Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease

Mazor, Yoav; Almog, Ronit; Kopylov, Uri; Hur, Dana Ben; Blatt, Alexandra; Dahan, Aviva; Waterman, Matti; Ben‐Horin, Shomron; Chowers, Yehuda

doi:10.1111/apt.12869

Cited by 169 publications

(107 citation statements)

References 30 publications

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“…FC is a highly accurate predictor of endoscopic activity in patients with IBD, and low FC (FC < 100 µg/g) was found to have a high correlation with clinical, endoscopic, and histological remission [17,19]. Our group reported a recent study in which serum adalimumab (ADL) levels were associated with the normalization of CRP and FC, with the drug levels being higher for patients with normal FC levels [18].…”

Section: Discussionmentioning

confidence: 99%

“…Some studies show that higher levels of anti-TNF drugs are detected in patients with lower FC and CRP [18,19]. In this study, we aimed to investigate the association of laboratory factors (including CRP and FC) and serum concentrations of IFX during induction treatment with primary nonresponse in patients with active CD to predict to what extent pharmacokinetic and inflammatory parameters can influence the clinical outcome of IFX induction therapy.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Beltrán

Iborra

Saéz-González

et al. 2018

Dig Dis

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Introduction: The association between infliximab (IFX) and fecal calprotectin (FC) levels on one hand, and the clinical and endoscopic response of patients with inflammatory bowel disease on the other, is well established. Objective and Methods: To investigate the association between inflammatory biochemical parameters and serum concentrations of IFX during induction treatment with a primary nonresponse in a prospective cohort of Crohn’s disease (CD) patients. Results: Of the 35 patients included, 8 (22.8%) had primary nonresponse at the end of induction. Induction IFX levels were lower among primary nonresponders at weeks 6 and 14 (week 6: median IFX level 7.3 vs. 11.2 μg/mL, respectively, p = 0.090; week 14: median IFX level 1.5 vs. 4.7 μg/mL, respectively, p = 0.020). FC levels were higher in patients with primary nonresponse versus primary response at weeks 0, 6, and 14 (week 0: median FC level 1,830 vs. 410 μg/g, respectively, p = 0.030; week 6: median FC level 1,150 vs. 230 μg/g, respectively, p = 0.074; week 14: median FC level 1,210 vs. 208 μg/g, respectively, p = 0.060). For the multivariate analysis, the median IFX level at week 14 and median FC level at week 0 were independently associated with primary nonresponse. A significant inverse correlation was determined between FC level at week 0 and IFX level at week 14 (Spearman’s rho correlation, 0.440; p < 0.05). Conclusions: IFX levels (at week 14) and baseline FC levels could predict primary nonresponse after induction IFX therapy in patients with CD. A high baseline inflammatory load might modify the pharmacokinetic processes of anti-tumor necrosis factor drugs. Drug level monitoring and measurement of baseline inflammatory parameters could improve the efficacy of IFX in the induction therapy of patients with active CD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Beltrán

Iborra

Saéz-González

et al. 2018

Dig Dis

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“…In inflammatory bowel disease a cut-off trough M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT level between 3 and 5.8 µg/ml for adalimumab may have the optimal sensitivity, specificity and positive likelihood ratio for prediction of clinical response. 48,88 In general, high serum concentrations of anti-TNF agents, measured just before the administration of the next dose, are associated with clinical improvement, whereas low levels are associated with poor responses. 7,26 All exogenous proteins are capable to induce immunogenicity.…”

Section: Serum Drug Levels and Anti-drug Antibodiesmentioning

confidence: 99%

Anti–tumor necrosis factor-α therapy in uveitis

Cordero‐Coma

Sobrin

2015

Survey of Ophthalmology

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“…The random-effects pooled estimate for the prevalence of LOR was 0.435 (95% CI 0.330 to 0.540); this is likely to be an overestimate owing to double-counting of patients from the Mazor et al 108 study. Given the meta-analysis values and the sensitivity, specificity and prevalence values, the point estimate for the probability of positive and negative test results is 0.253 (range 0.212-0.293) and 0.747 (range 0.707-0.788), respectively.…”

Section: Specificity (95% Ci)mentioning

confidence: 89%

“…108 reported results by test rather than by patient (there were 118 tests in 71 patients; authors stated that using the first test result for each patient did not alter the results). Sensitivity and specificity pairs are summarised in Figure 42. A single study of patients with LOR was identified 84 (as shown in Figure 43).…”

Section: Specificity (95% Ci)mentioning

confidence: 99%

Clinical effectiveness and cost-effectiveness of use of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [LISA-TRACKER® enzyme-linked immunosorbent assay (ELISA) kits, TNF-α-Blocker ELISA kits and Promonitor® ELISA kits] versus standard care in patients with Crohn’s disease: systematic reviews and economic modelling

Freeman

Connock

Auguste

et al. 2016

Health Technol Assess

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Background and objectivesSystematic reviews and economic modelling of clinical effectiveness and cost-effectiveness of therapeutic monitoring of tumour necrosis factor alpha (TNF-α) inhibitors [using LISA-TRACKER®enzyme-linked immunosorbent assay (ELISA) kits (Theradiag, Marne La Vallee, France, or Alpha Laboratories, Heriot, UK), TNF-α-Blocker ELISA kits (Immundiagnostik AG, Bensheim, Germany) and Promonitor®ELISA kits (Proteomika, Progenika Biopharma, Bizkaia, Spain)] versus standard care for Crohn’s disease (CD).MethodsMultiple electronic databases were searched from inception to December 2014 in order to identify primary studies and meta-analyses.PopulationPatients with moderate to severe active CD treated with infliximab (IFX) (Remicade®, Merck Sharp & Dohme Ltd, Kenilworth, NJ, USA) or adalimumab (ADA) (Humira®, AbbVie Inc., North Chicago, IL, USA).InterventionMonitoring of serum anti-TNF-α (IFX or ADA) and/or of anti-drug antibody levels using test assays with a test–treatment algorithm.ComparatorStandard care.OutcomesAny patient-related outcome, test agreement and cost-effectiveness estimates. The quality assessments used recognised checklists (Quality Assessment of Diagnostic Accuracy Studies-2, Cochrane, Philips and Consolidated Health Economic Evaluation Reporting Standards). Evidence was synthesised using narrative review and meta-analysis. A Markov model was built in TreeAge Pro 2013 (TreeAge Software, Inc., Williamstown, MA, USA). The model had a 4-week cycle and a 10-year time horizon, adopted a NHS and Personal Social Services perspective and used a linked evidence approach. Costs were adjusted to 2013/14 prices and discounted at 3.5%.ResultsWe included 68 out of 2434 and 4 out of 2466 studies for the clinical effectiveness and cost-effectiveness reviews, respectively. Twenty-three studies comparing test methods were identified. Evidence on test concordance was sparse and contradictory, offering scant data for a linked evidence approach. Three studies [two randomised controlled trials (RCTs) and one retrospective observational study] investigated outcomes following implementation of a test algorithm. None used the specified commercial ELISA immunoassay test kits. Neither of the two RCTs demonstrated clinical benefit of a test–treatment regimen. A meta-analysis of 31 studies to estimate test accuracy for predicting clinical status indicated that 20–30% of test results are likely to be inaccurate. The four cost-effectiveness studies suggested that testing results in small cost reductions. In the economic analysis the base-case analysis showed that standard practice (no testing/therapeutic monitoring with the intervention tests) was more costly and more effective than testing for IFX. Sensitivity and scenario analyses gave similar results. The probabilistic sensitivity analysis indicated a 92% likelihood that the ‘no-testing’ strategy was cost-effective at a willingness to pay of £20,000 per quality-adjusted life-year.Strengths and limitationsRigorous systematic reviews were undertaken; however, the underlying evidence base was poor or lacking. There was uncertainty about a linked evidence approach and a lack of gold standard for assay comparison. The only comparative evidence available for economic evaluation was for assays other than the intervention assays.ConclusionsOur finding that testing is not cost-effective for IFX should be viewed cautiously in view of the limited evidence. Clinicians should be mindful of variation in performance of different assays and of the absence of standardised approaches to patient assessment and treatment algorithms.Future work recommendationsThere is substantial variation in the underlying treatment pathways and uncertainty in the relative effectiveness of assay- and test-based treatment algorithms, which requires further investigation. There is very little research evidence on ADA or on drug monitoring in children with CD, and conclusions on cost-effectiveness could not be reached for these.Study registrationThis study is registered as PROSPERO CRD42014015278.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease

Abstract: SUMMARY BackgroundAdalimumab is an effective treatment for Crohn's disease (CD). Antiadalimumab antibodies (AAA) and low trough serum drug concentrations have been implicated as pre-disposing factors for treatment failure.

Cited by 169 publications

References 30 publications

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease

Anti–tumor necrosis factor-α therapy in uveitis

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