Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients With Crohn's Disease.

BACKGROUND: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. Understanding pharmacokinetics (PK) of ADL is essential to optimize individual dosing in daily practice. The aim of this study was to evaluate PK of ADL in patients with CD and to identify factors that influence PK of ADL. METHODS: In a retrospective cohort study, the authors reviewed the charts of 96 patients with CD receiving ADL induction and maintenance treatment. This patient cohort was used for external validation of population pharmacokinetic models of ADL available from literature. In addition, a novel population PK model was developed using nonlinear mixed-effects modeling. RESULTS: None of the literature models properly described the PK of ADL in our cohort. Therefore, a novel population pharmacokinetic model was developed. Clearance of ADL increased 4-fold in the presence of anti-ADL antibodies. Patients who received ADL every week had a 40% higher clearance compared with patients receiving ADL every other week. CONCLUSIONS: Clearance of ADL increased in the presence of anti-ADL antibodies and was associated with weekly ADL administrations. In clinical practice, the decision to intensify ADL treatment to weekly administrations is primarily based on disease activity. Increased disease activity may be the result of lower drug concentrations due to higher clearance. However, increased disease activity may also increase clearance due to increased target engagement. The causal relationship between these factors remains to be elucidated.

A Real-life Population Pharmacokinetic Study Reveals Factors Associated with Clearance and Immunogenicity of Infliximab in Inflammatory Bowel Disease.

BACKGROUND: Several factors influencing the pharmacokinetics of infliximab (IFX) in inflammatory bowel disease (IBD) have been identified. We studied the impact of patient, disease, and treatment characteristics on clearance and immunogenicity of IFX in a real-world patient-with-IBD cohort. METHODS: Serum concentrations of IFX and antibodies to IFX (ATIs) were measured in patients with IBD at a single center using an enzyme-linked immunosorbent assay and radioimmunoassay. Patient, disease, and treatment characteristics were retrospectively collected along with laboratory values. Pharmacokinetics and ATI titer were analyzed simultaneously by nonlinear mixed-effects modeling. RESULTS: Nine hundred ninety-seven IFX concentrations and 756 ATI measurements from 332 patients with IBD (253 Crohn's disease and 79 ulcerative colitis) were included. Mean (SD) IFX dose was 5.47 ± 1.33 mg/kg. ATIs were detected in 75/332 (23%) patients; insufficient exposure below an IFX trough level of 3 µg/mL was the most predictive factor of developing ATI and resulted in a 4-fold increased risk of ATI development. ATI titer was a better predictor of IFX clearance than ATI as a dichotomous parameter. ATI titers >30 AU/mL were consistently associated with undetectable IFX concentrations. IFX clearance was affected by body weight (40-149 kg) ranging from 0.27 to 0.53 L/d, serum albumin (2-5.4 g/dL) from 0.93 to 0.24 L/d, and titers of ATIs (0-53,000 AU/mL) from 0.36 L/d to 15.93 L/d (P < 0.001). Previously biologic-treated patients exhibited a higher clearance of IFX. CONCLUSIONS: IFX exposure below 3 µg/mL increases risk of ATIs. Identification of influential pharmacokinetics and ATI factors improves prediction of IFX levels, potentially allowing individualized dosing and cost reduction.

Performance of Common Disease Activity Markers as a Reflection of Inflammatory Burden in Ulcerative Colitis.

BACKGROUND: The inflammatory burden influences therapeutic decisions in patients with ulcerative colitis (UC). We aimed to study which commonly used markers of disease activity correlate best with inflammatory burden in patients with UC using leukocyte scintigraphy (single-photon emission computed tomography [SPECT-CT]) as the gold standard. METHODS: Patients with different severity of UC underwent colonoscopy with biopsies and leukocyte SPECT-CT scintigraphy. Serum C-reactive protein (CRP), fecal calprotectin, and clinical questionnaires were collected. The maximum uptake of technetium-labeled leukocytes was calculated as a SPECT score for each colon segment and a summed activity score for 5 colonic segments combined. RESULTS: Thirty patients with UC were included; 14 of 30 (47%) had left-sided colitis, and 16 of 30 (53%) had pancolitis. One patient (3%) had inactive UC, 5 of 30 (17%) had mild, 11 of 30 (37%) had moderate, and 13 of 30 (43%) had severe disease activity based on the endoscopic Mayo score. The endoscopic Mayo score correlated better with the SPECT score than with the ulcerative colitis endoscopic index of severity (UCEIS) (r = 0.50; P < 0.01 and r = 0.32; P = 0.08, respectively). The Geboes UC histologic score correlated equally well as the Mayo score (r = 0.50; P < 0.01). We found a significant correlation between scintigraphy and fecal calprotectin (r = 0.44; P = 0.02) but not with serum CRP (r = 0.25; P = 0.18). Fecal calprotectin reflected inflammatory burden significantly better in left-sided colitis (r = 0.80; P = 0.001) than in pancolitis (r = 0.22; P = 0.41). CONCLUSIONS: The inflammatory burden in patients with UC, measured by SPECT-CT, is better reflected by the endoscopic Mayo score and the Geboes histologic score than by the UCEIS. Fecal calprotectin is a more accurate inflammatory marker than CRP, predominantly in patients with left-sided colitis. REGISTRATION: This study was approved by the Ethics Committee Review at October 22, 2012 and, in accordance with Dutch legislation, prospectively registered at the CCMO (Dutch central commission for human research) https://www.toetsingonline.nl with NL39801.018.12.

Incidence and Severity of Prepouch Ileitis: A Distinct Disease Entity or a Manifestation of Refractory Pouchitis?

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the operation of choice for patients with treatment-refractory ulcerative colitis. However, after this intervention, up to 50% of patients develop pouchitis. Moreover, a subgroup will also develop inflammation in the afferent ileum proximal to the pouch, a condition named prepouch ileitis (PI). METHODS: Data on 546 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis were retrospectively collected from 3 tertiary inflammatory bowel disease referral centers in the Netherlands, Belgium, and England. PI was considered present if there was endoscopic and histological inflammation in the afferent limb proximal to the pouch. Crohn's disease was excluded by reviewing the histology of colectomy resection specimens. RESULTS: PI was present in 33/546 (6%) patients and all of these had concurrent pouchitis. One hundred forty-four (26%) patients had pouchitis without PI and 369 (68%) patients did not have inflammatory pouch disease. Of the 33 patients with PI, 6 (18%) received no specific treatment, 9 (27%) responded to antibiotics, and 18 (54%) required escalation in therapy to steroids/immunomodulators or anti-tumor necrosis factor agents. Potent immunosuppressive treatment was required more frequently in patients with PI than those with pouchitis alone. CONCLUSIONS: PI is less common and more treatment refractory than pouchitis alone. Once PI is diagnosed, clinicians should be aware that response to antibiotic therapy is less likely than in pouchitis alone. Immunomodulatory therapy and escalation to anti-tumor necrosis factor agents should be considered early in cases of nonresponse. The suggestion that PI represents misdiagnosed Crohn's disease could not be substantiated in our cohort.

Presenteeism in Inflammatory Bowel Diseases: A Hidden Problem with Significant Economic Impact.

BACKGROUND: Indirect costs associated with impaired productivity at work (presenteeism) due to inflammatory bowel disease (IBD) are a major contributor to health expenditures. Studies estimating indirect costs in the United States did not take presenteeism into account. We aimed to quantify work limitations and presenteeism and its associated costs in an IBD population to generate recommendations to reduce presenteeism and decrease indirect costs. METHODS: We performed a prospective study at a tertiary IBD center. During clinic visits, work productivity, work-related problems and adjustments, quality of life, and disease activity were assessed in patients with IBD. Work productivity and impairment were assessed in a control population as well. Indirect costs associated with lost work hours (absenteeism) and presenteeism were estimated, as well as the effect of disease activity on those costs. RESULTS: Of the 440 included patients with IBD, 35.6% were unemployed. Significantly more presenteeism was detected in patients with IBD (62.9%) compared with controls (27.3%) (P = 0.004), with no significant differences in absenteeism. Patients in remission experienced significantly more presenteeism than controls (54.7% versus 27.3%, respectively, P < 0.01), and indirect costs were significantly higher for remissive patients versus controls ($17,766 per yr versus $9179 per yr, respectively, P < 0.03). Only 34.3% had made adjustments to battle work-related problems such as fatigue, irritability, and decreased motivation. CONCLUSIONS: Patients with IBD in clinical remission still cope with significantly more presenteeism and work limitations than controls; this translates in higher indirect costs and decreased quality of life. The majority have not made any adjustments to battle these problems.

A systematic review of the measurement of endoscopic healing in ulcerative colitis clinical trials: recommendations and implications for future research.

BACKGROUND: Assessment of endoscopic disease activity, as measured by various endoscopic evaluative instruments, is an essential part of quantifying disease activity in clinical trials in patients with ulcerative colitis (UC). Evaluative instruments have specific definitions and operating properties that influence the interpretation of clinical trial results. Our objective was to systematically review all endoscopic evaluative instruments that measure endoscopic disease activity in UC and to describe their definitions and operating characteristics (reliability, responsiveness, and predictive validity). METHODS: We performed a systematic review of evaluative instruments assessing endoscopic disease activity in UC. MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and Digestive Disease Week abstracts of clinical trials were searched from inception to January 2013. RESULTS: In total, 5885 studies were identified and screened for inclusion criteria. Four hundred twenty-two studies involving 31 evaluative instruments were identified. Two types of indices were found, numerical scoring systems and stepwise grading scales. CONCLUSIONS: Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for UC. Currently, the sigmoidoscopic component of the Mayo Score and the ulcerative colitis endoscopic index of severity show the most promise as reliable evaluative instruments of endoscopic disease activity. However, further validation is required.

Effects of infliximab retreatment after consecutive discontinuation of infliximab and adalimumab in refractory Crohn's disease.

BACKGROUND: Switches between anti-tumor necrosis factor agents in the treatment of Crohn's disease (CD) occur in case of treatment failure, intolerance, or patient preference. No data are currently available on the usefulness of a second infliximab treatment after earlier discontinuation and previous switch to an alternative anti-tumor necrosis factor agent. In this study, we evaluated the clinical benefit of infliximab retreatment in patients with CD after sequential use of both infliximab and adalimumab. METHODS: Twenty-nine patients with CD who had received earlier treatments with sequential infliximab and adalimumab and were then restarted on infliximab were retrieved from a multicenter registry designed for the follow-up of adalimumab treatment for CD. Short-term and sustained effects of infliximab retreatment were evaluated retrospectively by reviewing clinical records. Follow-up was 18 months for all patients. RESULTS: In 13/29 (45%) patients, infliximab was reintroduced at intensified dosing schedule (>5 mg/kg or <8 wk) for 23/29 (79%) of patients similar to the schedule who were on at time of previous discontinuation. During the second infliximab treatment course, dosing was further intensified in 11 out of 29 (38%) patients. After 18 months 18/29 (62%), patients were still on continued therapy of their second infliximab treatment. Infliximab was discontinued (after a median of 7 mo) in 11 out of 29 patients for loss of response (n = 7 [24%]), intolerance (n = 3 [10%]), or non-compliance (n = 1 [3%]). Use of induction schedule or concomitant immunomodulators were not significantly associated with treatment benefit. CONCLUSIONS: The majority of patients with CD benefit from a second treatment with infliximab after previous treatment with infliximab and adalimumab, which offer a meaningful therapeutic option in often highly refractory patients.

Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy.

BACKGROUND: This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy. METHODS: This prospective multicenter study enrolled adult patients with UC in clinical remission under infliximab maintenance therapy. Fecal calprotectin levels were measured every 4 weeks. Sigmoidoscopies were performed at inclusion and at study end. Relapse was defined as a clinical need for change in treatment or an endoscopic Mayo subscore of ≥2 at week 52. Sustained deep remission was defined as a partial Mayo score <3 at all points and an endoscopic Mayo score 0 at week 52. RESULTS: Full analysis was possible for 87 of 113 included patients with UC (77%). Of these patients, 30 (34.4%) were considered to be in sustained deep remission and 13 (14.9%) to have relapsed. Calprotectin levels in patients with sustained deep remission remained very low (median < 40 mg/kg at all time points). Patients who flared had significantly higher calprotectin levels (median > 300 mg/kg) already 3 months before the flare. Further receiver operator curve analysis suggested that a calprotectin level >300 mg/kg had a reasonable sensitivity (58.3%) and specificity (93.3%) to model flare. Two consecutive calprotectin measurements of >300 mg/kg with 1-month interval were identified as the best predictor of flare (61.5% sensitivity and 100% specificity). CONCLUSIONS: Fecal calprotectin can be used in daily practice to monitor patients with UC receiving infliximab maintenance therapy. Two consecutive measurements >300 mg/kg is more specific than a single measurement for predicting relapse.