Serum drug levels of biologic agents in the management of rheumatoid arthritis and spondyloarthritis: a systematic review
The utility of monitoring drug levels in rheumatoid arthritis and spondyloarthritis patients on biological therapy is called into question. The objective was to study relevant clinical questions on the topic, i.e., (1) whether drug levels predict relapse in patients whose biologic was optimized because of remission or low disease activity; (2) whether information about drug levels influences the prognosis of patients with primary or secondary failure to a biological therapy; and (3) whether methotrexate (MTX) influences the association between drug levels and response. Medline, Embase, Cochrane databases were screened, from inception to December 2016 in search for all studies related to the three research questions about. Overall characteristics and outcomes of the studies were collected in a table of evidence and the quality of the studies was assessed with the Newcastle-Ottawa scale or the GRADEpro. Two studies responded the first question, 5 the second, and 7 the third. Studies were small and with limitations, but suggest that measurement drug levels may be useful in patients in remission; that higher drug levels predict a longer relapse-free optimization, and in patients with failure to a biological agent, treatment may need individual adjustment according to the presence of drug levels or antidrug-antibodies. In addition, MTX influences the association between response and drug levels. Monitoring drug levels would allow optimal use of current biological therapies, but more studies and of better quality are needed to draw definitive conclusions.
KeywordsRheumatoid arthritis Spondyloarthritis Drug levels TNF-inhibitors Tocilizumab Biologics Therapeutic drug monitoring
JCR conceived the project. MML and LC contributed to the design and implementation of the research, to the analysis of the results and to the writing of the manuscript. All authors discussed the results and were involved in the critical review of the final manuscript.
This review was funded by a grant from Asociación para la Investigación en Reumatología de Marina Baixa (AIRE-MB).
Compliance with ethical standards
Conflict of interest
All authors declare that there is no competing interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 1.Nam JL, Ramiro S, Gaujoux-Viala C, Takase K et al (2014) Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 73(3):516–528. https://doi.org/10.1136/annrheumdis-2013-204577 CrossRefPubMedGoogle Scholar
- 2.Sepriano A, Regel A, van der Heijde D, Braun J et al (2017) Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis. RMD Open 3(1):e000396. https://doi.org/10.1136/rmdopen-2016-000396 CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Corbett M, Soares M, Jhuti G, Rice S et al (2016) Tumour necrosis factor-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health Technol Assess 20(9):1-334, v-vi. https://doi.org/10.3310/hta20090 CrossRefPubMedGoogle Scholar
- 5.Takeuchi T, Miyasaka N, Inoue K, Abe T et al (2009) Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol 19(5):478–487. https://doi.org/10.1007/s10165-009-0195-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.St Clair EW, Wagner CL, Fasanmade AA, Wang B et al (2002) The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46(6):1451–1459. https://doi.org/10.1002/art.10302 CrossRefPubMedGoogle Scholar
- 7.Chen DY, Chen YM, Tsai WC, Tseng JC et al (2015) Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis. Ann Rheum Dis 74(3):e16. https://doi.org/10.1136/annrheumdis-2013-203893 CrossRefPubMedGoogle Scholar
- 8.Paramarta JE, Baeten DL (2014) Adalimumab serum levels and antidrug antibodies towards adalimumab in peripheral spondyloarthritis: no association with clinical response to treatment or with disease relapse upon treatment discontinuation. Arthritis Res Ther 16(4):R160. https://doi.org/10.1186/ar4675 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Kneepkens EL, Krieckaert CL, van der Kleij D, Nurmohamed MT et al (2015) Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 74(10):1825–1829. https://doi.org/10.1136/annrheumdis-2014-205213 CrossRefPubMedGoogle Scholar
- 10.Jani M, Isaacs JD, Morgan AW, Wilson AG et al (2017) High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. Ann Rheum Dis 76(1):208–213. https://doi.org/10.1136/annrheumdis-2015-208849 CrossRefPubMedGoogle Scholar
- 11.Kneepkens EL, Plasencia C, Krieckaert CL, Pascual-Salcedo D et al (2014) Golimumab trough levels, antidrug antibodies and clinical response in patients with rheumatoid arthritis treated in daily clinical practice. Ann Rheum Dis 73(12):2217–2219. https://doi.org/10.1136/annrheumdis-2014-205983 CrossRefPubMedGoogle Scholar
- 12.Benucci M, Meacci F, Grossi V, Infantino M et al (2016) Correlations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab. Biologics 10:53–58. https://doi.org/10.2147/BTT.S97234 PubMedPubMedCentralCrossRefGoogle Scholar
- 13.Mazilu D, Opris D, Gainaru C, Iliuta M et al. (2014) Monitoring drug and antidrug levels: a rational approach in rheumatoid arthritis patients treated with biologic agents who experience inadequate response while being on a stable biologic treatment. Biomed Res Int 2014:702701. https://doi.org/10.1155/2014/702701 PubMedPubMedCentralCrossRefGoogle Scholar
- 14.Wells G, Shea B, O’Connel D (2009 Feb 1) The Newcastle-Ottawa scale (NOS) for assessing the quailty of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 03 Mar 2018
- 15.Schünemann H, Brozek J, Guyatt G, Oxman A (2013) GRADE handbook for grading quality of evidence and strength of recommendations [Internet]. The GRADE Working Group. http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html. Accessed 03 Mar 2018
- 19.Garces S, Antunes M, Benito-Garcia E, da Silva JC et al (2014) A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis 73(6):1138–1143. https://doi.org/10.1136/annrheumdis-2013-203296 CrossRefPubMedGoogle Scholar
- 24.Eng GP, Bouchelouche P, Bartels EM, Bliddal H et al (2016) Anti-drug antibodies, drug levels, interleukin-6 and soluble TNF receptors in rheumatoid arthritis patients during the first 6 months of treatment with adalimumab or infliximab: a descriptive cohort study. PLoS One 11(9):e0162316. https://doi.org/10.1371/journal.pone.0162316 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Ducourau E, Mulleman D, Paintaud G, Miow Lin DC et al (2011) Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther 13(3):R105. https://doi.org/10.1186/ar3386 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA et al (2011) Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305(14):1460–1468. https://doi.org/10.1001/jama.2011.406 CrossRefPubMedGoogle Scholar
- 29.Krieckaert CL, Nair SC, Nurmohamed MT, van Dongen CJ et al (2015) Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects. Ann Rheum Dis 74(2):361–368. https://doi.org/10.1136/annrheumdis-2013-204101 CrossRefPubMedGoogle Scholar
- 31.Bendtzen K, Geborek P, Svenson M, Larsson L et al (2006) Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 54(12):3782–3789. https://doi.org/10.1002/art.22214 CrossRefPubMedGoogle Scholar
- 35.Garcia Ruiz de Morales JM, Pascual-Salcedo D, Llinares Tello F, Valor Mendez L (2016) [Anti-tumor necrosis factor drug therapy: The usefulness of monitoring drug levels and anti-drug antibodies in clinical practice]. Med Clin (Barc) 147 (9):410–416. https://doi.org/10.1016/j.medcli.2016.04.002
- 36.Bandres Ciga S, Salvatierra J, Lopez-Sidro M, Garcia-Sanchez A et al (2015) An examination of the mechanisms involved in secondary clinical failure to adalimumab or etanercept in inflammatory arthropathies. J Clin Rheumatol 21(3):115–119. https://doi.org/10.1097/RHU.0000000000000229 CrossRefPubMedGoogle Scholar