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The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy

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Bibliography

  • Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
  • Lima A, Monteiro J, Bernardes M, et al. Prediction of methotrexate clinical response in Portuguese rheumatoid arthritis patients: implication of MTHFR rs1801133 and ATIC rs4673993 polymorphisms. Biomed Res Int. 2014; 2014:368681.
  • Chaabane S, Marzouk S, Akrout R, et al. Genetic determinants of methotrexate toxicity in Tunisian patients with rheumatoid arthritis: a study of polymorphisms involved in the MTX metabolic pathway. Eur J Drug Metab Pharmacokinet. 2015. Published online 16 June 2015. DOI: 10.1007/s13318-015-0288-z.
  • Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71:1914–1915.
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  • Nash P, Nayiager S, Genovese MC, et al. Immunogenicity, safety, and efficacy of abatacept administered subcutaneously with or without background methotrexate in patients with rheumatoid arthritis: results from a phase III, international, multicenter, parallel-arm, open-label study. Arthritis Care Res (Hoboken). 2013;65:718–728.
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  • Hayashi H, Fujimaki C, Daimon T, et al. Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis. J Clin Pharm Ther. 2009;34:355–361.
  • Dervieux T, Greenstein N, Kremer J. Pharamcogenomic and metabolic biomarkers the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 2006;54:3095–3103.

• This study analyzed the contribution of MTX metabolites, folate polyglutamate levels and pharmacogenetic biomarkers in the folate pathway to the effects of MTX in patients with rheumatoid arthritis.

  • Hughes LB, Danila MI, Bridges SL. Recent advances in personalizing rheumatoid arthritis therapy and management. Per Med. 2009;6:159–170.
  • Kung TN, Dennis J, Ma Y, et al. FRC1 80G>A is a genetic determinant of methotrexate efficacy in rheumatoid arthritis. Arthritis Rheum. 2014;66:1111–1120.
  • Hayashi H, Tazoe Y, Tsuboi S, et al. A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacytokinet. 2013;28:164–168.
  • Takatori R, Takahashi KA, Tokunaga D, et al. ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients. Clin Exp Rheumatol. 2006;24:546–554.

•• The authors investigated whether ABCB1 C3435T, RFC1 G80A, ATIC C347G and TYMS gene are predictive of MTX sensitivity and its adverse effects.

  • Wessels JA, de Vries-Bouwstra JK, Hejimans BT, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum. 2006;54:1087–1095.

• This study analyzed the associations between MTX efficacy and toxicity and SNPs in genes coding for folate pathway enzymes in patients with early RA.

  • Campalani E, Arenas M, Marinaki AM, et al. Polymorphisms in folate pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007;127:1860–1867.
  • Bohanec-Grabar P, Leonardo-Garcia LJ, Inglada-Perez L, et al. Genetic variation in the SLC19A1 gene and methotrexate toxicity in rheumatoid arthritis patients. Pharamcogenomics. 2012;13:1583–1594.
  • Lima A, Bernardes M, Sousa H, et al. SLC19A1 80G allele as a biomarker of methotrexate-related gastrointestinal toxicity in Portuguese rheumatoid arthritis patients. Pharamocogenomics. 2014;15:807–820.

• The results of this study suggest that SLC19A1 G80A genotyping may be a useful tool for clinicians to identify patients at higher risk for developing gastrointestinal toxicity related to MTX treatment.

  • Lima A, Bernardes M, Azevedo R, et al. SLC19A1, SLC46A1 and SLCO1B1 polymorphisms as predictors of methotrexate-related toxicity in Portuguese rheumatoid arthritis patients. Toxicol Sci. 2014;142:196–209.

• Relatively recent study on SLC19A1 haplotype in MTX toxicity.

  • Gervasini G. Polymorphisms in methotrexate pathways: what is clinically relevant, what is not and what is promising. Curr Drug Metab. 2009;10:547–566.
  • Kato T, Hamada A, Mori S, et al. Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis. Drug Metab Pharmacokinet. 2012;27:192–199.
  • van der Straaten RJ, Wessels JA, de Vries-Bouwstra JK, et al. Exploratory analysis of four polymorphisms in human GGH and FPGS genes and their effect in methotrexate-treated rheumatoid arthritis patients. Pharmacogenomics. 2007;8:141–150.
  • Rego-Pérez I, Fernández-Moreno M, Blanco FJ. Gene polymorphisms and pharmacogenetics in rheumatoid arthritis. Curr Genomics. 2008;9:381–393.
  • Stanislawska-Sachadyn A, Brown KS, Mitchell LE, et al. An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women. Hum Genet. 2008;123:289–295.
  • Devila-Fajardo CL, Swen JJ, Cabeza-Barrera J, et al. Genetic risk factors for drug-induced liver injury in rheumatoid arthritis patients using low-dose methotrexate. Pharmacogenomics. 2013;14:63–73.
  • Stamp LK, Roberts RL. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases. Pharmacogenomics. 2011;12:1449–1463.
  • Kurzawski M, Pawlik A, Safranow K, et al. 677C>T and 1298A>C MTHRF polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics. 2007;8:1551–1559.
  • Urano W, Taniguchi A, Yamanaka H, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharamacogenetics. 2002;12:183–190.

• The authors have shown that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients.

  • Taniguchi A, Urano W, Tanaka E, et al. Validation of the associations between single nucleotide polymorphisms or haplotypes and responses to disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a proposal for prospective pharmacogenomic study in clinical practice. Pharmacogenet Genom. 2007;17:383–390.
  • Palomino-Morales R1, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, et al. A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis. Arthritis Res Ther. 2010;12:R71.
  • Soukup T, Dosedel M, Pavek P, et al. The impact of C677T and A1298C MTHFR polymorphisms on methotrexate therapeutic response in East Bohemian region rheumatoid arthritis patients. Rheumatol Int. 2015;35:1149–1161.
  • Lima A, Seabra V, Bernardes M, et al. Role of key TYMS polymorphisms on methotrexate therapeutic outcome in Portuguese rheumatoid arthritis patients. PLOS One. 2014;9:e108165.
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  • Jekic B, Lukovic L, Bunjevacki V, et al. Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients. Eur J Clin Pharmacol. 2013;69:377–383.
  • Sharma S, Das M, Mukar A, et al. Purine biosynthetic pathway genes and methotrexate response in rheumatoid arthritis patients among north Indians. Pharmacogenet Genomics. 2009;19:823–828.
  • Pawlik A, Herczynska M, Kurzawski M, et al. The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on rheumatoid arthritis treatment with leflunomide. Pharmacogenomics. 2009;10:303–309.
  • O’Doherty C, Schnabl M, Spargo L, et al. Association of DHODH haplotype variants and response to leflunomide treatment in rheumatoid arthritis. Pharmacogenomics. 2012;13:1427–1434.
  • Wiese MD, Schnabl M, O’Doherty C, et al. Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis. Arthritis Res Ther. 2012;14:R163.
  • Bohanec-Grabar P, Rozman B, Tomsic M, et al. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol. 2008;64:871–876.

• The results of this study suggest that genetic variability in leflunomide-metabolizing enzymes influences leflunomide metabolite concentrations that are associated with the treatment response.

  • Bohanec-Grabar P, Grabnar I, Rozman B, et al. 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;37:2061–2068.
  • Dziedziejko V, Kurzawski M, Safranow K, et al. The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenomics. 2011;12:41–47.
  • Dziedziejko V, Kurzawski M, Safranow K, et al. Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide. Eur J Clin Pharmacol. 2012;68:371–377.
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  • Wiese MD, Alotaibi N, O’Doherty C, et al. Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis. Pharmacogenomics J. 2014;14:350–355.
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  • Tanaka E, Taniguchi A, Urano W, et al. Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol. 2002;29:2492–2499.
  • Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907–916.
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  • Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:353–363.
  • Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2:473–488.
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  • Paleolog EM, Young S, Stark AC, et al. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 1998;41:1258–1265.
  • Charles P, Elliott MJ, Davis D, et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol. 1999;163:1521–1528.
  • Klimiuk PA, Sierakowski S, Domyslawska I, et al. Reduction of soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular endothelial growth factor levels in serum of rheumatoid arthritis patients following multiple intravenous infusions of infliximab. Arch Immunol Ther Exp. 2004;52:36–42.
  • Ulfgren AK, Andersson U, Engström M, et al. Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum. 2000;43:2391–2396.
  • Kubota A, Hasegawa K, Suguro T, et al. Tumor necrosis factor-alpha promotes the expression of osteoprotegerin in rheumatoid synovial fibroblasts. J Rheumatol. 2004;31:426–435.
  • Lee CK, Lee EY, Chung SM, et al. Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor kappaB, osteoprotegerin, and receptor activator of nuclear factor kappaB ligand. Arthritis Rheum. 2004;50:3831–3843.
  • Cohen G, Courvoisier N, Cohen JD, et al. The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2005;23:795–800.
  • Verweij CL. Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid arthritis. Ann Rheum Dis. 1999;58:120–126.
  • de Vries N, Tak PP. The response to anti-TNF-alpha treatment: gene regulation at the bedside. Rheumatology (Oxford). 2005;44:705–707.
  • Fonseca JE, Carvalho T, Cruz M, et al. Polymorphism at position −308 of the tumour necrosis factor alpha gene and rheumatoid arthritis Pharmacogenetics. Ann Rheum Dis. 2005;64:793–794.
  • Elahi MM, Asotra K, Matata BM, et al. Tumor necrosis factor alpha −308 gene locus promoter polymorphism: an analysis of association with health and disease. Biochim Biophys Acta. 2009;1792:163–172.
  • Hajeer AH, Hutchinson IV. Influence of TNFalpha gene polymorphisms on TNFalpha production and disease. Hum Immunol. 2001;62:1191–1199.
  • Mullighan CG, Fanning GC, Chapel HM, et al. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol. 1997;159:6236–6241.
  • Miceli-Richard C, Comets E, Verstuyft C, et al. A single tumour necrosis factor haplotype influences the response to adalimumab in rheumatoid arthritis. Ann Rheum Dis. 2008;67:478–484.
  • Maxwell JR, Potter C, Hyrich KL, et al. Association of the tumour necrosis factor-308 variant with differential response to anti-TNF agents in the treatment of rheumatoid arthritis. Hum Mol Genet. 2008;17:3532–3538.

• Large population in single polymorphism study.

  • Guis S, Balandraud N, Bouvenot J, et al. Influence of −308 A/G polymorphism in the tumor necrosis factor alpha gene on etanercept treatment in rheumatoid arthritis. Arthritis Rheum. 2007;57:1426–1430.
  • Seitz M, Wirthmuller U, Moller B, et al. The −308 tumour necrosis factor-{alpha} gene polymorphism predicts therapeutic response to TNF{alpha}-blockers in rheumatoid arthritis and spondyloarthritis patients. Rheumatology (Oxford). 2007;46:93–96.
  • Cuchacovich M, Ferreira L, Aliste M, et al. Tumour necrosis factor-alpha (TNF-alpha) levels and influence of –308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol. 2004;33:228–232.
  • Schmeling H, Horneff G. Tumour necrosis factor alpha promoter polymorphisms and etanercept therapy in juvenile idiopathic arthritis. Rheumatol Int. 2007;27:383–386.
  • Padyukov L, Lampa J, Heimburger M, et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis. 2003;62:526–529.
  • Mugnier B, Balandraud N, Darque A, et al. Polymorphism at position –308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum. 2003;48:1849–1852.
  • Marotte H, Pallot-Prades B, Grange L, et al. The shared epitope is a marker of severity associated with selection for, but not with response to, infliximab in a large rheumatoid arthritis population. Ann Rheum Dis. 2006;65:342–347.
  • Rodríguez-Rodríguez L, González-Juanatey C, Palomino-Morales R, et al. TNFA −308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis. 2011;216:125–130.
  • Kang CP, Lee KW, Yoo DH, et al. The influence of a polymorphism at position –857 of the tumour necrosis factor alpha gene on clinical response to etanercept therapy in rheumatoid arthritis. Rheumatology (Oxford). 2005;44:547–552.
  • van Heel DA, Udalova IA, De Silva AP, et al. Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(−kappa)B transcription factors. Hum Mol Genet. 2002;11:1281–1289.
  • Hohjoh H, Tokunaga K. Allele-specific binding of the ubiquitous transcription factor OCT-1 to the functional single nucleotide polymorphism (SNP) sites in the tumor necrosis factor-alpha gene (TNFA) promoter. Genes Immun. 2001;2:105–109.
  • Swierkot J, Bogunia-Kubik K, Nowak B, et al. Analysis of associations between polymorphisms within genes coding for tumour necrosis factor (TNF)-alpha and TNF receptors and responsiveness to TNF-alpha blockers in patients with rheumatoid arthritis. Joint Bone Spine. 2015;82:94–99.
  • Criswell LA, Lum RF, Turner KN, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum. 2004;50:2750–2756.
  • Ongaro A, De Mattei M, Pellati A, et al. Can tumor necrosis factor receptor II gene 676T > G polymorphism predict the response grading to anti-TNF-alpha therapy in rheumatoid arthritis?. Rheumatol Int. 2008;28:901–908.
  • Fabris M, Di PE, D’Elia A, et al. Tumor necrosis factor-alpha gene polymorphism in severe and mild-moderate rheumatoid arthritis. J Rheumatol. 2002;29:29–33.
  • Chatzikyriakidou A, Georgiou I, Voulgari PV, et al. Combined tumour necrosis factor-alpha and tumour necrosis factor receptor genotypes could predict rheumatoid arthritis patients’ response to anti-TNF-alpha therapy and explain controversies of studies based on a single polymorphism. Rheumatology (Oxford). 2007;46:1034–1035.
  • Toonen EJ, Coenen MJ, Kievit W, et al. The tumour necrosis factor receptor superfamily member 1b 676TNG polymorphism in relation to response to infliximab and adalimumab treatment and disease severity in rheumatoid arthritis. Ann Rheum Dis. 2008;67:1174–1177.
  • Avil-Pedretti G, Tornero J, Fernandez-Nebro A, et al. Variation at FCGR2A and functionally related genes is associated with the response to anti-TNF therapy in rheumatoid arthritis. PLoS One. 2015;10:e0122088.

• Recent study, and new genes identified associated with the response to anti-TNF treatment.

  • Canete JD, Suarez B, Hernandez MV, et al. Influence of variants of Fc gamma receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor alpha therapy in rheumatoid arthritis. Ann Rheum Dis. 2009;68:1547–1552.
  • Montes A, Perez-Pampin E, Narvaez J, et al. Association of FCGR2A with the response to infliximab treatment of patients with rheumatoid arthritis. Pharmacogenet Genomics. 2014;24:238–245.
  • Mathews RJ, Robinson JI, Battellino M, et al. Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann Rheum Dis. 2014;73:1202–1210.
  • Sode J, Vogel U, Bank S, et al. Anti-TNF treatment response in rheumatoid arthritis patients is associated with genetic variation in the NLRP3-inflammasome. PLoS One. 2014;9:e100361.
  • Potter C, Cordell HJ, Barton A, et al. Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways. Ann Rheum Dis. 2010;69:1315–1320.
  • Nishimoto T, Seta N, Anan R, et al. A single nucleotide polymorphism of TRAF1 predicts the clinical response to anti-TNF treatment in Japanese patients with rheumatoid arthritis. Clin Exp Rheumatol. 2014;32:211–217.
  • Houssiau FA, Devogelaer JP, Van Damme J, et al. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988;31:784–788.
  • Madhok R, Crilly A, Watson J, et al. Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis. 1993;52:232–234.
  • Lo SF, Huang CM, Lin HC, et al. Cytokine (IL-6) and chemokine (IL-8) gene polymorphisms among rheumatoid arthritis patients in Taiwan. Clin Exp Rheumatol. 2008;26:632–637.
  • Lee YH, Bae SC, Choi SJ, et al. The association between interleukin-6 polymorphisms and rheumatoid arthritis: a meta-analysis. Inflamm Res. 2012;61:665–671.
  • Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin‐6 (IL‐6) gene on IL‐6 transcription and plasma IL‐6 levels, and an association with systemic‐onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–1376.

• Important meta-analysis.

  • Hulkkonen J, Pertovaara M, Antonen J, et al. Elevated interleukin-6 plasma levels are regulated by the promoter region polymorphism of the IL-6 gene in primary Sjogren’s syndrome and correlate with the clinical manifestations of the disease. Rheumatology (Oxford). 2001;40:656–661.
  • Humphries SE, Luong LA, Ogg MS, et al. The interleukin-6 174 G/C polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J. 2001;22:2219–2220.
  • Davila-Fajardo CL, Marquez A, Pascual-Salcedo D, et al. Confirmation of −174G/C interleukin-6 gene promoter polymorphism as a genetic marker predicting antitumor necrosis factor treatment outcome. Pharmacogenet Genomics. 2014;24:1–5.
  • Jancic I, Arsenovic-Ranin N, Sefik-Bukilica M, et al. 174G/C interleukin-6 gene promoter polymorphism predicts therapeutic response to etanercept in rheumatoid arthritis. Rheumatol Int. 2013;33:1481–1486.
  • Lee YH, Bae SC, Song GG. Functional FCGR3A 158 V/F and IL-6 −174 C/G polymorphisms predict response to biologic therapy in patients with rheumatoid arthritis: a meta-analysis. Rheumatol Int. 2014;34:1409–1415.
  • Ceccarelli F, Perricone C, Fabris M, et al. Transforming growth factor β 869C/T and interleukin 6–174G/C polymorphisms relate to the severity and progression of bone-erosive damage detected by ultrasound in rheumatoid arthritis. Arthritis Res Ther. 2011;13:R111.
  • Hassan B, Maxwell JR, Hyrich KL, et al. Genotype at the sIL-6R A358 C polymorphism does not influence response to anti-TNF therapy in patients with rheumatoid arthritis. Rheumatology (Oxford). 2010;49:43–47.
  • Potter C, Hyrich KL, Tracey A, et al. Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis. Ann Rheum Dis. 2009;68:69–74.
  • Ogata A, Amano K, Dobashi H, et al. Longterm safety and efficacy of subcutaneous tocilizumab monotherapy: results from the 2-year open-label extension of the MUSASHI study. J Rheumatol. 2015;42:799–809.
  • McLaughlin M, Östör A. Safety of subcutaneous versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Expert Opin Drug Saf. 2015;14:429–437.
  • Narváez J, Díaz-Torné C, Magallares B, et al. Comparative efficacy of novel DMARDs as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with inadequate response to conventional DMARDs: a network meta-analysis. PLoS One. 2015;10:e0123392.
  • Genovese MC, Rubbert-Roth A, Smolen JS, et al. Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. J Rheumatol. 2013;40:768–780.
  • Wang J, Bansal AT, Martin M, et al. Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis. Pharmacogenomics J. 2013;13:235–241.

•• Large population examined in GWAS study.

  • Enevold C, Baslund B, Linde L, et al. Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis. Pharmacogenet Genomics. 2014;24:401–405.
  • Fabris M, Quartuccio L, Lombardi S, et al. Study on the possible role of the −174G>C IL-6 promoter polymorphism in predicting response to rituximab in rheumatoid arthritis. Reumatismo. 2010;62:253–258.
  • Fabris M, Quartuccio L, Lombardi S, et al. The CC homozygosis of the −174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis. Autoimmun Rev. 2012;11:315–320.
  • Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–445.
  • Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010;47:115–123.
  • Daïen CI, Fabre S, Rittore C, et al. TGF beta1 polymorphisms are candidate predictors of the clinical response to rituximab in rheumatoid arthritis. Joint Bone Spine. 2012;79:471–475.
  • Quartuccio L, Fabris M, Pontarini E, et al. The 158VV Fc gamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study. Ann Rheum Dis. 2014;73:716–721.
  • Kastbom A, Coster L, Arlestig L, et al. Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study. BMJ Open. 2012;2:e001524.
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• Important meta-analysis.

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