Background Antibodies to infliximab (ATI) are associated to loss of response, adverse effects and discontinuation of treatment in rheumatic patients1. However, the clinical relevance of measuring free versus total anti-drug antibodies (free plus drug-complexed antibodies) remains to be established.
Objectives To analyse the association between the clinical response and ATI measured as free and total content of immunoglobulins in a cohort of patients with spondyloarthritis.
Methods A retrospective pilot study was conducted including 12 patients with spondyloarthropathies (9 ankylosing spondylitis (AS) and 3 spondyloarthritis (SpA)) under maintenance infliximab (IFX) therapy (3–5 mg/kg every 8 weeks). Disease activity was assessed by BASDAI score every 6 months. Trough serum samples were consecutively collected every two months during a follow up period of 1±0.1 years. In total 75 samples were collected (average of 6.3 per patient). Ten patients (83%) received concomitant therapy with methotrexate. IFX levels were measured with Promonitor®-IFX (Progenika-Grifols, Spain). Free and total-ATI were measured with Promonitor® Anti-IFX (Progenika-Grifols, Spain) (PR) and IDKmonitor® Infliximab total ADA (IDK) (Immundiagnostik, Germany) ELISA kits, respectively. Cut-point of PR and IDK ATI assays is 5 and 10 AU/mL, respectively. FDA guidance for comparing two diagnostic tests in the absence of a gold standard was followed2.
Results Five (41.7%) and (83.3%) patients were positive for free and total-ATI using PR and IDK assays, respectively. Overall, positive (PPA) and negative (NPA) percent agreements between the two assays were 52%, 16% and 100%, respectively. All samples with positive free-ATI (7) had undetectable IFX levels (0.0±0.0 μg/mL); however, 72% of total-ATI positive samples (43) were also positive for IFX levels (1.7±1.7 μg/mL, min 0.035 μg/mL and max 6.4 μg/mL). Both outcomes are coherent with the intended use of each kit, which also explains the low PPA. However, total-ATI are positive in 40% of the samples even when the patient responds (BASDAI<4), which questions the utility of total-antibodies in a clinical setting. This evidences a low clinical specificity of total-ATI measurement using the cut-off of 10 AU/mL recommended by the manufacturer and therefore that the presence of total-ATI in the presence of detectable drug has little utility. Patients without free-ATI had significantly lower BASDAI than patients with free-ATI (2.7±2.0 without antibodies vs 5.0±0.9 with antibodies, p=0.049), whereas no statistically significant difference was observed between patients when total-ATI were used (3.1±2.2 without antibodies vs 2.9±2.0 with antibodies, p=0.969) (Fig. 1).
Conclusions Total-ATI do not correlate with disease activity in spondyloarthritis. The fact that many samples are positive to total-ATI even in patients with low disease activity makes very difficult interpretation of results. The explanation is that the fraction of ATI bound to IFX is not clinically relevant as long as there is free therapeutic drug in circulation.
Ducourau et al. Arthritis Res Ther 2011;13:R105
Statistical guidance on reporting results from studies evaluating diagnostic tests. 2007.FDA
Disclosure of Interest A. Ruiz del Agua Employee of: Employee of Progenika Grifols, J. Pascual Employee of: Employee of Progenika Grifols, N. Torres Employee of: Employee of Progenika Grifols, D. Pascual-Salcedo: None declared, A. Martínez: None declared, T. Jurado: None declared, C. Plasencia: None declared, A. Balsa: None declared, B. Ruiz-Argüello Employee of: Employee of Progenika Grifols, A. Maguregui Employee of: Employee of Progenika Grifols, A. Ametzazurra Employee of: Employee of Progenika Grifols, A. Martínez Employee of: Employee of Progenika Grifols, D. Nagore Employee of: Employee of Progenika Grifols