P408 Long-term impact of the decrease of infliximab trough levels on the disease course in Inflammatory Bowel Disease patients under maintenance treatment with infliximab

Abstract Background The measurement of infliximab trough levels (IFX-TLs) has been suggested as an important biomarker for the optimisation of treatment in patients with inflammatory bowel disease (IBD). We have previously reported that IFX-TLs of patients under maintenance treatment with IFX show decreasing patterns associated with an increasing pattern of CRP levels1. We aimed to study the clinical impact of this observation by recording the treatment changes that became necessary during a three year follow-up. Methods Consecutive asymptomatic patients on maintenance treatment with IFX were included. Two different measurements of IFX-TLs were made (ELISA, Eagle BioSciences) with a ten-month interval using serum samples drained before IFX infusion. After the second measurement patients were followed up for three years and all treatment modifications including IFX intensification, change of biologic agent or IBD-related surgical intervention were assessed. Results Among a total of 86 IBD patients under maintenance treatment with IFX, 64 [49 CD, 15 UC, 42 men, mean age 44.2 ± 15.2 years, 41 in combination therapy with immunomodulator, 6 in intensified dose], with 2 available measurements of IFX-TLs (A and B) were included in the study. Median levels of IF-TLs were 5.07 (IQR 1.60–12.73) μg/ml in measurement A and 4.68 (1.19–7.83) μg/ml in measurement B (p < 0.0001). Treatment was intensified in 8 patients after measurement A. Patients with stable IFX dose showed a significant reduction in median IFX-TLs from 5.65 to 3.8 μg/ml (p < 0.0001). Moreover, CRP levels were significantly increased in measurement B compared with measurement A [0.33 (03–4.4) mg/dl vs. 0.31 (0.3–3.8) mg/dl, p = 0.02]. During a 3 year follow-up, 22 (34%) patients needed treatment optimisation (6 IFX intensification, 7 change of agent, 6 surgery, 3 change of agent plus surgery). In three patients IFX was stopped for safety reasons. Fifty-eight hospitalisations in 19 patients were also recorded. The decrease of IFX-TLs between the two measurements was significantly more in patients with treatment optimisation compared with patients without treatment optimisation (p = 0.03). Conclusion IBD patients who are on maintenance treatment with infliximab showing decreasing patterns of IFX-TLs often need treatment optimisation during the follow-up due to clinical or endoscopic activity. These results probably suggest the importance of the proactive therapeutic drug monitoring and early treatment optimisation in these patients References

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Infliximab in young paediatric IBD patients: it is all about the dosing

European Journal of Pediatrics ◽

10.1007/s00431-020-03750-0 ◽

2020 ◽

Vol 179 (12) ◽

pp. 1935-1944 ◽

Cited By ~ 1

Author(s):

Maria M. E. Jongsma ◽

◽

Dwight A. Winter ◽

Hien Q. Huynh ◽

Lorenzo Norsa ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Treatment Regimen ◽

Bowel Disease ◽

Maintenance Treatment ◽

Young Patients ◽

Intensive Treatment ◽

Therapeutic Drug ◽

Infliximab Treatment ◽

Inflammatory Bowel ◽

Trough Levels

AbstractInfliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10–18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9–8.9) in YP compared with 14.3 years (IQR 12.8–15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0–12.9) vs. OP; 5.5 mg/kg (IQR 5.0–9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI − 1.2 to − 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers.•In 4.5–30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment.•Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment.•The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).

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Sa1890 DECREASING PATTERNS OF INFLIXIMAB TROUGH LEVELS IN ASYMPTOMATIC INFLAMMATORY BOWEL DISEASE PATIENTS UNDER MAINTENANCE TREATMENT WITH INFLIXIMAB; DOES IT MATTER?

Gastroenterology ◽

10.1016/s0016-5085(20)31849-7 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-467

Author(s):

Eleni Orfanoudaki ◽

Maria Gazouli ◽

Kalliopi Foteinogiannopoulou ◽

Eirini Theodoraki ◽

Evangelia Legaki ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Maintenance Treatment ◽

Inflammatory Bowel ◽

Trough Levels

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P277 Frequency and effectiveness of empirical anti-TNF dose intensification in Inflammatory Bowel Disease: systematic review with meta-analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.402 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S309-S309

Author(s):

L Guberna Blanco ◽

O P Nyssen ◽

M Chaparro ◽

J P Gisbert

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Medical Condition ◽

Cochrane Library ◽

Therapeutic Drug ◽

Dose Intensification ◽

Loss Of Response ◽

Subgroup Analyses ◽

Inflammatory Bowel

Abstract Background Loss of response to anti-TNF (tumor necrosis factor) therapies in inflammatory bowel disease occurs in a high proportion of patients. However, the precise incidence of dose intensification (DI) and its effectiveness remains unclear. Our aims were: 1) To evaluate the need of DI of anti-TNF therapy either by increasing the dose or decreasing doses’ interval; 2) To evaluate possible variables influencing its requirement; 3) To assess the effectiveness of empirical DI. Methods Bibliographical searches were performed in Pubmed, Embase, the Cochrane Library and CINAHL. Selection: prospective and retrospective studies assessing loss of response to anti-TNF therapy, considered as the need of DI, in Crohn’s disease (CD) and ulcerative colitis (UC) patients treated for at least 12 weeks with an anti-TNF drug [infliximab (IFX), adalimumab (ADA), certolizumab or golimumab]. Exclusion criteria: studies using anti-TNF as prophylaxis for postoperative recurrence in CD or those where DI was based on therapeutic drug monitoring. Data synthesis: Effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (UC vs. CD), anti-TNF drug and follow-up. Subgroup analyses were performed to explore heterogeneity. Results In total, 174 studies (32,031 patients) were included. The overall rate of DI requirement after 12 months follow-up was 27% (95%CI 23-31, I2=96%, 51 studies) in naïve patients and 38% (95%CI 31-46, I2=87%, 18 studies) in non-naïve patients. The rate of DI requirement was higher in patients with prior anti-TNF exposure (c²=6.5, P=0.01) and in UC patients (c²=4.7, P=0.03). The rate of DI requirement in naïve patients after 36 months follow-up was 35% (95%CI 27-43%; I2=98%; 22 studies). The overall short-term response and remission rates to empirical DI in naïve patients were 66% (95%CI 61-71%; I2=81%; 35 studies) and 48% (95%CI 35-62%; I2=97%; 27 studies), respectively. Subgroup analyses are presented in the tables. Conclusion Loss of response to anti-TNF agents ―and consequent DI― occur frequently in IBD (approximately in 1/4 at one year and in 1/3 at 3 years). DI requirement is higher in UC patients and in those with prior anti-TNF exposure. Empirical DI is a relatively effective therapeutic option.

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P481 Effectiveness and safety profile of biological therapy in inflammatory bowel disease: real life data from an active pharmacovigilance project

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.604 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S470-S471

Author(s):

A Viola ◽

M A Barbieri ◽

V Pisana ◽

P M Cutroneo ◽

W Fries ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Safety Profile ◽

Index Date ◽

Descriptive Analysis ◽

Real Life ◽

Biologic Agent ◽

Skin Reactions ◽

Inflammatory Bowel

Abstract Background Biological therapies are now the mainstay for the treatment of Inﬂammatory bowel disease (IBD). Post-marketing activities become crucial for monitoring the long-term safety. Aim of this project was to evaluate the eﬀectiveness and the safety proﬁle of biologics for the treatment of IBD patients during a prospective pharmacovigilance study. Methods From January 2017 to December 2020, all patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC) treated with at least one biologic agent at the start of the study or commenced a biologic during the study period were enrolled. Demographic, clinical, and disease-related data were collected. A descriptive analysis of patients’ characteristics at the index date was performed. Moreover, an analysis of all adverse events (AEs) and all primary/secondary failures expressed as number of AEs or failures/10 treatment years was carried out taking into account the total years of treatment for each biologic including all patients treated with a biologic at least once during the follow-up period. Results A total of 654 patients were enrolled, 58.4% with CD and 41.6% with UC. Mean age (±SD) was 44 ± 17 years and 59.0% were males. At the index date, the following treatments were used: 40.8% adalimumab (ADA), 33.3% inﬂiximab (IFX), 21.3% vedolizumab (VED), 2.4% ustekinumab (UST), and 2.1% golimumab (GOL). Patients naïve for biologic therapy were 79.1%. The total years of treatment were 887 yrs for ADA, 663 yrs for IFX, 309 yrs for VED, 89 yrs for UST, and 51 yrs for GOL. Data for AEs and failures were the following: IFX – 1.1 AEs and 0.8 failures, ADA – 0.8 and 0.9, VED – 1.1 and 1.8, GOL – 1.2 and 3.4, and UST - 1.4 and 0.9, respectively (Tab.1). During follow-up, 196 AEs were reported. Infections mainly occurred in patients treated with GOL and ADA (8.7% and 7.6%, respectively), skin reactions in patients treated with ADA (7.6%), while infusion related reactions with IFX (12.6%). A higher frequency of malignancies was observed in patients on treatment with VED (3.4%). Conclusion There were no major differences for AEs between the different treatments, but a higher frequency of failures with GOL and VED, both rarely used as first line therapies. Nevertheless, the acquisition of data from clinical practice should be endorsed to better define the safety and efficacy profile of new biologic agents in IBD.

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Clinical Relevance of Anti-TNF Antibody Trough Levels and Anti-Drug Antibodies in Treating Inflammatory Bowel Disease Patients

Inflammatory Intestinal Diseases ◽

10.1159/000511296 ◽

2020 ◽

pp. 1-10

Author(s):

Ilana Reinhold ◽

Sena Blümel ◽

Jens Schreiner ◽

Onur Boyman ◽

Jan Bögeholz ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Disease Activity ◽

Bowel Disease ◽

Clinical Disease ◽

Therapeutic Drug ◽

Real World Data ◽

Significant Treatment ◽

Infusion Reactions ◽

Inflammatory Bowel ◽

Trough Levels

Background and Aims: The majority of patients treated with anti-tumor necrosis factor (TNF) therapy develop anti-drug antibodies (ADAs), which might result in loss of treatment efficacy. Strict guidelines on measuring trough levels (TLs) and ADA in clinical routine do not exist. To provide real-world data, we took advantage of our tertiary inflammatory bowel disease (IBD) center patient cohort and determined indicators for therapeutic drug monitoring (TDM) and actual consequences in patient care. Methods: We retrospectively collected clinical data of 104 IBD patients treated with infliximab or adalimumab in our IBD clinic. Patients with TL and ADA measurements between June 2015 and February 2018 were included. Results: The main reason for determining TL was increased clinical disease. Subtherapeutic TLs were found in 33 patients, therapeutic TLs in 33 patients, and supratherapeutic TLs in 38 patients. Adjustments in anti-TNF therapy occurred more frequently (p = 0.01) in patients with subtherapeutic TL (24 of 33 patients; 73%) as compared to patients with therapeutic and supratherapeutic TLs (26 of 71 patients; 37%). No correlation could be found between TL and disease activity (p = 0.16). Presence of ADA was found in 16 patients, correlated with the development of infusion reactions (OR: 10.6, RR: 5.4, CI: 2.9–38.6), and was associated with subtherapeutic TL in 15 patients (93.8%). Treatment adaptations were based on TL and/or ADA presence in 36 of 63 patients. Conclusions: TDM showed significant treatment adaptations in patients with subtherapeutic TL. Conversely, in patients with therapeutic and supratherapeutic TLs, reasons for adaptations were based on considerations other than TL, such as clinical disease activity. Further studies should focus on decision-making in patients presenting with supratherapeutic TL in remission.

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

BMJ Open Gastroenterology ◽

10.1136/bmjgast-2021-000788 ◽

2021 ◽

Vol 8 (1) ◽

pp. e000788

Author(s):

Shaina Sekhri ◽

Bharat Rao ◽

Akanksha Mohananey ◽

Poonam Beniwal-Patel ◽

Alexandra Bruss ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Therapeutic Drug ◽

Extraintestinal Manifestation ◽

Cross Sectional ◽

Patient Reported ◽

Serum Trough ◽

Inflammatory Bowel ◽

Trough Levels ◽

Serum Trough Levels

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 rates of disease remission, the association between trough levels of infliximab and arthralgia activity characterised as an extraintestinal manifestation has yet to be defined.ObjectiveWe aimed to assess the association between serum trough levels of infliximab and peripheral arthralgia activity in patients with inflammatory bowel disease.DesignIn this cross-sectional study, we identified patients with inflammatory bowel disease on infliximab therapy with known history of arthralgias attributed to an extraintestinal manifestation. Collected variables included disease phenotype, medications (such as thiopurines or methotrexate), Harvey Bradshaw Index, partial Mayo score, C reactive protein, trough levels of infliximab and anti-infliximab antibodies. The primary outcome was active patient-reported arthralgia.ResultsOut of 267 patients included, 65 (24.4%) had active arthralgias at the time the trough level of infliximab was measured. No significant differences in trough levels were seen between those patients with and without arthralgias. Patients on combination therapy with methotrexate or thiopurines or those with detectable anti-infliximab antibodies were not more likely to have inactive arthralgias (OR 0.99, 95% CI 0.57 to 1.74, p=0.99 and OR 1.94, 95% CI 0.9 to 4.1, p=0.09, respectively).ConclusionsThis study suggests that although therapeutic drug monitoring of infliximab can have a role in the management of Crohn’s disease and ulcerative colitis, it does not seem to be useful in managing arthralgias associated with inflammatory bowel disease.

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P329 Comparative Assessment of Adalimumab Trough Levels between Point-of-Care Testing and current Standard of Care (enzyme linked immunosorbent assay) in patients with Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.453 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S353-S353

Author(s):

I Marsilio ◽

D Maniero ◽

G Lorenzon ◽

A Rigo ◽

R Cardin ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Whole Blood ◽

Point Of Care ◽

Enzyme Linked Immunosorbent Assay ◽

Therapeutic Drug ◽

Point Of Care Testing ◽

Deming Regression ◽

Inflammatory Bowel ◽

Trough Levels

Abstract Background Adalimumab (ADL) is a therapeutic monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and has been shown to effectively induce and maintain disease remission in patients with Inflammatory Bowel Disease (IBD). However, some patients fail to respond to this treatment, experiencing primary failure (no response to induction therapy), while others initially respond but lose efficacy over time (secondary failure). Therapeutic Drug Monitoring (TDM), in clinical practice, may lead to maintain therapeutic drug concentration thereby optimizing individual dosage regimen and improving treatment response. Recently, a point of care testing (POCT) has been developed to rapidly measure trough levels in patients taking ADL. Comparative data with current gold standard are lacking. Aim To determine the degree of analytical correlation between a recently developed POCT (ProciseDx) ADL assay which analyze capillary whole blood and the comparative enzyme linked immunosorbent assays (ELISA) from serum samples. Methods From December 2020 to February 2021, consecutive patients (aged ≥ 18 years) taking ADA (Humira, Amgevita, Imraldi) were recruited at Gastroenterology Unit, Padua University Hospital, during outpatient visits. In each patient, ADL levels from capillary whole blood collected by finger stick were performed using the ProciseDx ADL assay with reportable range between 1.3 µg/mL - 51.5 µg/mL; at the same time, a serum sample from venous blood was collected to carry out Grifols’ Promonitor ELISA test (range ≤ 0.024 – 12 µg/mL). A Deming regression test was used to identify the correlation between the two methods. Results Sixty patients were enrolled (67% males with mean age of 3±14), with 80% of them having CD, 17% UC and 3% an undetermined-Inflammatory Bowel Disease (IBD-U). The assessment with ProciseDx POCT was feasible and required a turnaround time of 3±0.2 minutes while serum ELISA analysis required the collection of at least 40 samples (around three weeks at our centre) and 3 hours to be performed. Thirty patients (63% males with mean age of 41±14) had therapeutic levels as assessed by ProciseDx ADL assay lower than 1.3 or greater than 12 µg/mL, in accordance with ELISA assessment. Among the remaining 30 patients (70% males with mean age of 43±15), the correlation between the two tests was high (r of 0.858 (95% CI 0.720 – 0.930)). Conclusion The ProciseDx POCT has similar accuracy but was more rapid and easy to be performed in providing the results of TDM in outpatients taking ADL. This could lead to a more rapid and effective optimization of the biological drug, thus avoiding treatment failure.

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P573 Frequency and effectiveness of empirical anti-TNF dose intensification in inflammatory bowel disease: an on-going systematic review with meta-analysis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.701 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S482-S483

Author(s):

L Guberna Blanco ◽

O P Nyssen ◽

M Chaparro ◽

J P Gisbert

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Therapeutic Option ◽

Random Effect ◽

Random Effect Model ◽

Therapeutic Drug ◽

Dose Intensification ◽

Loss Of Response ◽

Inflammatory Bowel

Abstract Background Loss of response to anti-TNF therapies in inflammatory bowel disease occurs in a high proportion of patients. However, the precise incidence of dose intensification (DI) and its effectiveness remain unclear. Our aims were: (1) To evaluate the need of DI of anti-TNF therapy either by increasing the dose or decreasing doses’ interval; (2) To evaluate possible variables influencing its requirement; (3) To assess the effectiveness of empirical DI. Methods Bibliographical searches were performed until January 2019. Selection: prospective and retrospective studies assessing the loss of response to anti-TNF therapy, considered as the need of DI, in Crohn’s disease (CD) and ulcerative colitis (UC) patients treated for at least 12 weeks with an anti-TNF drug. Exclusion criteria: Studies using anti-TNF as prophylaxis for postoperative recurrence in CD or those where DI was based on therapeutic drug monitoring. Data were analyzed by means of the inverse variance method using a random effect model and stratifying by medical baseline condition (UC vs. CD), anti-TNF drug and follow-up. Effectiveness was assessed by intention-to-treat analysis. Results Up to now, 107 studies (11,377 patients) were included. The overall rate of DI requirement for naïve patients after 12 and 36 months of follow-up was 35% (95% CI=26–45%, I2=95%, 15 studies) and 48% (41–55%, I2= 77%, 9 studies); respectively. Frequencies of DI requirement stratified by subgroup analysis are presented in the table (all patients being naïve except CD patients treated with adalimumab (ADA), including naïve and no naïve). The overall short-term response and remission rates to empirical DI were 67% (95% CI: 63–72%; I2=73%; 31 studies) and 45% (95% CI: 35–55%; I2=9%; 23 studies), respectively; subgroup analyses are summarised in the table. Conclusion Loss of response to anti-TNF agents and consequent DI occurs frequently in both UC and CD, with an overall rate of DI requirement of 35% at one year and 48% at 3 years. Empirical DI is a relatively effective therapeutic option. Further data extraction and analysis is necessary to confirm these findings.

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