Infliximab Levels Research Articles

Proactive measurement of infliximab drug levels in children with Crohn's disease.

BackgroundProactively monitoring infliximab levels is an emerging area of interest in pediatric Crohn’s disease. There are only limited data on therapeutic drug monitoring for children with Crohn’s disease. The goal of our study was to determine the utility of therapeutic drug monitoring in achieving clinical remission in a cohort of pediatric Crohn’s disease patients receiving infliximab.MethodsThis prospective single-center study enrolled 37 patients with Crohn’s disease at the start of infliximab infusions and monitored trough levels at 6-month intervals for 18 months. Each participant was matched to a historic control for the modified pediatric Crohn’s disease activity index (mPCDAI) at baseline, age and sex. The primary outcome was an mPCDAI score of ≤7.5 at 6, 12 and 18 months. A multivariate logistic regression analysis was performed.ResultsData were available for all 37 cases at 6 and 12 months and for 34 cases at 18 months. Demographics and disease characteristics were similar between groups. All 34 cases demonstrated clinical remission at 18 months (100% vs. 88%, P=0.114). Univariate and multivariate analyses did not show statistical significance. Dose intensification was seen more often in the cases at 18 months.ConclusionAll of our moderate-to-severe pediatric Crohn’s disease patients who received prospective therapeutic drug monitoring of infliximab were in clinical remission at follow up, but this was not statistically significantly different from the 88% clinical remission rate of the control group.

13115 Serum infliximab level in an infant delivered from a mother with psoriatic arthritis receiving infliximab

Infliximab (IFX) has been demonstrated to hinder progressive joint destruction induced by PsA. IFX is currently one of the non-contraindicated systemic treatment options during pregnancy. However, little is known about postnatal clearance of infliximab in neonates delivered from psoriasis patients. We measured serum IFX level in an infant delivered from a mother with PsA receiving IFX. A 36-year-old female patient with PsA received 6 mg/kg of IFX every eight weeks. After getting pregnant, she continued it until she was 26 weeks pregnant. She was treated with the same dose of IFX every four weeks from week 18 to 26. She delivered a healthy female baby by caesarean section at week 38 as scheduled. She breastfed her baby. She restarted IFX treatment five weeks after giving birth, and continued IFX treatment every four weeks for one year. Since the patient received IFX treatment during pregnancy and lactation, the serum IFX level in the baby was periodically measured. The concentration of IFX in the serum of the baby was 4.46 μg/mL at 24 days of age; 0.19 μg/mL at 155 days of age; and below the detection level limit at 278 days of age. To the best of our knowledge, there have been no papers reporting the serum IFX levels in a baby delivered from a mother with psoriasis receiving IFX. Further accumulation of case is needed to clarify the safety of IFX in pregnant women with psoriasis and their babies.

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

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

Correlation of serum levels of anti-tumor necrosis factor agents with perianal fistula healing in Crohn's disease: a narrative review.

With the overspread use of measurement of serum levels of anti-tumor necrosis factor (TNF) agents (therapeutic drug monitoring, TDM), new therapeutic strategies have been used in the management of Crohn’s disease (CD). Different targets are correlated with increased levels of circulating drugs. Recent evidence demonstrated that higher serum levels of anti-TNF agents may be associated to better outcomes in perianal fistulizing CD (PFCD). Overall, patients with healed fistulas had higher serum levels of infliximab and adalimumab as compared to those with active drainage. This was demonstrated in some cohort studies, in induction and maintenance, in adults and children with PFCD. In this narrative review, authors summarize current evidence on the use of serum level measurement of anti-TNF agents and its correlation with perianal fistula healing in CD patients. Data on the use of TDM in PFCD is discussed in detail. The retrospective design of the studies and the lack of objective parameters to measure fistula healing are the main limitations of published data. Prospective studies, with central reading of objective radiological parameters, such as pelvic magnetic resonance imaging scores, can improve the level of evidence on the possible advantages of TDM in perianal fistula in CD and are warranted.

Infliximab concentrations in two non-switching cohorts of patients with inflammatory bowel disease: originator vs. biosimilar

Biosimilars are replacing originator compounds due to their similar effectiveness, safety and pharmacokinetics. Our objective was to compare the differences in pharmacokinetics and clinical outcomes between the originator infliximab (Ifx) and the biosimilar CT-P13 in a patient cohort with inflammatory bowel disease (IBD). Our cohort study included 86 patients from a historical and a prospective cohort from the start of infliximab treatment to 22 weeks later. Serum infliximab, antidrug antibody levels and other serum biomarkers were measured at weeks 0, 2, 6, 14 and 22. Remission outcomes were evaluated at weeks 14 and 22. Drug levels were measured prospectively and analysed using MANOVA. Of the 86 patients, 44 (51%) and 42 (49%) were administered the originator and CT-P13, respectively. Originator trough levels were higher than the biosimilar trough levels (35 vs. 21, 20.1 vs. 11, 6.6 vs. 2.9 and 4.3 vs. 1.7 μg/mL at weeks 2, 6, 14 and 22, respectively). A post-hoc analysis demonstrated changes in mean serum drug levels over time (p < 0.001) and according to the drug employed (p = 0.001). At week 22, 13 (81%) patients administered the originator achieved clinical remission compared with 5 (19%) patients with the biosimilar (p = 0.02). None of the patients administered the originator withdrew from the treatment compared with 7 for the biosimilar. During the study, there were significant differences in serum infliximab levels between the originator and the CT-P13 in the patients with IBD. The clinical outcomes were influenced by the type of compound administered.

Clinical efficacy of infliximab level and anti-infliximab antibody measurement in patients with inflammatory bowel disease: An audit.

Infliximab (IFX) monitoring has been proposed for effective therapeutic management of inflammatory bowel disease (IBD). There is no data on infliximab levels and itsantibody measurement in Indian patients. We assessed the clinical efficacy of IFX level and antibodies to infliximab (ATI) monitoring in IBD patients. Infliximab trough level and antibody testing was done in 50 and 30 IBD patients, respectively using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The levels were correlated with the disease status, albumin, and C-reactive protein (CRP)levels. The clinical efficacy of level-based change in patient management was evaluated. Of 50 patients, IFX levels were therapeutic in 8, sub-therapeutic in 40, and supra-therapeutic in 2. High ATI titer was present in 8/30 patients. The IFX level did not correlate with the dose of 5 or 10mg/kg. Based on IFX level and ATI estimation, management was changed in 35 patients: increase in dose in 7, decrease in dosing interval in 17, increase in interval in 2, surgery in 2, change in biologic in 5, and cessation of IFX in 2 patients. Therapy modification based on IFX level improved the clinical response in 25 patients, of whom 5 are in remission at a median duration of 2years. Most (80%) of the IBDpatients had subtherapeutic IFX levels while high ATI titers were found in 27% of the patients. There was no correlation between infliximab dose and drug levels. Therapy modification based on drug level benefitted the majority. Our results suggest that measurement of IFXlevel assists in attaining therapeutic levels and improves clinical response.

S0874 Performance Characteristics of Homogenous Mobility Shift Assay Method Against World Health Organization International Standard for Infliximab Bioactivity and Impact of Dosing Regimens on Exposure

INTRODUCTION: Therapeutic drug monitoring (TDM) of Infliximab remains an important clinical decision tool to improve outcomes in Inflammatory bowel diseases (IBD). However, one limitation of TDM in clinical gastroenterology practice is the lack of standardization across available technology platforms. Recently, the 1st international standard for infliximab (IFX) bioactivity was characterized and produced by World Health Organization (WHO). Our objective was to evaluate the performance characteristics of the Homogenous Mobility Shift assay (HMSA) against WHO calibration. METHODS: All IFX testing was conducted in a clinical laboratory accredited by the American College of Pathologists (Prometheus Biosciences, San Diego) using liquid chromatography size exclusion HMSA calibrated in house using IFX standards purchased independently from WHO. WHO Standard (NIBSC code: 16/170) was purchased as lyophilized powder, re-suspended to a final concentration of 50 µg/ml in normal healthy serum and stored at -80°C. IFX concentrations measured using in-house and WHO calibration methods were compared using de-identified specimens submitted for IFX testing. Data were analyzed using Deming’s regression and linear mixed effect models for repeated measures. IFX levels in relation to dosing intervals from patient specimens presenting with ICD-10 specific IBD codes were also evaluated. RESULTS: Between run (n = 6) precision was 9.5% (median CV; range 3.9–19.4%) and 8.6% (range: 5.2–17.8%) for 28 IFX specimens measured using in-house and WHO calibration, respectively. As presented in Figure 1, IFX levels measured using in-house calibration method (mean 13.8 ± 0.9 µg/ml) were comparable to those recovered from WHO calibration method (mean 13.9 ± 0.9 µg/ml) (Deming’s slope 1.00 CI 95%: 0.97–1.03). Linear mixed effect models also indicated comparable IFX levels between calibrations (slope = 0.986 ± 0.012; intercept = 0.11 ± 0.22; R2 = 0.97). Table 1 highlights IFX exposure levels in a total of 19,013 specimens submitted with dosing information between 2015 and 2020. A 5mg/Kg every 8 weeks dosing interval associated with 57% specimens above 5 µg/ml. Shorter intervals resulted in higher exposure. CONCLUSION: Our data indicate that IFX levels measured by HMSA in the reference laboratory yield comparable estimates to those from WHO. Calibration with WHO standards may facilitate harmonization of TDM in clinical gastroenterology practice.Figure 1Table 1

S2245 A Whipping Case of Crohn's Disease

INTRODUCTION: Crohn’s disease (CD) is a chronic inflammatory disorder (CID) of the gastrointestinal (GI) tract characterized by an impaired gut immune response with an altered microbiome. Prevalence is higher in developed countries where immune system exposures may be limited by more sanitary environments. In developed countries, improved hygiene, the rarity of parasitic infections and the occasional clearing of beneficial bacteria from the intestinal tract are thought to possibly predispose individuals to develop immunologic diseases. Despite an expanding therapeutic armamentarium, CD can be difficult to treat, driving some patients to seek alternative therapies. Here we present a case describing the controversial use of helminthic therapy (HT) for self-treatment of CD. CASE DESCRIPTION/METHODS: A 50-year-old male with a history of iron deficiency anemia (IDA) and Crohn’s colitis maintained on infliximab and 6-mercaptopurine combination therapy, presented for a surveillance colonoscopy. In the distal sigmoid colon, there were scattered erosions and a few clean-based ulcerations with associated mucosal erythema and friability. Numerous, 3-5 mm, white, linear worms were also noted throughout the colon. Infliximab levels and thiopurine metabolites were sub-therapeutic, concerning for poor compliance. The patient later admitted to surreptitiously consuming whipworm eggs for CD self-treatment which he obtained online. Despite worsening IDA, weight loss and lack of improvement of symptoms related to CD, the patient declined treatment for whipworm. DISCUSSION: Helminths have been shown to reduce immune responsiveness in naturally colonized individuals and to diminish inflammation in experimental colitis. Helminths are thought to induce a strong Th2 response that counterbalances an overactive Th1/Th17 response seen in CIDs. The majority of studies with HT in this setting; however, have failed to demonstrate clinical efficacy; although, some report improvements in CD-related symptoms. Common complications related to HT include IDA, diarrhea, anorexia, dehydration and dysentery. Overall, HT for CD is not advised as it is controversial, of limited therapeutic efficacy, not FDA approved and can lead to more complications than therapeutic benefits.Figure 1.: Endoscopic image showing multiple white whipworms within the colon.Figure 2.: Endoscopic image of 5 mm, white, linear whipworm. Pseudopolyposis also seen in this image.

S2282 Use of Tofacitinib as Rescue Therapy in a Biologic-Experienced Patient Hospitalized With Acute Severe Ulcerative Colitis

INTRODUCTION: Acute-severe ulcerative colitis remains a potentially life-threatening condition associated with high morbidity and may result in colectomy in 40% of patients (1). We present a case of tofacitinib as rescue therapy in a biologic-experienced patient hospitalized with acute-severe ulcerative colitis. CASE DESCRIPTION/METHODS: A 46-year-old woman undergoing infliximab induction for recently diagnosed severely active ulcerative colitis was admitted to our facility with acute severe ulcerative colitis. She had recently tapered off steroids and received her second induction dose of 5mg/kg infliximab 29 days prior to admission. Azathioprine was started initially but discontinued when she developed nausea and oral ulcers after the first several days. At time of admission she noted more than 10 episodes of bloody diarrhea daily with tenesmus and abdominal pain. Laboratory evaluation revealed anemia with Hgb 9.8g/dL, albumin of 2.5g/dL, and CRP of 11.0mg/dL. Infectious workup including C.difficile toxin PCR was non-revealing. Flexible sigmoidoscopy on hospital day two revealed Mayo 3 colitis, biopsies were negative for CMV. Infliximab level was 3.22 mcg/mL. She received a dose of 10mg/kg infliximab on hospital day 2. At hospital day four, she had no improvement in symptoms, and CRP had risen to 18.0mg/dL. After discussion with the patient, we elected to pursue tofacitinib therapy to potentially avoid colectomy. Herpes zoster vaccination was administered inpatient. She was started on tofacitinib 10mg BID on hospital day five, which was increased to 10mg TID on hospital day seven after a partial response. At hospital day nine she reported improved pain and 1-2 episodes of non-bloody formed stool. CRP had fallen from 18.7 to 2.6mg/dL, and she was discharged. At hospital follow-up 12 days later, tofacitinib was decreased to 10mg BID. At 30 days post discharge she noted 1-2 formed stools daily without blood or tenesmus. She is pending follow-up endoscopy. DISCUSSION: Tofacitinib is an accepted agent for the induction of remission in patients with moderate to severely active ulcerative colitis; however, there is limited data regarding its use as rescue therapy for biologic experienced patients hospitalized with acute-severe ulcerative colitis. Our patient represents a case of tofacitinib initiation in the context of failed infliximab induction as a potential rescue agent to avoid colectomy.Figure 1Figure 2

S0750 A Decade Long Trend of Therapeutic Drug Monitoring at a Tertiary Referral Center: Shifting Focus From Reactive to Proactive - Is This Useful?

INTRODUCTION: Therapeutic drug monitoring (TDM) is routinely used for optimization of treatment of Crohn’s disease (CD) patients. There has been a gradual shift towards proactive TDM with its purported benefits of increasing drug levels, reducing loss of response from immunogenicity, and increasing the persistence of patients on infliximab (IFX). We herein report our experience at a tertiary referral IBD center on the trends of TDM since 2010 and determine the role it has played in the management of patients with CD. 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 11/31/2019. Variables assessed included demographics, disease behavior, surgical history, smoking history, prior anti-TNF exposure, IFX trough and antibody levels, IFX start and end dates, reasons for discontinuation, and pattern of TDM. Each TDM was classified as either proactive or reactive based on whether it was carried out as a response to loss of response (Reactive), or was it carried out at pre-defined time points to optimize drug levels (Proactive). RESULTS: Of a total of 1236 CD patients, 325 patients (median age at diagnosis 22 years, 56% men) were included. A total of 1,181 TDM assessments were carried out (892 proactive, 75%) with 24 immune-mediated events (15 immune-mediated loss of response, 9 infusion reactions) (Table 1). The frequency of proactive TDM increased across the study period with a concurrent decrease in rates of reactive TDM (P < 0.0001) (Figure 1). Similarly, the rate of IFX discontinuation decreased over the years (P < 0.0001) (Figure 2), whereas median IFX levels increased across the years (P < 0.0001) (Figure 3). On Kaplan Meier survival analysis, patients who underwent proactive assessment had a significantly lower IFX discontinuation rate compared to those who underwent reactive assessment (P < 0.0001) (Figure 4). CONCLUSION: In this large cohort of CD patients followed for 10 years at a tertiary IBD center we have observed an increase in the rate of proactive assessment for TDM. This has led to successively declining rates of IFX discontinuation and increased IFX drug levels. Furthermore, we observed that patients that were monitored proactively remained on IFX for longer periods of time. This study further advocates the need for gastroenterologists to incorporate proactive TDM in their day to day practice.Table 1.: TDM: Therapeutic drug monitoring, n: population, %: percentage, y: years, IQR: Inter-quartile range, CD: Crohn’s disease, IFX: Infliximab, Ab: antibodyFigure 1Figure 2

S2277 Role of Oral Vancomycin in Inducing Remission for Biologic Experienced Ulcerative Colitis With Concomitant Primary Sclerosing Cholangitis and Liver Transplantation

INTRODUCTION: Ulcerative colitis associated with primary sclerosing cholangitis (UC-PSC) is distinct entity. One third of patients with UC may experience worsening colitis despite on immunosuppression after liver transplantation (LT) for PSC. We report a case of severe UC after LT for PSC refractory to Vedolizumab and Infliximab that responded to oral vancomycin (OV). CASE DESCRIPTION/METHODS: A 51-year-old man with mild ulcerative pancolitis and PSC presented with worsening bloody diarrhea. His UC was diagnosed at age 12, is mild and responding to oral mesalamine. He had LT for PSC 7 months ago, with normal post-transplant course on mycophenolate mofetil (MMF) and tacrolimus. Stool testing for Clostridium difficile, ova/parasites, and cultures were negative. Colonoscopy showed severe active (Mayo score 3) ulcerative pancolitis (Figure 1). Pathology showed severe inflammation, crypt abscesses, and negative CMV. Prednisone showed improvement. MMF switched to delayed release MMF. Vedolizumab started with tapering steroids, however patient had recurrence of bloody diarrhea, led to increasing frequency of Vedolizumab at week 14 of treatment. Repeat colonoscopy at 20 weeks of initiating Vedolizumab showed severe pancolitis (Mayo score 3) (Figure 2). Vedolizumab switched to Infliximab. Patient responded, hence prednisone was tapered off. However, had episodes of bloody diarrhea requiring 2 courses of prednisone, frequency of Infliximab was increased after 22 weeks of treatment initiation. After another flare requiring prednisone, infliximab levels checked were adequate at 19 mcg/ml without antibodies. At this point, OV was started. In the following 3 months, had significant clinical improvement and did not require prednisone. Repeat colonoscopy showed resolution of inflammation-Mayo endoscopic score of 1 (Figure 3). Patient still on OV and reduced dose of Infliximab without flares. DISCUSSION: UC-PSC has its unique pathophysiology and genetics, and therefore it responds differently than UC. They have gut microbiota less diverse compared to healthy controls, which could explain the refractory course and the utility of OV. OV has poor oral absorption, concentrates in the intestine. It acts as immunomodulator, by reducing cytokine release from T cells,and antimicrobial agent. In patients refractory to conventional therapies (5-ASA, steroids); azathioprine, anti-tumor necrosis factor antibodies, or Vedolizumab are recommended. In severe refractory colitis, surgery can be curative, which can be avoided by using OV.Figure 1.: Severe (mayo 3) inflammation in the descending colon.Figure 2.: Severe (Mayo 3) colonic inflammation.Figure 3.: Endoscopic remission seen after initiation of Oral Vancomycin.

S0752 Infliximab Level &lt;3 µg/ml Predicts Immune-Mediated Loss of Response in Patients With Crohn’s Disease

INTRODUCTION: Therapeutic drug monitoring (TDM) is routinely used, whether proactively or reactively, for optimization of treatment of IBD patients. Infliximab (IFX) trough levels of ≥3–5 µg/ml are suggested as appropriate levels for clinical response. Patients treated with IFX can develop antibodies which can neutralize the drug, thus leading to loss of response. The aim of our study was to assess IFX trough levels that can predict immune-mediated loss of response (LOR). METHODS: This was a retrospective cohort study of Crohn’s disease (CD) patients who were exposed to IFX and had IFX trough/antibody levels (TDM) checked between 1/1/2010 and 11/31/2019. Variables assessed included demographics, smoking history, drug dose, prior anti-TNF exposure (other than IFX), IFX trough and antibody levels, IFX start and end dates, and reactive versus proactive TDM. Immune mediated LOR was defined as loss of response to IFX that was attributable to low drug levels and presence of neutralizing antibodies. Median drug levels over a patient’s total time on IFX were used for assessing immune-mediated LOR using receiver operating curve (ROC) analysis. RESULTS: A total of 333 patients with CD (median age at diagnosis 22 years, 57% men) were included. Immune-mediated LOR occurred in 16 (4.5%) patients. On univariable analysis, prior exposure to anti-TNF agents, higher median drug levels and at least 1 proactive TDM done during the patient’s disease course were associated with a lower risk of immune-mediated LOR (P = 0.04, <0.0001 and 0.002, respectively) (Table 1). On multivariable logistic regression, all three of these variables were associated with lower odds for immune mediated LOR (P = 0.04, 0.001 and 0.04, respectively) (Table 2). Furthermore, on ROC analysis, an IFX drug level cut-off value of <3.1 µg/ml had an 88% sensitivity and 83% specificity for predicting immune-mediated LOR (AUROC = 0.882, P < 0.0001) (Figure 1). CONCLUSION: Based on this study of a large cohort of CD patients, we propose that gastroenterologists should proactively target IFX trough levels >3 µg/ml in order to decrease the odds of developing immune-mediated LOR, particularly in patients that have never previously been exposed to anti-TNF alpha agents.Table 1Figure 1.: ROC curve-cutoff value of the IFX trough level in CD was calculated, as was association between IFX trough level and immune mediated loss of response, with corresponding sensitivity and specificity for CD. Cutoff value, 3.1 µg/mL; area under the ROC curve (AUROC), 88.2.

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown. To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6weeks and 3months or until undetectable. We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P<0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P=0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P<0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16weeks of age in all 12 infants completing follow-up testing. During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.

Current management of fistulizing perianal Crohn’s disease based on serum anti-tumor necrosis factor levels and magnetic resonance imaging monitoring

Perianal fistulizing Crohn’s disease (PFCD) is one of the most complex challenges in the colorectal surgery nowadays, because, even with combined clinical and surgical treatment, the rate of healing of the fistulas is approximately 50%. In this context, the monitoring of serum levels of anti-Tumor Necrosis Factor (anti-TNF) drugs appears as a crucial tool for the optimization of treatment, since there is a probable correlation between higher serum levels of infliximab and adalimumab with better outcomes of the disease, higher healing rates and lower recurrence rates. This review describes evidence on the use of serum anti-TNF levels and their relationship to clinical and radiological efficacy.

Duration of combination therapy and risk of treatment failure in patients with inflammatory bowel disease

Patients who receive infliximab (IFX) combined with a thiopurine, for inflammatory bowel disease, have a better clinical response and less frequent immunization towards IFX than those treated with IFX alone. The benefits of combination therapy must be weighed against the risks of infection and cancer. We studied the association between the duration of combination therapy and the risk of treatment failure by two year from initiation. Participants had Crohn's disease or ulcerative colitis and were in clinical and biological remission, 6 months after initiation of combination therapy. The risk of subsequent treatment failure (i.e., undetectable trough IFX levels and/or clinical relapse followed by surgical treatment or switch of maintenance treatment) was estimated using Kaplan-Meier method and adjusted Hazard Ratios (aHRs), in patients whohadreceived 6 to 11 months vs. 12 months or more of combination therapy. We performed a similar analysis in which the follow-up was started at discontinuation of the immunosuppressant. Among 139 patients (48% women; median age 31.1), with a median follow-up of 18.9 months, we observed 26 treatment failures (including 15 patients with undetectable trough IFX levels). After adjustment for gender and type of immunomodulator, a shorter duration of combination therapy was not associated with a higher risk of treatment failure (aHR=0.42; 95% confidence interval (95%CI): 0.13-1.40; p=0.16). When the follow-up was started at discontinuation of the immunosuppressant, a combination therapy of 6-11 months was associated with a numerically lower risk of treatment failure as compared with a longer combination therapy (HR=0.12; 95%CI: 0.01-1.05; p=0.055). Our results do not show any benefit for continuation of combination therapy for more than 12 months after achieving clinical remission in IBD patients.

P60 Efficacy of switching to infliximab biosimilar (Remsima®) in paediatric inflammatory bowel disease (PIBD): a 2-Year retrospective evaluation

AimTo evaluate patient outcomes 2 years post switching Infliximab therapy from Infliximab originator molecule Remicade® to biosimilar Remsima®.MethodsPatients with PIBD who experienced induction with Remicade® therapy, were &lt;18 years old at last follow-up and were receiving active treatment with Remsima® 2 years post switching were selected to be included for evaluation. Outcome measures included monitoring disease activity and treatment failure at baseline (before switching) and at selected time points up to 2 years post-switch. Disease activity was assessed looking at a range of parameters: disease activity scores; trough infliximab levels; haematological markers (HGB, platelets, WBC); LFTs (bilirubin, ALT, ALP); inflammatory markers (ESR, CRP) and faecal calprotectin levels. Patients who failed therapy were assessed for adverse reactions and infliximab antibody formation. Data was analysed with the Cochran Q test, repeated measures ANOVA test and Friedman test; with post-hoc Bonferroni and Wilcoxon Signed-Ranks tests if appropriate.ResultsData was available for 18 patients after exclusion criteria were applied. There was a significant increase in trough infliximab levels by the end of the period from an average of 5 ug/L to 12 ug/L at 2 years. The average dose/kg increased over 2 years by 1.5 mg/kg. Disease activity markers showed no changes between time points except a decrease in ALP levels from baseline to 1 year, but values remained within normal ranges. Four patients were discontinued from Remsima® due to side effects or loss of efficacy. The average time to treatment failure on Remsima® was 38 months (~19/20 doses). Three out of four patients developed infliximab antibodies, 2 of these patients went on to suffer adverse reactions; 1 exhibited joint pain which settled weeks after each infusion and the other developed an immediate infusion reaction in the form of a rash with urticaria on the 3rd infusion of Remsima®.ConclusionInfliximab biosimilars, such as Remsima®, were approved for use in PIBD by the EMA after studies in adult populations with rheumatic diseases.1 2 Induction studies have shown efficacy in PIBD but data on switching is limited and short-term.3 4 Our data shows no significant differences in clinical patient outcomes over a 2-year period in a cohort switched from Remicade® to Remsima®. In fact, a significant increase in trough infliximab levels in patients remaining on Remsima® suggests efficacy in producing therapeutic levels in PIBD patients. Increased levels may be explained by dose intensification used by the PIBD multi-disciplinary team (MDT), reflecting careful dose optimisation strategies used at this trust throughout the time period. Patients losing response were not unexpected and are likely not due to the biosimilar switch but rather due to the length of time the patients were on treatment. The small sample size and retrospective nature of this study mean larger cohort studies are required over prolonged time periods to confirm these findings. PIBD MDTs should continue to monitor patients for adverse reactions, particularly in those who develop infliximab antibodies.ReferencesPark W, Hrycaj P, Jeka S, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis 2013;72:1605–1612.Yoo DH, Hrycaj P, Miranda P, et al. Extended report: a randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when co-administered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72:1613.Sieczkowska J, Jarzębicka D, Banaszkiewicz A, et al. Switching Between Infliximab Originator and Biosimilar in Paediatric Patients with Inflammatory Bowel Disease. Preliminary Observations. J Crohn’s Colitis 2016;10:127–132.Sieczkowska J, Jarzębicka D, Meglicka M, et al. Experience with biosimilar infliximab (CT-P13) in paediatric patients with inflammatory bowel diseases. Therap Adv Gastroenterol 2016;9:729–735.

Infliximab Level Between Venous and Capillary Blood Using Novel Device Strongly Correlate in Paediatric Inflammatory Bowel Disease Patients.

Blood to measure infliximab (IFX) levels is typically obtained with venipuncture. Dried blood sampling (DBS), using capillary blood obtained from a finger prick, would be an alternative to measure IFX blood levels while being more patient friendly. The aim of this study is to compare IFX blood level measured by venipuncture versus DBS in patients with paediatric inflammatory bowel disease (PIBD) to assure accuracy. A prospective clinical pilot study was performed in patients with PIBD. Before IFX infusion, blood was collected simultaneously through venipuncture and DBS from a finger prick, using Mitratips (Neoteryx). All IFX concentrations were measured by an enzyme-linked immunosorbent assay. The Bland-Altman analysis was used to measure limits of agreement. The interrater reliability was measured with the interclass correlation coefficient and Cohen kappa. To calculate Cohen kappa, IFX levels were categorized into 3 groups; low <5 μg/mL, adequate 5 to 10 μg/mL, and high >10 μg/mL. Twenty patients were included. Median age was 12.1 year (interquartile range 8-16 year). The mean difference between the 2 methods was -0.14 as calculated with Bland-Altman plot. The limits of agreement were between -1.39 and 1.12. The interclass correlation coefficient was with 0.998 excellent. The Cohen kappa between 3 IFX level categories was strong K = 0.911 (P = 0.0001). There was a strong correlation between venous IFX serum levels and DBS (r = 0.991, P = 0.0001) in the included patients. This is the first study in patients with PIBD to show that bloodspot technology is a patient friendly alternative method to measure IFX blood levels in PIBD.

Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier.

A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n = 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n = 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 μg/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 μg/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 μg/mL. ADA were seldom detected in patients with >1 μg/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.

The effect of early trough level of infliximab on subsequent disease course in patients with Crohn disease

Decreased trough level of infliximab (TLI) is associated with diminished efficacy in patients with Crohn disease (CD). We examined whether TLI at 14 weeks subsequent to the start of infliximab (IFX) treatment would impact long-term clinical course.Serum IFX levels and antibodies to IFX (ATI) at 14 and 54 weeks after IFX administration were measured in 12 patients with mild to moderate CD. We examined patient background, clinical severity, blood test values, and the relationship between ATI and TLI up to 108 weeks.We compared the group with TLI < 3 μg/mL at 14 weeks (TLI(14) < 3 group) the group with TLI > 3 μg/mL (TLI(14) ≥ 3 group). Patients in the TLI(14) ≥ 3 group were significantly more likely to use immunomodulators before IFX treatment induction (P = .01). At 54 weeks, 2 cases of ATI production were observed in the TLI(14) < 3 group, but no ATI production was observed in the TLI(14) ≥ 3 group. TLI in the TLI(14) ≥ 3 group at 54 weeks was significantly higher than in the TLI(14) < 3 group (6.5 μg/mL vs 1.0 μg/mL; P < .01). Although CD activity index and serum albumin values in the TLI(14) ≥ 3 group at 14, 54, and 108 weeks significantly improved compared to baseline, these improvements were not observed in the TLI(14) < 3 group. The remission maintenance rate at 108 weeks evaluated with the Kaplan–Meier method was significantly higher in the TLI(14) ≥ 3 group than the TLI(14) < 3 group (100% vs 33.3%; P = .02).The TLI 14 weeks after IFX treatment in patients with CD affects long-term outcome.

Pharmacogenetics of trough serum anti-TNF levels in paediatric inflammatory bowel disease.

Identifying DNA variants associated with trough serum anti-tumour necrosis factor (TNF) levels could predict response to treatment in inflammatory bowel disease (IBD). To date, no specific studies have been performed in children. The aim of this study was to identify genetic variants associated with trough serum anti-TNF levels and whether these variants are differential markers for infliximab and adalimumab. We included 154 children (age < 18 years) from 17 hospitals who had been diagnosed with IBD and actively treated with infliximab or adalimumab. Twenty-one polymorphisms were genotyped using real-time PCR. Trough serum anti-TNF levels were measured using enzyme-linked immunosorbent assay (ELISA). The association between DNA polymorphisms and the therapeutic range or the absolute values of anti-TNF drugs was analysed by Fisher exact test, student's t-test and logistic regression. The variants rs5030728 (TLR4) and rs11465996 (LY96) were associated with subtherapeutic infliximab levels. rs1816702 (TLR2) was associated with supratherapeutic levels and rs3397 (TNFRSF1B) with subtherapeutic levels of adalimumab (P < .05). In addition, rs1816702 (TLR2) and rs2569190 (CD14) were associated with absolute values of trough serum adalimumab, and rs2569190 (CD14) was associated with absolute values of trough serum adalimumab and infliximab (P < .05). Genotyping of these DNA variants before starting treatment may help to select the best anti-TNF drug in paediatric patients. The SNP rs1816702 is the most promising marker for tailoring the anti-TNF regimen in children with IBD. For the first time, DNA variants are associated with trough serum anti-TNF levels.