
[4] Xuran Chu, Chengshui Chen, Chaolei Chen, Jin-San Zhang, Saverio Bellusci, Xiaokun Li. Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors[J]. Front. Med., 2020, 14(3): 262-272.
[5] Guangbiao Zhou, Saijuan Chen, Zhu Chen. Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies[J]. Front. Med., 2020, 14(2): 117-125.
[6] Qiaoshuai Lan, Shuai Xia, Qian Wang, Wei Xu, Haiyan Huang, Shibo Jiang, Lu Lu. Development of oncolytic virotherapy: from genetic modification to combination therapy[J]. Front. Med., 2020, 14(2): 160-184.
[7] Jie Pan, Zhengchao Shi, Dingsai Lin, Ningmin Yang, Fei Meng, Lang Lin, Zhencheng Jin, Qingjie Zhou, Jiansheng Wu, Jianzhong Zhang, Youming Li. Is tailored therapy based on antibiotic susceptibility effective ? A multicenter, open-label, randomized trial[J]. Front. Med., 2020, 14(1): 43-50.
[8] Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu. Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer[J]. Front. Med., 2020, 14(1): 60-67.
[9] Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li. NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation inhibition[J]. Front. Med., 2019, 13(6): 646-657.
[10] Rui Zhou, Yuanshu Liu, Wenjun Huang, Xitong Dang. Potential functions of esophageal cancer-related gene-4 in the cardiovascular system[J]. Front. Med., 2019, 13(6): 639-645.
[11] Xin Qin, Ping Zhang. ECRG4: a new potential target in precision medicine[J]. Front. Med., 2019, 13(5): 540-546.
[12] Xiao He, Chentao Jin, Mindi Ma, Rui Zhou, Shuang Wu, Haoying Huang, Yuting Li, Qiaozhen Chen, Mingrong Zhang, Hong Zhang, Mei Tian. PET imaging on neurofunctional changes after optogenetic stimulation in a rat model of panic disorder[J]. Front. Med., 2019, 13(5): 602-609.
[13] Haolin Sun, Chun Liu, Shunlun Chen, Yanjie Bai, Huilin Yang, Chunde Li, Lei Yang. Effect of surgical factors on the augmentation of cement- injectable cannulated pedicle screw fixation by a novel calcium phosphate-based nanocomposite[J]. Front. Med., 2019, 13(5): 590-601.
[14] Hudan Pan, Yanfang Zheng, Zhongqiu Liu, Zhongwen Yuan, Rutong Ren, Hua Zhou, Ying Xie, Liang Liu. Deciphering the pharmacological mechanism of Guan-Jie-Kang in treating rat adjuvant-induced arthritis using omics analysis[J]. Front. Med., 2019, 13(5): 564-574.
[15] Tianyuan Li, Renbing Jia, Xianqun Fan. Classification and treatment of orbital venous malformations: an updated review[J]. Front. Med., 2019, 13(5): 547-555.
Full text