Infliximab Levels Research Articles

COMBINATION BIOLOGIC AND SMALL MOLECULE THERAPY FOR REFRACTORY ULCERATIVE COLITIS

Some inflammatory bowel disease (IBD) patients do not achieve remission with maximal medical therapy. We present a case of refractory UC who achieved clinical, endoscopic, and histologic remission after combining biologic and small molecule therapy. A 25-year-old Caucasian male was referred to our clinic for refractory UC. Since diagnosis four years prior, he failed mesalamine, azathioprine (intolerant), adalimumab (secondary nonresponse), vedolizumab (secondary nonresponse) with inability to taper prednisone. Upon presentation to our clinic he was at week 14 of infliximab therapy without clinical improvement. Therapeutic drug monitoring revealed adequate infliximab levels without antibodies. Colonoscopy revealed mayo 2-3 disease with discrete ulcerations (Figure 1). Due to primary non-response, he was initiated on ustekinumab (UST). He remained clinically active despite dose escalation up to evey four weeks and prednisone use. Tofacitinib was initiated with initial clinical improvement, then worsening after 3 months. The Tofacitinib dosing was increased from twice daily to three times daily and repeat colonoscopy revealed pan-colitis with Mayo 2 disease. Due to refractory disease the patient was started on combined therapy of tofacitinib twice daily with UST. On dual therapy the patient experienced progressive clinical improvement. After a year of dual treatment colonoscopy showed no disease activity, and biopsies showed no evidence of cryptitis, or crypt abscesses or active inflammatory infiltrate (Figure 2). This case highlights the benefit of combination biologic therapy with small molecule therapy in medically refractory IBD. There are limited prospective data to endorse the widespread implementation of combination therapy. A meta-analysis of thirty studies, involving 279 patients, reported 59% were able to achieve clinical remission and 34% achieved endoscopic remission with treatment of dual biologic or small molecule therapy1. Concerns involving safety of combination biologic and small molecule therapy continue to be evaluated. In our case, the patient achieved clinical, endoscopic, and histologic remission with tofacitinib and UST without adverse effects. We present this case to support the safety and efficacy of combination therapy in medically refractory patients. Ahmed W, Galati J, Kumar A et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021. https://doi.org/10.1016/j.cgh.2021.03.034.Figure 2Colonoscopy after 1 year of dual therapyView Large Image Figure ViewerDownload Hi-res image Download (PPT)

Effect of antinuclear antibodies on pharmacokinetics of anti-TNF therapy in patients with inflammatory bowel disease.

The detection of antinuclear antibodies (ANA) in serum of patients with inflammatory bowel disease (IBD) has been associated with a worse response to anti-TNF therapy and the development of cutaneous or arthritic manifestations. The aim of this study was to investigate a possible association of serum ANA with infliximab (IFX) and adalimumab (ADA) trough levels (TLs) and anti-drug antibodies in IBD patients treated with IFX or ADA. Consecutive IBD patients under maintenance therapy with IFX or ADA in whom there was at least one available measurement of anti-TNF TLs, antibodies to IFX or ADA, and ANA in serum were included. The correlation of ANA positivity with demographics, clinical characteristics, treatment, TLs and anti-drug antibodies, of all patients was analyzed. One hundred two IBD patients under maintenance therapy with IFX or ADA were enrolled. Of these, 53 (52%) were ANA positive with 28 (27.5%) positive also to anti-ds-DNA in serum. In the univariate analysis ANA positivity was found to be correlated with age (P = 0.008), female gender (P = 0.03), duration of treatment (P = 0.06), arthralgias (P = 0.04) and TLs (P = 0.005). However, in multivariate logistic regression analysis only age and TLs remained significantly associated with the presence of ANA positivity (P = 0.04 and P = = 0.006, respectively). No significant association of ANA positivity with the development of cutaneous or rheumatological manifestations was found. InIBD patients under maintenance therapy with anti-TNF ANA positivity is associated with lower TLs. The clinical significance of this finding remains to be defined in future larger prospective studies.

Clinical and Immunological Factors Associated with Recommended Trough Levels of Adalimumab and Infliximab in Patients with Crohn's Disease.

Introduction: Up to 40% of patients with Crohn’s disease do not respond to treatment with anti-TNF or lose response after the initial benefit. Low drug concentrations have been proposed as the main predictor of treatment failure. Our aim was to study the immunological profile and clinical evolution of patients with Crohn’s disease according to the anti-TNF dose and serum trough levels. Methods: Crohn’s disease patients in remission treated with infliximab or adalimumab at stable doses for at least for 3 months were included. Serum levels of anti-TNF, TNF-α, interferon-γ, and interleukin IL-12, IL-10, and IL-26 were determined in blood samples taken just before drug administration. Patients were classified according to anti-TNF levels below, within, or above the target level range and the use of intensified doses. Clinical evolution at 6 months was analyzed. Results: A total of 62 patients treated with infliximab (8 on intensified schedule) and 49 treated with adalimumab (7 on intensified schedule) were included. All infliximab-treated patients showed levels within the recommended range, but half of adalimumab-treated patients were below the recommended range. A significant negative relationship between body weight and adalimumab levels was observed, especially in patients treated with intensified doses. Patients with infliximab levels over 8 µg/ml presented higher median IL-10 than patients with in-range levels (84.0 pg/ml, interquartile range [IQR] 77.0–84.8 vs. 26.2 pg/mL, IQR 22.6–38.0; p < 0.001), along with lower values of interferon-γ (312.9 pg/ml, IQR 282.7–350.4 vs. 405.6 pg/ml, IQR 352.2–526.6; p = 0.005). Patients receiving intensified versus non-intensified doses of infliximab showed significantly higher IL-26 levels (91.8 pg/ml, IQR 75.6–109.5 vs. 20.5 pg/ml, IQR 16.2–32.2; p = 0.012), irrespective of serum drug levels. Patients with in-range levels of adalimumab showed higher values of IL-10 than patients with below-range levels (43.3 pg/ml, IQR 35.3–54.0 vs. 26.3 pg/ml, IQR 21.6–33.2; p = 0.001). Patients treated with intensified vs regular doses of adalimumab had increased levels of IL-12 (612.3 pg/ml, IQR 570.2–1353.7 vs. 516.4 pg/mL, IQR 474.5–591.2; p = 0.023). Four patients with low adalimumab levels (19%) and four treated with intensified doses were admitted to a hospital during a follow-up compared to none of the patients with levels within the range. Conclusion: Patients with Crohn’s disease treated with infliximab and adalimumab exhibit differences in serum levels of cytokines depending on the drug, dose intensification, and steady state trough serum levels.

Monitoring of infliximab treatment in inflammatory bowel diseases – basic knowledge and current data based on clinical trials in a population of Polish patients

Introduction and aim. Infliximab is the oldest biological drug belonging to the group of tumor necrosis factor antagonists. Despite the availability of many new biological therapies, this drug still plays an important role in the treatment of inflammatory bowel diseases. However, a significant problem related to pharmacotherapy is the high inter-individual variability of the response. Material and methods. This study presents results of the research on the treatment with infliximab in the inflammatory bowel disease (IBD) patients including our own experience in Polish IBD patients. Analysis of the literature. Therapeutic failure while using infliximab can be attributed partly to inadequate serum concentrations of the drug and the development of anti-drug antibodies. Many studies have attempted to find a relationship between the specific level of infliximab and the achieved healing effect. These analyses show that the optimal level of the drug differs depending on the type of disease, its phenotype, and therapeutic goal and that the optimization of infliximab therapy remains an open topic. Two studies involving the population of Polish IBD patients examined the level of infliximab during and after induction, as well as the frequency of anti-drug antibodies. Two studies involving a population of Polish IBD patients examined the level of infliximab during and after induction, as well as the frequency of anti-drug antibodies. These studies demonstrated the need for monitoring infliximab treatment at weeks 6 and 14. Conclusion. Reactive monitoring is believed to enable the most rational treatment decisions; however, experts also recommend that proactive monitoring should measure infliximab concentrations at the end of induction and at least once during maintenance treatment.

Supratherapeutic Infliximab Levels Do Not Predict Risk of Short-term Complications in Adults With Crohn's Disease.

It is uncertain if higher infliximab trough levels (TLs) confer a greater risk of infectious/noninfectious complications (IC/NIC). We aimed to assess the risk of IC and NIC in patients with different TLs. We retrospectively evaluated a cohort of Crohn's disease (CD) patients treated with infliximab who underwent therapeutic drug monitoring (TDM), at a tertiary inflammatory bowel disease center, between January 1, 2010, and December 1, 2019. TDM was defined as checking of infliximab trough and antibody levels within a 48-hour period before administration. Patients with a minimum of 3-month assessment pre-TDM and post-TDM were included. In the case of multiple TDMs, the highest TL was considered, and patients were distributed across 4 predefined TL groups (A: <5 µg/mL, B: 5 to 10 µg/mL, C: 10 to 15 µg/mL, and D: ≥15 µg/mL). Rates of IC and NIC during the 3-month prior and following TDM were compared across the groups. In addition, duration of exposure, in terms of months up to TDM, was collected to analyze differences in rates of IC and NIC. Our study included 341 CD patients (median age: 35 y, 58% men). IC and NIC occurred in 52 (15%) and 30 (9%) patients, respectively. Rates of IC and NIC were similar across the 4 TL groups ( P =0.9 and 0.7, respectively for IC and NIC). On multivariable analysis, exposure to infliximab >40 months (as determined by receiver operating characteristic curve analysis) was associated with decreased odds for IC (adjusted odds ratio=0.51, P =0.04), but not NIC (adjusted odds ratio=0.72, P =0.46). In this large CD cohort, there was no association between infliximab TL and risk of short-term IC or NIC. Interestingly, a shorter duration of exposure predicted higher rates of IC. This supports the safety of targeting higher infliximab TLs when necessary and greater vigilance during the early stages of treatment.

The Association Between Genetic Variants, Pharmacokinetics, and Infliximab Efficacy in Pediatric Patients With Crohn's Disease in China.

Background: Infliximab is an effective therapy for Crohn's disease (CD). Early non-invasive predictors of disease remission allow for modification of treatments. The aim of this study was to investigate the associations between genetic variants, pharmacokinetics, and infliximab efficacy in pediatric patients with CD.Methods: This retrospective observational study included CD patients under infliximab therapy between August 2015 and December 2020. Information on demographics, laboratory tests, medication data, and disease activity index was collected. The trough levels of infliximab (TLI) and antibodies to infliximab (ATI) were measured at week 14, and reactive drug monitoring was performed during follow-up. Ten single-nucleotide polymorphisms involved in the NF-κB-mediated inflammatory response, pharmacokinetics, and therapeutic response to infliximab were genotyped.Results: A total of 62 pediatric CD patients were enrolled. The clinical remission (CR) rate was 69.4 and 63.2% at week 14 and week 30, respectively. TLI at week 14 was significantly independently associated with CR at week 14 and mucosal healing (MH) at week 30 (p = 0.007 and p = 0.025, respectively). The optimal TLI threshold level capable of distinguishing between the CR and non-CR groups was 2.62 μg/ml (p < 0.001, area under the curve = 0.79, sensitivity = 69.2%, specificity = 78.9%), while that capable of distinguishing between the MH and non-MH groups was 3.34 μg/ml (p < 0.001, area under the curve = 0.85, sensitivity = 78.6%, specificity = 79.4%). Rs3397 in TNFRSF1B was associated with time to ATI production in CD patients (p < 0.001).Conclusions: Higher TLI contributed to achieving MH. Genotyping rs3397 in TNFRSF1B may identify patients who are prone to generating immunogenicity to drugs.

P010 Precision Dosing Tool Forecasts Trough Infliximab and Associates With Disease Status in Inflammatory Bowel Diseases.

Substantial inter- and intra-individual variability of infliximab (IFX) pharmacokinetics (PK) necessitates tailored dosing approaches. Here, we evaluated the performances of a Model Informed Precision Dosing (MIPD) Tool in forecasting trough Infliximab (IFX) levels in association with disease status and circulating TNF-α in patients with Inflammatory Bowel Diseases (IBD). Consented patients undergoing every 8-week maintenance therapy with IFX were enrolled. Midcycle specimens were collected, IFX, antibodies to IFX, albumin were determined and analyzed with weight using nonlinear mixed effect models coupled with Bayesian data assimilation to forecast trough levels. Accuracy of forecasted as compared to observed trough IFX levels were evaluated using Demings regression. Association between IFX levels, CRP-based clinical remission and TNF-α levels were analyzed using logistic regression and linear mixed effect models. In 41 patients receiving IFX (median dose = 5.3 mg/Kg), median IFX levels decreased from 13.0 to 3.9 µg/ml from mid to end of cycle time points, respectively. Midcycle IFX levels forecasted trough with Deming's slope = 0.90 and R2 =0.87. Observed end cycle and forecasted trough levels above 5µg/mL associated with CRP-based clinical remission (OR = 7.2 CI95%: 1.7-30.2; OR = 21.0 CI95%: 3.4-127.9, respectively) (p < 0.01). Median TNF-α levels increased from 4.6 to 8.0 pg/ml from mid to end of cycle time points, respectively (p < 0.01). CRP and TNF-α levels associated independently and additively to decreased IFX levels (p < 0.01). These data establish the value of our MIPD tool in forecasting trough IFX levels in patients with IBD. Serum TNF-α and CRP are reflective of inflammatory burden which impacts exposure.

P013 Resolution of Infliximab Associated Infusion Hypersensitivity After Switching to Biosimilar Infliximab-dyyb.

Background: Administration of infliximab for the treatment of inflammatory bowel disease has a well-recognized risk of infusion-related (IR) adverse events. The recent introduction of the biosimilar infliximab-dyyb (Inflectra®) has been shown to have similar efficacy with comparable safety profile when compared to infliximab; however, although the active ingredients are similar, the inactive ingredients are different. We present a case of a 26-year-old female with ulcerative colitis who had resolution of her IR hypersensitivity when switched from infliximab to infliximab-dyyb. A 26-year-old female with a past medical history of ulcerative pancolitis presented to our clinic with the chief complaint of rash associated with her infliximab infusions. She described pruritic raised lesions which would occur on her upper and lower extremities during her infusions. She denied any shortness of breath or wheezing, and her symptoms were well controlled with methylprednisolone 40mg IV prior to her infusions. Previously, she had been treated for her UC with oral mesalamine, azathioprine and intermittent prednisone and did not have any adverse reactions to these medications. She has no known allergies to other medications and her peripheral eosinophil count was 1.6%. She was initially started on infliximab 5mg/kg every 8 weeks since 2013 and had achieved clinical as well as endoscopic remission with her most recent colonoscopy graded as Mayo 0. On account of her infusion reaction, drug antibodies were checked but were not detected. Infliximab level was 8.8 μg/ml. Due to insurance she was required to switch to infliximab-dyyb. After switching to the biosimilar, she has not had any infusion related reactions and no longer requires premedication with methylprednisolone with her infusions. Immediate IR reactions have been reported in 5-23% of IBD patients receiving infliximab and those who develop antibodies towards infliximab have a 2-fold risk of acute IR events. Side effects have been reported to be the primary reason for discontinuation of infliximab, and studies have shown that discontinuation can lead to an increased risk of relapse of inflammatory bowel disease. Although infliximab and infliximab-dyyb have analogous active ingredients, the inactive ingredients differ. Specifically, infliximab-dyyb lacks monobasic sodium phosphate and dibasic sodium phosphate, which acts as an emulsifier which we believe contributed to her IR with originator biologic infliximab. It is important to recognize these differences as IR hypersensitivities may be attributed to inactive ingredients; especially when antibodies are negative. Our case report suggests that a switch to biosimilar infliximab in patients may provide added benefit especially in those that have reactions occurring from inactive ingredients in the originator biologic.

Levels of Biosimilar Infliximab during and after Induction Treatment in Crohn's Disease and Ulcerative Colitis-A Prospective Polish Population Study.

Background: Primary lack or secondary loss of response to therapy with infliximab is a significant problem. This study aimed to evaluate the response to treatment in patients with Crohn’s disease (CD) and ulcerative colitis (UC) achieving therapeutic and sub-therapeutic trough levels of biosimilar infliximab (CT-P13). Results: A total of 65 patients (32 with CD and 33 with UC) were recruited. The overall response rate in both CD and UC patients exceeded 80%. There were no significant differences in treatment response and CT-P13 levels for patients with CD or UC. We did not find significant differences in the percentage of patients achieving drug levels of 3 μg/mL at week 6, 10, or 12; a significant decrease was observed at week 14. Up to 55.5% of patients with CD and 64.3% of patients with UC with sub-therapeutic CT-P13 levels at week 14 primarily responded to treatment. Conclusions: Intermediate measurements of drug levels at weeks 10 and 12 did not capture any pronounced decrease in infliximab concentrations below therapeutic levels in either group, thus suggesting no clinical usefulness. A significant percentage of patients primarily responded to treatment despite sub-therapeutic drug levels after the induction phase.

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...

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data.

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.

The effect of infliximab dose escalation in inflammatory bowel disease patients with antibodies to infliximab.

Infliximab dose escalation (DE) can be used in inflammatory bowel disease patient; however, the long-term benefit remains unclear, especially in those with antibodies to infliximab (ATI). The aim was to assess the effect of DE in patients with ATI on drug level, clinical response and ATI status. All patients undergoing infliximab DE (a reduction in dose interval between infusions <8 weeks ± an increase in dose up to 10 mg/kg) at a referral centre between April 2016 and August 2019 were included. Ninety-two patients were DE: 51 were men, 50 had CD and 63 were receiving immunosuppression. A total of 87 people received DE for a median of 44 weeks (range 4-176). Five stopped infliximab after 1 dose of DE: 2 for loss of response and 3 for infusion reaction. In patients with ATI ≤10 vs. >10 AU/mL, DE significantly increased drug levels: median infliximab levels of 1.4 and 0.9 at baseline, respectively, to 3.2 and 3.5 at week 24. After DE, 21/35 ATI-positive patients had a fall in ATI ≤10 AU/mL. At week 24 following DE 62/92 patients were in clinical remission. Duration of clinical remission was shorter in those with ATI >10 AU/mL (median 24 weeks, range 0-88) than in those with transient/ATI ≤10 AU/mL (median 36 weeks, range 0-126, P = 0.06). A strategy of DE for selected patients receiving infliximab is associated with an increase in drug levels and reduced ATI positivity. This is associated with clinical remission in approximately 70% of patients at 6 months.

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

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

Association of Infliximab and Vedolizumab Trough Levels with Reported Rates of Adverse Events: A Cross-Sectional Study.

Infliximab and vedolizumab are effective treatments for inflammatory bowel disease (IBD), although associated with adverse events (AE). While low or non-existent drug levels and positive antidrug antibodies have been associated with therapeutic failure, there is no clear association between higher drug levels and AE. A cross-sectional study consisting of Crohn’s disease (CD) and ulcerative colitis (UC) patients receiving infliximab or vedolizumab at the Sheba Medical Center was performed. Patients completed a questionnaire regarding AEs related to biological therapy. Serum trough levels obtained on the same day were analyzed. Objective measures of outcomes were retrieved from medical records. Questionnaires were completed by infliximab (n = 169) and vedolizumab (n = 88)-treated therapy patients. Higher infliximab levels were only numerically associated with the occurrence of at least one AE (p = 0.08). When excluding fatigue and abdominal pain, higher infliximab levels were statistically associated with the occurrence of at least one AE (p = 0.03). Vedolizumab drug levels > 18 μg/mL were also linked with the occurrence of more AEs. No specific association was observed between the increased levels of either infliximab or vedolizumab and specific AEs (neurological symptoms, upper GI symptoms, infectious complications, and musculoskeletal symptoms). As significant AEs are very rare, additional multi-center studies are required.

Adalimumab and Infliximab Impair SARS-CoV-2 Antibody Responses: Results from a Therapeutic Drug Monitoring Study in 11 422 Biologic-Treated Patients.

Background and AimsInfliximab attenuates serological responses to SARS-CoV-2 infection. Whether this is a class effect, or if anti-tumour necrosis factor [anti-TNF] level influences serological responses, remains unknown.MethodsSeroprevalence and the magnitude of SARS-CoV-2 nucleocapsid antibody responses were measured in surplus serum from 11 422 (53.3% [6084] male; median age 36.8 years) patients with immune-mediated inflammatory diseases, stored at six therapeutic drug monitoring laboratories between January 29 and September 30, 2020. Data were linked to nationally held SARS-CoV-2 PCR results to July 11, 2021.ResultsRates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates were lower in infliximab- and adalimumab- than vedolizumab-treated patients (infliximab: 3.0% [178/5893], adalimumab: 3.0% [152/5074], vedolizumab: 6.7% [25/375], p = 0.003). The magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab-treated patients (median 4.30 cut-off index [COI] [1.94–9.96] vs 5.02 [2.18–18.70], p = 0.164), but higher in vedolizumab-treated patients (median 21.60 COI [4.39–68.10, p < 0.004). Compared to patients with detectable infliximab and adalimumab drug levels, patients with undetectable drug levels [<0.8 mg/L] were more likely to be seropositive for SARS-CoV-2 antibodies. One-third of patients who had PCR testing prior to antibody testing failed to seroconvert, all were treated with anti-TNF. Subsequent positive PCR-confirmed SARS-CoV-2 was seen in 7.9% [12/152] of patients after a median time of 183.5 days [129.8–235.3], without differences between drugs.ConclusionAnti-TNF treatment is associated with lower SARS-CoV-2 nucleocapsid seroprevalence and antibody reactivity when compared to vedolizumab-treated patients. Higher seropositivity rates in patients with undetectable anti-TNF levels support a causal relationship, although confounding factors, such as combination therapy with a immunomodulator, may have influenced the results.

An observational study of switching infliximab biosimilar: no adverse impact on inflammatory bowel disease control or drug levels with first or second switch.

Biologics account for a significant cost in inflammatory bowel disease (IBD) management; however, switching from infliximab originator to its biosimilars has enabled cost saving without compromising disease control. The effects on IBD activity and infliximab trough levels of a second switch to another biosimilar are, however, uncertain. To assess the effects on disease activity and infliximab trough levels associated with switching from infliximab biosimilar CT-P13 to another biosimilar SB2 and compare outcomes in those switching for the first and second time. IBD patients on CT-P13, including some previously switched from originator, were prospectively followed during a switch to SB2. C-reactive protein (CRP), trough infliximab level and clinical disease activity indices were collected at baseline, Infusion 3 or 4 ('early' after switch), and 1year. One hundred eighty-six patients (n=99 second switch) on stable infliximab dosing underwent switching. Compared with baseline, there was no significant change in CRP, clinical disease activity scores or median trough infliximab level at the early time point among first-switch (baseline vs early: 5.7 vs 6.6µg/mL, P=0.05) and second-switch (4.3 vs 4.9µg/mL, P=0.07) patients nor at 1year (median infliximab trough levels, baseline vs 1year, in first-switch [5.7 vs 5.7µg/mL, P=0.37] and second-switch [4.3 vs 4.7µg/mL, P=0.06] patients). The proportion of patients in clinical remission did not significantly change at the early (92% vs 91% at baseline, P=0.75) or 1year (95% vs 91% at baseline, P=0.16) time points. There was no significant difference in time to loss of response between patients switching for the first or second time (P=0.69). Switching from one infliximab biosimilar to another had no adverse impact on infliximab trough levels, and clinical and biochemical disease activity, regardless of whether switching for the first or second time.

Management Decisions in Crohn's Disease Are Changed by Knowledge of Proactive and Reactive Testing of Antitumor Necrosis Factor Drug Levels.

There is controversy about the proactive clinical application of therapeutic drug monitoring (TDM) of biologic drugs in Crohn's disease (CD). One way to practically assess this is to examine how TDM influences management decisions. We examined how knowledge of proactive and reactive antitumor necrosis factor (anti-TNF) drug levels changes management in a variety of clinical scenarios. In this retrospective cohort study, all adults with CD having trough level infliximab or adalimumab measurements at Liverpool Hospital between June 2013 and July 2016 were included. Demographics, indications for testing, anti-TNF drug levels, and treatment details were collected along with subsequent management decisions. The decision made by the treating clinician after receiving the drug level was compared to a consensus decision from a panel of 3 gastroenterologists based on the clinical, laboratory, imaging, and/or endoscopic results without the drug level. When these 2 decisions were discrepant, the anti-TNF drug level was deemed to have changed management. One hundred and eighty-seven trough levels of infliximab or adalimumab from 108 patients were analyzed. Overall, assessment of anti-TNF levels affected management in 46.9% of the instances. Knowledge of the drug level was also more likely to result in management change when the test was performed for reactive TDM compared to proactive TDM (63% vs 36%, P = .001). The addition of TDM of anti-TNF agents to routine investigations alters management decisions in adult CD patients on anti-TNF therapy in both proactive and reactive settings.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

Pharmacogenetic variants of infliximab response in young patients with inflammatory bowel disease.

Infliximab is commonly used in inflammatory bowel disease (IBD), however, differences in clinical response among patients are common. Several studies have considered the possibility that these differences are caused by genetic variability even if no unique marker has been yet identified in pediatric patients. We evaluated the impact of two candidate single‐nucleotide polymorphisms (SNPs) rs396991 in FCGR3A and rs1800629 in TNFα genes on infliximab response in an Italian cohort of 76 pediatric patients with IBD. Results showed that patients with the variant FCGR3A allele had a reduced clinical response at the end of induction (p value = 0.004), at 22 weeks (p value = 0.001), and at 52 weeks of treatment (p value = 0.01). A significant association between the FCGR3A variant and median infliximab levels measured during maintenance therapy was also observed: patients with wild type genotype had higher infliximab levels compared to patient with variant allele. Furthermore, patients with the variant allele had a higher probability to produce antidrug antibodies (ADAs). No association was found among the TNFα SNP, clinical response, and infliximab levels. This study addressed for the first time in pediatric patients with IBD, the association of FCGR3A SNP, infliximab response, and ADA production.

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

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