Serum Infliximab Trough Levels Research Articles

Development and validation of a novel therapeutic drug monitoring-based nomogram for prediction of primary endoscopic response to anti-TNF therapy in active Crohn's disease.

Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Cross-sectional study. The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 μg/mL) and ADA (8.80 μg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.

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.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.

Safety and Durability of Accelerated Infliximab Dosing Strategies in Pediatric IBD: A Single Center, Retrospective Study.

Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1-9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis ( P ≤ 0.01) and patients with extensive disease ( P = 0.01) had lower durability, despite a higher starting dose of IFX ( P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs ( P = 0.01). Use of combination therapy had no impact on risk of AEs ( P = 0.78). We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

Transmural Healing Evaluated by Intestinal Ultrasound in Patients with Crohn’s Disease Treated with Infliximab

Background and Aims: Transmural healing (TH) has been recently proposed as a measure of deep remission in Crohn’s disease (CD). This study aimed to explore the rate of TH evaluated by intestinal ultrasound (IUS) in patients with CD treated with infliximab (IFX) and its predictive value for long-time clinical remission. Methods: Sixty-four consecutive active CD patients prescribed IFX were retrospectively recruited and followed for at least 2 years. Patients underwent IUS evaluation including bowel wall thickness, stratification, vascularity and mesenteric fat alteration at baseline and 14 weeks after IFX initiation. TH (normalization of all IUS parameters) was assessed at 14 weeks. Results: Fifteen (23.4%) patients achieved TH at 14 weeks, who were at lower risk of clinical relapse during the maintenance period than patients without TH [relative risk (RR) 0.132, P = 0.020]. The multivariate analysis indicated that TH (RR = 0.076, 95% CI: 0.007 - 0.773, P = 0.029) at 14 weeks were negative independent predictors of clinical relapse for patients who achieved steroid-free CR after the induction period. Patients with serum IFX trough levels >3 ug/ml were more likely to achieve TH at 14 weeks (34.3% vs. 10.7%, P = 0.029). Conclusion: IUS is useful in assessing TH, which predicts long-term clinical remission in patients with CD prescribed infliximab.

Serum trough levels of infliximab are not associated with peripheral arthralgia activity in patients with inflammatory bowel disease

BackgroundInfliximab is an efficacious therapy for inflammatory bowel disease and may play a role in management of some extraintestinal manifestations. While higher trough levels of infliximab are associated with higher...

Early monitoring of infliximab serum trough levels predicts long-term therapy failure in patients with axial spondyloarthritis

Objective To evaluate whether serum infliximab trough levels (ITL) during the early stages of treatment are predictive of long-term clinical failure in patients with axial spondyloarthritis (axSpA). Methods Longitudinal observational study involving 81 patients with axSpA monitored during infliximab therapy. Serum ITL were measured before starting infliximab treatment and at weeks 2 (W2), W6 and W12 of treatment. Disease activity was assessed by Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline, W24 and W52, and every 6 months thereafter until treatment discontinuation, regardless of the reason. Non-clinically important improvement was defined by ΔASDAS<1.1. The association between serum levels during the early stages and clinical outcomes (non-clinically important improvement at W52, drug survival and drop-out due to secondary inefficacy) was investigated through logistic regression models and Kaplan Meier curves. Receiver operating characteristic (ROC) curves were employed to determine the best cut-off for serum ITL. Results Out of the 81 patients, 45 (56%) did not achieve clinical improvement at W52. These patients had lower serum ITL at W12 compared to those who improved: ITL [median (IQR)]: 4.1(0.9-8.3) µg/mL vs 7.1 (4.3–11.3) µg/mL, respectively;p = 0.007). ITL<6.7 µg/mL at W12 was significantly associated with: i) not achieving clinical improvement at W52 (OR: 2.3; 95%CI: 1.3–3.9); ii) shorter drug survival (5.0 years (95% CI 3.8–6.2) vs 7.0 years (95% CI 4.8–6.9; p = 0.04), and iii) higher drop-out rates due to secondary inefficacy (OR: 3.5; 95% CI: 1.2–10.2). Conclusion Low serum ITL at W12 were associated with long-term clinical failure in patients with axSpA, due to secondary inefficacy.

Quality Improvement Methodology Optimizes Infliximab Levels in Pediatric Patients with Inflammatory Bowel Disease.

We participated in Intermediate Improvement Science Series, a course at Cincinnati Children's Hospital Medical Center designed to catalyze change using quality improvement methodology. We implemented interventions through plan-do-study-act cycles. Our outcome measure was balanced by 2 process measures to determine what actions impacted improvement. These measures included the percentage of infusion plans revised in response to a drug level <5 μg/mL and the proportion of plans for which a follow-up drug level was ordered. We increased the percentage of infusion plans revised before the next infusion from 63% to 87% and the percentage of plans that had an appropriate drug level recheck from 61% to 83% from July 2017 to January 2018. We increased the percentage of patients with an infliximab level >5 μg/mL, and results checked in the last 12 months, from 73% to 80%. Quality improvement methodology was effective in improving provider adherence to infliximab therapeutic drug monitoring guidelines. Improvement in adherence to guidelines directly improved the percentage of patients achieving target infliximab levels at any time during infliximab therapy.

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.

Early serum infliximab trough level and mucosal healing could be predictors for one-year outcome after initiating therapy in Crohn’s disease

Background and aims Serum infliximab trough level(S-IFX) and antibody were documented to correlate with clinical response. The aim of this study was to identify the relationship between early S-IFX, early mucosal healing (MH) and one-year outcome in a cohort on maintenance IFX therapy in Crohn’s disease (CD). Methods The study group comprised of retrospectively enrolled patients diagnosed for Crohn’s disease (n = 108). Patients received scheduled maintenance therapy after response to IFX induction, and had undergone the early S-IFX test and endoscopic examination at week 14. Clinical outcomes were evaluated during maintenance therapy until week 52. Results Early S-IFX was 4.78 ± 6.16 ug/ml in all the patients and 19% (21/108) of them developed antibodies, and 52 patients reached early MH. During 52 weeks’ follow-up. Twenty-eight percent (30/108) of patients showed loss of response to IFX. Patients who lost response had lower early S-IFX than those who had sustained response (3.01 ± 3.66 vs. 5.47 ± 6.79 ug/ml, p = .02; 48 vs. 23%, p = .02). At week 52, 73 patients had repeated endoscopy and 42% of them reached MH. Early S-IFX had a predictive value on MH at week 52. When early S-IFX > 2.5 ug/ml, the sensitivity for predicting MH at week 52 was 87%, and the specificity were 61% (AUC = 0.73, p < .01). The combined predictive value of early S-IFX and early MH became stronger. Only 6% (1/18) of those patients who had low early S-IFX and had not reached early MH could reach MH at week 52. Conclusions Early S-IFX and early MH could predict one-year response after initiating IFX therapy in Crohn’s disease.

Monitoring of infliximab trough levels and anti-infliximab antibodies in inflammatory bowel diseases: A comparison of three commercially available ELISA kits

BackgroundThere are many studies presenting data of biologics and several ELISA kits commercially available for monitoring infliximab serum trough levels (s-IFXt) and anti-drug antibodies (ADAb). We propose to compare technical characteristics and results of three different assays on a cohort of 35 patients under infliximab (IFX) and suffering from inflammatory bowel disease (IBD). Patients and methodss-IFXt and ADAb were systematically measured with three ELISA kits: Lisa-Tracker® Duo infliximab (Theradiag®), Ridascreen® IFX Monitoring (R-Biopharm AG®) and Promonitor® IFX (Progenika Biopharma SA®). ResultsThe main technical features that differed between kits for measuring s-IFXt were: (i) TNF coating, (ii) immune complexes revelation strategy and/or (iii) interference with other anti-TNFα agents. For kits measuring ADAb, they were revelation steps and unit of results. There was an excellent mathematical correlation of s-IFXt between assays however Bland-Altman analysis denoted (i) s-IFXt were on average 48 to 69% higher in Ridascreen® than in the other two assays, and (ii) elevated s-IFXt were higher with Promonitor® compared to Lisa-Tracker®. As a consequence, there were some substantial discrepancies between assays for classification of s-IFXt into concentration ranges. Despite unstandardized units, pairwise qualitative comparison showed a perfect agreement between the three pairs of ADAb assays. ConclusionOur data show that the evaluated assays are not quantitatively interchangeable due to substantial variations in some results that could lead, for some patients, to divergent therapeutic decisions. We remind to be cautious when comparing study results issued from different kits and recommend using the same assay for the longitudinal follow-up of IBD patients.

Anti-drug antibodies and low serum trough infliximab levels correlate with disease activity measures in spondyloarthritis patients on an as-needed infliximab treatment.

In India, many centers use infliximab at lower doses of 3-5mg/kg without the loading dose for spondyloarthritis (SpA) patients. It is then continued on an as-required basis, rather than a fixed schedule. Our study was undertaken to see if the trough drug levels and anti-drug antibodies in patients with SpA treated with as-needed infliximab dosing correlated with the disease activity measures. Thirty-five adult SpA patients in the age group 18-70years were recruited. They had received three or more infusions of infliximab at 3-5mg/kg over the past 6 to 12months. Patient's serum tumor necrosis factor-α, trough infliximab levels and anti-drug antibodies were measured by enzyme-linked immunosorbent assay technique. The disease activity was quantified by Ankylosing Spondylitis Disease Activity Score - erythrocyte sedimentation rate/ C-reactive protein (ASDAS-ESR/CRP) scores. Correlation between quantitative variables was analyzed by the Spearman's correlation assay. The difference in mean trough infliximab and ASDAS between the drug antibody positive and negative patients was assessed using the Mann-Whitney U test. There was a significant negative correlation between the trough infliximab levels and the ASDAS-ESR (rs = -0.57, P<0.01) and ASDAS-CRP scores (rs=-0.53, P<0.01). Anti-drug antibodies were positive in 68.7% of the patients and in comparison to the antibody negative patients, had significantly higher ASDAS-ESR and ASDAS-CRP scores. Spondyloarthritis patients on low-dose, as-needed infliximab therapy, have both the trough infliximab and anti-drug antibodies correlate significantly with the measures of disease activity. We hypothesize that trough infliximab levels and anti-drug antibodies may be used to predict a suboptimal response due to secondary resistance in SpA patients.

Serum Infliximab Cutoff trough Level Values for Maintaining Hematological Remission in Pediatric Inflammatory Bowel Disease

Background/AimsInfliximab (IFX) often loses its therapeutic effect in initial responders with inflammatory bowel disease (IBD) over time. Low serum IFX trough levels (TLs) are linked to poor clinical response and outcomes. Maintenance of optimal therapeutic IFX concentrations is important for sustaining response and achieving good clinical outcomes. Measurement of serum IFX TLs is helpful for determining a further proper therapeutic plan. However, adequate therapeutic IFX TLs in pediatric IBD is uncertain. We aimed to identify the cutoff values for IFX TLs associated with laboratory response to IFX maintenance therapy.MethodsPatients with pediatric IBD who had received IFX infusions between December 2008 and March 2015 at Samsung Medical Center were retrospectively investigated. We analyzed 239 blood samples that were collected from 103 pediatric patients. We measured IFX TLs at induction (6 and 14 weeks) and during maintenance therapy (>22 weeks, 8 weeks interval) by fluid-phase radioimmunoassays.ResultsA significant association was found between the erythrocyte sedimentation rate (ESR) and IFX TLs during maintenance (correlation coefficient, −0.11; p=0.0005). A cutoff value of 18 mm/hr for ESR was used to define higher levels. Receiver operating characteristic analysis identified optimal cutoff values: IFX TL >1.58 μg/mL (sensitivity 82% and specificity 73%).ConclusionsCutoff values are considered a prerequisite for further investigating the clinical usefulness of measurements of IFX in patients maintained with IFX treatment.

Association of Infliximab Levels With Mucosal Healing Is Time-Dependent in Crohn's Disease: Higher Drug Exposure Is Required Postinduction Than During Maintenance Treatment.

Infliximab levels have been reported to be associated with mucosal healing (MH) in Crohn's disease (CD). However, whether the association differs between postinduction (week 14) and maintenance (week 30) has seldom been investigated. We aimed to analyze the association between serum infliximab trough levels and MH at the 2 different time points. A retrospective study of CD patients treated with infliximab in a tertiary referral center between January 2012 and May 2018 was conducted. MH was defined as absence of ulceration by endoscopy. Correlations between infliximab level and MH were investigated at 2 specific time points, weeks 14 and 30. Median infliximab levels were higher in patients with MH than those without at weeks 14 (7.5 vs 1.5 μg/mL; P < 0.001) and 30 (5.9 vs 0.5 μg/mL; P < 0.001). The median levels in patients with MH at week 14 were higher than at week 30 (7.5 vs 5.9 μg/mL; P < 0.05). Multivariate analysis showed that infliximab level was independently associated with MH (both P < 0.001 at weeks 14 and 30). Infliximab level above 4.85 μg/mL and 2.85 μg/mL identified patients with MH at week 14 (area under the curve [AUC], 0.796; P < 0.001) and week 30 (AUC, 0.780; P < 0.001) with 80% specificity. The rates of MH reached a plateau (>85%) when infliximab levels were above 10 and 6 μg/mL at weeks 14 and 30, respectively. Infliximab levels correlated with MH at weeks 14 and 30 in CD patients. Higher levels might be required to achieve MH at postinduction than during maintenance treatment.

Outcomes of Patients With Inflammatory Bowel Diseases Switched From Maintenance Therapy With a Biosimilar to Remicade

There is evidence that it is safe and effective for patients with inflammatory bowel diseases (IBD) to switch from maintenance therapy with an original infliximab drug to a biosimilar, but little is known about outcomes of reverse switches and/or multiple switches. We aimed to evaluate the effects of a reverse switch (from a biosimilar to Remicade) in a real-life cohort. We performed a prospective observational study of 174 unselected and consecutive patients with IBD (136 with Crohn's disease [CD] and 38 with ulcerative colitis [UC]) who received maintenance therapy with the biosimilar in Hungary. In September 2017, patients were switched from the biosimilar (CT-P13) to Remicade, due to reimbursement policies. In our cohort, 8% (n= 14) patients had been previously exposed to the originator Remicade. We collected clinical and biochemical information from patients at baseline (time of the switch) and 16 and 24 weeks thereafter. Clinical remission was defined as a Crohn's disease activity index <150 points or no fistula drainage, or a partial Mayo score <3 points for patients with UC. Serum drug trough levels and anti-drug antibodies were measured at baseline and week16. There was no significant difference in the proportion of patients in clinical remission at week 8 before the switch (82.5% with CD and 82.9% with UC), at baseline (80.6% with CD and 81.6% with UC), at week 16 (77.5% with CD and 83.7% with UC), or at week 24 (CD 76.3% with CD and 84.9% with UC) (P = .60 among groups for patients with CD and P = .98 among groups for patients with UC). For all patients, mean serum trough levels of infliximab were 5.33 ± 4.70 μg/mL at baseline and 5.69 ± 4.94 μg/mL at week 16 (P = .71); we did not find significant differences in prevalence of anti-drug antibody at baseline (16.2%) compared with week 16 (16.9%) (P = .87). Four infusion reactions occurred, until week 24 of follow up. There was no difference in outcomes or trough or antidrug antibody levels between patients with or without previous exposure to Remicade. We collected data from a real-life cohort of patients with CD or UC who were switched from maintenance therapy with a biosimilar to Remicade or were treated with only Remicade. No significant changes were observed in remission, trough levels, or antidrug antibodies in patients switched from the biosimilar to Remicade. No new safety signals were detected.

Infliximab Trough Levels Are Associated With Mucosal Healing During Maintenance Treatment With Infliximab in Paediatric Crohn's Disease.

Mucosal healing is an important treatment goal in Crohn's disease. We investigated the association between serum infliximab trough levels and mucosal healing, and the infliximab cut-off levels required for mucosal healing in paediatric patients. In this multicentre, retrospective, cross-sectional study, medical records and electronic data of paediatric patients with luminal Crohn's disease, who had received infliximab for ≥1 year, were examined. Ileocolonoscopy was performed on the same day as the infliximab infusion, and serum samples for trough levels were collected immediately before infusion. Mucosal healing was defined as a Simple Endoscopic Score for Crohn's Disease of 0. Univariate, multivariate logistic regression, and receiver operating characteristic curve analyses were performed. Overall, 105 patients [median age 14.8 years] were included, with mucosal healing observed in 48.6%. Median serum infliximab trough levels were higher in patients with mucosal healing [4.5 µg/mL] than without [3.3 µg/mL, p = 0.002]. In the final multivariate model, infliximab trough level ≥4.2 µg/mL [p = 0.002] and ≥1-year duration from diagnosis to infliximab treatment [p = 0.003] were positively and negatively associated with mucosal healing, respectively. The infliximab trough level for achieving mucosal healing with a specificity of 80% was ≥5 µg/mL. Associations between serum infliximab trough concentrations and mucosal healing were observed in paediatric patients. Identification of the infliximab trough level that positively associates with mucosal healing in most paediatric patients with Crohn's disease [≥5 µg/mL] may guide treatment decisions to optimise therapeutic response in the era of treat-to-target.

Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn's Disease in Children.

There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula healing. A total of 667 children with Crohn's disease were recruited, with 85 (12.7%) patients diagnosed with fistulizing PCD. There were 27 of 52 (52%) children in whom pre-fourth infusion IFX levels were measured (mean age, 12.57 ± 5.12 years). At week 24, 14 of 27 (52%) patients responded with healing/healed PCD, whereas the rest had ongoing active fistulizing disease. The median IFX pre-fourth dose level in the responders was 12.7 ug/mL, compared with 5.4 ug/mL in the active disease group (P = 0.02). There was a strong correlation between IFX levels and healing of fistulizing PCD at week 24 (r = 0.65; P < 0.001). The AUROC was 0.80 (95% confidence interval, 0.64-0.97; P = 0.007) for pre-fourth IFX level to predict response of fistulizing PCD at week 24, and a level of 12.7 ug/mL best predicted fistula healing. Higher trough IFX levels are associated with healing of fistulizing perianal CD.

Predictive value of the combination of infliximab trough levels and C reactive protein in secondary loss of response to infliximab after induced remission

Objective To evaluate the role of infliximab trough levels (IFX-TL) and C reactive protein (CRP) concentration in prediction secondary loss of response (LOR) to infliximab (IFX) in patients with Crohn′s disease (CD) during IFX maintenance therapy since 14 weeks after induced treatment. Methods From November 2015 to October 2016, 43 CD patients received IFX treatment were enrolled. IFX was initially given at zero, two, and six weeks at 5 mg/kg as induced therapy, and then the same dose was given every eight weeks as long-term maintenance treatment. Serum IFX-TL and CRP concentration were measured at 14th week after the first IFX injection. The disease activity of CD was assessed by the Harvey-Braddshaw index. According to the follow-up results, the enrolled patients were divided into LOR group and continuous response group, and then the differences in IFX-TL and CRP concentrations at the 14th week after induced therapy were compared between two groups. Mann-Whitney U test and receiver operating characteristic (ROC) curve were performed for statistical analysis. Results After a median 54 weeks of follow-up, 18 (41.9%) of 43 CD patients achieved a sustained response to IFX therapy, while 11 patients (25.6%) were LOR to IFX therapy. At the 14th week after induced therapy, serum IFX-TL of LOR group was 2.30 μg/mL (0.52 μg/mL, 2.92 μg/mL), which was lower than that of continuous response group (5.10 μg/mL (3.54 μg/mL, 9.34 μg/mL)), and the difference was statistically significant (Z=-3.236, P=0.001). The CRP concentration of LOR group was 3.10 mg/L (0.38 mg/L, 21.70 mg/L), which was higher than that of continuous response group (0.51 mg/L (0.27 mg/L, 1.50 mg/L)), and the difference was statistically significant (Z=-1.732, P=0.015). The results of ROC curve analysis indicated that at 14th week after induced therapy the area under curve (AUC) value of predictive role of serum IFX-TL and CRP level in LOR to IFX was 0.864 (95% confidence interval (CI) 0.728 to 0.999), sensitivities were 83.3% and 81.8%, specificities were 94.4% and 54.5%, cut-off values of accuracies were 3.115 μg/mL and 5.93 mg/L. Conclusion IFX-TL 5.93 mg/L at 14th week since IFX induced therapy might be used as effective predictors of LOR in CD patients during maintenance therapy. Key words: Crohn disease; C reactive protein; Infliximab, trough levels; Loss of response

P543 Higher post-induction infliximab serum trough levels are associated with healing of fistulising perianal Crohn’s disease in children

There are no data regarding the association of response of fistulising perianal Crohn’s disease (PCD) with serum infliximab (IFX) levels in children. In a multi-centre national inception cohort using prospectively collected data, we aimed to determine serum trough IFX levels at starting maintenance (pre-dose 4) that are associated with healing of fistulising PCD at Week 24. The Canadian Children IBD Network brings together 12 academic paediatric IBD centres from across Canada. Patients younger than 17 years of age presenting with new-onset IBD were enrolled in an inception cohort study. Baseline and longitudinal phenotypic data were prospectively collected using standardised forms, which included a “perianal disease report form”. Consecutive children with fistulising PCD identified via clinical and/or magnetic resonance pelvic examination and treated with IFX between April 2013 and June 2017 and had IFX trough pre-dose 4 levels measured were included in the study. Response was defined as cessation or significant improvement of fistula drainage as defined by physician assessment. Correlation between IFX levels and response of fistulising PCD at Week 24 was examined using Pearson correlation analysis. Area under the receiver-operating characteristic curve (AUROC) was determined, with sensitivity and specificity calculated for the best cut-off of IFX level. A total of 667 children with Crohn’s disease were recruited with 85 (12.7%) patients diagnosed with fistulising PCD. Twenty-seven (mean age 12.5 + 5.1 years, 63% males) of 52 (52%) children with fistulising PCD on IFX had their pre-dose 4 IFX trough levels measured. All patients received three induction doses (median 6 mg/kg) of IFX at 0, 2, 6 weeks with dose 4 given at a median time interval from dose 3 of 50 days. At Week 24, 14 of 27 (52%) patients were classified as respondents with healing/healed PCD while the rest had on-going active fistulising PCD. The median IFX trough pre-dose four level in the respondents was 12.7 μg/ml (interquartile range (IQR) = 6.6–15.5) compared with 5.4 μg/ml (IQR = 2.7–8.4) in the active disease group (p = 0.02). There was a strong correlation between IFX level and healing of fistulising PCD at Week 24 (r = 0.65, p < 0.001). AUROC was 0.80 (95% confidence interval 0.64–0.97, p = 0.007) for pre-dose four level to predict response of fistulising PCD at Week 24, and a level of 12.7 μg/ml predicted fistula healing at Week 24 with sensitivity 0.62 and specificity 0.65. Following induction phase, higher trough IFX levels are associated with a better outcome for fistulising PCD in children. Our results need to be confirmed in larger prospective studies that include measurements of IFX levels and antibodies during the induction phase.

Predictive Value of Serum Infliximab Levels at Induction Phase in Rheumatoid Arthritis Patients.

Background:The Infliximab, has proven effective in treating rheumatoid arthritis (RA). A good clinical response is usually associated with high serum drug levels. Development of antibodies toward Infliximab (ATI) can increase drug clearance, leading to treatment failure.Aims:To analyze whether serum Infliximab trough levels (ITL) at the induction phase are associated with Infliximab clearance and clinical outcomes at week(W) 54 and to investigate the association with immunogenicity development.Methods:Observational retrospective study in which ITL from 66 RA patients were measured by capture ELISA at W0, W2, W6, W14 and 22. Patients were classified as ITLpos if Infliximab was detectable at W54 and ITLneg otherwise. ATI were assayed by bridging ELISA and by two drug-tolerant assays. ITL cut-off values were established by ROC curves. The association between ITL at early-stage and clearance of Infliximab at W54 was analyzed by univariable and multivariable logistic regression.Results:ITLneg patients (n=25) always had significantly lower Infliximab levels than ITLpos (n=41). An ITL value of 4.4 μg/mL at W6 best predicted W54 Infliximab absence. In the multivariable analysis, only ITL below the cut-off at W6 (OR: 86.6; 95%CI: 6.58-1139.99) and non-use of methotrexate (OR: 6.9; 95%CI: 1.04-45.84) remained significantly associated with W54 Infliximab absence. ATI were more frequent in patients with ITL below the cut-off at W6.Conclusions:In RA, ITL at induction phase are inversely associated with Infliximab clearance and clinical outcomes at W54. ATI was the main reason for low early ITL. A predictive value of ITL at W6 was found as a useful prognostic measure of treatment efficacy.