An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials

Background & Aims: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. Methods: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. Results: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. Conclusions: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty

Proteolytic cleavage and loss of function of biologic agents that neutralize tumor necrosis factor in the mucosa of patients with inflammatory bowel disease

BACKGROUND & AIMS: Many patients with inflammatory bowel disease (IBD) fail to respond to anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab, and etanercept is not effective for treatment of Crohn’s disease. Activated matrix metalloproteinase 3 (MMP3) and MMP12, which are increased in inflamed mucosa of patients with IBD, have a wide range of substrates, including IgG1. TNFneutralizing agents act in inflamed tissues; we investigated the effects of MMP3, MMP12, and mucosal proteins from IBD patients on these drugs. METHODS: Biopsy specimens from inflamed colon of 8 patients with Crohn’s disease and 8 patients with ulcerative colitis, and from normal colon of 8 healthy individuals (controls), were analyzed histologically, or homogenized and proteins were extracted. We also analyzed sera from 29 patients with active Crohn’s disease and 33 patients with active ulcerative colitis who were candidates to receive infliximab treatment. Infliximab, adalimumab, and etanercept were incubated with mucosal homogenates from patients with IBD or activated recombinant human MMP3 or MMP12 and analyzed on immunoblots or in luciferase reporter assays designed to measure TNF activity. IgG cleaved by MMP3 or MMP12 and antihinge autoantibodies against neo-epitopes on cleaved IgG were measured in sera from IBD patients who subsequently responded (clinical remission and complete mucosal healing) or did not respond to infliximab. RESULTS: MMP3 and MMP12 cleaved infliximab, adalimumab, and etanercept, releasing a 32-kilodalton Fc monomer. After MMP degradation, infliximab and adalimumab functioned as F(ab’)2 fragments, whereas cleaved etanercept lost its ability to neutralize TNF. Proteins from the mucosa of patients with IBD reduced the integrity and function of infliximab, adalimumab, and etanercept. TNF-neutralizing function was restored after incubation of the drugs with MMP inhibitors. Serum levels of endogenous IgG cleaved by MMP3 and MMP12, and antihinge autoantibodies against neo-epitopes of cleaved IgG, were higher in patients who did not respond to treatment vs responders. CONCLUSIONS: Proteolytic degradation may contribute to the nonresponsiveness of patients with IBD to anti-TNF agents

Mucosal Healing in Ulcerative Colitis: A Comprehensive Review

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such as rectal bleeding, diarrhea and weight loss, and may require hospitalization and even colectomy. Long-term complications of UC include decreased quality of life and productivity and an increased risk of colorectal cancer. Mucosal healing (MH) has gained progressive importance in the management of UC patients. In this article, we review the endoscopic findings that define both mucosal injury and MH, and the strengths and limitations of the scoring systems currently available in clinical practice. The basic mechanisms behind colonic injury and MH are covered, highlighting the pathways through which different drugs exert their effect towards reducing inflammation and promoting epithelial repair. A comprehensive review of the evidence for approved drugs for UC to achieve and maintain MH is provided, including a section on the pharmacokinetics of anti-tumor necrosis factor (TNF)-alpha drugs. Currently approved drugs with proven efficacy in achieving MH in UC include salicylates, corticosteroids (induction only), calcineurin inhibitors (induction only), thiopurines, vedolizumab and anti-TNF alpha drugs (infliximab, adalimumab, and golimumab). MH is of crucial relevance in the outcomes of UC, resulting in lower incidences of clinical relapse, the need for hospitalization and surgery, as well as reduced rates of dysplasia and colorectal cancer. Finally, we present recent evidence towards the need for a more strict definition of complete MH as the preferred endpoint for UC patients, using a combination of both endoscopic and histological findings.info:eu-repo/semantics/publishedVersio

Infliximab Pharmacokinetics are Influenced by Intravenous Immunoglobulin Administration in Patients with Kawasaki Disease.

BackgroundInfliximab, a monoclonal antibody directed against tumor necrosis factor-α, is being evaluated as adjunctive therapy to intravenous immunoglobulin (IVIG) for treatment of young children with acute Kawasaki disease (KD).ObjectiveThe aim of this study was to develop a population pharmacokinetic (PopPK) model for infliximab in children with KD, and to evaluate the impact of covariates on infliximab disposition. Specifically, we wanted to investigate the effect of body weight and IVIG administration on PK parameters.MethodsIn the current PopPK analysis, 70 subjects with a median (interquartile range) age of 2.9 years (1.3-4.4) were included from two randomized controlled trials. Infliximab concentration-time data were best described by a two-compartment model with first-order elimination using non-linear mixed-effects modeling (NONMEM 7.3).ResultsThe clearance, volume of distribution of the central (V1) and peripheral (V2) compartment, and intercompartmental clearance estimates (95% confidence interval) from the PopPK analysis were 0.117 (0.091-0.134) L/day, 0.801 (0.545-0.960) L, 0.962 (0.733-1.759) L, and 0.692 (0.482-1.779) L/day, respectively. Allometric body weight was included on all parameters of the structural model and a covariate analysis revealed that administering infliximab after IVIG, as opposed to before, resulted in a 50% decrease in V2.ConclusionsOur study shows that the timing of infliximab administration relative to IVIG administration affects the disposition of the monoclonal antibody. These results may have important implications for other monoclonal antibodies administered in combination with IVIG for treating inflammatory diseases

New visions of welfare

Background Formation of antibodies to infliximab (ATI) inversely correlates with functional drug levels and clinical outcome. Comparison of drug levels and anti-drug antibody monitoring is hampered by lack of standardisation. Aim To determine the correlation between three different assays for measuring infliximab and ATI. Methods Serum samples and spiked controls (total 62) were evaluated in a blinded way in infliximab and ATI assays developed by Sanquin Amsterdam, Netherlands (A), Laboratory for Pharmaceutical Biology, KU Leuven, Belgium (B) and a commercially available kit from Biomedical Diagnostics (BMD), Paris, France (C) performed by the University Medical Center Groningen (UMCG), Netherlands. Results All infliximab assays showed a linear quantitative correlation (Pearson r = 0.91 for A vs. B, 0.83 for A vs. C and 0.73 for B vs. C). Assay C detected infliximab in 11 samples (18%) not detected by A and B, including samples containing only ATI. All ATI assays showed a good linear correlation (Pearson r = 0.95 for A vs. B, 0.99 for A vs. C and 0.97 for B vs. C). Assay A detected ATI in five samples with low ATI that were not detected by assays B and C. Assay B did not detect ATI in three patient samples with low ATI according to assays A and C. Conclusions There is a good correlation of infliximab and antibodies to infliximab measurements between these assays. Nevertheless, the Biomedical Diagnostics kit detected false positive infliximab levels in 18% of the samples