Prediction of treatment failure during infliximab induction therapy in inflammatory bowel disease patients based on pharmacokinetic and pharmacodynamic modeling

Abstract Background Drug use in the treatment of inflammatory bowel disease (IBD) might negatively impact lipid levels. In this study, we assessed drug-induced changes in the lipid profile after IBD induction therapy. Methods In this single center, prospective study IBD patients aged ≥17 years who started systemic drug therapy (corticosteroids, thiopurines, methotrexate, infliximab, adalimumab, vedolizumab, ustekinumab and tofacitinib) for IBD were included. Exclusion criteria were pregnancy, history of liver transplantation and use of lipid lowering drugs. Data on cardiovascular risk profile, disease activity (HBI, SCCAI, CRP, FCP) and concomitant medication use were collected. To calculate mean lipid changes after induction therapy, nonfasting lipid levels (total cholesterol (TC), HDL-c, LDL-c, triglycerides (TG)) were measured before and 8–10 weeks after start of therapy. Pearson correlation test was performed to assess the association between lipid changes and CRP. Results A total of 183 patients (87 males (48%), median age 36 years (IQR 28–48), 128 Crohn’s disease (70%), 46 CU (3%), 9 IBD-U (7%)) were included. (Table 1) Fourty-nine patients were on concomitant steroids at baseline (31%). Relative increases in TC, HDL-c and LDL-c were significant after treatment with corticosteroids and tofacitinib (+9%, +17%, +8% and +19%, +29%, +24%, respectively) and decrease in TG after treatment with corticosteroids, thiopurines, infliximab, adalimumab, ustekinumab and tofacitinib (-9%, -14%, -10%, -8%, -11%, -8%, respectively). (Table 2, Figure 1) A significant inverse relationship was found between CRP and TC (R -.171), HDL-c (R -.202), LDL-c (R -.153) but not with TG. Conclusion Serum lipid levels increased most after start of corticosteroids and tofacitinib as compared to other drug therapies. Whether these changes are explained by the control of inflammation or by the mechanism of action of these agents remains undetermined.

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PWE-065 Antibodies-to-infliximab post induction can help identify inflammatory bowel disease patients at risk of treatment failure

10.1136/gutjnl-2018-bsgabstracts.197 ◽

2018 ◽

Author(s):

Gloria Shwe Zin Tun ◽

Sister Laura Marshall ◽

Sister Kerry Robinson ◽

Sister Alison Wright ◽

Dr Alenka Brookes ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

At Risk ◽

Treatment Failure ◽

Bowel Disease ◽

Post Induction ◽

Patients At Risk ◽

Inflammatory Bowel ◽

Risk Of Treatment

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

Archives of Disease in Childhood ◽

10.1136/archdischild-2020-nppg.68 ◽

2020 ◽

Vol 105 (9) ◽

pp. e37.2-e38

Author(s):

Fatima Yaqub ◽

Joanne Crook ◽

John Fell

Keyword(s):

Inflammatory Bowel Disease ◽

Treatment Failure ◽

Disease Activity ◽

Patient Outcomes ◽

Bowel Disease ◽

Adverse Reactions ◽

Double Blind ◽

Time Points ◽

Parallel Group ◽

Inflammatory Bowel

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 <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.

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Outcomes After Primary Infliximab Treatment Failure in Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1097/mib.0000000000001117 ◽

2017 ◽

Vol 23 (7) ◽

pp. 1210-1217 ◽

Cited By ~ 10

Author(s):

Sine Buhl ◽

Casper Steenholdt ◽

Maria Rasmussen ◽

Märta K. Borghede ◽

Jørn Brynskov ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Treatment Failure ◽

Bowel Disease ◽

Infliximab Treatment ◽

Inflammatory Bowel

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Combined Biologic and Immunomodulatory Therapy is Superior to Monotherapy for Decreasing the Risk of Inflammatory Bowel Disease-Related Complications

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa050 ◽

2020 ◽

Vol 14 (10) ◽

pp. 1354-1363 ◽

Cited By ~ 2

Author(s):

Laura E Targownik ◽

Eric I Benchimol ◽

Charles N Bernstein ◽

Harminder Singh ◽

Aruni Tennakoon ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Combination Therapy ◽

Treatment Failure ◽

Real World ◽

Bowel Disease ◽

Proportional Hazards ◽

Meta Analysis ◽

Cox Proportional Hazards ◽

Inflammatory Bowel ◽

The Impact

Abstract Background and Aims The combination of infliximab and azathioprine is more efficacious than either therapy alone for Crohn’s disease [CD] and ulcerative colitis [UC]. However, it is uncertain whether these benefits extend to real-world clinical practice and to other combinations of biologics and immunomodulators. Methods We collected health administrative data from four Canadian provinces representing 78 413 patients with inflammatory bowel disease [IBD] of whom 11 244 were prescribed anti-tumour necrosis factor [anti-TNF] agents. The outcome of interest was the first occurrence of treatment failure: an unplanned IBD-related hospitalization, IBD-related resective surgery, new/recurrent corticosteroid use or anti-TNF switch. Multivariable Cox proportional hazards modelling was used to assess the association between the outcome of interest and receiving combination therapy vs anti-TNF monotherapy. Multivariable regression models were used to assess the impact of choice of immunomodulator or biologic on reaching the composite outcome, and random effects generic inverse variance meta-analysis of deterministically linked data was used to pool the results from the four provinces to obtain aggregate estimates of effect. Results In comparison with anti-TNF monotherapy, combination therapy was associated with a significant decrease in treatment ineffectiveness for both CD and UC (CD: adjusted hazard ratio [aHR] 0.77, 95% confidence interval [CI] 0.66–0.90; UC: aHR 0.72, 95% CI 0.62–0.84). Combination therapy was equally effective for adalimumab and infliximab in CD. In UC azathioprine was superior to methotrexate as the immunomodulatory agent (aHR = 1.52 [95% CI 1.02–2.28]) but not CD (aHR = 1.22 [95% CI 0.96–1.54]). Conclusion In an analysis of a database of real-world patients with IBD, combination therapy decreased the likelihood of treatment failure in both CD and UC.

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P478 Immunogenicity is not the driving force of treatment failure in vedolizumab-treated inflammatory bowel disease patients

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy222.602 ◽

2019 ◽

Vol 13 (Supplement_1) ◽

pp. S351-S351

Author(s):

N Van den Berghe ◽

B Verstockt ◽

S Tops ◽

M Ferrante ◽

S Vermeire ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Treatment Failure ◽

Bowel Disease ◽

Driving Force ◽

Inflammatory Bowel

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Proactive Infliximab Monitoring Following Reactive Testing is Associated With Better Clinical Outcomes Than Reactive Testing Alone in Patients With Inflammatory Bowel Disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjy039 ◽

2018 ◽

Vol 12 (7) ◽

pp. 804-810 ◽

Cited By ~ 43

Author(s):

Konstantinos Papamichael ◽

Ravy K Vajravelu ◽

Byron P Vaughn ◽

Mark T Osterman ◽

Adam S Cheifetz

Keyword(s):

Inflammatory Bowel Disease ◽

Treatment Failure ◽

Bowel Disease ◽

Cox Regression ◽

Drug Discontinuation ◽

Cox Regression Analysis ◽

Loss Of Response ◽

Group A ◽

Inflammatory Bowel ◽

Group B

Abstract Background and Aims Reactive testing has emerged as the new standard of care for managing loss of response to infliximab in inflammatory bowel disease [IBD]. Recent data suggest that proactive infliximab monitoring is associated with better therapeutic outcomes in IBD. Nevertheless, there are no data regarding the clinical utility of proactive infliximab monitoring after first reactive testing. We aimed to evaluate long-term outcomes of proactive infliximab monitoring following reactive testing compared with reactive testing alone in patients with IBD. Methods This was a retrospective multicenter cohort study of consecutive IBD patients on infliximab maintenance therapy receiving a first reactive testing between September 2006 and January 2015. Patients were divided into two groups; Group A [proactive infliximab monitoring after reactive testing] and Group B [reactive testing alone]. Patients were followed through December 2015. Time-to-event analysis for treatment failure and IBD-related surgery and hospitalization was performed. Treatment failure was defined as drug discontinuation due to either loss of response or serious adverse event. Results The study population consisted of 102 [n = 70, 69% with CD] patients [Group A, n = 33 and Group B, n = 69] who were followed for (median, interquartile range [IQR]) 2.7 [1.4–3.8] years. Multiple Cox regression analysis identified proactive following reactive TDM as independently associated with less treatment failure (hazard ratio [HR] 0.15; 95% confidence interval [CI] 0.05–0.51; p = 0.002) and fewer IBD-related hospitalizations [HR: 0.18; 95% CI 0.05–0.99; p = 0.007]. Conclusions This study showed that proactive infliximab monitoring following reactive testing was associated with greater drug persistence and fewer IBD-related hospitalizations than reactive testing alone.

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