Background Despite the beneficial effects of aTNF alpha agents on the systemic rheumatic and inflammatory bowel diseases, a significant proportion of patients cannot sustain a therapeutic response over time. An increasing body of literature highlights immunogenicity as one of the main factors behind therapeutic failure and infusion-related adverse events^1-5. Given the recent recommendations by the EMA to monitor immunogenicity in clinical practice⁶, it is important to reevaluate the impact of anti-biologic antibodies on drug efficacy and safety.

Objectives We conducted a meta-analysis to assess the influence antibodies against infliximab, adalimumab and etanercept on therapeutic efficacy/effectiveness and the influence of concomitant immunosuppression in anti-biologic antibodies production, in patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease and ulcerative colitis.

Methods A systematic literature search of Medline, Embase and Cochrane Library was conducted through Dec 2011, complemented with the reference lists of articles and consultation with experts. We included clinical trials and observational studies. Nineteen studies met our inclusion criteria. Random-effects models according to the Laird method were used for clustering results. Heterogeneity examined by calculating the Qui2 test for heterogeneity and the I2 measure of inconsistency. Meta-regression and sub-group analysis were used to evaluate the effect size modification by: a) type of disease; b) proportion of patients co-treated with Methotrexate (MTX); c) proportion of patients who underwent aTNF dose escalation; d) proportion of patients who started with higher initial doses of aTNF; d) scheduled treatment regimens; e) type of assay for ABAs detection; f) population and individual study characteristics.

Results In studies where the proportion of patients co-treated in MTX was less than 79%, the presence of ABAs reduced therapeutic response by 80% (RR 0.20, 95% CI 0.12-0.36), while in studies where that proportion was ≥79%, the effect size reduction of drug response was attenuated to 50% (RR 0.50, 95% CI 0.36 to 0.69). Concomitant immunosuppressive therapy reduced detectable ABAs by 65% (RR 0.35 95% CI 0.24 to 0.51) when RIA was used to detect ABAs, while when ELISA methods were used the effect size reduction of detectable ABAs was attenuated to 36% (RR 0.64, 95% CI 0.54 to 0.75). No definitive conclusions can be drawn regarding the effect size modification by the other evaluated factors.

Conclusions There is evidence of an increased risk of therapeutic failure in patients with anti-biologic antibodies. Concomitant immunosuppression reduces but does not abrogate anti-biological antibodies production. The type of assays employed to assess anti-biologic antibodies can influence the results. Routine assessment of immunogenicity may clarify the reason behind therapeutic failure, which might be of high relevance to optimize the use of biologic therapies.

1. Baert et al. N Engl J Med 2003;348:601-8.

2. Maini et al. Arthritis Rheum 1998;41:1552-63.

3. Pascual-Salcedo et al. Rheumatology 2011;50(8):445-52.

4. Bartelds et al. JAMA 2011;305:1460-8.

5. Jamnistski et al. Ann Rheum Dis 2011;70:284-8.

6. E.M.A. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdf;

Disclosure of Interest None Declared