Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Withdrawal of immunomodulators (IMMs) or tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel diseases (IBDs) in remission on combination therapy is attractive. We evaluated the efficacy and safety of (1) IMM, or (2) TNF antagonist withdrawal in patients with IBD in sustained remission on combination therapy. METHODS: Through a systematic review till March 31, 2023, we identified randomized controlled trials (RCTs) that compared the efficacy and safety of IMM or TNF antagonist withdrawal vs continued combination therapy, in patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy. Primary outcome was risk of relapse and serious adverse events at 12 months. We conducted meta-analysis to calculate relative risk (RR) and 95% confidence interval (CI) and used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. RESULTS: We identified 8 RCTs with 733 patients (77% with Crohn's disease, 91% on infliximab-based combination therapy). On meta-analysis of 5 RCTs, there was no difference in the risk of relapse between patients with IMM withdrawal (continued TNF antagonist monotherapy) vs continued combination therapy (16.8% vs 14.9%; RR, 1.15; 95% CI, 0.75-1.76) without heterogeneity (low certainty of evidence). TNF antagonist withdrawal (continued IMM monotherapy) was associated with 2.4-times higher risk of relapse compared with continuing combination therapy (31.5% vs 11.2%; RR, 2.35; 95% CI, 1.38-4.01), with minimal heterogeneity (low certainty of evidence). There was no difference in the risk of serious adverse events with IMM or TNF antagonist withdrawal vs continued combination therapy. CONCLUSIONS: In patients with IBD in sustained corticosteroid-free clinical remission for >6 months on combination therapy, de-escalation with TNF antagonist withdrawal, but not IMM withdrawal, was associated with an increased risk of relapse.

The role of chest X-rays when screening for latent tuberculosis infection in patients with inflammatory bowel disease before starting biologic treatment.

BACKGROUND: Guidelines generally recommend a combination of immunological assays and chest X-ray imaging (CXR) when screening for latent tuberculosis infection (LTBI) prior to biologic treatment in inflammatory bowel disease (IBD). OBJECTIVE: To investigate whether CXR identify patients with suspected LTBI/TB who were not identified with QuantiFERON tests (QFT) when screening for LTBI/TB before starting biologic treatment in IBD patients. METHODS: Single-center, retrospective cohort study of patients with inflammatory bowel disease who had a QFT and a CXR prior to initiation of biologic treatment in a 5-year period (October 1st, 2017 to September 30th, 2022). RESULTS: 520 patients (56% female, mean age 40.1 years) were included. The majority had none or few risk factors for TB (as reflected by the demographic characteristics) but some risk factors for having false negative QFT results (concurrent glucocorticoid treatment and inflammatory activity). QFT results were positive in 8 patients (1.5%), inconclusive in 18 (3.5%) and negative in 494 (95.0%). Only 1 patient (0.19%) had CXR findings suspicious of LTBI. This patient also had a positive QFT and was subsequently diagnosed with active TB. All patients with negative or inconclusive QFT had CXR without any findings suggesting LTBI/TB. One patient developed active TB after having initiated biologic treatment in spite of having negative QFT and a normal CXR at screening. CONCLUSION: In a population with low risk of TB, the benefits of supplementing the QFT with a CXR are limited and are unlikely to outweigh the cost in both patient test-burden, radioactive exposure, and economic resources.

Drug Levels Associated With Optimal Discrimination Between Remission and Nonremission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease.

BACKGROUND: To implement therapeutic drug monitoring-based strategies for infliximab (IFX) in inflammatory bowel disease, the authors assessed IFX levels for optimal discrimination between remission and nonremission and compared assays for anti-IFX antibodies (Abs). METHODS: The retrospective cohort comprised 163 bionaive patients with inflammatory bowel disease who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for 1 year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n = 690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels < limit of detection (n = 102) were analyzed by 2 binding assays [enzyme-linked immunosorbent assay (ELISA)] and functional reporter gene assay/drug-tolerant enzyme immunoassay. RESULTS: At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 mcg/mL was associated with clinical remission during the entire first year of therapy [sensitivity 54% (49-59), specificity 73% (67-78), AUCROC 0.65 (0.60-0.69), P < 0.0001]; these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n = 131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure [OR 2.9 (1.4-6.0), P < 0.01], irrespective of persistency or transiency. All performed assays detected anti-IFX Abs were picked up by all assays in ∼2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. CONCLUSIONS: IFX at ∼5 mcg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for therapeutic drug monitoring.

A systematic monitoring approach to biologic therapies in inflammatory bowel disease: patients' and physicians' preferences and adherence.

OBJECTIVES: Treatment of patients with inflammatory bowel disease (IBD) should aim at achieving mucosal healing. However, monitoring schedules to support this goal remain undefined. We aimed to identify patients' and physicians' preferences regarding monitoring strategy and investigated the feasibility of such a strategy. METHODS: Elements considered relevant for monitoring were identified in questionnaire surveys among 1) patients with IBD receiving biologic agents (n = 172) and 2) their physicians (n = 87). Adherence to a monitoring strategy incorporating these elements was investigated in a retrospective cohort of patients with IBD treated with biologic agents (n = 139). RESULTS: Patients considered blood and stool samples, endoscopies, and magnetic resonance imaging (MRI) to be relevant aspects of monitoring their disease. However, patients also considered stool samples and endoscopies unpleasant. Physicians considered blood samples (99%), medical consultations (99%), fecal calprotectin (85%), endoscopy (78%), and MRI (71%) to be important aspects of IBD monitoring but considered endoscopies and MRI relevant only at clinical signs of relapse. A review of the clinical use of monitoring strategies including the elements identified above revealed high adherence for blood samples and disease activity indices (92%), but low adherence for fecal calprotectin (38%), therapeutic drug monitoring (38%), and endoscopies (32%). CONCLUSION: Important tools for evaluating mucosal healing (e.g., endoscopy) were rated highly unpleasant by patients, and physicians found endoscopies/MRI relevant only in case of relapse. These findings were reflected by low rates of adherence to use of these monitoring tools. In defining monitoring schedules to help achieve treatment goals, these important barriers must be addressed.

Fatigue is a systemic extraintestinal disease manifestation largely independent of disease activity, chronicity, and nutritional deficiencies in inflammatory bowel disease on biologics.

BACKGROUND: Fatigue is a common symptom reported by patients with chronic immunoinflammatory diseases and with profound negative implications on health-related quality of life. This study aimed to delineate underlying components contributing to fatigue in patients with inflammatory bowel disease (IBD) receiving biologic therapy. METHODS: Cross-sectional questionnaire study of all patients with IBD receiving any biologic therapy at a tertiary IBD center. Fatigue was assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Disease activity and quality of life were evaluated by generic questionnaires. Principal component analysis (PCA) was used to identify components of variables explaining fatigue. RESULTS: Three hundred patients with IBD were included. Moderate-to-severe fatigue defined as FACIT-F ≤ 39 was present in half of the included patients. PCA condensed variables associated with fatigue into three main components contributing to 49% of observed fatigue. The first component, explaining 21% of fatigue, included factors related to disease chronicity, e.g., long disease duration, high number of previously used biologic therapies, presence of previous intestinal surgery, and increasing age. The second component explained 14% of fatigue and comprised disease activity-related aspects, e.g., disease activity indices and C-reactive protein. The third explained 14% of fatigue and comprised various nutritional deficiencies. CONCLUSION: Fatigue can partly be explained by chronicity, disease activity, and nutritional deficits. However, the cause of fatigue is unexplained in approximately half of the patients with IBD supporting that fatigue can be an independent, systemic extraintestinal disease manifestation in IBD.

Treatment to target in patients with inflammatory bowel disease. What is the evidence?

Background: Inflammatory bowel diseases (IBD) are chronic, progressive diseases of the gastrointestinal tract. Current therapy has not been able to change the long-term course of the disease, but treatment to a specific therapeutic target could be a game-changer.Objectives: To assess the evidence of a treat to target (T2T) algorithm being superior to clinical management in the treatment of IBD, a systematic review of the literature is conducted.Search methods: A comprehensive survey of PubMed and Embase covering the period April 2018 to July 2019 including articles referenced in relevant studies.Selection criteria: Both randomized clinical trials (RCT) and observational studies were included. To be eligible for inclusion, the studies had to describe or analyze the effects of T2T on remission and/or recurrence of disease in patients with IBD.Main results: Twenty-two studies were included in this review, seven RCTs, eight comparative and seven non-comparative observational studies. Large heterogeneity between T2T algorithms applied, type of IBD investigated and outcomes evaluated characterized the studies.Authors' conclusions: The comprehensive search identified only 22 heterogeneous studies. Out of these, a total of 14 indicated a positive effect of a T2T algorithm. Out of the seven RCT studies, four indicated a positive effect. Thus, T2T algorithms may be superior to the clinical management of IBD. However, the evidence is sparse and inconsistent.

Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease.

BACKGROUND: Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. METHODS: A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 (n = 148) and 6 (n = 108). Circulating TNFα was measured in matched primary non-responders (n = 29) and responders (n = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients. RESULTS: In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 µg/mL vs. 23.3, p < .05. Week 6: 8.4 vs. 17.0, p < .05). Optimal IFX thresholds associated with response was 22.9 µg/mL at week 2 (sensitivity 51%, specificity 80%, AUCROC 0.67, p < .05) and 11.8 at week 6 (72%, 77%, 0.71, p < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8-67.5], p < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn's disease. CONCLUSION: IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn's disease.

Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure.

BACKGROUND: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. METHODS: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. RESULTS: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. CONCLUSIONS: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.

Inflammatory bowel disease with primary sclerosing cholangitis: A Danish population-based cohort study 1977-2011.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) may be complicated by primary sclerosing cholangitis (PSC). We aimed to assess the characteristics of Danish PSC-IBD patients and to compare their prognosis with IBD patients without PSC. METHODS: A retrospective nationwide population-based cohort of 257 PSC-IBD patients was assessed through Danish national registries and manual scrutiny of patient files. RESULTS: For all PSC-IBD patients diagnosed after 1976 (n = 222) and 8231 IBD controls (ie, without PSC), the cumulative probability of resective surgery, liver transplantation, cancer, and survival from 1977 through 2011 was estimated and compared by log-rank test and Cox regression. PSC-IBD patients primarily had ulcerative colitis (UC) (72%), were diagnosed in young adulthood (median age at IBD diagnosis, 23 years), and 9% were smokers. Among PSC-UC patients 78% had pancolitis at diagnosis. Among patients with PSC and Crohn's disease (CD) 91% had colonic involvement. The PSC-IBD patients had a significantly higher probability of receiving resective surgery (HR; 2.13, 95% CI: 1.50-3.03); of developing colorectal cancer (CRC) (HR; 21.4, 95% CI: 9.6-47.6), of cholangiocarcinoma (HR; 190, 95% CI: 54.8-660), and of dying (HR; 4.39, 95% CI: 3.22-6.00) as compared to non-PSC-IBD controls. The 25-year cumulative risk of liver transplantation was high (53%). CONCLUSIONS: This unselected population-based study shows that PSC-IBD patients not only have an extensive phenotype of IBD, they are also treated more intensively than other patients with IBD. However, the prognosis remains poor and without any apparent improvement over calendar time.

Outcome of continued infliximab therapy in Crohn's disease patients with response but without remission after one year of infliximab - a retrospective cohort study.

BACKGROUND: Optimal management of Crohn's disease patients having responded to infliximab but without achieving remission is not well defined. The present study examined if these patients benefit from continued long-term infliximab maintenance therapy. METHOD: Retrospective cohort study including all patients treated with infliximab for 1 year until the end of 2017 who have had a response but not reached remission on infliximab. Clinical outcomes were defined by the physicians' global evaluation, supported by clinical indices and objective markers of disease activity. RESULTS: In total, 376 Crohn's disease patients received infliximab. Among these, 76 (20%) were classified as having response but non-remission (RNR) after 1 year of therapy. A great majority (n = 54; 71%) experienced no additional therapeutic benefit after a further year of infliximab maintenance therapy, thus still having RNR. Nineteen patients (25%) obtained remission during continued infliximab, whereas only 4% (n = 3) experienced treatment failure. Although infliximab therapy beyond 2 years (follow-up median 35 months, IQR: 23-55) was accompanied by a higher proportion attaining remission (40%), nearly half (46%) still failed to improve. Among patients who had discontinued infliximab while having RNR (n = 21), half (n = 11) experienced disease flare within five months (median 22 weeks, IQR: 12-31). CONCLUSION: Most patients (71%) had no additional therapeutic benefit after an additional year of infliximab therapy, and after a median maintenance infliximab treatment period of 3 years, half still failed to improve further. Considering the importance of achieving complete remission, these patients appear to have an unmet medical need.

Interactions Between Thiopurine Metabolites, Adalimumab, and Antibodies Against Adalimumab in Previously Infliximab-Treated Patients with Inflammatory Bowel Disease.

BACKGROUND: Interactions between thiopurines and infliximab presumably contribute to superior effect of infliximab-thiopurine combination therapy in patients with inflammatory bowel disease (IBD). We examined whether principal cytotoxic thiopurine metabolites influence adalimumab (ADL) and anti-ADL antibodies (Abs). METHODS: Ninety-eight IBD patients previously treated with infliximab (96%) in whom trough ADL and anti-ADL Abs had been assessed as part of their clinical care were included. Thiopurine metabolites [6-thioguanine nucleotides (6-TGN) and methylated mercaptopurine metabolites (6-MeMP)] were determined at similar time points. RESULTS: ADL-thiopurine combination therapy was not associated with reduced anti-ADL Ab positivity compared to ADL monotherapy: 8/31 (26%) versus 19/67 (28%), p = 1.00. Concentrations of thiopurine metabolites were similar in anti-ADL Ab-positive and negative patients (6-TGN median 109 pmol/8 × 108 RBC vs. 112, p = 0.80; 6-MeMP 448 RBC vs. 720, p = 0.94). ADL trough levels did not differ between anti-ADL Ab-negative patients on ADL-thiopurine combination therapy and those on monotherapy (9.5 µg/mL vs. 7.6, p = 0.31). ADL levels were also comparable between patients on ADL mono- and combination therapy after stratification for 6-TGN/6-MeMP quartiles. There were no correlations between levels of 6-TGN and ADL (rP = - 0.17, p = 0.45; rS = - 0.38, p = 0.08), or 6-MeMP and ADL (rP = - 0.23, p = 0.31; rS = - 0.35, p = 0.11). Anti-ADL Ab positivity was associated with ADL treatment failure (OR 6 [2-20], p < 0.01). Higher trough ADL (9.6 µg/mL vs. 7.3, p < 0.05), but not concomitant thiopurine treatment, metabolite levels, or dosage, was associated with clinical remission. CONCLUSION: Effectiveness of ADL therapy associated with circulating ADL levels and anti-ADL Ab formation. In this study, there appeared no direct interactions between thiopurine metabolites and ADL or anti-ADL Abs.

Metabonomics uncovers a reversible proatherogenic lipid profile during infliximab therapy of inflammatory bowel disease.

BACKGROUND: One-third of inflammatory bowel disease (IBD) patients show no response to infliximab (IFX) induction therapy, and approximately half of patients responding become unresponsive over time. Thus, identification of potential treatment response biomarkers are of great clinical significance. This study employs spectroscopy-based metabolic profiling of serum from patients with IBD treated with IFX and healthy subjects (1) to substantiate the use of spectroscopy as a semi-invasive diagnostic tool, (2) to identify potential biomarkers of treatment response and (3) to characterise the metabolic changes during management of patients with tumour necrosis factor-α inhibitors. METHODS: Successive serum samples collected during IFX induction treatment (weeks 0, 2, 6 and 14) from 87 IBD patients and 37 controls were analysed by 1H nuclear magnetic resonance (NMR) spectroscopy. Data were analysed with principal components analysis and orthogonal projection to latent structures discriminant analysis using SIMCA-P+ v12 and MATLAB. RESULTS: Metabolic profiles were significantly different between active ulcerative colitis and controls, active Crohn's disease and controls, and quiescent Crohn's disease and controls. Metabolites holding differential power belonged primarily to lipids and phospholipids with proatherogenic characteristics and metabolites in the pyruvate metabolism, suggestive of an intense inflammation-driven energy demand. IBD patients not responding to IFX were identified as a potentially distinct group based on their metabolic profile, although no applicable response biomarkers could be singled out in the current setting. CONCLUSION: 1H NMR spectroscopy of serum samples is a powerful semi-invasive diagnostic tool in flaring IBD. With its use, we provide unique insights into the metabolic changes taking place during induction treatment with IFX. Of distinct clinical relevance is the identification of a reversible proatherogenic lipid profile in IBD patients with active disease, which partially explains the increased risk of cardiovascular disease associated with IBD.

Time Course and Clinical Implications of Development of Antibodies Against Adalimumab in Patients With Inflammatory Bowel Disease.

BACKGROUND: Antibodies (Abs) against adalimumab (ADL) have been associated with low ADL levels and treatment failure. AIM: To characterize the temporal characteristics of anti-ADL Ab appearance and possible disappearance, and determine the clinical significance on drug efficacy and disease course. METHODS: Cohort study including inflammatory bowel disease patients in whom anti-ADL Abs had been assessed by radioimmunoassay (RIA) and, in case of disappearance, by enzyme immunoassay, and functional reporter gene assay. RESULTS: Anti-ADL Abs were evaluated in 133 serum samples from 72 patients. Seventeen patients (24%) tested positive after median of 194 days, interquartile range of 66 to 361. The proportion with anti-ADL Abs was 22% after 1 year, and 32% from 21 months onwards. Anti-ADL Abs generally persisted at repeat assessments during continued ADL therapy (n=8). Disappearance of anti-ADL Abs during therapy (n=3) was presumably caused by methodological biases due to detection of nonfunctional nonpersistent anti-ADL Abs by RIA, or false-negative measurement at reassessment by RIA and reporter gene assay. Anti-ADL Abs appeared pharmacologically active as judged by a median ADL concentration below limit of detection versus 7.4 µg/mL in anti-ADL Ab-negative samples (P<0.0001). Anti-ADL Abs associated with loss of response (odds ratio estimated 67, P<0.0001), and shorter treatment duration (P<0.0001). CONCLUSIONS: Abs against ADL appear in approximately one fourth of inflammatory bowel disease patients with decreasing frequency over time and usually within 1 year of therapy. Anti-ADL Abs generally persist during continued ADL therapy, and are associated with elimination of drug and treatment failure. Therefore, ADL cessation should be considered when anti-ADL Abs are detected and supported by clinical observations.

Systematic Information to Health-Care Professionals about Vaccination Guidelines Improves Adherence in Patients With Inflammatory Bowel Disease in Anti-TNFα Therapy.

OBJECTIVES: Implementation of guidelines for prevention of infectious diseases during anti-TNFα therapy in patients with inflammatory bowel disease (IBD) is important but difficult. We investigated whether systematic information to health-care professionals about these guidelines improves patients' adherence. METHODS: The study comprised three parts: (1) cross-sectional evaluation of baseline vaccination status in all IBD patients in anti-TNFα therapy (reference group; n=130); (2) prospective interventional study, where health-care professionals received systematic oral and written information about vaccination guidelines at baseline and at 2-month intervals for 6 months, followed by reassessment of vaccination status (intervention group; n=99); (3) cross-sectional evaluation of representative gastroenterologists' knowledge of guidelines (n=53). Outcomes were assessed by validated questionnaires. RESULTS: Patients' adherence to vaccination guidelines increased significantly after a period of systematic information to health-care professionals. Hence, complete adherence increased from 5 to 26%, partial adherence from 38 to 56%, and complete non-adherence decreased from 57 to 18% (P<0.0001). Adherence to all individual vaccinations except human papilloma virus increased significantly (P≤0.0021). Improvement was independent of disease type and anti-TNFα agent. At baseline, only 8% of physicians could identify all elements in the reference guideline. Additional barriers reported by physicians were forgetfulness (32%) and insufficient consultation time (26%). Patient-perceived barriers were costs of vaccinations (35%) and forgetfulness (25%). CONCLUSIONS: Gastroenterologists' limited knowledge of vaccination guidelines during anti-TNFα therapy can be overcome by systematic education of health-care professionals. This inexpensive and easily accessible intervention immediately results in markedly improved patient adherence. Remaining obstacles for adherence comprise high vaccination costs and forgetfulness.

Individualized Therapy Is a Long-Term Cost-Effective Method Compared to Dose Intensification in Crohn's Disease Patients Failing Infliximab.

BACKGROUND: In Crohn's disease patients failing infliximab therapy, interventions defined by an algorithm based on infliximab and anti-infliximab antibody measurements have proven more cost-effective than intensifying the infliximab regimen. AIM: This study investigated long-term economic outcomes at the week 20 follow-up study visit and after 1 year. Clinical outcomes were assessed at week 20. METHODS: Follow-up from a 12-week, single-blind, clinical trial where patients with infliximab treatment failure were randomized to infliximab intensification (5 mg/kg every 4 weeks) (n = 36), or algorithm-defined interventions (n = 33). Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry. RESULTS: At the scheduled week 20 follow-up study visit, response and remission rates were similar in all study subpopulations between patients treated by the algorithm or by infliximab intensification. However, the sum of healthcare costs related to Crohn's disease was substantially lower (31 %) for patients randomized to algorithm-based interventions than infliximab intensification in the intention-to-treat population: $11,940 versus $17,236; p = 0.005. For per-protocol patients (n = 55), costs at the week 20 follow-up visit were even lower (49 %) in the algorithm group: $8,742 versus $17,236; p = 0.002. Figures were similar for patients having completed the 12-week trial as per protocol (50 % reduction in costs) (n = 45). Among patients continuing the allocated study intervention throughout the entire 20-week follow-up period (n = 29), costs were reduced by 60 % in algorithm-treated patients: $7,056 versus $17,776; p < 0.001. Cost-reduction percentages remained stable throughout one year. CONCLUSION: Economic benefit of algorithm-based interventions at infliximab failure is maintained throughout 1 year.

Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial.

OBJECTIVE: Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn's disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. DESIGN: Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohn's Disease Activity Index (CDAI) decrease ≥ 70, or ≥ 50% reduction in active fistulas) and accumulated costs related to treatment of Crohn's disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector. RESULTS: Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: € 6038 vs € 9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (-19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€ 4062 vs € 9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference -5% (-33% to 22%)). CONCLUSIONS: Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy. TRIAL REGISTRATION NO: NCT00851565.

Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn's disease: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Cost-effective guidance of therapeutic strategy in Crohn's disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by radioimmunoassay (RIA). This study investigated implications of using other techniques for this purpose. METHODS: This is a post hoc analysis of randomized clinical trial including 66 Crohn's disease patients with IFX failure in whom IFX and anti-IFX Ab measurements by RIA had been used for therapeutic guidance. Samples were additionally assessed by enzyme-linked immunosorbent assay (ELISA), homogeneous mobility shift assay (HMSA), and functional cell-based reporter gene assay (RGA). RESULTS: IFX detection was comparable between assays (82% RIA, 76% ELISA, 88% HMSA, and 74% RGA), and it correlated significantly (Pearson's r=0.91-0.97, P<0.0001). However, IFX concentrations varied systematically between all pair of assays except RIA-RGA. Anti-IFX Ab detection was variable (27% RIA, 9% ELISA, 33% HMSA, and 11% RGA), but correlated significantly (Pearson's r=0.77-0.96; P<0.0001). Anti-IFX Abs detected by RIA and HMSA were often from sera without drug-neutralizing activity (RGA). Assays agreed on classification of underlying mechanism for treatment failure in most cases (79-94%). The majority (74-88%) failed IFX owing to pharmacodynamic problems, or had noninflammatory pathophysiology for symptoms resembling relapse. Applied threshold for therapeutic vs. subtherapeutic IFX level influenced classifications. The four different assays did not differ in terms of the ability to predict response to interventions defined by the algorithm. CONCLUSIONS: Despite variable analytical properties, common assays result in similar classifications and interventions in patients with IFX treatment failure, and with comparable clinical outcomes. Implications are, however, profound for the minority classified differently.

Comparison of techniques for monitoring infliximab and antibodies against infliximab in Crohn's disease.

BACKGROUND: Several techniques are used to measure infliximab (IFX) and anti-IFX antibodies (Abs) in Crohn's disease. The aim of this study was to compare different assays for this purpose. METHODS: Fluid-phase radioimmunoassay (RIA), solid-phase enzyme-linked immunosorbent assay (ELISA), reporter gene assay (RGA), and enzyme immunoassay (EIA; anti-IFX Ab only) were assessed. IFX was added to pooled serum from 13 patients with inactive Crohn's disease to yield concentrations of 0, 1, 3, and 9 µg/mL. Anti-IFX Abs were assessed in 6 patients. RESULTS: IFX assessments: RIA and RGA had lower limit of detection than ELISA (0.07 µg/mL and 0.13 versus 0.26). Maximal inaccuracies were 39%, 24%, and 23%. Imprecisions (coefficients of variation) were ≤20% within IFX concentrations between 1 and 9 µg/mL. All assays showed linear correlations (R = 0.97-0.99), but sample concentrations differed by up to 1.55 µg/mL for RIA and RGA, 1.41 µg/mL for ELISA and RIA, and 0.48 µg/mL for ELISA and RGA (P < 0.05). Anti-IFX Ab assessments: RGA gave highly reproducible results (coefficients of variation ≤ 7%) compared with all others (24%-26%). All assays had linear correlations (R = 0.71-0.93), except ELISA versus RGA and EIA. Assays disagreed on anti-IFX Ab titers with mean difference -420 (-1200 to 210) in RGA and EIA, and up to 4500 (-2700 to 11,800) in RIA and RGA. A contributing factor to these discrepancies was inability of ELISA to detect IgG4 anti-IFX Abs. CONCLUSIONS: Performances of assays for IFX and anti-IFX Abs are comparable. However, IFX concentrations and anti-IFX Ab titers show systematic differences, and in individual patients, only the same assay should be used. Problems may arise when different assays are used to manage therapies in the same patient.