Background and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to ...anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.
Summary
Background
The presence of antibodies towards infliximab (ATI) is associated with lower infliximab (IFX) trough concentrations and loss of response. IFX treatment intensification is effective ...for restoring response in most, but not all patients with Crohn's disease (CD).
Aim
To compare outcome, pharmacokinetics and immunogenicity of treatment intensification strategies in patients with CD who lost clinical response to IFX.
Methods
A retrospective cohort study was conducted, including 103 patients with CD who lost clinical response during IFX maintenance therapy and therefore received a double dose IFX (10 mg/kg) and/or a next infusion after a shortened interval. IFX and ATI concentrations were measured in consecutive trough samples, just before (T0) and after (T+1) treatment intensification.
Results
Clinical response (physicians' global assessment) and biological response and remission (CRP) were restored in 63%, 42% and 24% of patients (evaluated at T+1). Treatment intensification increased IFX trough concentrations from 1.2 μg/mL 0.3‐3.6 at T0 to 3.6 μg/mL 0.5‐10.2 at T+1 (P < .0001). Using a drug tolerant assay, ATI were detected in the T0 sample of 47% of patients. ATI negatively impacted the achieved IFX trough concentration (Spearman r −0.57, P < .0001) and the probability of clinical response (P = 0.034) at T+1. When ATI were quantifiable but <282 ng/mL eq. at T0, combined interval shortening and dose doubling was more effective for restoring therapeutic IFX trough concentrations (≥3 μg/mL at T+1) than dose doubling alone, which in turn was more effective than interval shortening alone (P < .001).
Conclusion
Antibodies towards infliximab can guide clinical decision‐making on treatment intensification.
Linked ContentThis article is linked to Ben‐Horin paper. To view this article visit https://doi.org/10.1111/apt.14489.
The understanding that differences in biological epistasis may impact disease risk, diagnosis, or disease management stands in wide contrast to the unavailability of widely accepted large-scale ...epistasis analysis protocols. Several choices in the analysis workflow will impact false-positive and false-negative rates. One of these choices relates to the exploitation of particular modelling or testing strategies. The strengths and limitations of these need to be well understood, as well as the contexts in which these hold. This will contribute to determining the potentially complementary value of epistasis detection workflows and is expected to increase replication success with biological relevance. In this contribution, we take a recently introduced regression-based epistasis detection tool as a leading example to review the key elements that need to be considered to fully appreciate the value of analytical epistasis detection performance assessments. We point out unresolved hurdles and give our perspectives towards overcoming these.
Background and aims:This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn’s disease (CD) from a single centre during a median ...follow-up of 55 months (interquartile range (IQR) 27–83).Methods:The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed.Results:10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group.Conclusions:In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.
The emphasis on implementation of value-based healthcare (VBHC) has increased in the Dutch healthcare system. Yet, the translation of the theoretical principles of VBHC towards actual implementation ...in daily practice has been rarely described. Our aim is to present a pragmatic step-by-step approach for VBHC implementation, developed and applied in Amsterdam UMC, to share our key elements. The approach may inspire others and can be used as a template for implementing VBHC principles in other hospitals.
The local approach is developed in a major academic hospital in the Netherlands, based at two locations with 15,000 employees in total. Experience-based co-design is used, building on our learning experiences from implementing VBHC for 14 specific patient groups. The described steps and activities devolved from iterative and participative co-design sessions with various experienced stakeholders involved in the implementation of one or more VBHC pathways.
The approach includes five phases; preparation, design (team introduction, outcome selection, action agenda), building (outcome set integration in daily practice), implementation (training, outcome registration and implementation) and the continuous improvement cycle. We described two cases for illustration of the approach; the Cleft Lip and Palate and the Chronic Kidney Disease patient groups. For a good start, involvement of a clinical leader as driving force, ensuring participation of patient representatives and sufficient resources are needed.
We have experienced that several defining features of the development and implementation of this approach may have contributed to its completeness and applicability. Key elements for success have been organisational readiness and clinical leadership. In conclusion, the approach has provided a first step towards VBHC in our hospital. Further research is needed for evaluation of its effectiveness including impact on value for patients.
Background and aims: Elicitation of an innate immune response to bacterial products is mediated through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs) and the NODs. The ...recently characterised Asp299Gly polymorphism in the lipopolysaccharide (LPS) receptor TLR4 is associated with impaired LPS signalling and increased susceptibility to Gram negative infections. We sought to determine whether this polymorphism was associated with Crohn’s disease (CD) and/or ulcerative colitis (UC). Methods: Allele frequencies of the TLR4 Asp299Gly polymorphism and the three NOD2/CARD15 polymorphisms (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were assessed in two independent cohorts of CD patients (cohort 1, n = 334; cohort 2, n = 114), in 163 UC patients, and in 140 controls. A transmission disequilibrium test (TDT) was then performed on 318 inflammatory bowel disease (IBD) trios. Results: The allele frequency of the TLR4 Asp299Gly polymorphism was significantly higher in CD (cohort 1: 11% v 5%, odds ratio (OR) 2.31 (95% confidence interval (CI) 1.28–4.17), p = 0.004; and cohort 2: 12% v 5%, OR 2.45 (95% CI 1.24–4.81), p = 0.007) and UC patients (10% v 5%, OR 2.05 (95% CI 1.07–3.93), p = 0.027) compared with the control population. A TDT on 318 IBD trios demonstrated preferential transmission of the TLR4 Asp299Gly polymorphism from heterozygous parents to affected children (T/U: 68/34, p = 0.01). Carrying polymorphisms in both TLR4 and NOD2 was associated with a genotype relative risk (RR) of 4.7 compared with a RR of 2.6 and 2.5 for TLR4 and NOD2 variants separately. Conclusion: We have reported on a novel association of the TLR4 Asp299Gly polymorphism with both CD and UC. This finding further supports the genetic influence of PRRs in triggering IBD.
Background and aims: Several antibodies have been associated with Crohn’s disease and are associated with distinct clinical phenotypes. The aim of this study was to determine whether a panel of new ...antibodies against bacterial peptides and glycans could help in differentiating inflammatory bowel disease (IBD), and whether they were associated with particular clinical manifestations. Methods: Antibodies against a mannan epitope of Saccharomyces cerevisiae (gASCA), laminaribioside (ALCA), chitobioside (ACCA), mannobioside (AMCA), outer membrane porins (Omp) and the atypical perinuclear antineutrophilic cytoplasmic antibody (pANCA) were tested in serum samples of 1225 IBD patients, 200 healthy controls and 113 patients with non-IBD gastrointestinal inflammation. Antibody responses were correlated with the type of disease and clinical characteristics. Results: 76% of Crohn’s disease patients had at least one of the tested antibodies. For differentiation between Crohn’s disease and ulcerative colitis, the combination of gASCA and pANCA was most accurate. For differentiation between IBD, healthy controls and non-IBD gastrointestinal inflammation, the combination of gASCA, pANCA and ALCA had the best accuracy. Increasing amounts and levels of antibody responses against gASCA, ALCA, ACCA, AMCA and Omp were associated with more complicated disease behaviour (44.7% versus 53.6% versus 71.1% versus 82.0%, p < 0.001), and a higher frequency of Crohn’s disease-related abdominal surgery (38.5% versus 48.8% versus 60.7% versus 75.4%, p < 0.001). Conclusions: Using this new panel of serological markers, the number and magnitude of immune responses to different microbial antigens were shown to be associated with the severity of the disease. With regard to the predictive role of serological markers, further prospective longitudinal studies are necessary.
The Standardized Uptake Value (SUV) in single lesions on 18F-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this ...study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up.
In 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed.
S-100B was elevated (>0.15 μg/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R2 = 0.19). S-100B was correlated to both MATV (R2 = 0.375) and TLG (R2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p < 0.001) and also in patients with elevated LDH (>250 U/l) (p < 0.001). There was no association between the biomarkers and SUVmean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival.
In newly diagnosed stage IV melanoma patients S-100B correlates with 18F-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis.
Abstract Genes of innate immunity may be involved in early onset of chronic Pa ( Pseudomonas aeruginosa ) colonization (c Pa C) in cystic fibrosis (CF) patients. We studied 19 single nucleotide ...polymorphisms (SNPs) in 5 genes coding for proteins of the lectin complement pathway: MBL2 ( Mannose binding lectin 2 ), MASP 1 , 2 , 3 (MBL-associated serine Protease) and FCN 1 , 2 ( Ficolin ) gene in 96 CF patients. Association survival analysis using different genetic models was performed looking for an association between SNPs and age at onset of c Pa C. CF patients who are MBL deficient are earlier chronic Pa colonized compared to MBL sufficient patients. Also patients with MBL2 genotype YO/YO, YO/XA, XA/XA, YA/YO and YA/XA are earlier chronic Pa colonized. CF patients heterozygous or homozygous for mutant alleles of two linked SNPs in the FCN1 gene (rs2989727 and rs1071583) are earlier colonized with Pa. Similarly, earlier onset of Pa colonization is seen in CF patients heterozygous for linked SNPs of FCN2 gene (rs7865453 and rs7851696) and MASP3 gene (rs7851696). Variants in MBL2 , FCN1 , FCN 2 and MASP3 genes are significantly associated with earlier onset of chronic P. aeruginosa colonization.
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