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.

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.

Continuous therapy with certolizumab pegol maintains remission of patients with Crohn's disease for up to 18 months.

BACKGROUND & AIMS: The safety and efficacy of maintenance therapy with the anti-tumor necrosis factor certolizumab pegol has not been reported beyond 6 months. We assessed the long-term efficacy, safety, and immunogenicity of continuous versus interrupted maintenance therapy with subcutaneous certolizumab pegol in patients with Crohn's disease. METHODS: Patients who responded to induction therapy at week 6 of the PEGylated Antibody Fragment Evaluation in Crohn's Disease: Safety and Efficacy (PRECiSE) 2 trial were assigned randomly to groups given certolizumab pegol (continuous) or placebo (drug-interruption) during weeks 6 to 26. Patients who completed PRECiSE 2 were eligible to enter PRECiSE 3, an ongoing, prospective, open-label extension trial in which patients have received certolizumab pegol (400 mg) every 4 weeks for 54 weeks to date, and were not offered the option to increase their dose. Disease activity was measured by the Harvey-Bradshaw Index. RESULTS: Harvey-Bradshaw Index responses at week 26 for the continuous and drug-interruption groups were 56.3% and 37.6%, respectively; corresponding remission rates were 47.9% and 32.4%, respectively. Of patients responding at week 26, response rates at week 80 after the start of PRECiSE 2 in the continuous and drug-interruption groups were 66.1% and 63.3%, respectively; among patients in remission at week 26, week 80 remission rates were 62.1% and 63.2%, respectively. More patients in the drug-interruption group developed antibodies against certolizumab pegol (and had lower plasma concentrations of certolizumab pegol) than the continuously treated group. CONCLUSIONS: Certolizumab pegol effectively maintains remission of Crohn's disease for up to 18 months. Continuous therapy is more effective than interrupted therapy.

Outcomes After Primary Infliximab Treatment Failure in Inflammatory Bowel Disease.

BACKGROUND: Primary infliximab treatment failure is common in patients with inflammatory bowel disease and represents a challenge to clinicians. Treatment options are limited. This study assessed the prognosis, defined as surgery-free survival, in patients with primary infliximab treatment failure as compared to patients without primary failure (initial responders). Furthermore, this study assessed the specter of medical therapies used after primary infliximab treatment failure along with treatment outcomes. METHODS: Retrospective, observational, cohort study of patients with inflammatory bowel disease treated with infliximab as first-line anti-tumor necrosis factor treatment at a tertiary center. Primary infliximab treatment failure was defined as no clinical improvement during infliximab induction therapy resulting in discontinuation of infliximab therapy. RESULTS: A total of 560 patients (Crohn's disease n = 353 and ulcerative colitis n = 207) were treated with infliximab. Among these, 81 (15%) had primary infliximab treatment failure after a median of 3 infusions (weeks 0, 2, and 6) (interquartile range 2-4). The median surgery-free survival was 196 days from first infusion. One year after primary infliximab treatment failure, the majority of patients (n = 51, 63%) had inflammatory bowel disease-related surgery (Crohn's disease n = 19, 58%; ulcerative colitis n = 32, 67%; P = 0.49). There was a markedly increased risk of surgery in patients with primary infliximab treatment failure as compared to initial responders: odds ratio 6.3 (3.8-10.6), P < 0.0001. Among 30 patients handled by medical therapies, 16 (53%) still had active disease 1 year after primary infliximab treatment failure. CONCLUSIONS: Primary infliximab treatment failure is associated with poor outcome including high risk of surgery or sustained active disease despite medical interventions.

Magnitude of Increased Infliximab Clearance Imposed by Anti-infliximab Antibodies in Crohn's Disease Is Determined by Their Concentration.

Antibodies (Abs) against infliximab (IFX) increase IFX clearance and can result in treatment failure and acute hypersensitivity reactions. However, interpretation of their clinical value is complicated by individual differences in Ab responses and methods used for quantification. The increase in IFX clearance imposed by anti-IFX Abs has generally been evaluated using a binary classification, i.e., positive or negative. This analysis aimed to investigate if anti-IFX Ab concentrations provide a more adequate prediction of alterations in clearance. Data originated from a clinical trial on Crohn's disease patients with IFX treatment failure. The trial was not originally designed for pharmacokinetic analysis. Therefore, published pharmacokinetic models were utilized as priors to enable covariate investigation. The impact of anti-IFX Abs on clearance was assessed using different mathematical relationships and exploiting information from two different quantification assays, measuring semi-quantitative "total" or "unbound neutralizing" concentrations of anti-IFX Ab, respectively. Inclusion of anti-IFX Ab status/concentration improved the model's performance for all investigated relationships. The anti-IFX Ab concentrations were superior to the binary classifications, indicating that the magnitude of increase in IFX clearance imposed by anti-IFX Abs closely relates to their concentration. Furthermore, total anti-IFX Ab concentrations appeared superior to the unbound neutralizing fraction in identifying high clearance individuals. Simulations showed that even at low concentrations, anti-IFX Abs lead to sub-therapeutic IFX concentrations, supporting a need of treatment interventions in all anti-IFX Ab positive patients. The developed model can serve as a basis for further investigations to refine treatment recommendations for patients with anti-IFX Abs.

Implications of Infliximab Treatment Failure and Influence of Personalized Treatment on Patient-reported Health-related Quality of Life and Productivity Outcomes in Crohn's Disease.

BACKGROUND: This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation. METHODS: Sixty-nine Crohn's disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health-related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks. RESULTS: Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non-responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX. CONCLUSION: Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease-related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes.

Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease.

BACKGROUND AND AIMS: Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS: We performed a post hoc analysis of a randomized clinical trial including 42 Crohn's disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. RESULTS: Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 µg/mL, p = 0.035; HMSA, 9.9 versus 4.7 µg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 µg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. CONCLUSION: Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.

Clinical implications of variations in anti-infliximab antibody levels in patients with inflammatory bowel disease.

BACKGROUND: The aim of the study was to investigate variations in anti-infliximab (IFX) antibody (Ab) levels and clinical implications thereof in patients with inflammatory bowel disease (IBD). METHODS: A retrospective, explorative, single-center study of patients with IBD who developed anti-IFX Ab and in whom anti-IFX Ab were reassessed. RESULTS: IFX was administered to 316 patients; anti-IFX Ab was determined in 180 patients and detected in 83 (46%). During ongoing IFX maintenance therapy, anti-IFX Ab disappeared at later reassessment in two-thirds of patients with clinical response after median 4 (3-5) infusions. In contrast, anti-IFX Ab persisted in all patients without clinical response. Anti-IFX Ab appeared pharmacologically active, as IFX levels were high when anti-IFX Ab disappeared (median 3.7 µg/mL, interquartile range [IQR] 2.8-5.5), while undetectable or low when anti-IFX Ab persisted (median 0 µg/mL, IQR 0-0). In 56 patients, anti-IFX Ab were assessed after IFX discontinuation. The proportion of patients with anti-IFX Ab gradually declined over time, with a few patients having anti-IFX Ab up to about 4 years after initial assessment. No variables were associated with anti-IFX Ab disappearance in multivariate analysis. CONCLUSIONS: Discontinuation of IFX is advisable in patients with inadequate response and repeat positive anti-IFX Ab measurements. Anti-IFX Ab can persist for years after discontinuation, which could impact efficacy and safety at retreatment. Continued IFX treatment may, however, be considered in patients with clinical response and a single positive anti-IFX Ab measurement, as anti-IFX Ab disappears in two-thirds of these during continued treatment.

World Gastroenterology Organization Practice Guidelines for the diagnosis and management of IBD in 2010.

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohn's disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.

Budesonide and mesalazine in active Crohn's disease: a comparison of the effects on quality of life.

OBJECTIVES: Controlled ileal release budesonide and slow release mesalazine are both used to treat mild to moderate active Crohn's disease, although data show that budesonide is more effective in inducing remission. When comparing different treatment options, the effects of agents on health-related quality of life must be considered as well as efficacy. In this study, we sought to compare the effects of budesonide and mesalazine on the health-related quality of life of patients with active Crohn's disease. METHODS: The study included 182 patients with Crohn's Disease Activity Index scores between 200 and 400. Patients were randomized in a double blind, double dummy, multicenter study to receive 9 mg of budesonide, once daily (n = 93), or 2 g of mesalazine, b.i.d. (n = 89), for 16 wk. Quality of life was assessed at baseline and after 2, 4, 8, 12, and 16 wk of treatment using the Psychological General Well-Being index. In addition, a physician's global evaluation was used to assess how symptoms affected patients' normal activities. RESULTS: Patients treated with budesonide experienced significantly greater improvement in Psychological General Well-Being scores than the group treated with mesalazine after 2, 8, 12, and 16 wk. All components of this index showed greater improvements in the budesonide-treated group than in the mesalazine group at 12 and 16 wk. The physician's global evaluation showed significantly greater improvements in the budesonide group than in the mesalazine group at all visits. CONCLUSION: Budesonide (9 mg once daily) improves health-related quality of life to a greater extent than mesalazine (2 g b.i.d.) in patients with mild to moderate active Crohn's disease.