Anti-infliximab Antibodies Research Articles

N11 Switching from intravenous to subcutaneous infliximab enhances trough levels and can facilitate de-escalation of concomitant immunomodulation, irrespective of the HLA DQA1*05 status: a prospective real-world study

Abstract Background There is emerging data on the continued efficacy of infliximab when switched from intravenous (IV) to subcutaneous (SC) route in Inflammatory bowel disease (IBD). The impact of cessation of concomitant immunomodulators (IMMs) following switch on trough levels or development of anti-drug antibodies (ADAs) is not evaluated in real world practice. We aimed to study the impact of cessation of IMMs following switch of infliximab from IV to SC route and determine relationship with HLA- DQA1 *05 status. Methods Consecutive patients who participated in a planned switch programme were prospectively included. Clinical, biomarker and pharmacokinetic data were collected pre-switch, and at 8 weekly intervals post switch for 6 months. Trough levels and remission status in patients who discontinued or reduced the dose of IMMs were compared with those who remained or continued same dose on IMMs. All patients had HLA-DQA1*05 status determined at initiation of Infliximab and we evaluated the impact of HLA status on development of anti-Infliximab antibodies post switch. Results One hundred and fifteen patients (M: F=1.4:1, Median age 44 years (13-76), UC/CD (48/67) who completed 6 month follow up were included. All patients were in clinical and biomarker remission prior to the switch. 72 patients (62.6%) were on concomitant IMMs and 46 (40.86%) was HLADQA1*05 positive. The mean infliximab trough level prior to switch was 5.54 µg/mL which increased 8 weeks post switch to 12.52 µg/mL (p=0.006). The enhancement of levels persisted at 16 weeks (Mean 16.28) and at week 24 (17.25). 36 patients (32%) were positive for ADAs before switch; in 8 patients (22%) the ADAs disappeared at 8 weeks and in further 4 (total 33%) by 6 months. In total antibody titre reduced or become negative in 17 patients (48.6%), static in 14 patients (40%) but increased in 5 patients (14%) without significant lowering of trough levels. 18 of the 72 patients (25%) had IMMs discontinued, and dose reduced in further 21 patients. The total de-escalation rate was 54% and none of these patients developed ADAs at 6 months irrespective of the HLADQA1*05 status (HR = 0.76, 95% = 0.64 to 1.73, p 0.12). One patient switched back to IV due to personal preference. At 6 months none of the patients discontinued SC infliximab or were switched within or out of class. Conclusion Switch from IV to SC infliximab is effective in maintaining and enhancing trough levels with positive impact on reducing ADAs. It is feasible to de-escalate concomitant IMMs in a considerable proportion of patients following switch. Economic analysis of switch should be incorporated in the feasibility of IMMs withdrawal.

Therapeutic Monoclonal Antibody─Antidrug Antibody Affinity Constant Determination Using Capillary Electrophoresis-Tandem Mass Spectrometry.

Monoclonal antibody (mAbs) therapeutics cannot evade the occurrence of adverse effects. Thus, mAbs are commonly triggering immune responses corresponding to the expression of antidrug antibodies. Antidrug antibodies can neutralize mAbs, leading to their inhibition and hasten clearance, which dramatically hampers their therapeutic effects. Therefore, studies concerning the affinity between a mAbs and the corresponding antidrug antibody are demonstrating a growing interest to further understand the outcome of biotherapeutics after administration. We describe a novel analytical approach for the determination of the dissociation constant (Kd) between a mAb and an antidrug antibody using capillary electrophoresis coupled to mass spectrometry (CE-MS/MS). The CE-MS/MS method employs a competitive assay, followed by the quantification of the residual amount of the active mAbs. The methodology allowed for the measurement of Kd using serum samples without the implementation of immobilization to achieve protein-protein interaction. This characteristic enabled us to generate the interaction in conditions reflecting the physiological environment. A mathematical treatment was developed to calculate Kd from MS/MS data, taking into account the stoichiometry of the mAbs/antidrug antibody complex and the bivalent properties of the two immunoglobulins. Prior to CE-MS/MS analysis, the interaction of the two proteins was studied by using mass photometry (MP) to determine equilibrium conditions and complexation stoichiometry. CE-MS/MS was used to investigate the interaction between infliximab and a neutralizing anti-infliximab antibody. Results allowed to measure a Kd of 14.4 ± 2.9 nM. MS instrumentation sensitivity and specificity showed to be relevant to achieve accurate and robust Kd measurements for strong interactions in the nanomolar range.

Long-term Safety Monitoring and Efficacy Status of Infliximab and its Biosimilars in Psoriasis Management

Abstract: Infliximab (INF), a murine human monoclonal antibody, is a substantially more successful biologic than topical drugs for treating mild to severe psoriasis because it clears the skin rapidly due to its fast onset of action. Loss of responsiveness over time and some adverse effects, especially the experience of infusion reactions, are the major causes of non-compliance with INF medication. Therefore, evaluation of the long-term reliability of anti-tumor necrosis factor (TNF) medications is necessary for the assessment of the risks associated with long-term anti-TNF therapy. For psoriasis, there are registered safety statistics; however, these individuals might not receive the same level of care as those in a randomized study. Few assessments of the safety of anti- TNF medications across indications, including their biosimilars, are present, but it’s still unknown how anti-infliximab antibodies arise and produce harmful effects. INF biosimilars, when subjected to human studies to reduce cost and improve access, provide therapeutic benefits with associated adverse events, showing variations in incidence depending upon varying patient populations and no new safety indications. During therapy, certain individuals develop antibodies against INF, which are believed to be linked to a loss of response (LOR). Additional research aimed at identifying individuals who are susceptible to treatment resistance is likely to assist doctors in accurately selecting the appropriate candidates for anti-TNF-α therapy and enhancing the long-term effectiveness of the treatment. From clinical studies, we expect to learn about how to utilize INF or its biosimilars more effectively in the management of psoriasis. Therefore, the paper focuses on the efficacy and safety monitoring of INF and developed biological therapies.

Risk factors for anti-infliximab antibody formation among patients with inflammatory bowel disease

Risk factors for anti-infliximab antibody formation among patients with inflammatory bowel disease

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.

Observational Study to Compare Biological Drug Concentration Quantification Techniques and Immunogenicity in Patients with Immune-Mediated Diseases.

Measuring biological drugs' trough concentrations and the concentrations of anti-drug antibodies is a valuable practice for treatment optimization. ELISA techniques are the gold standard for biological drug concentration quantification, but new techniques such as chemiluminescence immunoassays present some advantages. The aim of this unicentric prospective observational study is to compare the infliximab, adalimumab, vedolizumab and ustekinumab trough levels and anti-adalimumab and anti-infliximab antibodies concentrations obtained when using a chemiluminescent instrument (i-TRACK®, Theradiag, Croissy-Beaubourg, France) and an ELISA instrument (TRITURUS®, Griffols, Barcelona, Spain). Linear regression, Pearson or Spearman tests, Bland-Altman plots and the Cohen kappa test were applied for every sample. The correlation was excellent for both assays in the measurement of all drug concentrations. In general, values were lower when measured using i-TRACK than when using TRITURUS, especially when the values were high. Both techniques proved valuable in clinical practice for monitoring adalimumab and infliximab drug concentration. However, the results were modest for ustekinumab and vedolizumab, so caution is recommended and further research is needed. The limited number of anti-drug antibody-positive samples precluded a comparison between the techniques.

P1070 Utilization of HLA-DQA1*05 haplotype testing in routine clinical practice to stratify advanced therapies: A prospective pilot study

Abstract Background A potential association between HLA-DQA1*05 allele and development of anti-drug antibodies in Anti-TNF treated Crohn’s Disease patients is reported in the PANTS study. The utility of stratifying treatment based on the HLA-DQA1*05 status has not been evaluated in a biomarker stratified clinical trial and there are no prospective studies evaluating the impact of using HLADQA1*05 in routine clinical practice to decide on monotherapy versus combo therapy while initiating on anti-TNFs. We aimed to determine the impact of carriage of HLADQA1*05 allele to guide the need for concomitant immunomodulators in IBD patients planned for Infliximab therapy. Methods In our prospective study, 97 adult IBD patients were included. All patients were screened for HLADQ2 haplotype as part of their routine pre-biologic screen. Stratification was done according to the presence of HLA-DQA1*05 haplotype. HLADQA1*05 positive patients were assigned combo therapy with Infliximab combined with either methotrexate or azathioprine. HLADQA1*05 negative patients were given infliximab monotherapy unless another indication for concomitant immunomodulation was present. Patients were followed for a minimum of one year after drug initiation. Primary outcome was drug persistence, expressed as time to discontinuation of infliximab, segregated by the treatment decision based on HLA-DQA1*05 status. Secondary outcomes were proportion of patients developing anti-drug antibodies and time to antibody development. Statistical analysis was done using Kaplan-Meier curves and log-rank test. Results Baseline characteristics are detailed in Table 1. HLA-DQA1*05 was positive in 41/97(42%) of patients and combo therapy was offered to 33/41(80%) of those patients. Immunomodulators were avoided in 39/97(40.2%) patients representing the subset of patients with negative HLADQA*105 to whom no immunomodulator was offered. There was no statistically significant difference in drug persistence rates between the groups treated based on HLA-DQA*105 status. 54/97(55.6%) of the patients developed anti-infliximab antibodies during their follow-up (25/41(60.9 %) in HLA positive and 29/56 (51.7%) in HLA negative). Neutralizing drug antibodies with absent drug levels were detected in 15/97(15.5%) of patients (8/41(19.5%) in HLA positive, 7/56(12.5%) in HLA negative). The median time to antibody development was 33.5 weeks (IQR 22-46.7). Conclusion This is the first prospective study suggesting HLA-DQA1*05 haplotype testing can be used in routine clinical practice to stratify therapy based on the need for immunomodulators in infliximab treated IBD patients. HLA-DQA1*05 negative patients may be started on monotherapy with potential for improving safety and reducing costs of immunomodulator monitoring.

Early monitoring of anti-infliximab antibodies by drug-tolerant assay predicts later immunogenicity and drug survival in rheumatic diseases.

To investigate the appearance of anti-drug antibodies (ADA) against infliximab (IFX) determined by drug-sensitive and drug-tolerant assays and their relationship with drug levels and drug survival. This longitudinal observational study included 45 patients with RA and 61 with SpA. Serum samples were obtained at weeks 2, 6, 12, 24 and 52. Serum IFX levels were measured by a capture ELISA and ADA by an in-house drug-sensitive two-site (bridging) ELISA (bELISA) and a commercially available drug-tolerant ELISA (IDK, Immundiagnostik, Germany). ADA were detected earlier by IDK than by bELISA. Once ADA appeared, positivity persisted throughout the study period. Patients who were bELISA ADA+ had higher IDK ADA levels (than bELISA ADA- patients). Circulating IFX levels were detected in all patients except those found to be bELISA ADA+. Serum IFX levels were lower in IDK ADA+ than in IDK ADA- patients. Most patients (64%) discontinued due to inefficacy. The early onset of immunogenicity was related to IFX survival. In both RA and SpA, the median survival (years) was shorter in patients with earlier development of ADA (IDK+ before or at week 24) than those who became IDK+ later (after week 24) or never developed ADA. A drug-tolerant assay detects ADA during IFX therapy earlier and more frequently than a drug-sensitive assay. The onset of immunogenicity detected by drug-tolerant assays is related to the subsequent detection of ADA by drug-sensitive assays and drug survival.

Evaluation of selected serum biomarkers levels in response to the infliximab reference product (Remicade®) versus its biosimilar (Remsima®) in a sample of ulcerative colitis patients: a cross-sectional study

Background: Biologic therapies like Remicade® (infliximab originator) and Remsima® (infliximab biosimilar) have emerged as valuable options for the management of ulcerative colitis (UC) over the years. The purpose of the present study was to provide comprehensive comparison of the efficacy of Remicade® and Remsima® in the treatment of UC by performing a comprehensive analysis of key biomarkers. Methods: The study utilized a cross-sectional observational design. It was conducted at Baghdad Teaching Hospital in Baghdad, Iraq, spanning from July 2022 to February 2023. The study population consisted of individuals aged 21 to 57 years who had previously received a diagnosis of ulcerative colitis (UC). Results: A total of 43 patients were included in the analysis. The mean infliximab trough levels in the Remicade group were 3.264 ng/mL, while in the Remsima group were 3.248 ng/mL. eight Remicade patients developed anti-infliximab antibodies, while 9 Remsima patients tested positive. The mean serum calprotectin level was 5596 μg/ml in the Remicade group and 5795μg/ml in the Remsima group. The mean ESR value was 18.33mm/hr in the Remicade group and 16.43mm/hr in the Remsima group. The mean CRP value was 17.65mg/dl in the Remicade group and 16.19mg/dl in the Remsima group. The mean serum TNFa level measured was 159.5pg/ml in the Remicade group and 158.5pg/ml in the Remsima group. The mean serum Oncostatin M level measured was 107.3ng/ml in the Remicade group and 107.5ng/ml in the Remsima group Conclusion: These findings study suggest that Remsima, as a biosimilar to Remicade, holds promise as a cost-effective alternative in UC management

Performance of a New Rapid Point-of-Care Test for Infliximab Levels in Patients with Inflammatory Bowel Disease: A Comparison to ELISA

BackgroundTherapeutic drug monitoring of infliximab levels in patients with inflammatory bowel disease (IBD) optimizes patients’ treatment. The reference technique is based on enzyme-linked immunosorbent assay (ELISA) although point of care (POC) assays are being developed.AimsTo assess the performance of a new rapid immunochromatographic POC assay (Promonitor Quick IFX) compared with ELISA technique to measure infliximab levels in patients with IBD.MethodsA prospective, observational, unicentric study was performed on capillary blood samples from patients with IBD before infliximab infusion (trough levels). Infliximab levels and anti-infliximab antibodies were measured using the ELISA technique (Promonitor IFX) and the POC assay. Correlation between both techniques was assessed by Pearson’s coefficient. Quantitative differences were evaluated by Bland–Altman analysis. Samples were stratified according to infliximab therapeutic ranges (< 3 μg/mL, 3–8 μg/mL, and > 8 μg/mL).ResultsA total of 135 experimental samples were assessed. Infliximab levels showed a high correlation between POC and ELISA tests (r = 0.84, P < 0.001). The mean difference between tests was 1.46 μg/mL (P < 0.001), being minimal for concentrations < 8 μg/mL. POC and ELISA assays showed an overall concordance of 87.4%. Most samples were in the same therapeutic range, which lead to equivalent therapeutic decisions. POC and ELISA assays detected the presence of anti-infliximab antibodies in 2.2% and 3.7% of the samples, respectively.ConclusionsPOC assay results in blood samples from patients with IBD were comparable to those obtained with the reference ELISA technique. The POC assay could be considered for routine testing based on its ease of use and rapidity.

Development and validation of enzyme-linked immunosorbent assays for the measurement of infliximab and anti-drug antibody levels

Infliximab and its anti-drug antibody (ADA) serum concentrations exhibit a strong correlation with clinical response and loss of response. The use of therapeutic drug monitoring to measure the concentration of infliximab and ADA can facilitate clinical decision-making, helping patients attain optimal therapeutic effects. However, there are still limitations to the existing infliximab and its ADA detection methods. Therefore, this study aimed to develop and validate enzyme-linked immunosorbent assay (ELISA)-based methods for measuring infliximab and its ADA levels in human plasma according to the general recommendations for immunoassays. Free infliximab is bound by recombinant TNF-α and detected using HRP-labeled anti-human antibody. The ADA is captured by on-plate-coated infliximab and recognized by biotin-labeled infliximab. Two bridging ELISA assays were developed and after assay optimization and validation, these assays have been applied in ten patients with inflammatory bowel disease (IBD). In infliximab detection assay, a standard curve ranging from 0.10μg/mL to 8.0μg/mL with great precision and accuracy has been established. Drug tolerance of the ADA assay was that 100ng/mL ADA could tolerate at least 5.0μg/mL infliximab in the plasma using a commercially available monoclonal anti-infliximab antibody as the positive control. The ADA screening and confirmatory assays achieved a sensitivity of 36.74ng/mL and 37.15ng/mL, respectively. All other assay characteristics met the requirements. The mean concentration of infliximab in eight patients with IBD was 7.88 (1.87-21.1) μg/mL, and the ADA levels were all negative. Moreover, the concentrations of infliximab in the remaining two patients were below the LLOQ and the ADAs were positive. Thus, accurate and sensitive ELISA methods have been developed and validated for the detection of infliximab and its ADA concentrations and have been successfully applied to clinical therapeutic drug monitoring.

OA20 Combining B cell depletion and JAKi for difficult-to-treat rheumatoid arthritis

OA20 Combining B cell depletion and JAKi for difficult-to-treat rheumatoid arthritis

Risk factors for anti infliximab antibody formation among patients with inflammatory bowel disease

Risk factors for anti infliximab antibody formation among patients with inflammatory bowel disease

A203 EARLY PROACTIVE DRUG MONITORING STRATEGY OF INFLIXIMAB AS MONOTHERAPY FOR INFLAMMATORY BOWEL DISEASE IN PAEDIATRIC PATIENTS IS ASSOCIATED WITH GOOD SUSTAINED CLINICAL REMISSION

Abstract Background Monotherapy with Infliximab (IFX) can be as efficient as combotherapy with immunomodulators in the treatment and maintenance of remission for children with inflammatory bowel disease (IBD) if an early proactive therapeutic drug monitoring strategy is adequately performed. This strategy may allow optimization of blood levels of IFX in order to obtain a sustained clinical response. Purpose This study demonstrated that with appropriate early trough levels of IFX before dose #3 and dose #4 , monotherapy was very efficient in inducing remssion at week 52 . Method A retrospective study was conducted at CHU Sainte-Justine, Montréal,Canada .Children with IBD 2 to 18 years old diagnosed between 01/2018 and 06/2020 and treated with IFX less than 30 days after diagnosis were included .IFX blood levels were collected before the 3rd and/or 4th dose of IFX and regularly thereafter. Adjustments were done in IFX dose per infusion according to blood levels and clinical response. The primary outcome was clinical remission at one year after diagnosis.The secondary outcomes included: (1) At 52 weeks, the median (IQR) dose of IFX (mg/kg) and the intervals between IFX infusions ; (2) the median (IQR) number of IFX dose changes and the median (IQR) number of blood trough levels of IFX done. Result(s) 101 patients were included : 56.4% males; 81CD; 18 UC; 2 IBDU. Mean age at diagnosis was 13.2 years (IQR = 11.20 to 15. 20). Median time to IFX initiation after diagnosis was 5 days (IQR :3-14).Median IFX dose #1: was 8.4 mg/kg (IQR = 5. 8 to 10). 90% of patient had an IFX optimisation (increasing dose and/or shortening intervals) after dose 3 or dose 4. At week 52, 36,5% of patients were receiving IFX infusion every 4 weeks and 30,6% every 6 weeks. The median IFX dose per infusion was 8,9mg/kg (IQR = 7.4- 9,8 ). The IFX doses at week 52 varied greatly according to age at diagnosis The median number of IFX blood level dosage was 4 per patient over a year (IQR=3-5).At week 52, 83 patients (84.6%) achieved clinical remission with a median IFX level of 10.96 (7.05-15.59). 74 /83 (89%) were on monotherapy and 9/83(10.8%) on combotherapy Image Conclusion(s) Early treatment for IBD with IFX as monotherapy and an early proactive optimization strategy is associated with a good sustained steroid free clinical remissionAt week 52, 83 patients (84.6%) achieved clinical remission with a median IFX level of 10.96 (7.05-15.59). 74 /83 (89%) were on monotherapy and 9/83(10.8%) on combotherapy.The majority of the patients required IFX optimization during their first year of treatment. We therefore recommend to proactively monitor blood levels of IFX before the third and fourth dose of IFX and thereafter, in order to lower the risk of treatment failure and anti-infliximab antibodies occurrence. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest C. Girard: None Declared, S. Ackhar: None Declared, S. Sassine: None Declared, L. Chapuy: None Declared, P. Jantchou: None Declared, C. Deslandres Speakers bureau of: moderator and speaker Abbvie and Janssen

Surface plasmon resonance assays for the therapeutic drug monitoring of infliximab indicate clinical relevance of anti-infliximab antibody binding properties.

The therapeutic antibody infliximab (IFX) has improved the life quality of numerous autoinflammatory disease patients. However, IFX can trigger the generation ofanti-drug antibodies (ADA), whose optimal evaluation andmanagement are currently subject of controversial discussions. We present two novel surface plasmon resonance (SPR) biosensor assays for therapeutic drug monitoring of IFX and characterization of ADA and investigated the diagnostic value of ADA binding properties. IFX and ADA were quantified via developed SPR biosensor assays (IFXmon and ADAmon, respectively) and diagnostics-approved ELISA in sera from inflammatory bowel disease patients. Pre-analytic ADA enrichment with magnetic beads enabled analytical drug tolerance of the ADAmon assay. The dissociation ratio (DissR) as an index forADA:IFX binding stability was calculated from the SPR sensorgrams of ADA quantification runs. IFX levels determined by IFXmon assay and ELISA showed high agreement, whereas ADA quantification concordance between ADAmon assay and ELISA was poor. In patients, DissR was predominantly constant over time and differed significantly between therapy outcomes. A DissR cut-off of 1.524 indicated undetectable IFX levels with 71.4% sensitivity and 88.9% specificity. Additionally, the SPR reference surface was exploited as serum-individual negative control to check result plausibility within multi-sample run sequences. Overall, both SPR biosensor assays exhibited reliable quantitative performance with accuracies superior to their ELISA counterparts and precision inferior to ELISA only for ADAmon. DissR presented itself as promising ADA binding parameter and could contribute to both earlier and more tailored therapeutic decisions.

Immunogenicity of the biosimilar CT-P13 infliximab or the original infliximab in Iraqi patients with Ankylosing spondylitis does not correlate with their demographic characteristics

Background: Ankylosing spondylitis is a rare disease affecting people with hereditary factors. Its treatment includes life style modification and use of drugs such as the biologic agent infliximab or its biosimilar, CT-P13 infliximab. Despite their therapeutic usefulness, these agents are associated with a number of serious adverse effects such as immunogenicity. Objectives: The aim of current study was to investigate if immunogenicity of the biosimilar CT-P13 infliximab or the original infliximab, in Iraqi patients with Ankylosing spondylitis, is affected by any of the patients’ demographic characteristics. Methods: A retrospective open-label study was conducted from December 2021 to March 2022 at the Rheumatology Unit, Baghdad Teaching Hospital/Medical City, Baghdad. Forty-four patients were taking Infliximab, and another 50 patients were taking CT-P13, both at a dose of 5mg/kg for 3 months prior to recruitment in current study. Disease activity was assessed by ASDAS-CRP score while antibodies and C-reactive protein were tested by Enzyme-Linked Immunosorbent Assay technique. Statistical analyses were performed using SPSS statistical package for Social Sciences version 20.0. The level of significance was considered at P&lt;0.05. Results: There was non-significant correlation between anti-infliximab antibodies and demographic data of patients (P&gt;0.05). Similar data were reported regarding the biosimilar CT-P13 infliximab except for smoking and disease activity which exhibited significant correlation with development of anti-CT-P13 antibodies (P&lt;0.05). Conclusion: Immunogenicity of the biosimilar CT-P13 infliximab, but not that of the original Infliximab, may be influenced by demographic characteristics or disease activity in patients with ankylosing spondylitis.

Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab

The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics. This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs). A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8× 108 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8× 108 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P= .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8× 108 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8× 108 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts. Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9AU/ml for infliximab and ≥6AU/ml for adalimumab. In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p=0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Safety, satisfaction and cost savings of accelerated infusions of standard and intensified-dose infliximab for inflammatory bowel disease.

Infliximab remains a mainstay for the treatment of inflammatory bowel disease (IBD), but a long infusion duration and subsequent monitoring can be burdensome to patients and healthcare providers. To assess the safety of accelerated infusions for standard and dose-intensified infliximab regimens, and the effect on patient satisfaction and potential cost savings. Patients with IBD on a stable maintenance dose of infliximab and in clinical remission received one or more accelerated infusions: over 30 min if receiving a standard dose (5 mg/kg), or over 60 min if receiving dose-intensified infliximab (up to 10 mg/kg). Outcomes included incidence of reactions (acute or delayed), patient satisfaction and potential cost savings. We also explored infliximab trough levels after one and three accelerated infusions. Fifty-two patients who received 150 infusions were studied. Incidence of reactions to accelerated infusions was 3.3% (3 out of 89) with a standard dose and 0% (out of 61) with dose-intensified infliximab. Reactions were delayed, mild and self-limiting. None required drug cessation. Patient satisfaction was improved with shortened infusion time as compared with the patients' previous experiences (P = 0.00002). Mean plasma trough level of infliximab reduced from 9.3 mg/L (±4.9) to 7.9 mg/L (±4.1) (P = 0.02) with accelerated infusions, but none developed anti-infliximab antibodies. Nursing cost savings were estimated as $123.52 and $247.04 per patient per year for standard and dose-intensified infliximab respectively. Accelerated infliximab infusions for standard and dose-intensified regimens seem to be safe and improved patient satisfaction. Potential impact on drug trough levels requires further investigations.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn's disease.

BACKGROUNDTumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn’s disease (CD), but not all patients achieve fistula healing.AIMTo determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODSIn this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test, t test or Mann-Whitney U test.RESULTSOne hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5) vs 3.0 (0.3-6.2) mg/L, P = 0.003; adalimumab: 9.2 (6.5-12.0) vs 5.4 (2.5-8.3) mg/L, P = 0.004]. For patients on infliximab, fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age. For patients on adalimumab, fistula healing was associated with higher rates of combination therapy with an immunomodulator. Serum trough levels for patients with and without fistula closure were not significantly different for infliximab [6.9 (4.3-10.2) vs 5.5 (2.5-8.3) mg/L, P = 0.105] or adalimumab [10.0 (6.6-12.0) vs 7.8 (4.2-10.0) mg/L, P = 0.083].CONCLUSIONHigher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.