Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis

Immunology Unit, Hospital La Paz, Paseo de La Castellana 261, 28046 Madrid, Spain.
Rheumatology (Oxford, England) (Impact Factor: 4.48). 03/2011; 50(8):1445-52. DOI: 10.1093/rheumatology/ker124
Source: PubMed


To analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time.
Clinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.4-10.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years).
Antibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (P = 0.05 at 6 months, P = 0.02 at 1 year, P = 0.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (P = 0.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (P = 0.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (P = 0.073) and longer survival (P = 0.015) on treatment.
The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.

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Available from: Antonio Martínez, Jan 20, 2014
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    • "It identifies those patients who will benefit from dose escalation versus those who are unlikely to respond to this strategy (high titers of anti-drug antibodies) [33]. Drug immunogenicity is one of the main mechanisms behind therapeutic failure also for RA patients [34] [35] [36] [37] [38]. "
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    ABSTRACT: Clinical response in patients with rheumatoid arthritis (RA) treated with biologic agents can be influenced by their pharmacokinetics and immunogenicity. The present study evaluated the concordance between serum drug and antidrug levels as well as the clinical response in RA patients treated with biological agents who experience their first disease exacerbation while being on a stable biologic treatment. 154 RA patients treated with rituximab (RTX), infliximab (IFX), adalimumab (ADL), or etanercept (ETN) were included. DAS28, SDAI, and EULAR response were assessed at baseline and reevaluated at precise time intervals. At the time of their first sign of inadequate response, patients were tested for both serum drug level and antidrug antibodies level. At the next reevaluation, patients retreated with RTX that had detectable drug level had a better EULAR response (P = 0.038) with lower DAS28 and SDAI scores (P = 0.01 and P = 0.03). The same tendency was observed in patients treated with IFX and ETN regarding EULAR response (P = 0.002 and P = 0.023), DAS28 score (P = 0.002 and P = 0.003), and SDAI score (P = 0.001 and P = 0.026). Detectable biologic drug levels correlated with a better clinical response in patients experiencing their first RA inadequate response while being on a stable biologic treatment with RTX, IFX, and ETN.
    BioMed Research International 05/2014; 2014:702701. DOI:10.1155/2014/702701 · 2.71 Impact Factor
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    • "The immunogenicity of biological therapies has been shown to influence secondary inefficacy in rheumatic diseases [17,28,42-52]. The frequency of ADA development in SpA patients varies between different studies (25.5 to 29% for antibodies to Ifx and 31% for antibodies to Ada) [17,19,20,49-51]. "
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    ABSTRACT: Anti-TNF drugs have proven to be effective against Spondyloarthritis (SpA), although 30% of patients fail to respond or experience adverse events leading to treatment discontinuation. In rheumatoid arthritis, the presence of anti-drug antibodies (ADA) against the first TNF inhibitor influences the outcome after switching. Our aim was to assess whether the response to a second anti-TNF is related to the previous development of ADA to the first anti-TNF drug in SpA patients. Forty two SpA patients began a second anti-TNF drug after failing to respond to the first anti-TNF. Clinical activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline (at the beginning of the 1st and 2nd anti-TNF) and at 6 months after switching. The drug and ADA levels were measured by ELISA before each administration. All patients were treated with anti-TNF drugs and mainly due to inefficacy were switched to a second anti-TNF. Out of 42 patients, 11 (26.2%) developed ADA during the first biologic treatment. At baseline, no differences in ASDAS were found in patients with or without ADA to the first (3.52 +/- 1.03 without ADA vs 3.14 +/- 0.95 with ADA, P=0.399) and to the second (3.36 +/- 0.94 without ADA vs 3.09 +/- 0.91 with ADA, P=0.466) anti-TNF. At 6 months after switching, patients with previous ADA had lower disease activity (1.62 +/- 0.93 with ADA vs 2.79 +/- 1.01 without ADA, P=0.002) and most patients without ADA had high disease activity state by the ASDAS (25 out of 31 (80.6%) without ADA vs 3 out of 11 (27.3%) with ADA, P=0.002). In SpA, the failure to respond to the first anti-TNF drug due to the presence of ADA predicts a better clinical response to a second anti-TNF drug.
    Arthritis research & therapy 07/2013; 15(4):R79. DOI:10.1186/ar4258 · 3.75 Impact Factor
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    • "Recently several studies also demonstrated the potential use of monitoring of pharmacokinetics during the maintenance phase of infliximab treatment in RA patients, next to the initiation phase [13-16]. Therefore, an interesting possible predictor for successful dose tapering could be infliximab serum trough levels and anti-infliximab antibody levels. "
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    ABSTRACT: Background To get insight in the prevalence of high, or low/no serum infliximab trough levels in patients with low disease activity and if serum trough levels are stable and reliable longitudinally we conducted a prospective cohort study Methods In a longitudinal, observational cohort of RA patients treated with infliximab for at least 6 months, treatment interval, DAS28, infliximab trough levels and anti-infliximab antibodies were assessed. Prevalence of low (<1 mg/l) and high (>5 mg/l) infliximab serum trough levels and anti-infliximab antibodies was recorded. Relationship of a change in anti-infliximab antibodies and treatment interval was described. Reliability of consecutive infliximab serum trough levels and anti-infliximab antibodies in patients with stable DAS28 and treatment was analysed with Spearman correlation and kappa-analysis. Results 147 patients with a mean disease duration of 11 years (sd7) and DAS28 of 3.5 (sd1.3) at baseline were followed during 1.5 years. Inter-individual variability in infliximab levels in patients with low DAS28 was high (median 1.4 mg/L, IQR 3.35), with 31% (95%CI: 20-42%) having low (<1 mg/L) and 14% (95%CI 5–22) high trough levels (>5 mg/L). Interestingly also in RA patients with DAS28 ≤ 3.2, anti-infliximab antibodies were found in one-third of the patients, with half of them having antibodies every visit during a median of more than one year. Agreement for consecutive measurements of serum trough levels and anti-infliximab antibodies was high in stable patients: r = 0.97 (p = 0.00001) and kappa = 1.0 (SE 0.14) Anti-infliximab antibody appearance was influenced by interval increases (relative risk (RR) 5.2, 2.6-10.7), but patients still showed low infliximab levels. Conclusions Low (and high) infliximab serum trough levels are prevalent, interestingly also in patients with low disease activity. Consecutive measurements of serum trough levels and anti-infliximab antibodies are reliable in stable patients. These test could be used to lower or stop infliximab in selected patients.
    BMC Musculoskeletal Disorders 09/2012; 13(1). DOI:10.1186/1471-2474-13-184 · 1.72 Impact Factor
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