Many therapies are now available for patients with rheumatoid arthritis (RA) who have an inadequate response to methotrexate including tumor necrosis factor inhibitors, abatacept, tocilizumab, and rituximab. Clinical response to drugs varies widely between individuals. A part of this variability is due to the characteristics of the patient such as age, gender, concomitant therapies, body mass index, or smoking status. Clinical response also depends on disease characteristics including disease activity and severity and presence of autoantibodies. Genetic background, cytokine levels, and immune cell phenotypes could also influence biological therapy response. This review summarizes the impact of all those parameters on response to biological therapies. 1. Introduction Many biological therapies are now available for patients with rheumatoid arthritis (RA) who have an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARD) especially methotrexate (MTX) or to a first tumor necrosis factor (TNF) inhibitor (TNFi). They can be treated with either TNFi (etanercept (ETN), infliximab (IFX), adalimumab (ADA), certolizumab, or golimumab), or a T cell targeting therapy (CTLA4-Ig abatacept (ABA)) or an anti-IL-6 receptor drug (tocilizumab (TCZ)), or a B cell targeting therapy, mostly represented by anti-CD20 antibodies like rituximab (RTX). Clinical response to drugs varies widely between individuals. A part of this variability is due to drug concentration and pharmacokinetic which is influenced by the characteristics of the patient such as age, gender, renal and liver functions, body mass index (BMI), or smoking status. Concomitant therapies and drug immunogenicity also influence drug concentrations. Clinical response depends on disease state and disease characteristics as well. Indeed, there are different subtypes of RA with different genetic backgrounds, that is, seropositive or seronegative RA [1] and benign or destructive RA [2–4]. Depending on patients, the RA could be preferentially mediated by one cytokine; for example, some diseases are very dependent on TNF, whereas others are not [5]. One immune cell type can also be more important in some patients than others (i.e., B or T cells, Th1 or Th17 [6], etc.). Although all these parameters may influence therapeutic response, tools which could be used in daily practice to predict response to biological drugs are lacking. This review synthesizes the largest studies on factors influencing response to TNFi, ABA, RTX, and TCZ therapy (Table 1). Table 1: Main studies presented in this review. 2.
References
[1]
S. Viatte, D. Plant, J. Bowes et al., “Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients,” Annals of the Rheumatic Diseases, vol. 71, no. 12, pp. 1984–1990, 2012.
[2]
D. P. C. De Rooy, N. G. Yeremenko, A. G. Wilson et al., “Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 72, no. 5, pp. 769–775, 2013.
[3]
T. Suzuki, K. Ikari, K. Yano et al., “PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: results from the IORRA cohort study,” PloS One, vol. 8, no. 4, Article ID e61045, 2013.
[4]
M. P. M. Van Der Linden, A. L. Feitsma, S. Le Cessie et al., “Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 60, no. 8, pp. 2242–2247, 2009.
[5]
H. Marotte, W. Maslinski, and P. Miossec, “Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients treated with infliximab: link to clinical response,” Arthritis Research & Therapy, vol. 7, no. 1, pp. R149–R155, 2005.
[6]
D-Y. Chen, Y-M. Chen, H-H. Chen, C-W. Hsieh, C-C. Lin, and J-L. Lan, “Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy,” Arthritis Research & Therapy, vol. 13, no. 4, article R126, 2011.
[7]
S. Kleinert, H-P. Tony, A. Krause et al., “Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study,” Rheumatology International, vol. 32, no. 9, pp. 2759–2767, 2011.
[8]
G. R. Burmester, G. Ferraccioli, R-M. Flipo et al., “Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study,” Arthritis Care & Research, vol. 59, no. 1, pp. 32–41, 2008.
[9]
D. Van Der Heijde, L. Klareskog, R. Landewé et al., “Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 56, no. 12, pp. 3928–3939, 2007.
[10]
K. L. Hyrich, D. P. M. Symmons, K. D. Watson, and A. J. Silman, “Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: results from the British society for rheumatology biologics register,” Arthritis & Rheumatism, vol. 54, no. 6, pp. 1786–1794, 2006.
[11]
L. E. Kristensen, M. C. Kapetanovic, A. Gülfe, M. S？derlin, T. Saxne, and 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, vol. 47, no. 4, pp. 495–499, 2008.
[12]
H. Yamanaka, Y. Tanaka, E. Inoue et al., “Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study),” Modern Rheumatology, vol. 21, no. 2, pp. 122–133, 2011.
[13]
H. C. Leffers, M. ？stergaard, B. Glintborg et al., “Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry,” Annals of the Rheumatic Diseases, vol. 70, no. 7, pp. 1216–1222, 2011.
[14]
J. E. Gottenberg, P. Ravaud, A. Cantagrel et al., “Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the “Orencia and Rheumatoid Arthritis“ registry,” Annals of the Rheumatic Diseases, vol. 71, no. 11, pp. 1815–1819, 2012.
[15]
M. M. Soliman, K. L. Hyrich, M. Lunt, K. D. Watson, D. P. M. Symmons, and D. M. Ashcroft, “Effectiveness of rituximab in patients with rheumatoid arthritis: observational study from the British society for rheumatology biologics register,” The Journal of Rheumatology, vol. 39, no. 2, pp. 240–246, 2012.
[16]
R. Klaasen, C. A. Wijbrandts, D. M. Gerlag, and P. P. Tak, “Body mass index and clinical response to infliximab in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 63, no. 2, pp. 359–364, 2011.
[17]
E. Gremese, A. Carletto, M. Padovan et al., “Obesity and reduction of the response rate to anti-tumor necrosis factor ? in rheumatoid arthritis: an approach to a personalized medicine,” Arthritis Care & Research, vol. 65, no. 1, pp. 94–100, 2013.
[18]
K. L. Hyrich, K. D. Watson, A. J. Silman, D. P. M. Symmons, and British Society for Rheumatology Biologics Register, “Predictors of response to anti-TNF-α therapy among patients with rheumatoid arthritis: results from the British society for rheumatology biologics register,” Rheumatology, vol. 45, no. 12, pp. 1558–1565, 2006.
[19]
A. Abhishek, S. Butt, K. Gadsby, W. Zhang, and C. M. Deighton, “Anti-TNF-α agents are less effective for the treatment of rheumatoid arthritis in current smokers,” Journal of Clinical Rheumatology, vol. 16, no. 1, pp. 15–18, 2010.
[20]
H. Canh？o, A. M. Rodrigues, A. F. Mour？o et al., “Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis,” Rheumatology, vol. 51, no. 11, pp. 2020–2026, 2012.
[21]
S. Saevarsdottir, S. Wedrén, M. Seddighzadeh et al., “Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the epidemiological investigation of rheumatoid arthritis and the Swedish Rheumatology Register cohorts,” Arthritis & Rheumatism, vol. 63, no. 1, pp. 26–36, 2011.
[22]
D. Jawaheer, J. Olsen, M. Lahiff et al., “Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA Study,” Clinical and Experimental Rheumatology, vol. 28, no. 4, pp. 454–461, 2010.
[23]
D. Jawaheer, R. F. Lum, P. K. Gregersen, and L. A. Criswell, “Influence of male sex on disease phenotype in familial rheumatoid arthritis,” Arthritis & Rheumatism, vol. 54, no. 10, pp. 3087–3094, 2006.
[24]
M. Ahlmén, B. Svensson, K. Albertsson, K. Forslind, I. Hafstr？m, and BARFOT Study Group, “Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage,” Annals of the Rheumatic Diseases, vol. 69, no. 1, pp. 230–233, 2010.
[25]
V. Ruiz-Esquide, J. A. Gómez-Puerta, J. D. Ca？ete et al., “Effects of smoking on disease activity and radiographic progression in early rheumatoid arthritis,” The Journal of Rheumatology, vol. 38, no. 12, pp. 2536–2539, 2011.
[26]
N. G. Papadopoulos, Y. Alamanos, P. V. Voulgari, E. K. Epagelis, N. Tsifetaki, and A. A. Drosos, “Does cigarette smoking influence disease expression, activity and severity in early rheumatoid arthritis patients?” Clinical and Experimental Rheumatology, vol. 23, no. 6, pp. 861–866, 2005.
[27]
M. Ueno, J. L. Ferreiro, B. Desai et al., “Cigarette smoking is associated with a dose-response effect in clopidogrel-treated patients with diabetes mellitus and coronary artery disease: results of a pharmacodynamic study,” JACC: Cardiovascular Interventions, vol. 5, no. 3, pp. 293–300, 2012.
[28]
S. Garcês, J. Demengeot, and E. Benito-Garcia, “The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis,” Annals of the Rheumatic Diseases, vol. 72, no. 12, pp. 1947–1955, 2013.
[29]
K. Chatzidionysiou, E. Lie, E. Nasonov et al., “Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries,” Annals of the Rheumatic Diseases, vol. 70, no. 9, pp. 1575–1580, 2011.
[30]
L. Quartuccio, M. Fabris, S. Salvin et al., “Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNF agents failed are associated with response to rituximab in rheumatoid arthritis,” Rheumatology, vol. 48, no. 12, pp. 1557–1559, 2009.
[31]
C. Potter, K. L. Hyrich, A. Tracey 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,” Annals of the Rheumatic Diseases, vol. 68, no. 1, pp. 69–74, 2009.
[32]
R. J. Maneiro, E. Salgado, L. Carmona, and J. J. Gomez-Reino, “Rheumatoid factor as predictor of response to abatacept, rituximab and tocilizumab in rheumatoid arthritis: systematic review and meta-analysis,” Seminars in Arthritis and Rheumatism, vol. 43, no. 1, pp. 9–17, 2013.
[33]
T. R. D. J. Radstake, M. Svenson, A. M. Eijsbouts et al., “Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 68, no. 11, pp. 1739–1745, 2009.
[34]
G. M. Bartelds, C. A. Wijbrandts, M. T. Nurmohamed et al., “Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 66, no. 7, pp. 921–926, 2007.
[35]
A. Jamnitski, C. L. Krieckaert, M. T. Nurmohamed et al., “Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients,” Annals of the Rheumatic Diseases, vol. 71, no. 1, pp. 88–91, 2012.
[36]
D. Pascual-Salcedo, C. Plasencia, S. Ramiro et al., “Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis,” Rheumatology, vol. 50, no. 8, pp. 1445–1452, 2011.
[37]
E. C. Keystone, M. H. Schiff, J. M. Kremer 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 & Rheumatism, vol. 50, no. 2, pp. 353–363, 2004.
[38]
C. I. Da？en, V. Da？en, E. Parussini, A.-M. Dupuy, B. Combe, and J. Morel, “Etanercept concentration in patients with rheumatoid arthritis and its potential influence on treatment decisions: a pilot study,” The Journal of Rheumatology, vol. 39, no. 8, pp. 1533–1538, 2012.
[39]
A. Jamnitski, G. M. Bartelds, M. T. Nurmohamed et al., “The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept,” Annals of the Rheumatic Diseases, vol. 70, no. 2, pp. 284–288, 2011.
[40]
B. Mugnier, N. Balandraud, A. Darque, C. Roudier, J. Roudier, and D. Reviron, “Polymorphism at position -308 of the tumor necrosis factor α gene influences outcome of infliximab therapy in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 48, no. 7, pp. 1849–1852, 2003.
[41]
J. Cui, S. Saevarsdottir, B. Thomson et al., “Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor α therapy,” Arthritis & Rheumatism, vol. 62, no. 7, pp. 1849–1861, 2010.
[42]
D. Plant, R. Prajapati, K. L. Hyrich et al., “Replication of association of the PTPRC gene with response to anti-tumor necrosis factor therapy in a large UK cohort,” Arthritis & Rheumatism, vol. 64, no. 3, pp. 665–670, 2012.
[43]
D. Plant, J. Bowes, C. Potter et al., “Genome-wide association study of genetic predictors of anti-tumor necrosis factor treatment efficacy in rheumatoid arthritis identifies associations with polymorphisms at seven loci,” Arthritis & Rheumatism, vol. 63, no. 3, pp. 645–653, 2011.
[44]
A. Ruyssen-Witrand, S. Rouanet, B. Combe et al., “Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab,” Annals of the Rheumatic Diseases, vol. 71, no. 6, pp. 875–877, 2012.
[45]
L. Quartuccio, M. Fabris, E. Pontarini et al., “The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study,” Annals of the Rheumatic Diseases, 2013.
[46]
G. Cartron, L. Dacheux, G. Salles et al., “Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγrIIIa gene,” Blood, vol. 99, no. 3, pp. 754–758, 2002.
[47]
K. Sarsour, J. Greenberg, J. A. Johnston et al., “The role of the FcGRIIIa polymorphism in modifying the association between treatment and outcome in patients with rheumatoid arthritis treated with rituximab versus TNF-α antagonist therapies,” Clinical and Experimental Rheumatology, vol. 31, no. 2, pp. 189–194, 2013.
[48]
K. Kayakabe, T. Kuroiwa, N. Sakurai et al., “Interleukin-1β measurement in stimulated whole blood cultures is useful to predict response to anti-TNF therapies in rheumatoid arthritis,” Rheumatology, vol. 51, no. 9, pp. 1639–1643, 2012.
[49]
C. A. Wijbrandts, M. G. W. Dijkgraaf, M. C. Kraan et al., “The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium,” Annals of the Rheumatic Diseases, vol. 67, no. 8, pp. 1139–1144, 2008.
[50]
S. M. Zivojinovic, N. N. Pejnovic, M. N. Sefik-Bukilica, L. V. Kovacevic, I. I. Soldatovic, and N. S. Damjanov, “Tumor necrosis factor blockade differentially affects innate inflammatory and Th17 cytokines in rheumatoid arthritis,” The Journal of Rheumatology, vol. 39, no. 1, pp. 18–21, 2012.
[51]
K. Shimamoto, T. Ito, Y. Ozaki et al., “Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis,” The Journal of Rheumatology, vol. 40, no. 7, pp. 1074–1081, 2013.
[52]
T. Takeuchi, N. Miyasaka, Y. Tatsuki et al., “Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 70, no. 7, pp. 1208–1215, 2011.
[53]
W. Hueber, B. H. Tomooka, F. Batliwalla et al., “Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis,” Arthritis Research & Therapy, vol. 11, no. 3, article R76, 2009.
[54]
J. Wang, A. Platt, R. Upmanyu et al., “IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis,” BMJ Open, vol. 3, no. 8, Article ID 003199, 2013.
[55]
G. Ferraccioli, B. Tolusso, F. Bobbio-Pallavicini et al., “Biomarkers of good EULAR response to the B cell depletion therapy in all seropositive rheumatoid arthritis patients: clues for the pathogenesis,” PloS One, vol. 7, no. 7, Article ID e40362, 2012.
[56]
J. Sellam, S. Rouanet, H. Hendel-Chavez et al., “Blood memory B cells are disturbed and predict the response to rituximab in patients with rheumatoid arthritis,” Arthritis & Rheumatism, vol. 63, no. 12, pp. 3692–3701, 2011.
[57]
J. Sellam, H. Hendel-Chavez, S. Rouanet et al., “B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis a six-month, national, multicenter, open-label study,” Arthritis & Rheumatism, vol. 63, no. 4, pp. 933–938, 2011.
[58]
E. M. Vital, S. Dass, A. C. Rawstron et al., “Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment,” Arthritis & Rheumatism, vol. 62, no. 5, pp. 1273–1279, 2010.
[59]
B. M？ller, D. Aeberli, S. Eggli et al., “Class-switched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis,” Arthritis Research & Therapy, vol. 11, no. 3, article R62, 2009.
[60]
R. M. Thurlings, K. Vos, C. A. Wijbrandts, A. H. Zwinderman, D. M. Gerlag, and P. P. Tak, “Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response,” Annals of the Rheumatic Diseases, vol. 67, no. 7, pp. 917–925, 2008.
[61]
M. Scarsi, T. Ziglioli, and P. Airo’, “Baseline numbers of circulating CD28-negative T cells may predict clinical response to abatacept in patients with rheumatoid arthritis,” The Journal of Rheumatology, vol. 38, no. 10, pp. 2105–2111, 2011.
[62]
M. Scarsi, T. Ziglioli, and P. Airo’, “Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response,” The Journal of Rheumatology, vol. 37, no. 5, pp. 911–916, 2010.
