Antibodies To Infliximab Levels Research Articles

P408 Anti-Drug Antibodies Detected in the Presence of Adequate Infliximab Drug Levels In IBD Patients in Clinical Remission have Limited Clinical Significance

Abstract Background Immunogenicity, with the development of antibodies-to-infliximab (ATI) increases drug clearance and can lead to loss of infliximab (IFX) response in inflammatory bowel disease(IBD). Reporting of ATI is variable between commercial assays with some assays having high sensitivity for low-titre antibodies. Uniform thresholds for clinically relevant antibody titres are lacking. It is unclear how ATI affect treatment outcome when adequate trough IFX concentrations are present and ATI are detected. Methods We aimed to assess the impact of ATI detected in the presence of adequate IFX levels on the outcome of IFX therapy in IBD patients in clinical remission. A proactive therapeutic drug monitoring(TDM) strategy was utilized in our unit with IFX and ATI levels, assessed at trough, in all IBD patients receiving IFX. Baseline demographics were collected. Patients were grouped based on disease activity. An adequate trough IFX level was a concentration > 3 µg/mL, with low levels defined as < 3 µg/mL. ATI positivity was defined as a concentration > 10 AU/mL. Receiver operating characteristic analysis was performed to evaluate the classifying performance of ATI concentration for low IFX levels. Survival analysis was performed to determine IFX persistence in patients with adequate IFX levels and positive ATI. Follow up TDM assessments, where available, were documented to determine changes in ATI concentration over time in patients with adequate IFX levels. Results 108 patients were included. Median age 36years. 46% were female. 36% had ulcerative colitis, 60% Crohn’s disease. 35% were receiving concomitant immunomodulators. 56% of patients were in remission at the time of TDM assessment. 44%, 30% and 26% of patients had IFX levels < 3 µg/mL, 3 – 7 µg/mL and > 7 µg/mL. Median [range] ATI concentration was 11 AU/mL [0 – 800]. ATI positivity occurred in 25%, 19% and 8% of IFX groups with levels < 3 µg/mL, 3 – 7 µg/mL and > 7 µg/mL. There was a weak inverse correlation between trough ATI and IFX concentration (p=0.01)(Figure 1). ATI concentration performed poorly as a classifier of low IFX levels (AUC 0.568)(p=0.39). 83%(15/18) of IBD patients in remission with adequate IFX levels and positive ATI remained on IFX for the duration of follow up with a mean cumulative time on IFX of 111.2 weeks (95% CI 105.1 – 117.3)(Figure 2). In this group, there was no significant change in ATI titre comparing index with follow up TDM assessments (p=0.14)(Figure 3). Conclusion ATI positivity in the presence of adequate IFX levels is common with proactive TDM. For patients in clinical remission ATI positivity in the presence of adequate IFX levels has limited clinical significance. Care should be taken to avoid unnecessary therapy alterations in this patient subgroup.

Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM. Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured. ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM. ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.

Dynamics of serum concentrations of antibodies to infliximab: a new approach for predicting secondary loss of response in inflammatory bowel diseases.

Background:Antibodies to infliximab (ATI) in serum are associated with secondary loss of response (LOR) to infliximab (IFX) therapy in patients with inflammatory bowel disease (IBD). However, feasible ATI-related predictors of therapy success are lacking and knowledge about individual ATI dynamics is limited. Therefore, this study analyzed whether ATI dynamics are able to predict LOR to IFX therapy and compared their predictive power with known predictors of LOR to IFX.Methods:This was a retrospective study of patients with Crohn’s disease (CD) or ulcerative colitis (UC) on IFX maintenance therapy and proactive IFX and immunogenicity monitoring in an outpatient clinic in Germany. Slopes of ATI (SATI) and IFX levels (dynamic parameters) and medians of ATI, IFX, C-reactive protein, and fecal calprotectin (static parameters) were calculated over a defined period of time after ATI emergence. Dynamic and static parameters were analyzed for associations with end points infliximab discontinuation due to secondary LOR and total IFX discontinuation.Results:In all, 500 visits from 38 IBD patients (28 CD, 10 UC) with a median IFX maintenance duration of 68.2 weeks were evaluated. Grouping by SATI (ATI-N = ATI nondetectable, ATI-↓ = negative SATI, ATI-↑ = positive SATI) yielded significant differences for outcomes LOR (p = 0.004) and total IFX discontinuation (p = 0.01). Patients in the ATI-↓ group survived significantly longer LOR-free compared with the ATI-↑ group (p = 0.02). Cox regression confirmed SATI to be a significant risk factor for LOR (p = 0.002). An SATI cut-off of approximately 2.0 AU mL−1 week−1 was determined to predict LOR with 83.3% sensitivity and 93.8% specificity.Conclusion:The ATI slope-based index SATI is a new feasible diagnostic predictor of LOR in IBD patients. SATI may facilitate quick therapeutic decisions after ATI emerge.

Intermittent Appearance of Antibodies to Infliximab Is Not Associated With Reduced Efficacy in Patients With Inflammatory Bowel Diseases.

To assess the clinical significance of antibodies to infliximab (ATI) formation in patients with inflammatory bowel disease (IBD). Infliximab therapy in patients with IBD is highly effective though up to 50% of patients lose response to infliximab. ATI formation occurs in 6% to 60% of patients on scheduled infliximab maintenance therapy. Infliximab trough levels and ATI at trough were prospectively determined in patients with IBD on maintenance infliximab therapy. Patients on infliximab maintenance therapy with at least 3 ATI measurements were included. Patients were divided into 2 groups: sustained negative (<1 µg/mL) ATI levels, and fluctuating ATI levels (at least 1 sample with ATI <1 and at least one >1 µg/mL). Forty-eight patients with IBD with available clinical data and serum samples were included. 25 patients had sustained low ATI levels and 23 patients had fluctuating ATI levels. Both groups were similar in IBD subtype distribution (Crohn's disease in 73.9% and 60%), mean serum albumin levels (4.2 vs. 3.9 g/dL), and mean trough serum infliximab levels (3.3 vs. 4.6 µg/mL) in fluctuating ATI and low ATI groups, respectively. There were no significant differences in the rate of clinical response (64% vs. 76%) and mean serum C-reactive protein levels (9.4 vs. 8.5 mg/dL, ULN=5) in the fluctuating ATI and low ATI groups. Similar rates of clinical response in the fluctuating ATI and low ATI groups were observed in ulcerative colitis (33% vs. 40%) and Crohn's disease (76% vs. 100%). The fluctuating pattern of appearance of ATI in patients with IBD was not associated with loss of clinical response or a rise in C-reactive protein. The authors suggest that in clinical decision making, only sustained appearance of ATI should be considered as an adverse therapeutic factor.

Development and Characterization of a New Endoscopic Drug-Eluting Platform With Proven Efficacy in Acute and Chronic Experimental Colitis.

Background and Aims: Mucosal lesions refractory to biological treatments represent unmet needs in patients with inflammatory bowel disease (IBD) that require new treatment modalities. We developed and characterized a new endoscopic drug-eluting hydrogel (CoverGel) with proven efficacy in acute and chronic experimental colitis (EC) in rats.Methods: CoverGel was developed based on appropriate rheological, drug release, gelation, structural, and degradation property capacities to allow endoscopic application. Experimental colitis (EC) was induced by TNBS application in rats. In acute EC 40, rats were randomized in five groups (eight each): Sham, Control, CoverGel, CoverGel + Infliximab (IFX) and CoverGel + Vedolizumab (VDZ). In chronic EC, 12 rats were randomized in two groups (six each): IFX s.c. and CoverGel + IFX. Endoscopic, histological, and blood test were performed during follow-up to evaluate clinical success. Antibodies to IFX (ATIs) were evaluated in chronic EC animal study.Results: CoverGel is a biocompatible and bioadhesive reverse thermosensitive gelation hydrogel with a macroporous structure and drug release capacity. In acute EC animals treated with CoverGel + IFX or CoverGel + VDZ showed significantly clinical success (weight recovery, mucosal restoration, and bacterial translocation) as compared with controls and animals without a bioactive drug. In a chronic EC animal study, clinical efficacy was comparable in both groups. Levels of ATIs were significantly lower in animals treated with CoverGel + IFX vs. IFX s.c. (0.90 ± 0.06 μg/mL-c vs. 1.97 ± 0.66 μg/mL-c, p = 0.0025).Conclusions: CoverGel is an endoscopic vehicle to locally deliver biological drugs with proven efficacy in acute and chronic EC in rats and induce less immunogenicity reaction.

Development of a C1q-immobilized (Cim) assay to measure total antibodies to infliximab and its clinical relevance in patients with inflammatory bowel disease

ObjectiveDetermination of antibodies to infliximab (ATI) is desirable for the management of patients with inflammatory bowel disease (IBD) who receive infliximab. Conventional ligand-binding ATI-assays detect only free-form of ATI, potentially increasing the proportion of patients with undetectable ATI, but with adequate trough infliximab (TRI) level who experience loss of response (LOR) to infliximab. We investigated this assertion using a novel ATI-Cim assay. MethodsAn ATI-Cim assay was developed by utilizing a C1q-immobilized plate, detecting free-form and ATI-infliximab complexes. Plasma ATI in 137 consecutive IBD patients, 56 with sustained clinical response (SCR), 76 with LOR and 5 with infusion reactions was measured. ResultsATI levels reached a plateau following addition of up to 25 μg/mL infliximab to different concentrations of free-form ATI. ATI concentration did not significantly change during infliximab infusion (P = 0.4316). ATI concentration > 0.153 μg/mL was associated with LOR (odds ratio 3.0: 95%, confidence interval 1.5 to 6.1, P = 0.0029). The number of patients with undetectable ATI was higher in SCR than in LOR, 53.6% vs 22.4% (P = 0.0004). Patients with SCR and LOR were divided into 4 subgroups by combined cut-off ATI and TRI values. (A) ATI > 0.153 μg/mL and TRI ≤ 2 μg/mL; (B) ATI > 0.153 μg/mL and TRI > 2 μg/mL; (C) ATI ≤ 0.153 μg/mL and TRI ≤ 2 μg/mL; (D) ATI ≤ 0.153 μg/mL and TRI > 2 μg/mL. The frequency of LOR showed a decreasing trend from subgroup A to D, 80.8%, 64.1%, 55.2% and 36.8%, respectively (P = 0.0003). ConclusionsThe measured ATI level appeared to define the patients’ response to infliximab. Combining ATI and trough infliximab levels should help to understand the mechanism of LOR and make therapeutic algorithms.

Full Interchangeability in Regard to Immunogenicity Between the Infliximab Reference Biologic and Biosimilars CT-P13 and SB2 in Inflammatory Bowel Disease.

Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2. Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman's coefficient and percentages of agreement were used to study the correlation between each assay. In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman's 0.98 to 1.0, P < 0.0001). ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

A review of six methods for monitoring infliximab concentrations and antibodies to infliximab .

Anti-TNF-α therapy, such as infliximab (IFX), has profoundly changed treatment to induce and maintain remission for inflammatory bowel diseases patients who do not respond to conventional therapies. Unfortunately, IFX, as a chimeric protein, is potentially immunogenic, and antibodies to infliximab (ATI) may interfere with the pharmacodynamics and pharmacokinetics of the drug, thus resulting in a loss of response for a substantial proportion of patients. The clinical efficacy of IFX is correlated with the levels of IFX and ATI. Therefore, monitoring patients for the trough levels of IFX and the presence of ATI is very important. The procedures and characteristics of six assays for monitoring IFX and ATI are described in this review, and the comparisons between them are also discussed. To date, there has been no optimal assay for monitoring IFX and ATI. Therefore, many technical problems need to be solved to make therapeutic drug and immunogenicity monitoring a part of routine clinical management. .

Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients: results of a 12-month observational prospective cohort study.

The objective of this study is to apply therapeutic drug monitoring (TDM) as an objective tool to monitor the switch from infliximab innovator (INX) to infliximab biosimilar (INB) in our diverse rheumatic cohort in daily clinical practice. All rheumatic patients on INX treatment (Remicade®) and ≥18years were switched to INB (Inflectra®) as part of routine care, but in a controlled setting. Patients were monitored by taking blood samples just before the first infusion of INB (T1), and after the second (T2), fourth (T3), and seventh (T4) infusion of INB. T4 reflects the patients' status after ∼12months. Infliximab trough levels, antibodies-to-infliximab (ATI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and validated disease activity scores (if possible) were measured. Our population consisted of 27 patients with seven different rheumatic diseases who had received INX for 143 (58-161) months (median (IQR)). Half of the patients (52%) received concomitant immunosuppressives. We found widely varying infliximab levels, with only 56% within the proposed therapeutic range of 1-5μg/mL. One patient had very high ATI levels (>880au/mL), and two had low ATI levels (≤30au/mL). After switching to INB, seven patients (26%) discontinued the therapy, partially due to subjective reasons. No difference in infliximab levels, CRP levels, and disease activity scores was found between the four time points (p≥0.2460). In conclusion, no pharmacokinetic or clinical differences were found between INX and INB in our diverse rheumatic cohort. TDM is a helpful tool to monitor patients switching from INX to INB.

Calprotectin and the Magnitude of Antibodies to Infliximab in Clinically-stable Ulcerative Colitis Patients are More Relevant Than Infliximab Trough Levels and Pharmacokinetics for Therapeutic Escalation

Although infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics among clinically-asymptomatic UC patients. This was a multicentric and prospective study involving 65 UC patients in the maintenance phase of IFX therapy. There were no significant differences between patients with positive and negative clinical, endoscopic and histological outcomes concerning their IFX trough levels (TLs), area under the IFX concentration vs. time curve (AUC), clearance and antibodies to infliximab (ATI) levels. However, the need to undergo therapeutic escalation later in disease development was significantly associated with higher ATI levels (2.62μg/mL vs. 1.15μg/mL, p=0.028). Moreover, and after adjusting for disease severity, the HR (hazard ratio) for therapeutic escalation was significantly decreased for patients with an ATI concentration below 3μg/mL (HR=0.119, p=0.010), and increased for patients with fecal calprotectin (FC) level above 250μg/g (HR=9.309, p=0.018). In clinically-stable UC patients, IFX pharmacokinetic features cannot predict therapeutic response on a short-term basis. However, high levels of ATIs or FC may be indicative of a future therapeutic escalation.

Clinical correlations of infliximab trough levels and antibodies to infliximab in South Korean patients with Crohn's disease.

AIMTo investigate the clinical implications of infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATI) levels in Crohn’s disease (CD) patients in Asian countries.METHODSIFX-TL and ATI level were measured using prospectively collected samples obtained with informed consent from CD patients being treated at Asan Medical Center, South Korea. We analyzed the correlations between IFX-TLs/ATI levels and the clinical activity of CD (quiescent vs active disease) based on the CD activity index, C-reactive protein level, and physician’s judgment of patients’ clinical status at enrollment. The impact of concomitant immunomodulators was also investigated.RESULTSThis study enrolled 138 patients with CD (84 with quiescent and 54 with active disease). In patients with quiescent and active diseases, the median IFX-TLs were 1.423 μg/mL and 0.163 μg/mL, respectively (P < 0.001) and the median ATI levels were 8.064 AU/mL and 11.209 AU/mL, respectively (P < 0.001). In the ATI-negative and -positive groups, the median IFX-TLs were 1.415 μg/mL and 0.141 μg/mL, respectively (P < 0.001). In patients with and without concomitant immunomodulator use, there were no differences in IFX-TLs (0.632 μg/mL and 1.150 μg/mL, respectively; P = 0.274) or ATI levels (8.655 AU/mL and 9.017 AU/mL, respectively; P = 0.083).CONCLUSIONIFX-TL/ATI levels were well correlated with the clinical activity in South Korean CD patients. Our findings support the usefulness of IFX-TLs/ATI levels in treating CD patients receiving IFX in clinical practice.

The association of infliximab trough levels with disease activity in pediatric inflammatory bowel disease

Objective. Low serum trough levels (TLs) of infliximab (IFX) and antibodies to IFX (ATIs) are associated with the loss of therapeutic response in adults with inflammatory bowel disease (IBD) receiving IFX. Until now, pediatric data are scarce. Therefore, we aimed to cross-sectionally investigate the association between ATIs and IFX TLs, and clinical and biochemical disease activity in children receiving IFX for IBD. Material and methods. Children aged <18 years receiving IFX maintenance treatment for Crohn’s disease (CD) or ulcerative colitis (UC) at three Dutch hospitals were included. Prior to two consecutive IFX infusions, IFX TLs and ATI levels were measured. Clinical disease activity was determined by Pediatric Crohn’s Disease Activity Index (PCDAI) and Pediatric Ulcerative Colitis Activity Index (PUCAI), for CD and UC, respectively. Biochemical disease activity was assessed by serum C-reactive protein (CRP) and fecal calprotectin (FC). Clinical remission was defined as a PUCAI or PCDAI score of <10. Therapeutic range of IFX was considered 3–7 µg/ml. Results. Thirty-nine patients were included (31 CD; 16 females). Median age was 15 years. Median IFX TL was 3.5 µg/ml [IQR 2–7]. Subtherapeutic and supratherapeutic TLs were found in 38% and 23% of children, respectively. ATIs were detected in four patients. A correlation was found between IFX TL and CRP [rs = −0.51; p < 0.01] and FC [rs = −0.49; p < 0.01]. However, when only clinical disease activity was considered, no difference in median TL was found between remission and active disease (resp. 3.5 µg/ml [IQR 2–5] and 2.3 µg/ml [IQR 0.3–4.6]; p = 0.2). Conclusions. IFX TLs are related to biochemical markers of disease activity. This could provide a rationale for monitoring TLs in children receiving IFX for IBD.

Tu1315 Loss of Response in IBD Patients on Infliximab Treatment: Assay of Infliximab Trough Levels and Total Antibodies to Infliximab

Optimization of infliximab therapy in inflammatory bowel disease (IBD) patients who lose the clinical response is currently performed empirically. The assay of antibodies to infliximab (ATI) and infliximab trough levels (TL) could be helpful in the clinical decision. We collected sera from 102 IBD patients who were in maintenance treatment with infliximab. Fifty-five patients had experienced a loss of response (LOR) and most of them (45/55) had their infliximab dose already been optimized at 7.5 to 10 mg/kg. As a control group we studied 47 patients in stable clinical response. Blood was drawn for ATI, TL and C-reactive protein (CRP) assay immediately before the next infliximab infusion. We assayed ATI and TL by an ELISA kit (Immundiagnostik AG, Bensheim, FRG) that measures both free and bound antibodies even in the presence of circulating in fliximab. ATI results were expressed as arbitrary units (AU)/ml. TL were expressed as ug/ml. The subsequent clinical decisions were made blinded to ATI and TL levels. Clinical activity and CRP were also assessed after 12 months. Fifty-one patients had Crohn's disease and 51 had ulcerative colitis. Twenty-three were on concomitant immune modulators. In the whole patient population, median ATI were 24,5 AU/ml (IQR 7,4 to115,8) while median TL were 2,3 ug/ml (IQR 0 to 5,6). ATI and TL were negatively correlated (Spearman's rho -0,579, p 2,08 ug/ml for predicting clinical response at 12 months with 56,4% sensitivity and 70,8% specificity (AUC 0,628, 95% CI 0,527 to 0,722, p= 0,038). Among patients with LOR, 62% had ATI > 26,3 AU/ml, as compared to 32% of those maintaining the response (p=0,003 by Fisher's exact test). A significant correlation was detected between ATI and CRP levels both at baseline (Spearman's rho 0,218, p= 0,0287) and after 12 months (rho 0,284, p= 0,0043). Prospective studies will determine the utility of these cut off values in the management of LOR to infliximab in IBD.

Clinical Utility of Next Generation Infliximab and Antibodies to Infliximab Assay

Purpose: An assay to measure serum infliximab (IFX) and antibodies to infliximab (ATI) has been available since 2006 (Prometheus Laboratories, San Diego, CA). The first-generation enzymelinked immunosorbent assay (ELISA) could only measure ATI in the absence of IFX, due to IFX interference with the assay. A novel liquid-phase mobility shift assay was developed recently, allowing for measurement of IFX and ATI levels even when serum IFX is present (Anser IFX©, Prometheus Laboratories, San Diego, CA). The aim of this study is to investigate the clinical utility of this new test. Methods: We conducted a retrospective review of the electronic medical records of all inflammatory bowel disease (IBD) patients at our institution who underwent IFX/ATI testing between January 1, 2010 and December 31, 2012. The assay type, results, testing indication, and clinical management were obtained. Results: One hundred forty eight tests using ELISA assay and 57 tests using Anser IFX© assay were performed. Test results are summarized in Table 1. Fifty-two percent (77/148) of ELISA tests and 47% (27/57) of Anser IFX© tests were performed to evaluate inadequate/loss of response (LOR) to IFX. Overall, 48% (49/103) of patients experiencing LOR had therapeutic IFX levels. Using the ELISA assay, 11/31 patients (35%) with undetectable IFX levels were ATI-positive, as compared to 10/11 patients (91%) tested with the Anser IFX© assay. In addition, 2/13 (15%) of patients with subtherapeutic IFX concentrations using the Anser IFX© assay were ATI-positive (ATIs could not be measured in 41 patients with subtherapeutic IFX concentrations tested using the ELISA assay). In total, 12/24 patients (50%) with undetectable or subtherapeutic IFX concentrations, as measured by Anser IFX©, had detectable ATI, compared to 11/72 patients (15%) measured by ELISA assay.Table 1: Comparison of Anser IFX© versus ELISA assayConclusion: Use of mobility shift Anser IFX© assay is associated with a marked increase in proportion of patients with undetectable or subtherapeutic IFX concentrations who are found to be ATI-positive. These preliminary findings should be confirmed prospectively in a study with paired ELISA and Anser IFX© assays in the same patients. If confirmed, these findings suggest the Anser IFX© assay may explain the underlying reason (immunogenicity) for undetectable or subtherapeutic IFX concentrations in a larger proportion of patients. Disclosure - Dr. Sandborn - Consultant and Grant/Research Support: Janssen Biotech, Inc, Consultant: Prometheus Laboratories, Inc.; Dr. Levesque - Consultant: Prometheus Laboratories, Inc.

The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab

ObjectiveTo characterise the temporal evolution of antibodies to infliximab (ATI).DesignProspective observational study of infliximab-treated patients with inflammatory bowel disease between 2009 and 2012.InterventionsTrough levels of infliximab and ATI were measured...

THU0219 The Infliximab Dose Increase is Not Correlated with Clinical Improvement in RA Patients

BackgroundThe anti-TNF therapy is an effective treatment in RA patients, however a considerable percentage of patients develop clinical inefficacy (primary or secondary); part of which can be explained by the...

Antibody Response to Infliximab and its Impact on Pharmacokinetics can be Transient

Infliximab (IFX) is successfully used in the treatment of inflammatory bowel diseases but some patients generate antibodies to IFX (ATI) jeopardizing the pharmacokinetics of the drug. Little is known about the factors influencing ATI formation and whether or not this immune reaction is permanent. Our aim was to investigate the kinetics of ATI formation and drug levels in relation to inflammatory markers and the clinical evolution of the patients. IFX trough and ATI levels were measured retrospectively in 1,232 consecutive serum samples of 90 (64 Crohn's disease and 26 ulcerative colitis) patients, 57 with previously detected and 33 without antibodies with a new homogenous mobility shift assay. Testing with new assay confirmed ATI in 53/90 patients (59%) and 37/90 patients (41%) were ATI negative. In 15/53 patients (28%), ATI disappeared over time whereas in 38/53 patients (72%) ATI persisted. The 26/38 (68%) patients with sustained ATI needed to discontinue IFX treatment compared with 2/15 (13%) patients with transient ATI (relative risk 5.1; 95% confidence interval 1.4-19.0; P=0.0005). An IFX trough level at week 14<2.2 μg/ml predicted IFX discontinuation due to persistent loss of response (LOR) or hypersensitivity reactions with 74% specificity and 82% sensitivity (likelihood ratio 3.1; P=0.0026). ATI may be transient and do not always lead to a worse clinical outcome. Sustained high levels of ATI, however, lead to permanent LOR. Patients with low IFX trough levels at week 14 are at risk for ATI formation and IFX discontinuation. Therefore, we recommend to measure IFX trough levels at week 14 and at time of LOR. When undetectable or low, ATI should be determined and if positive followed up on consecutive time points to rule out sustained ATI.

ASSESSMENT OF LOSS OF RESPONSE TO INFLIXIMAB THERAPY IN INFLAMMATORY BOWEL DISEASES USING ANTIBODIES TO INFLIXIMAB AND TROUGH LEVELS

Event Abstract Back to Event ASSESSMENT OF LOSS OF RESPONSE TO INFLIXIMAB THERAPY IN INFLAMMATORY BOWEL DISEASES USING ANTIBODIES TO INFLIXIMAB AND TROUGH LEVELS Luisa Guidi1*, Gianluca Andrisani1, Manuela Marzo1, Alfredo Papa1, Carla Felice1, Daniela Pugliese1, Silvia Canestri1, Barbara Tolusso1, Elisa Gremese1 and Alessandro Armuzzi1 1 Università Cattolica del Sacro Cuore, Italy Currently the management of inflammatory bowel disease (IBD) patients on infliximab therapy who lose response is mostly empirical: an increase of dose up to double or a decrease of treatment intervals is the common clinical practice, with a consequent increase of drug use and high costs. Measuring trough levels (TL) and antibodies to infliximab (ATI) may be of great benefit in optimizing therapy. We aimed to evaluate the relationship of TL and ATI assay with loss of response and infusion reactions in an Italian IBD unit. Methods: Sera were obtained from 82 IBD patients on infliximab maintenance therapy from at least 6 months. Patients were classified as being or not in clinical response. The occurrence of acute reactions to infliximab infusions was recorded. ATI and TL were measured by a commercial ELISA (Immundiagnostik AG, Bernsheim, Germany). Results: ATI were detected in 18 patients (22%), 50% of which were in clinical response as compared to 80% of patients without detectable serum ATI levels (p=0.0271 by χ2 test). 5/18 (28%) of ATI positive patients had infusion reactions as compared to 2/64 (3%) ATI negative (p=0.0047 by χ2 test). 60/82 patients had infliximab TL >0,1 µg/ml and 80% of them were in clinical response, as compared with 54% of patients with TL lower than 0,1 ug/ml (p=0.0043 by χ2 test). Median TL were not significantly different among clinical responders and non-responders. Conclusion: The combination of ATI and infliximab TL assay could help in managing loss of clinical response in IBD. Keywords: Inflammatory Bowel Diseases, infliximab, anti drug antibodies, Crohn's disease, ulcerative colitis Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Guidi L, Andrisani G, Marzo M, Papa A, Felice C, Pugliese D, Canestri S, Tolusso B, Gremese E and Armuzzi A (2013). ASSESSMENT OF LOSS OF RESPONSE TO INFLIXIMAB THERAPY IN INFLAMMATORY BOWEL DISEASES USING ANTIBODIES TO INFLIXIMAB AND TROUGH LEVELS. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00736 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Prof. Luisa Guidi, Università Cattolica del Sacro Cuore, Roma, Italy, lguidi@rm.unicatt.it Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Luisa Guidi Gianluca Andrisani Manuela Marzo Alfredo Papa Carla Felice Daniela Pugliese Silvia Canestri Barbara Tolusso Elisa Gremese Alessandro Armuzzi Google Luisa Guidi Gianluca Andrisani Manuela Marzo Alfredo Papa Carla Felice Daniela Pugliese Silvia Canestri Barbara Tolusso Elisa Gremese Alessandro Armuzzi Google Scholar Luisa Guidi Gianluca Andrisani Manuela Marzo Alfredo Papa Carla Felice Daniela Pugliese Silvia Canestri Barbara Tolusso Elisa Gremese Alessandro Armuzzi PubMed Luisa Guidi Gianluca Andrisani Manuela Marzo Alfredo Papa Carla Felice Daniela Pugliese Silvia Canestri Barbara Tolusso Elisa Gremese Alessandro Armuzzi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Addition of an Immunomodulator to Infliximab Therapy Eliminates Antidrug Antibodies in Serum and Restores Clinical Response of Patients With Inflammatory Bowel Disease

There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies.

Clinical Experience with Measurement of Serum Infliximab and Antibodies to Infliximab Using a New Homogenous Mobility Shift Assay: Results of a Multi-center Observational Study

Purpose: To characterize utilization of a new test for monitoring serum infliximab (IFX) and antibodies to infliximab (ATI) in Inflammatory Bowel Disease (IBD) patients on IFX therapy. The main advantage of this new test, using a liquid phase homogeneous assay, over the existing ELISA is that serum IFX does not interfere with quantification of ATI. Therefore, physicians can measure serum levels of IFX and ATI at any time during IFX therapy. Methods: IBD patients undergoing IFX therapy were enrolled in the study if their treating physician determined a need to measure IFX and ATI levels at any time during the course of therapy. Indications for the test, clinical status, and dosing information were collected at the time of blood draw. IFX and ATI levels were communicated to the physicians within 7 days and actions taken in response to the test results were documented. Results: As of this analysis, baseline data were available for 48 patients (28 CD, 19 UC and 1 indeterminate colitis). Mean age was 48y, mean BMI was 26.4 kg/m2 and mean duration of disease was 9.3 years. Forty-two percent of physicians ordered the test because their patients had an inadequate response or loss of response whereas 58% ordered the test in the absence of a lack or loss of response. Median IFX concentration was 9.45 μg/mL and 14 of 48 patients (29%) were positive for ATI. Among ATI-positive patients, 86% had IFX concentrations < 3 μg/mL, whereas only 9% of ATI-negative patients had IFX concentrations < 3 μg/mL (Odds Ratio = 0.02; p <<0.0001, Fisher's Exact test). Median IFX concentrations were 1 μg/mL and 20 μg/mL in ATI-positive and ATI-negative patients, respectively. Patients with lower disease scores had higher median IFX concentrations (median IFX = 9.3 μg/mL for HBI <7 vs. 5.2 μg/mL for HBI ≥7 in CD and median IFX = 34.00 μg/mL for partial Mayo score < 6 vs. 14.25 μg/mL for partial Mayo score ≥ 6 in UC). Changes made to the treatment regimen in response to knowing results of IFX/ATI testing included increasing the dose of IFX, changing the dosing interval, switching to another biologic, or performing additional work-up. Follow-up data for these patients will assess the clinical impact of adjusting therapy based on IFX / ATI levels. Conclusion: Results of this study are consistent with previous reports in the literature demonstrating that ATI development is negatively associated with serum IFX concentrations and clinical status. Physicians appear to find the measurement of serum IFX and ATI levels useful in multiple clinical scenarios including inadequate response or loss of response. Disclosure: Dr. Wolf: None Dr. Shringarpure: Employee of Prometheus Laboratories Inc. Dr. Lockton: Employee of Prometheus Laboratories Inc. Dr. Corey: None. Dr. Woods: None. Dr. Aguilar: None. Dr. Chuang: Employee of Prometheus Laboratories Inc. This research was supported by an industry grant from Prometheus Laboratories Inc.