Anti-infliximab Antibodies In Patients Research Articles

Long-Term Follow-Up of Anti-Infliximab Antibodies in Patients With Radiographic Axial Spondyloarthritis: A Marker of Drug Survival and Tapering.

The aim of this study was to evaluate the influence of anti-infliximab (IFX) antibodies on three different points of care: response/tolerance to IFX, tapering strategy, and in a subsequent treatment with a second tumor necrosis factor inhibitor (TNFi). A prospective cohort of 60 patients with radiographic axial spondyloarthritis who received IFX were evaluated retrospectively regarding clinical/laboratorial data, IFX levels, and anti-IFX antibodies at baseline, after 6, 12 to 14, 22 to 24, 48 to 54, 96 to 102 weeks, and before tapering or switching. Anti-IFX antibodies were detected in 27 patients (45%), of whom 23 (85.1%) became positive in the first year of IFX treatment. In comparison to the group that was negative for anti-IFX antibodies, patients who were positive for anti-IFX antibodies demonstrated the following: less use of methotrexate as a concomitant treatment to IFX (5 [18.5%] vs 14 [42.4%]; P = 0.048), more infusion reactions at 22 to 24 weeks (P = 0.020) and 48 to 54 weeks (P = 0.034), more treatment failures (P = 0.028) at 48 to 54 weeks, reduced overall IFX survival (P < 0.001), and lower sustained responses (P = 0.044). Of note, patients who were positive for anti-IFX antibodies exhibited a shorter tapering survival (9.9 months [95% confidence interval (CI) 4.0-15.8] vs 63.4 months [95% CI 27.9-98.8]; P = 0.004) in comparison with patients who were negative for anti-IFX antibodies. Conversely, for patients who failed IFX, patients who were positive for anti-IFX antibodies had better clinical response to the second TNFi at three months (15 [83.3%] vs 3 [27.3%]; P = 0.005) and six months (15 [83.3%] vs 4 [36.4%]; P = 0.017) than the patients who were negative for anti-IFX antibodies after switching. This study provided novel data that anti-IFX antibodies is a parameter for reduced tapering survival, reinforcing its detection to guide clinical decision. Additionally, we confirmed in a long-term cohort the anti-IFX antibody association with worse IFX performance and as predictor of the second TNFi good clinical response.

Surface plasmon resonance unveils important pitfalls of enzyme-linked immunoassay for the detection of anti-infliximab antibodies in patients\u2019 sera

Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients receiving infliximab for inflammatory bowel diseases. The two methods indicated very similar serum concentrations of the drug, but there were striking differences as regards ADA. All the sera showing ADA by ELISA (14) also showed ADA by SPR, but the absolute amounts were different, being 7–490 times higher with SPR, with no correlation. Eight patients showed ADA only with SPR, and these ADA had significantly faster dissociation rate constants than those detectable by both SPR and ELISA. The underestimation, or the lack of detection, of ADA by ELISA is likely to reflect the long incubation steps which favor dissociation of the patient’s low-affinity ADA, while the commercial, high-affinity anti-infliximab antibodies used for the calibration curve do not dissociate. This problem is less important with SPR, which monitors binding in real time. The possibility offered by SPR to detect ADA in patients otherwise considered ADA-negative by ELISA could have important implications for clinicians.

IMPORTANCE OF MEASURING LEVELS OF INFLIXIMAB IN PATIENTS TREATING INFLAMMATORY BOWEL DISEASE IN A BRAZILIAN COHORT.

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases. In such pathologies, there is an increased production of alpha tumor necrosis factor (TNF-α). Patients, in whom the conventional immunosuppressant treatment fails, require the use of immunobiological therapy, such as anti-TNF-α, a monoclonal antibody. Infliximab is an anti-TNF-α drug, a chimerical immunoglobulin, with a murine component, which is responsible for the generation of immunogenicity against the drug and formation of anti-TNF-α antibodies. The presence of anti-drug antibodies may be responsible for adverse events and reduction of the drug's effectiveness. Patients with inflammatory bowel diseases undergoing therapy with biological medication, such as infliximab, can relapse overtime and this may not be translated into clinical symptoms. Thus, there is a need for a method to evaluate the efficacy of the drug, through the measurement of serum infliximab levels, as well as antibodies research. This study aimed to measure serum infliximab levels and anti-infliximab antibodies in patients with inflammatory bowel diseases post-induction phase and during maintenance therapy, and describe the therapeutic modifications that took place based on the serum levels results. It was a retrospective study, that included forty-five patients, with a total of 63 samples of infliximab measurement. Twenty-one patients had an adequate infliximab serum level, 31 had subtherapeutic levels and 11 had supratherapeutic levels. Seven patients had their medication suspended due to therapeutic failure or high levels of antibodies to infliximab. In conclusion, only a third of the patients had adequate infliximab levels and 36% presented with subtherapeutic levels at the end of the induction phase. Therapy optimization occurred based in about 46% of the samples results, demonstrating the importance of having this tool to help the clinical handling of patients with inflammatory bowel diseases ongoing biologic therapy.

Sa1912 - Rapid Point-of-Care Monitoring of Anti-Infliximab Antibodies in Patients with Inflammatory Bowel Disease Treated with the Reference Infliximab or CT-P13 in Routine Clinical Practice

Sa1912 - Rapid Point-of-Care Monitoring of Anti-Infliximab Antibodies in Patients with Inflammatory Bowel Disease Treated with the Reference Infliximab or CT-P13 in Routine Clinical Practice

P503 Rapid point-of-care monitoring of anti-infliximab antibodies in patients with inflammatory bowel disease treated with the reference infliximab or CT-P13 in routine clinical practice

P503 Rapid point-of-care monitoring of anti-infliximab antibodies in patients with inflammatory bowel disease treated with the reference infliximab or CT-P13 in routine clinical practice

Sa1258 The Clinical and Immunological Significance of Low Level of Infliximab in the Absence of Anti-Infliximab Antibodies in Patients With IBD

Sa1258 The Clinical and Immunological Significance of Low Level of Infliximab in the Absence of Anti-Infliximab Antibodies in Patients With IBD

P122 The clinical and immunological significance of low level of infliximab in the absence of anti-infliximab antibodies in patients with IBD

P122 The clinical and immunological significance of low level of infliximab in the absence of anti-infliximab antibodies in patients with IBD B. Ungar1 *, A. Anafy1, M. Yavzori1, O. Picard1, E. Fudim1, U. Kopylov1, Y. Ron2, H. Yanai2, I. Dotan2, Y. Chowers3, R. Eliakim1, S. Ben-Horin1. 1Chaim Sheba Medical Center, Gastroenterology, Ramat Gan, Israel, 2Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, IBD Center, Department of Gastroenterology and Liver Diseases, Tel Aviv, Israel, 3Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Gastroenterology department, Haifa, Israel

Management of Infliximab Treated Patients with Psoriasis Based On Infliximab Plasma Levels and Antibodies to Infliximab

Background: Infliximab is the fastest acting biological agent in psoriasis treatment due to the possibility of intravenous administration and a well-conducted induction phase of treatment (week 0, 2, and 6). Another advantage is the weight-based dosing. However, disadvantages include the risk of infusion reactions and the production of neutralizing antibodies that are responsible for the secondary loss of efficacy. Objectives: To analyze the dynamics of infliximab levels during one maintenance interval as well as the levels of anti-infliximab antibodies in patients with psoriasis treated with infliximab for a period of at least 22 weeks. Methods: We followed 25 patients with psoriasis treated with infliximab for a period of at least 22 weeks at a dose of 5 mg/kg. Based on the clinical picture at the time of blood sample collection, the patients were divided into responders, partial responders and non-responders. Plasma levels of infliximab and antibodies to infliximab were examined in venous blood samples taken during one maintenance interval. The levels of infliximab were examined in week 0, 2, 4, 6, 7 and 8 and anti-infliximab antibodies were examined in week 8. Results: According to the obtained data of infliximab levels and anti-infliximab antibodies, we divided the patients into 4 groups-responders, responders with shortened period of efficacy, non-responders with production of antibodies, and non-responders without production of antibodies. The dynamics of infliximab levels and the production of antiinfliximab antibodies were characteristic for each group. A definitive therapeutic management was created specifically for each group of patients. Conclusions: Monitoring the dynamics of infliximab levels and anti-infliximab antibodies is not only of scientific importance, but it may be crucial in daily clinical practice, enabling an objective management of infliximab treatment.

SAT0129 Incidence and clinical outcome of anti-drug antibodies in infliximab-treated patients

BackgroundInfliximab (chimeric monoclonal antibody against TNF-α) reduces the severity of symptoms and induces remission of active disease. However, some patients may experience adverse drug reactions (ADR) or loss of efficacy...

The frequency of anti-infliximab antibodies in patients with rheumatoid arthritis treated in routine care and the associations with adverse drug reactions and treatment failure

To investigate the frequency of anti-infliximab antibodies in patients with RA and the associations with adverse drug reactions and treatment failure. Based on the DANBIO registry, patients with RA who initiated treatment with infliximab at Hvidovre Hospital between 2000 and 2008 and had available serum samples were identified. The patients were followed for 52 weeks. Anti-infliximab antibodies were determined prior to infusion at baseline and during follow-up (weeks 2, 6, 14 and 52 or at withdrawal) using the IMPACT indirect assay (Roche Diagnostics) and merged with clinical data prospectively registered in the DANBIO registry. A total of 218 patients with RA were included (80% females, median age 56 years, disease duration 10 years, 65% RF positive, median DAS28 = 5.0). During the 52-week follow-up, 28 patients (13%) withdrew due to adverse events and 50 (23%) due to treatment failure. Antibodies were detected in 118 patients (54%) during follow-up. Patients with detectable anti-infliximab antibodies after 6 weeks had an increased risk of adverse drug reactions [hazard ratio (HR) = 5.06, 95% CI 2.36, 10.84; P < 0.0001] compared with patients without anti-infliximab antibodies. Similar results were observed in patients with anti-infliximab antibodies after 14 weeks (HR = 3.30, 95% CI 1.56, 6.99; P = 0.0009). Patients with detectable anti-infliximab antibodies during the 52-week follow-up were less likely to achieve sustained minimal disease activity and remission. Early anti-infliximab antibody formation increased the risk of adverse drug reactions, including infusion reactions. Anti-infliximab antibody formation during the 52-week follow-up decreased the likelihood of minimal disease activity and remission in patients with RA treated in routine care.

P551 Detection of anti infliximab antibodies in patients with inflammatory bowel disease (IBD) in the presence of infliximab by homogeneous liquid phase anti infliximab mobility shift assay

P551 Detection of anti infliximab antibodies in patients with inflammatory bowel disease (IBD) in the presence of infliximab by homogeneous liquid phase anti infliximab mobility shift assay

Detection of Anti Infliximab Antibodies in Patients with Inflammatory Bowel Disease (IBD) in the Presence of Infliximab by Homogeneous Liquid Phase Anti Infliximab Mobility Shift Assay

Purpose: Trough levels (TL) as well as c-max levels have been positively associated with efficacy and negatively with immunogenicity of infliximab (IFX) in patients with IBD. Degradation of IFX is mainly determined by the presence of anti drug antibodies (ADA), increasing its clearance between 1.4 and 2.7 fold. With evidence accumulating in favour of the concept of therapeutic drug monitoring, standard enzyme linked immunosorbent assays (ELISA) for the detection of ADA reach their limits, as the presence of high IFX levels strongly interferes with the detection of ADA. Here we assess the perfomance of a new assay for the detection of ADA at midinfusion timepoints as compared to samples immediately prior to the next IFX infusion. Methods: 90 consecutive patients with established IBD (66 with Crohn's disease, 24 with Ulcerative Colitis) under maintenance therapy with IFX were asked to participate. Serum samples were acquired at half time between two infusions and immediately prior to the subsequent infusion. IFX drug levels were measured by ELISA (Immundiagnostik, Germany) and ADA were assessed by homogeneous liquid phase anti Infliximab mobility shift assay (HLPA) (Prometheus Labs Inc. CA) for all time points. Results: Patients were receiving a median dose of IFX of 5,51 mg/kg body-weight (4,08-10,94), yielding a median TL of 8.98 yg/ml IFX. Infliximab serum levels were significantly higher at mid infusion versus TL (p=0.000). ADA were detectable in 19 patients and 23 patients at mid infusion and trough timepoints, respectively. 17 patients were concordantly positive, 2 were positive soley at mid infusion and 6 at time of trough sampling. The agreement for the outcome positive ADA measured at week 4 versus week 8 yields a Cohen's kappa of 0,80, with a correlation of t=0,651 (p=0.001). ADA occurred most frequently in patients with non-detectable or very low TL (Table 1).Table: IFX trough levels and presence of ADAConclusion: With HLPA, it is feasible to detect ADA against IFX with excellent accordance not only at low levels of circulating infliximab but also earlier within an infusion interval, when IFX concentrations are high and interfering with conventional ELISAs. ADAs are preferrentially detected in patients with negative or low TLs. Disclosure: The work presented here was supported by Prometheus Labs Inc. who performed the mentioned analyses free of charge. This research was supported by an industry grant from Pormetheus Labs Inc.

Low infliximab serum trough levels and anti-infliximab antibodies are prevalent in rheumatoid arthritis patients treated with infliximab in daily clinical practice: results of an observational cohort study

BackgroundTo 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 studyMethodsIn 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.Results147 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.ConclusionsLow (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.

Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease

Introduction. Reasons for infliximab failure in Crohn's disease and ulcerative colitis are debated. Serum levels of infliximab and anti-infliximab antibodies have been associated with loss of response. We aimed at determining cut-off levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to infliximab maintenance therapy. Methods. Patients with inflammatory bowel disease (n = 106) were retrospectively classified as having maintained response or loss of response to infliximab maintenance therapy. Trough concentrations were measured by fluid-phase radioimmunoassays. Results. Infliximab levels were significantly lower, and anti-infliximab antibody levels significantly higher, in Crohn's disease patients with loss of response (median infliximab 0 μg/ml, median anti-infliximab antibodies 35 U/ml) compared to patients with maintained response (median infliximab 2.8 μg/ml, median anti-infliximab antibodies 0 U/ml; p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cut-off values: infliximab <0.5 μg/ml, which was associated with loss of response with sensitivity 86% [64–97] and specificity 85% [72–94]; and anti-infliximab antibodies ≥10 U/ml yielding a sensitivity of 81% [61–93] and specificity 90% [79–96]. Combined measurements of infliximab and anti-infliximab antibodies using these cut-off values had higher accuracy yielding a sensitivity of 81% [57–94] and specificity 94% [82–98]. Similar pattern was observed in a smaller cohort of patients with ulcerative colitis. Conclusions. Combined measurements of infliximab and anti-infliximab antibodies using cut-off levels provided high accuracy for discriminating between clinical response types to infliximab maintenance therapy. Cut-off levels are considered a prerequisite to further investigations of clinical usefulness of measurements of infliximab and anti-infliximab antibodies in patients failing infliximab therapy.

A single course of rituximab does not abrogate anti-infliximab antibodies in patients with rheumatoid arthritis

The development of anti-infliximab antibodies in 8% to 43% of infliximab-treated patients is associated with decreased efficiency and increased risk of adverse effects.1–3 An intervention that can diminish anti-infliximab antibody...