anti-IFX Antibodies 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.

P890 Usefulness of subcutaneous Infliximab in patients with Inflammatory Bowel Disease in clinical practice: are increased levels associated with clinical benefit?

Abstract Background Switch from intravenous Infliximab (IFXiv) to subcutaneous Infliximab (IFXsc) in Inflammatory Bowel Disease (IBD) has been associated with an increase in trough levels. However, whether this increase is correlated with additional clinical benefit has not thus far been evaluated in clinical practice. Methods Single-center retrospective study of IBD patients who switched from IFXiv to IFXsc (for at least 3 months), between July 2021 and August 2023, due to unfavorable pharmacokinetics (IFX serum levels &amp;lt;3 +/- anti-IFX antibodies). Disease activity was defined as clinically: Simple Clinical Colitis Activity Index (SCCAI) ≥2 for Ulcerative Colitis (UC), Harvey Bradshaw Index (HBI) ≥5 for Crohn´s Disease (CD) or perianal fistulae with active drainage; and biochemical: C-reactive protein (CRP) &amp;gt;5 mg/L and/or fecal calprotectin (FC) &amp;gt;250 µg/g in UC and &amp;gt;150 µg/g in CD. Primary endpoint was to evaluate the effectiveness of IFXsc switch: achieving clinical response (decrease of SCCAI ≥2, IHB ≥3 or ≥50% in fistula drainage) or remission (SCCAI ≤1, IHB ≤4 or absence of active fistula drainage) with biomarkers normalization, or maintenance of remission, in patients with and without previous activity, respectively. Secondary endpoints were to assess IFX levels change and safety of IFXsc switch. Results Twenty-five patients (23 CD, 2 UC) were included (Table 1). Previous IFXiv therapy lasted for a median of 55 (20.6-74.1) months (100% with intensified dose and 48% with combined therapy). Median baseline IFX level was 1.7 (0.4-3) μg/mL, with anti-IFX antibodies in two cases. At baseline, 7 patients were in remission and 18 had active disease: 15/18 clinical or both clinical and biochemical (3/15 luminal, 11/15 perianal or 1/15 both), and 3/18 biochemical only. Median follow-up was 15.2 (10.2-19.2) months. After IFXsc switch, an increase of IFX level was achieved in 96% of cases, with a median final level of 12.4 μg/mL (9.2-18) (Figure 1). None of the patients in remission at the beginning relapsed during follow-up. Of patients with previous clinical activity, 66.6% achieved clinical remission (53.3%) or response (13.3%), which was seen in 50% of patients with luminal and 66.7% with perianal activity, after a median of 79 (75-210) days. CRP and FC normalization was reported in 53.3% of patients with previous biochemical activity. Treatment was discontinued only in one patient due to inefficacy. IFXsc was intensified in 8% and concomitant treatment could be withdrawn in four patients. No adverse events we reported. Conclusion Switching to IFXsc in patients with previous therapy with intensified IFXiv is not only associated with a more favorable pharmacokinetic profile but also with a greater effectiveness.

Carriage of the HLA-DQA1⋆05 haplotype is associated with a higher risk of infratherapeutic drug concentration and higher immunogenicity in patients undergoing treatment with anti-TNF for inflammatory bowel disease.

The success of anti-tumor necrosis factor (TNF) drug strategies in the treatment of inflammatory bowel disease (IBD) is altered by the development of anti-drug antibodies that reduce their efficacy. Studies have shown that the HLA-DQA1⋆05 allele increases the risk of immunogenicity to anti-TNF drugs approximately twofold. Analyze whether the presence of the HLA-DQA1⋆05 allele is associated with the development of immunogenicity and to evaluate the disease response to anti-TNF drugs (infliximab (IFX) and adalimumab (ADA)), according to the presence of this allele. This is an observational retrospective cohort study, single center, to determine the impact of HLA-DQA1⋆05 on disease activity in patients with IBD at the Hospital Universitario Virgen Macarena. In total, 200 IBD patients were included: 109 treated with IFX and 91 with ADA. Data were collected using the computerized medical records from the DIRAYA program of the Servicio Andaluz de Salud. Response-defined as improvement-and remission-defined as the disappearance of symptoms and analytical/endoscopic signs-were assessed using activity indices (partial Mayo, Harvey-Bradshaw) in all patients. Anti-TNF drug levels were also determined, as well as the presence or absence of anti-IFX and anti-ADA antibodies. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement. The HLA-DQA1⋆05 haplotype was present in 70 (35%) patients, including 39 (36%) treated with IFX and 31 (34%) with ADA. The risk of withdrawal, intensification, as well as antibody development, was higher in patients carrying the allele and on treatment with IFX or ADA. In our study, we demonstrated that there is an increased risk of immunogenicity in patients carrying the HLA-DQA1⋆05 genotype, which would support the idea of screening for this genetic variant before starting anti-TNF therapy, as its prevalence is high in the general population and increases the risk of treatment discontinuation due to loss of response.

Subcutaneous Infliximab in Refractory Crohn's Disease Patients: A Possible Biobetter?

A subcutaneous formulation of infliximab (IFX-SC) approved to treat patients with inflammatory bowel disease may offer improved efficacy versus intravenous infliximab. Patients with refractory Crohn's disease (CD, n = 32) previously treated unsuccessfully with at least 2 biologics were treated with IFX-SC and followed from baseline at Week 0 (W0) to Week 30 (W30). The study's primary endpoint was the treatment's persistence at W30, while secondary goals included the analysis of serum infliximab trough levels (TL IFX), dynamics of anti-IFX antibodies (ATIs), and clinical, serum and fecal markers of CD activity during IFX-SC treatment. Midterm treatment persistence with the continuation of treatment after W30 was 53%. TL IFX median values showed rapid, significant upward dynamics and exceeded 15.5 μg/mL at W30, whereas median ATI levels significantly declined. Among ATI-negative patients at W0 (n = 15), only one showed IFX immunogenicity with newly developed ATIs at W30. Among ATI-positive patients at W0, ATI seroconversion from ATI-positive to ATI-negative status was observed in 10 of 17 patients (58.8%). Patients who had continued IFX-SC treatment at W30 showed significant decreases in C-reactive protein (P = .0341), fecal calprotectin (P = .0002), and Harvey-Bradshaw index (P = .0029) since W0. Patients with refractory CD previously treated with at least 2 biologics exhibited clinically relevant improvement with IFX-SC, which showed less immunogenic potential than IFX-IV and highly stable TL IFX.

P404 Persistence of subcutaneous infliximab after switching from intravenous in a French national cohort of IBD patients in remission

Abstract Background Subcutaneous infliximab (IFX-SC) was launched in France for the treatment of patients with inflammatory bowel disease (IBD) in 2021. Real-life and pharmacokinetic (PK) data after switching from intravenous infliximab (IFX-IV) to IFX-SC are needed. The PEREM study is a French multicenter prospective cohort aiming to describe the persistence of IFX-SC after switch from IFX-IV. Methods IBD patients in steroid-free clinical remission [Harvey Bradshaw Index (HBI) ≤ 4 for Crohn’s disease (CD) and partial Mayo score (PMS) ≤ 2 with each subscore ≤ 1 for UC] for at least 6 months on IFX-IV therapy were proposed to switch to IFX-SC as part of routine care. Patients were included in 40 centers between Oct 2021 and May 2022. Clinical scores (HBI, PMS), biological samples (CRP and fecal calprotectin - FC), PK and anti IFX antibodies (ATI) were evaluated 3, 6, 12 and 24 months after switch. In case of IFX-SC discontinuation, time and reason for withdrawal were documented. Safety and adverse events of interest were recorded. The primary endpoint was IFX-SC persistence at 12 months. As not all patients met this primary endpoint at the time of writing this abstract, we present here the results at 6 months (M6). Results Among the 444 patients included [44% female, median age: 37 years (Min, Max: 18-88), 72% Crohn’s], 71% were receiving IFX-IV at a dose of 5 mg/kg every 8 weeks and 84% were treated on monotherapy. Among the 417 patients analyzed, five withdrew their consent before the M6 visit and 324 were assessed at M6; 25/324 (7.7%) discontinued IFX-SC before M6 (seven for relapse, twelve for intolerance, two for pregnancy, four for unknown reasons) including one (0.3%) switch back to IFX-IV. Rate of survival without IFX-SC discontinuation at M6 was 92.6% (95% CI 89.3-95.1). Among the patients evaluated at M6, median clinical scores did not vary between inclusion and M6: HBI from 0 (IQR: 0-1) to 0 (IQR: 0-1), PMS from 0 (IQR: 0-0) to 0 (IQR: 0-0), respectively. The median CF and CRP levels were respectively 52 μg/g (IQR: 19-142) at inclusion and 37 μg/g (IQR: 14-129) at M6, and 1 mg/L (IQR: 1-4) at inclusion and 1 mg/L (IQR 0-4) at 6 months. At baseline, median infliximab levels were 6.6 μg/mL (min, max: 0-29) and 20 μg/mL (min, max: 0.3- 79.2) at M6. No major safety signals were recorded. Conclusion In a national real-life multicenter cohort, rate of persistence of IFX-SC after 6 months was 92.6% in IBD patients switched in remission, without significant clinical or biological changes. Treatment switch was associated with an increase in IFX levels. These data are confirming the good efficacy and safety of IFX-SC after switch.

P705 Switching from intravenous to subcutaneous infliximab: clinical and patient experience outcomes

Abstract Background Intravenous (IV) infliximab (IFX) monotherapy is associated with significant loss of response. Therapeutic drug monitoring shows an association with low serum trough drug levels and development of anti-IFX antibodies. Combination therapy with immunomodulators is not always possible, and IFX dose escalation leads to higher drug costs and time pressure on infusion units. Both approaches have raised heightened patient safety concerns due to the Covid-19 pandemic. Subcutaneous (SC) IFX pharmacokinetics lead to improved drug trough levels, which could lead to better clinical outcomes. Methods The NHS Greater Glasgow and Clyde biologics database was used to identify selected patients currently treated with IV IFX for IBD for suitability for SC switch. Patients were contacted to allow informed choice to opt in or out of switch. Baseline clinical data was collected, and patients were reviewed at week 8 and week 24 for assessment of clinical disease activity scores, IFX trough levels/anti-drug antibody levels, and faecal calprotectin. Patient experience outcomes were assessed using a quality of life questionnaire (CUCQ-8). Results 31 patients consented to switch; F:M = 17:14. The majority of patients (16) had Crohn’s disease, with 13 with UC and 2 IBDU. Mean duration of disease was 9.1 years and duration of prior IV therapy was 3.3 years. 28 patients were reviewed at week 8 and 24 at week 24. At week 24, 71% of patients were in clinical remission (Harvey-Bradshaw index score &amp;lt;5 or partial Mayo score &amp;lt;2), 96% had CRP &amp;lt;5 mg/Land 87% had FCP &amp;lt;250µg/g. 21% of patients had subtherapeutic IFX trough levels at baseline, all had increased by week 8 and there were no subtherapeutic levels measured by week 24. One patient had detectable antibodies at week 24, compared with 9 patients at baseline. Three patients required oral steroid therapy during the 24-week follow up period. There were no hospital admissions, significant infections or adverse reactions within the cohort. 15 patients submitted CUCQ-8 scores, of these 7 patients’ scores had worsened at week 8 but by week 24 13/15 were stable or improved compared to baseline. Conclusion Switching from IV to SC infliximab is welcomed by most patients. The efficacy, tolerability, increased drug level and safety which has previously been demonstrated is reproduced in our cohort. This study is the first to explore patient experience outcomes. The finding of initial worsening of the CUCQ-8 score, but overall improvement by week 24 opens further opportunity for engaging patient involvement in switch programmes.

SUBCUTANEOUS INFLIXIMAB IN REFRACTORY CROHN'S DISEASE PATIENTS AFTER THE MULTIPLE TREATMENT FAILURES - SHORT TREATMENT OUTCOMES

Abstract BACKGROUND Subcutaneous administration of infliximab shows an increased benefit in terms of pharmacokinetics and pharmacodynamics effects compared to the intravenous infliximab. The practical question arises whether routine administration in refractory CD patients who have failed prior biological therapy will provide "biobetter" clinical efficacy. AIMS We propose a single center study designed to evaluate SC-IFX treatment outcomes in patients with active CD after the previous failures of other biologicals (TMAbs). Such a refractory CD cohort was chosen because there is currently insufficient appropriate medication therapy available for these patients and the identification of parameters predicting response to SC-IFX treatment could be of great benefit to some of them. PATIENTS &amp; METHODS A total of 32 CD patients were included, with the median age of 34.5 years and median CD duration of 11 years; &amp;gt;90% of them with stricturing and/or penetrating disease behavior, &amp;gt;80% with ileocolic involvement, and about 40% with the active perianal disease. Eighteen of 32 patients (56%) have failed on ≥3 previous TMAbs, the rest on 2 previous TMAbs. Twenty (62.5%) of n = 32 have had IV-IFX in past; in this sub-cohort, 85% of patients have positive anti-IFX antibodies (ATI). In ATI-positive sub-cohort, induction of SC-IFX was realized with four 120 mg SC doses weekly. Two induction IV infusions of 5 mg/kg IFX were administered in 2-week intervals in ATI-negative sub-cohort. Maintenance treatment in whole cohort consisted of 120 mg SC IFX bi-weekly. RESULTS Of the 32 patients, 7 individuals have failed the treatment during the induction phase: one because of heart disease progression, and 6 patients due to delayed hypersensitivity reactions with systemic manifestation. In 25/32 patients who continued their treatment up to W14, the initial median Harvey-Bradshaw index (HBI) of 6 (min 1, max 28) did not decrease significantly within the 14 weeks of treatment (p=0.067). However, both the serum CRP level (p=0.039) and fecal calprotectin level (p=0.027) have shown significant decrease. Median trough IFX levels have increased from 6 μg/mL at W2 to 10 μg/mL at W14 (p&amp;lt;0.001), and median ATI levels dropped from median of 38 ng/mL to 5 ng/mL (p= 0.0004). None of the patients with initial zero ATI levels have shown new ATI formation. Moreover, in 10 of 17 patients (59%) with the initial ATI positivity, ATI serum levels have decreased significantly even to the cut-off levels. The only risk factor for SC-IFX discontinuation before W14 was a high serum levels of ATIs (p &amp;lt; 0.001). CONCLUSIONS Our short-term experience with SC-IFX shows the treatment efficacy and tolerability in complicated CD patients after multiple TMAbs failures.The research gap in information about biobetters in patients with IBD must be filled and predictive factors for the response to SC-IFX must be found.

Association of Neutrophil Extracellular Traps with Fistula Healing in Patients with Complex Perianal Fistulizing Crohn's Disease.

Perianal fistulizing Crohn's disease [pfCD] is a disabling phenotype of Crohn's disease [CD] with suboptimal outcomes. We assessed neutrophil extracellular traps [NETs] in perianal fistulas and implicated their roles in pfCD healing. Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NET components, including myeloperoxidase [MPO], neutrophil elastase [NE] and citrullinated histone H3 [CitH3], were identified using immunofluorescence. Serum infliximab [IFX], anti-IFX antibodies, and tissue levels of IFX, adalimumab [ADA], MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV [PAD4], tumour necrosis factor [TNF]-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with quantitative PCR. Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-sequencing revealed differences in neutrophil associated pathways between unhealed and healed fistulas. NET components [MPO/NE/CitH3] were detectable in the fistulas and were parallel with the levels of PAD4. Eleven of 21 [52%] patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.

The use of drug monitoring of infliximab and adalimumab to optimize the treatment of inflammatory bowel diseases in children

Introduction. The effectiveness of the use of TNF inhibitors in patients with inflammatory bowel diseases (IBD) has been shown. 20-40% of patients are known to fail to respond to received therapy, and 10-30% of patients experience a loss of effect by the year of therapy. Objective is to evaluate the information content of therapeutic drug monitoring (TDM) for effective treatment with TNF blockers (infliximab - IFX, adalimumab - ADA) in IBD children. Materials and methods. There were examined seventy four children on IFX therapy including 66 children on ADA therapy. The age of the children ranged from 3.4 to 18 years. Residual levels of IHF and ADA were determined using a lateral flow immunoassay. Statistical data processing was performed using the Statistica 10.0, SPSS 16 software. Differences between groups were assessed using the nonparametric Mann-Whitney U test. Results. IFX levels (less than 3 µg/ml) were detected in 64% of cases, ADA (less than 5 µg/ml) in 21% of cases. The residual level of IFX and ADA in remission significantly exceeded the level of drugs in groups of children in exacerbation. An inverse relationship was observed between the residual level of IFX (r = -0.68, p = 0.000) and ADA (r = -0.31, p = 0.000) and the number of days after drug administration. Anti-IFX antibodies were found in 27.3% in the exacerbation group and in 5.8% in remission (p &lt; 0.001). Antibodies to ADA in children with IBD were found in 4 patients with a low concentration of the drug (2.57 ± 0.45 µg/ml) in the serum in a state of exacerbation. In patients on anti-TNF therapy, empirical dose selection revealed a residual level lower than in children in whom dose adjustment was carried out taking into account the residual concentration of drugs. Conclusion. The use of TDM TNF blockers in combination with the determination of antibodies to drugs can significantly increase the effectiveness of therapy in IBD children.

Drug Levels Associated With Optimal Discrimination Between Remission and Nonremission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease.

To implement therapeutic drug monitoring-based strategies for infliximab (IFX) in inflammatory bowel disease, the authors assessed IFX levels for optimal discrimination between remission and nonremission and compared assays for anti-IFX antibodies (Abs). The retrospective cohort comprised 163 bionaive patients with inflammatory bowel disease who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for 1 year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n = 690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels < limit of detection (n = 102) were analyzed by 2 binding assays [enzyme-linked immunosorbent assay (ELISA)] and functional reporter gene assay/drug-tolerant enzyme immunoassay. At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 mcg/mL was associated with clinical remission during the entire first year of therapy [sensitivity 54% (49-59), specificity 73% (67-78), AUCROC 0.65 (0.60-0.69), P < 0.0001]; these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n = 131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure [OR 2.9 (1.4-6.0), P < 0.01], irrespective of persistency or transiency. All performed assays detected anti-IFX Abs were picked up by all assays in ∼2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. IFX at ∼5 mcg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for therapeutic drug monitoring.

Population Pharmacokinetics of Infliximab in Children with Juvenile Idiopathic Arthritis.

The recommended infliximab (IFX) dose in (pediatric) rheumatology practice is 3-6 mg/kg every 4-8 weeks. Higher dosage regimens (>10 mg/kg) of IFX are effective and safe. To optimize IFX treatment in patients with juvenile idiopathic arthritis (JIA), therapeutic drug monitoring might be beneficial. To support routine therapeutic drug monitoring of IFX and regimen optimization for patients with JIA, in-depth knowledge of the pharmacokinetic (PK) variability of IFX is needed. As soon as the optimal therapeutic drug ranges are known, PK model-based simulation can be used to individualize drug dosing recommendations. In this study, a population PK model for IFX is described for patients with JIA. Data including IFX trough concentrations and anti-IFX antibodies of 27 pediatric patients with JIA on IFX maintenance treatment were retrieved from electronic charts. Three population PK models from the literature were validated for the authors' data set using the nonlinear mixed-effects modeling program NONMEM. A novel population PK model was developed based on the study data. A total of 65 blood samples obtained after a median of 32 days after the last IFX infusion (interquartile range 28-42) were analyzed. The 3 published models underpredicted the observed trough concentrations. A newly developed one-compartment model best described the data corresponding to IFX serum concentration over time in patients with JIA. This study shows a novel PK model for IFX in patients with JIA. The data show that different PK models are needed for different age categories (children or adults) and different diseases.

P599 Azathioprine in the prevention of anti-infliximab antibody formation: A pilot dose-finding study

Abstract Background The infliximab (IFX) therapy is associated with production of the anti-IFX antibodies (ATI), that can lead to infusion reactions and affect the therapeutic response. Concomitant use of azathioprine (AZA) in patients treated with IFX is recommended. A lower dosage is suggested however without further specification. The aim of this study is to determine the threshold dose of AZA to prevent ATI formation during IFX therapy. Methods The Retrospective, multicenter (Zlin, Prague, Czech rep.), observational study. The adult patients with ulcerative colitis or Crohn’s disease, treated with IFX in scheduled regimen (5mg/kg á 8 weeks), on concomitant azathioprine therapy (&amp;gt; 3 month), without any other immunomodulator or steroids, who were tested for IFX and ATI levels, were enrolled. The primary outcome measure was the dose of AZA and ATI positivity (cut-off &amp;gt; 3 AU/ml), secondary measure included interval to the appearance of ATI. ROC analysis was used to evaluate AZA dose and interval predictive of the ATI positivity. Results Of the 62 patients analyzed (53% female, mean age 34.1 years), 76% had Crohn’s disease. 29 (47%) subjects were treated with biosimilar IFX. The mean dose of AZA was 1.5 ± 0.5 mg/kg, and the duration of IFX treatment was 44.2 ± 41.4 months. ATI ′s were present in 23 subjects (37.1%), with no difference between original and biosimilar IFX. ATI positivity was associated with lower mean IFX levels (1.8 ± 2.4 vs 6.0 ± 5.1ug/ml, p=0.002). The threshold dose of AZA for ATI positivity was predicted to 1.2 mg/kg (95% CI 0.6–1.8, p=0.02, AUC 0.682) and the time to antibody appearance to 13.0 months (95% CI 5.0–49.1, p=0.02, AUC 0.672). Conclusion The dose of AZA lower than 1.2 mg/kg was associated with a higher chance of anti-IFX antibodies development. Their appearance may be expected after 1 year from the initiation of the combo IFX therapy. ATI′s are associated with reduced IFX through levels.

P241

Abstract Background In recent decades, biological drugs targeting anti-tumour necrosis factor-α (TNF-α) have represented the cornerstone in the treatment of inflammatory bowel diseases. Currently, anti- TNF-α represents a breakthrough in patient care. However, 20–50% of patients experience primary or secondary loss of response. This may be due to pharmacodynamic and/or pharmacokinetic issues, resulting in subtherapeutic drug concentrations, frequently related to the development of anti-drug antibodies (ADA). In this context, therapeutic drug monitoring (TDM) is essential to patients’ management in order to pinpoint the basis of reduced efficacy. Indeed, a fast and reliable assessments of TDM is mandatory to allow rapid intervention, to avoid toxicity and improve treatment efficacy. In this study we assess the analytical performance of a novel fully automated chemiluminescent assay in measuring biological drugs levels and ADA serum concentration and to compare its performances to the current diagnostic method (ELISA). Methods Serum levels of biological drugs (Infliximab and Adalimumab) and their respective ADA were measured in twenty infliximab (IFX)-treated IBD patients and twenty adalimumab (ADL)-treated IBD patients using both the Promonitor® ELISA kits (Grifols) and the i-TRACKER chemiluminescent (CLIA) kits (Theradiag Results The CLIA method is a random-access platform that allows the continuous loading of samples, while the ELISA is a time-consuming manual method to be planned in advance to reduce expenses. Actually, in our laboratory is performed only twice a month. A very good correlation was observed both for Infliximab (Spearman r=0.9695, 95%CI = 0,92-0,99, p&amp;lt;0.0001) and Adalimumab serum levels (Spearman r=0.9476, 95%CI = 0,86-0,98, p&amp;lt;0.0001). Among the patients with undetectable IFX serum levels, 6/8 (75%) resulted ADA positive by ELISA versus 8/8 (100%) by CLIA. Moreover, CLIA disclosed very high ADA concentration in 3 samples compared to borderline results by ELISA. Regarding ADL, all the 9 patients with undetectable serum levels presented similar ADA concentration as tested with ELISA or CLIA. Conclusion In conclusion, the i-TRACKER CLIA Infliximab and Adalimumab assays showed a very good correlation for serum-based drugs level quantification as compared to the related ELISA methods. Furthermore, a good agreement was observed for ADA analysis, with a higher sensitivity against anti-IFX antibodies by CLIA compared to ELISA. Our data clearly highlighted that a fully automated assay for TDM would certainly reduce costs and significantly improve the management of IBD patients in terms of a shorter turn-around time.

P400 Evolution of clinical and pharmacological parameters after switching from intra-venous to subcutaneous infliximab in patients with inflammatory bowel disease: the REMSWITCH study

Abstract Background Owing to similar efficacy, switching from intravenous (IV) to subcutaneous (SC) infliximab (IFX) is an attractive option, but the feasibility of switching patients with intensified IFX therapy remains unknown. We assessed the clinical and pharmacological evolution after switching from IV to SC IFX in IBD patients to evaluate the feasibility and to determine the equivalence between IV and SC doses. Methods All IBD patients in clinical remission (CDAI &amp;lt;, 150 or partial Mayo score ≤, 2) were consecutively included in, 3 IBD centers and were switched to SC IFX, 120mg/2 weeks (wk) (regardless of IV dose) at the theoretical day of IV infusion (visit, 0 = V0) and were followed every, 4 to, 8 weeks according to the initial IV regimen for, 6 months. Results Among, 246 screened patients, 65 (26.4%) were not eligible (no clinical remission or physician’s decision), and, 71.8% (130/181) accepted to switch to SC IFX (Crohn’s disease = 73,1%, concomitant immunosuppressant = 25.4%, median faecal calprotectin = 35 µg/g [16–104])., 43.1% of the, 130 patients received, 5mg/kg/8 wk. In, 130 patients, clinical relapse leading to therapeutic escalation was observed in, 11.1% including, 4.0%, 8.6%, 11.1% and, 40.0% in patients treated with, 5mg/kg/8wk, 10 mg/kg/8wk, 10mg/kg/6 wk and, 10mg/kg/4 wk, respectively. Dose increase (240 mg/2 wk) induced clinical remission in, 92.3% of relapsers. Infliximab trough levels (TL) were significantly higher after switching from IV to SC IFX:, 9.8 ±6.4 vs, 14.4 ±5.7 (p&amp;lt;0.0001). TL increased in patients receiving, 5 mg/kg/8 wk (6.3 ±, 3.4 vs, 14.7 ±5.7; p&amp;lt;0.0001) or, 10 mg/kg/8 wk (8.4 ±5.6 vs, 13.7 ±6.6; p=0.001) but remained stable in those treated with, 10 mg/kg/6 wk (11.1 ±7.6 vs, 13.1 ±5.1; p=0.31) or, 10 mg/kg/4 wk (17.8 ±4.2 vs, 15.8 ±4.6; p=0.12) (Figure, 1). Infliximab TL remained stable (variation V1-V0 &amp;lt; ±, 1) in, 4.3%, 15.0 %, 33.3 % and, 50.0 % of the patients with the following IV doses:, 5 mg/kg/8 wk, 10 mg/kg/8 wk, 10 mg/kg/6 wk and, 10 mg/kg/4 wk, respectively (p=0.003). No patient developed anti-IFX antibodies. TL before the switch (8.4 ±5.6 for non-relapsers vs, 12.0 ±7.2 for relapsers; p=0.12) and TL after the switch (14.5 ±5.6 vs, 13.6 ±5.6; p=0.63) were not significantly associated with the risk of relapse. In contrast, the risk of relapse was higher in patients with stable or decreasing TL after the switch compared to those with increased TL (31.8% vs, 7.1%; p=0.024). The type of IBD and concomitant immunosuppressant were not associated with the risk of relapse. Patients’ acceptability was better with SC injections compared to IV infusions (10pts-acceptability numerical scale = 8.7 ±1.6 vs, 6.8 ±0.9; p&amp;lt;0.0001). Conclusion Switching from IV to SC IFX is feasible and well-accepted leading to a low risk of relapse in patients with IBD.

S895 Long-term Outcomes of High versus Low Anti-infliximab Antibody Titers in Patients with Crohn’s Disease: A Tertiary Referral Center Experience

Introduction: Immune-mediated loss of response to infliximab (IFX) via formation of anti-IFX antibodies (ATI) is a common problem encountered in practice. However, there is a paucity of data regarding long-term implications of low versus high ATI titers on outcomes. In this study, we compare patients with low and high ATI with respect to drug levels, rates of IFX discontinuation, and health care utilization. Methods: This was a retrospective cohort study of CD patients who were exposed to IFX and had IFX trough/antibody levels (TDM) checked between 1/1/2010 and 12/31/2019. Each TDM was classified as either proactive or reactive based on whether it was carried out secondary to loss of response (reactive) or at pre-defined time points to optimize drug levels (proactive). Patients were then dichotomized as “proactive” or “reactive” depending on which TDM method predominated (>50% during study period). ATI and drug levels were selected from the first recorded TDM within the specified time frame. Low and high titer cutoffs were defined by the specified assays (Prometheus, San Diego, CA; Labcorp, Burlington, NC; Esoterix, Austin, TX and ARUP, Salt Lake City, UT). Patients with undetectable ATI were excluded from the study. Patients were compared on objective lab parameters (median albumin, C-reactive protein, fecal calprotectin), overall health care utilization, and endoscopic and histologic outcomes. Results: A total of 66 CD patients (median age at diagnosis 22 years, 58% male) were included in the study, and 37 (56.1%) were found to have high ATI. High ATI were associated with lower median infliximab levels (p = 0.019), increased IFX discontinuation rates (p = 0.026), and higher IBD related health care utilization per year (p= 0.009) (Table 1). The differences in rates of IFX discontinuation were the most prominent within the first 5 years of IFX therapy as shown by the Kaplan- Meier survival curve analysis (Figure 1). When these patients were prospectively followed, those who underwent a predominantly proactive drug monitoring strategy had lower rates of high ATI titer formation (34% vs 59%, p=0.04). Conclusion: In this cohort of CD patients, high ATI titers showed higher rates of IFX discontinuation and health care utilization, as well as lower IFX drug levels, when compared to patients who had low ATI titers. This study further emphasizes the need for proactive optimization of IFX while treating patients with CD, in order to achieve better results, especially during the first few years of therapy.Figure 1.: Kaplan-Meier survival curve comparing Infliximab discontinuation rates when comparing high versus low antibody titers.Table 1.: Univariable analysis of factors/co-variates associated with high versus low antibody titers (significant values bolded and italicized); n: population, %: percentage, IFX: infliximab, IBD: inflammatory bowel disease, BMI: body mass index, IQR: inter quartile range.

P555 Outcomes of multiswitching from original infliximab to biosimilars in patients with inflammatory bowel disease

Abstract Background Since 2013 multiple Infliximab (IFX) biosimilars became available in the market. While there is evidence that switching from original IFX (RemicadeÒ) to an approved biosimilar product is safe and effective, little is known about outcomes of reverse switching and multiple switching among biosimilars in IBD patients. As the access to biosimilars at competitive prices increases, it is necessary to evaluate multiple switches to provide data on their interchangeability. Our aim was to evaluate the efficacy, safety and pharmacokinetic profile in a cohort of IBD patients who experienced multiple switches. Methods This is a cohort retrospective observational study, enrolling patients with IBD who were successively switched from original IFX to one or more biosimilars (multiswitching). We compared clinical disease activity, assessed using the Harvey-Bradshaw index (HBI) and partial Mayo Score (pMS), biochemical markers (hemoglobin, C-reactive protein (CRP) and albumin), IFX trough levels (ITL) and anti-IFX antibodies (ADA) immediately before and after multiswitching. Adverse and infusion-related events leading to drug discontinuation were registered. Results We included 26 patients (59% male, mean age 35±12 years), 85% (n=22) with Crohn’s Disease (CD) and 15% (n=4) with ulcerative colitis (UC) or indeterminate colitis. The mean disease duration from diagnosis was 9±6 years. According to Montreal classification, most patients were A2 (68%), had ileocolonic disease (L1 51%; L2 9%; L3 50%) and an inflammatory phenotype (B1 41%; B2 23% and B3 36%). Perianal disease was present in 44%. Half of patients had pancolitis (E3). About 51% of the patients had a prior resection surgery and 27% was on combination therapy when the first switch occurred. In 35% (n=9) of the patients three switches were observed. The mean follow-up from the first switch was 15±18 months. There was no significant difference in the proportion of patients in clinical remission (HBI &amp;lt; 5; Mayo score &amp;lt; 3) (91% vs 96%, p=NS). We found no differences in laboratory markers such as CRP (0,79 vs 0,67 mg/dl, p=NS), hemoglobin (13,83 vs 13,75g/dl, p=NS) and albumin (3,98 vs 4,37mg/dl, p=NS) before and after the multiswitching. No significant difference was observed in mean ITL (4,9 vs 4,05 μg/mL, p=NS) or in the proportion of patients with ITL&amp;gt;3ug/ml (p=0.205). None of patients developed ADA, infusion-related events or loss of response leading to drug discontinuation. During our follow-up none of patients was operated. Drug persistence was 100%. Conclusion In our cohort, no significant changes in efficacy, safety or immunogenicity were observed when IBD patients experienced multiple switches between the original IFX and its biosimilars.

Comparison of a new rapid method for determination of serum anti-adalimumab and anti-infliximab antibodies with two established ELISA kits

BackgroundAdalimumab (ADL), infliximab (IFX) and their biosimilars are widely used biological drugs. Some patients, however, generate neutralizing antibodies that hamper the effectiveness of these drugs. Evidence shows therapeutic drug monitoring of serum levels ADL/IFX and anti-drug antibodies (ADA) is useful to improve treatment effectiveness. We evaluated a new rapid quantitative method, Quantum Blue (QB), for determining serum anti-ADL and anti-IFX antibodies (Research Use Only labelling) by comparing it with two established ELISA kits, Promonitor (PM) and Lisa-Tracker (LT). MethodsEighty samples (40 for each drug type) were analysed. Percentage of agreement and kappa statistic were used to compare positive/negative ADA results. Clinical implications for drug treatment in the patients with discordant results were evaluated. The Chi-square test was used to analyze differences for ADA detection in patients with disease flare and without concomitant immunosuppressant treatment. ResultsAgreement exceeded 80 % among anti-ADL methods. Although LT ELISA showed a lower capacity in detecting anti-ADL antibodies, discrepancies were found for levels close to the cut-off concentration, thus having minimal impact on clinical decisions. Conversely, QB anti-IFX displayed low agreement with PM and LT ELISA kits (67.5 % and 50 %, respectively), and was unable to detect high levels of antibodies, therefore having major clinical implications. Agreement between PM and LT ELISA anti-IFX kits was 82.5 % with all discordant results being undetected for PM and slightly positive for LT. ConclusionQB anti-ADL shows similar performance to ELISA kits while QB anti-IFX needs further improvements to achieve reliable antibody detection.

Значение мониторинга уровня инфликсимаба и антител к нему в сыворотке крови для оптимизации терапии воспалительных заболеваний кишечника у детей

Objective. To evaluate the prognostic value of serum levels of infliximab (IFX) and anti-IFX antibodies for predicting treatment efficacy in children with inflammatory bowel disease (IBD). Patients and methods. This study included 123 children with IBD (65 patients with ulcerative colitis (UC) and 58 patients with Crohn's disease (CD)) aged between 3 and 18 years. Children were examined upon the completion of an induction course of therapy and then after 1 year of therapy and between 1 and 3 years of treatment. The induction course was administered according to the scheme of 0–2–6 weeks; maintenance therapy was administered with 6-week and 8-week intervals. The residual level of IFX and the level of anti-IFX antibodies in serum were measured using enzyme-linked immunosorbent assay. Results. We observed a significant increase in the IFX level during clinical remission of CD (remission – 5.21 [3.32; 7.43] μg/mL; exacerbation – 2.42 [0.42; 4.51] μg/mL, p = 0.001) and UC (remission – 4.57 [3.4; 6.74] μg/mL; exacerbation – 0.63 [0.4; 3.27] μg/mL, p = 0.000). ROC analysis demonstrated high accuracy of our model based on measuring residual IFX level for distinguishing between exacerbation and remission in both CD patients (AUC = 0.812) and UC patients (AUC = 0.851). The optimal minimum level of IFX for maintaining clinical remission was 3.7 μg/mL in children with CD and 3.4 μg/mL in children with UC. Anti-IFX antibodies were detected in 18% of patients; children with exacerbation were 4.7 times more likely to have detectable level of anti-IFX antibodies than those in clinical remission. Conclusion. Monitoring of serum levels of IFX and anti-IFX antibodies is a promising method for predicting treatment efficacy and its optimization in children with IBD. Key words: inflammatory bowel disease, tumor necrosis factor-α, infliximab, residual level of infliximab, anti-infliximab antibodies

Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis

This study aimed to directly analyze the potential relationship of anti-nuclear antibodies (ANA) before and after the administration of TNF-α inhibitors (TNFi) with the appearance of anti-drug antibodies (ADrA) in patients with rheumatoid arthritis (RA). A total of 121 cases, viz., 38, 53, and 30 cases treated with infliximab (IFX), adalimumab (ADA), and etanercept (ETN), respectively, were enrolled. The ANA titers were measured using indirect immunefluorescence assay (IF-ANA) and multiplex flow immunoassay (ANA Screen) before and serially during the therapy. The anti-IFX antibodies (HACA) and anti-ADA antibodies (AAA) were measured with a radioimmunoassay. ADrA turned positive in 14 (36.8%) among 38 patients treated with IFX, and 16 (30.2%) among 53 treated with ADA. All of them were positive for IF-ANA before TNFi administration, while ADrA never appeared in any of the 15 patients negative for IF-ANA (< 40). IF-ANA of high titers (≥ 320 and ≥ 640) before IFX treatment showed a significant association with the appearance of HACA 52 weeks after IFX (P = 0.040 and 0.017, respectively), whereas AAA appearance was not related to IF-ANA titers before treatment. Moreover, IF-ANA of high titers before IFX treatment was significantly associated with inefficacy and discontinuation of the treatment. The positivity of anti-SS-A antibodies before therapy might be a risk factor for ADrA appearance in patients treated with IFX or ADA. The percentage of patients whose IF-ANA titers increased was significantly higher with IFX than with ADA or ETN treatments (P = 0.026 and 0.022, respectively). High ANA titers and positive ANA Screen after IFX therapy showed a significant association with HACA appearance and possibly led to treatment failure. Among the three TNFi, only IFX showed a close relationship with IF-ANA and ADrA appearance, suggesting the interaction of immunogenicity with autoimmunity as well as the advantage of ANA measurement before TNFi therapy.

Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease

Background Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. Methods A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 (n = 148) and 6 (n = 108). Circulating TNFα was measured in matched primary non-responders (n = 29) and responders (n = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients. Results In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 μg/mL vs. 23.3, p < .05. Week 6: 8.4 vs. 17.0, p < .05). Optimal IFX thresholds associated with response was 22.9 μg/mL at week 2 (sensitivity 51%, specificity 80%, AUCROC 0.67, p < .05) and 11.8 at week 6 (72%, 77%, 0.71, p < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8–67.5], p < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn’s disease. Conclusion IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn’s disease.