Background Anti-drug antibodies (ADA) develop in up to one third of patients treated with biologic agents, immunogenicity being one of the main reasons for loss of efficacy and tolerance of the biodrug.

Objectives To investigate the clinical relevance of anti-drug antibodies, drug levels and their relationship with disease outcomes in rheumatoid arthritis (RA) patients receiving TNF-inhibitors (TNF-i).

Methods We performed a prospective observational study in a cohort of forty-eight consecutive RA treated with adalimumab (ADL; 24), infliximab (IFX; 15) or etanercept (ETN; 9). Disease activity, clinical outcomes and adverse events were evaluated at baseline and during study visit, while serum TNF-i and ADA levels collected as a single-point data in both bio-naïve and bio-experimented patients.

Lab assays (IgG-ADA, TNF-i) were measured following the manufacturer's instructions using ELISA Progenika kits, with detection limit set at 10AU/mL for anti-ADL, 142AU/mL for anti-ETN and 5AU/mL for anti-IFX, 0.024μg/mL ADA, 0.035μg/mL ETN, 0.035μg/mL IFX.

Statistical analysis was conducted in SPSS-19 (p<0.05).

Results ADA were detected in 8/48 (16.7%) patients (5/24 ADL, 20.8%; 3/9 IFX, 33.3%; while no anti-ETN) and associated with lower functional serum drug (2.17 vs 5.53μg/mL ADL; 2.10 vs 3.82μg/mL IFX; p<0.01), higher disease activity (DAS28: 3.5 vs 3.3 in ADL-group p<0.05; 3.6 vs 3.0 in IFX-group), less remission (p<0.01) compared to ADA negative. Moreover, high ADA levels predict therapy discontinuation (p<0.01).

Treatment failure was demonstrated in 12/48 (25%) cases, strongly associated with ADA status (p<0.01) and drug levels (p<0.01), with a specific profile for secondary non-responders meaning ADA positivity at higher titers (62.51 vs 101.54AU/mL anti-ADL; 5.41 vs 39.80AU/mL anti-IFX; p<0.01), lower free serum TNF-i (6.14 vs 1.64μg/mL ADL; 3.01 vs 4.08μg/mL IFX; p<0.01), lower biologic exposure (32.2 vs 38.58 months for ADL, 40.17 vs 73.33 months for IFX; p<0.01), lower DAS28 at baseline (6.14 vs 6.7 for ADL, p<0.05; 6.88 vs 7.04 for IFX; p<0.05).

No difference in immunogenicity for ETN-treated cases (p>0.05), although lower levels of drug in non-responders (1.92 vs 2.89μg/mL, p<0.05). In addition, adverse events happened more often in ADA positive then ADA negative status (p<0.01)

Conclusions Immunogenicity to ADL and IFX but not to ETN have large impact on clinical practice (disease activity, treatment failure) and may represent key findings towards optimizing biological therapeutics in RA during long-term follow-up.

1. Arstikyte I et al. Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNFα Blockers in Rheumatoid Arthritis and Spondyloarthritis Patients. BioMed Research International 2015

2. Hoxha A, et al. The clinical relevance of early anti-adalimumab antibodies detection in rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: A prospective multicentre study. Joint Bone Spine 2015

3. Mazilu D et al. Monitoring Drug and Anti-drug Levels: A Rational Approach in Rheumatoid Arthritis Patients Treated with Biologic Agents Who Experience Inadequate Response While Being on a Stable Biologic Treatment. BioMed Research International 2014

Disclosure of Interest None declared