OBJECTIVE: To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes. METHODS: This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected. RESULTS: Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low. CONCLUSION: ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA. TRIAL REGISTRATION: This study was registered on www.ClinicalTrials.gov (NCT01981473).

Aintree University Hospital University of Liverpool Liverpool United Kingdom

Hospital de Clinicas Porto Alegre Brazil

Institute of Rheumatology Prague Czech Republic

Kaohsiung Medical University Kaohsiung City Taiwan

Mafraq Hospital Abu Dhabi United Arab Emirates

Pfizer Collegeville Pennsylvania United States of America

Tuen Mun Hospital Hong Kong People's Republic of China

PLoS One. 2017 Jun 5;12(6):e0179308. doi: 10.1371/journal.pone.0179308. PubMed

See more in PubMed

Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E (2014) Diagnosis and classification of rheumatoid arthritis. J Autoimmun 48–49: 26–30. PubMed

Ma VY, Chan L, Carruthers KJ (2014) Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil 95: 986–995.e981. 10.1016/j.apmr.2013.10.032 PubMed DOI PMC

Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP (2008) Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 117: 244–279. 10.1016/j.pharmthera.2007.10.001 PubMed DOI

Conti F, Ceccarelli F, Massaro L, Cipriano E, Di Franco M, Alessandri C, et al. (2013) Biological therapies in rheumatic diseases. Clin Ter 164: e413–428. 10.7417/CT.2013.1622 PubMed DOI

AbbVie Inc (2002) HUMIRA (adalimumab) injection, Prescribing Information.

Amgen (1998) Enbrel® (etanercept), Prescribing Information. Immunex Corporation.

Janssen Biotech, Inc. (1998) REMICADE® (infliximab), Prescribing Information.

Hwang WY, Foote J (2005) Immunogenicity of engineered antibodies. Methods 36: 3–10. 10.1016/j.ymeth.2005.01.001 PubMed DOI

Anderson PJ (2005) Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin Arthritis Rheum 34: 19–22. PubMed

van Schouwenburg PA, Rispens T, Wolbink GJ (2013) Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 9: 164–172. 10.1038/nrrheum.2013.4 PubMed DOI

Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, et al. (2009) Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 68: 1739–1745. 10.1136/ard.2008.092833 PubMed DOI

Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. (2011) Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305: 1460–1468. 10.1001/jama.2011.406 PubMed DOI

Garcês S, Demengeot J, Benito-Garcia E (2013) The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis 72: 1947–1955. 10.1136/annrheumdis-2012-202220 PubMed DOI

Pascual-Salcedo D, Plasencia C, Ramiro S, Nuño L, Bonilla G, Nagore D, et al. (2011) Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford) 50: 1445–1452. PubMed

Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T (2006) Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 54: 3782–3789. 10.1002/art.22214 PubMed DOI

Korswagen LA, Bartelds GM, Krieckaert CL, Turkstra F, Nurmohamed MT, van Schaardenburg D, et al. (2011) Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum 63: 877–883. 10.1002/art.30209 PubMed DOI

Finckh A, Dudler J, Wermelinger F, Ciurea A, Kyburz D, Gabay C, et al. (2010) Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine 77: 313–318. PubMed

Dore RK, Mathews S, Schechtman J, Surbeck W, Mandel D, Patel A, et al. (2007) The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol 25: 40–46. PubMed

de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT, Aarden LA, Stapel SO, Peters MJ, et al. (2009) Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis 68: 531–535. 10.1136/ard.2008.089979 PubMed DOI

Menting SP, van Lümig PP, de Vries AC, van den Reek JM, van der Kleij D, de Jong EM, et al. (2014) Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. JAMA Dermatol 150: 130–136. 10.1001/jamadermatol.2013.8347 PubMed DOI

Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C (2013) Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 72: 165–178. 10.1136/annrheumdis-2012-202545 PubMed DOI

Switching to Biosimilar SDZ-ADL in Patients with Moderate-to-Severe Active Rheumatoid Arthritis: 48-Week Efficacy, Safety and Immunogenicity Results From the Phase III, Randomized, Double-Blind ADMYRA Study