Introduction

Advances in medical management of Crohn’s disease (CD) have improved disease outcomes; however, significant gaps remain. Approximately 30% of patients experience primary non-response to induction therapy with biologics, and over 40% will experience loss of response. There is an urgent need to identify new adjunct therapies, including diet, that can alter the disease course. Dietary patterns characterized by increased intakes of fibre, fruit, vegetables and decreased intakes of processed foods, sugar and omega-6 fatty acids are linked to a reduced prevalence of CD and decreased biomarkers of intestinal and systemic inflammation; however, the effects upon mucosal inflammation are unknown in patients who have lost response to usual medical treatments. We developed the CD Therapeutic Dietary Intervention (CD-TDI), a novel dietary approach incorporating best practices and current evidence to determine its therapeutic potential in reducing inflammation in patients with active CD who have lost response to their usual therapies.

Aims & Methods

This 13-week RCT aimed to explore the efficacy of the CD-TDI compared with conventional management (CM) to reduce clinical disease activity (Harvey-Bradshaw Index (HBI) <5) and reduce mucosal inflammation, as measured by fecal calprotectin (FCP) in mild-to-moderately active luminal CD. Patients with mild to moderately active disease, determined by endoscopic, cross-sectional imaging or FCP >100 ug/g, on stable medical therapy 8 weeks prior to recruitment were eligible to participate (n=28). Upon randomization, the CD-TDI group (n=16) met virtually with a registered dietitian trained in the CD-TDI protocol weekly for 13 weeks. Participants assigned to CM (n=12) followed their habitual diet and met with the same registered dietitian as participants in the CD-TDI group at week 0 (W0) and week 13 (W13) to capture their dietary recall. FCP, HBI, and C-reactive protein (CRP) were assessed at W0 and W13.

Results

Twenty-eight participants (53% females, age 40 years (IQR:31-55); BMI 27 kg/m² (IQR:24-31)) were enrolled. Medical therapy did not differ between groups, with 54% (15/28) of participants receiving no drug therapy, 29% (8/28) 5-ASA monotherapy, 21% (6/28) biologic therapy, 11% (3/28) corticosteroids or 14% (4/28) immunomodulators. At W0, the FCP, HBI and CRP did not differ significantly between groups. In the CD-TDI group, FCP decreased significantly from 130 ug/g (IQR: 38-411) at W0 to 72 ug/g (IQR:3-153) at W13 (p= 0.01) and significantly differed between the CM group at W13 (p=0.04). In a sub-group analysis (n=11) of participants with FCP >250 ug/g at W0, at W13 the FCP decreased significantly from 632 ug/g (IQR: 356-1013) to 166 ug/g, (IQR:52-701) (p=0.06) within the CD-TDI group, however, this same trend was not observed in the CM (W0:337 ug/g IQR:324-1013 vs. W13:431 ug/g, IQR:46-1770, p=0.69). At W13, between-group differences in the CRP were found between the CD-TDI group (1.0 mg/L, IQR:0.6-2.4) and the CM group (4.5 mg/L, IQR:2.6-13.0) (p=0.002). The CD-TDI group experienced a significant decrease in HBI from W0 to W13 (W0: 3.0, IQR:1.0-5.3; W13: 2.0, IQR:0-3.0; p=0.05), however, this was not observed in the CM group.

Conclusion

At W13, the CD-TDI significantly decreased clinical and biochemical markers of inflammation in patients with mild-to-moderately active CD. This preliminary analysis suggests that CD-TDI could be a potential adjunct management strategy for reducing inflammation in CD. We hope to confirm these promising results with an adequately powered sample.

Introduction

Based on the Chicago classification, HREM diagnosis is classically based on metrics obtained with wet swallows carried out in the supine position. However, both patients and physicians often feel that this is not a physiological position to conduct the test as it may not translate to the real world experience. With the patient in the upright/sitting position, the test would more closely simulate real-life behaviour and may be safer for elderly patients at risk of aspiration.

Aims & Methods

In an Asian tertiary centre, a total of 104 patients had undergone high resolution esophageal manometry (HREM) with retrospective data analysis comparing both conventional supine position with the upright position. The latter is generally favoured by all patients as this represents the physiological posture during meals.

Results

Using 2-tailed paired sample T-test, comparison across all cases showed a consistently lower median Integrated Relaxation Pressure (IRP) [6.0 mmHg vs to 8.7 mmHg; p <0.01] and lower mean Distal Contractile Integral (DCI) [1463 mmHg/cm/sec vs 1864 mmHg/cm/sec; p =0.014] in the upright posture compared to supine position although the mean Distal Latency (DL) difference was not significant [6.21secs vs 6.27 secs; p =0.491]. During upright and supine position comparison respectively, subgroup analysis on subjects with normal HREM diagnosis showed even lower median IRP [4.9 mmHg vs 7.5 mmHg; p <0.01] and lower mean DCI results [1436 mmHg/cm/sec vs 1695 mmHg/cm/sec; p <0.01] with mean DL in this subgroup showing no significant statistical difference [6.29 secs vs 6.38secs; p=0.545]. The final HREM diagnosis in upright position is concordant with the conventional supine position up to 81.7% and showed an even higher concordance in terms of management similarity up to 98.1%. Only 2 cases (2/104) showed a significant discordance between supine and upright HREM diagnosis [normal HREM vs esophagogastric juntion –outflow obstruction(EGJ-OO) and hypercontractile esophagus vs normal HREM]. Minor diagnostic discordance [normal HREM vs ineffective esophageal motility (IEM)] was noted in 17/104 cases which had no major clinical impact on patients and may be overcome by adopting a lower cut-off for mean DCI for upright group.

Conclusion

In patients who are unable to perform HREM in supine position, adopting the upright position shows a high clinical concordance and may be considered a more physiological approach in the HREM protocol.

References

Riva CG, Siboni S, Ferrari D, Sozzi M, Capuzzo M, Asti E, Ogliari C, Bonavina L. Effect of Body Position on High-resolution Esophageal Manometry Variables and Final Manometric Diagnosis. J Neurogastroenterol Motil. 2020 Jul 30;26(3):335-343. doi: 10.5056/jnm20010. PMID: 32606256; PMCID: PMC7329148.

Introduction

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, predominantly diagnosed in patients with chronic liver diseases. The absence of specific biomarkers and the typically asymptomatic progression of the disease lead to delayed diagnosis. Patients with liver disease, including HCC, exhibit alterations in the gut microbiome and increased bacterial permeability, factors that may influence disease progression and patient outcomes. In recent years, there has been a growing interest in exploring circulating microbiome signatures as potential indicators of liver disease stutus, providing a new avenue for understanding HCC.

Aims & Methods

Aims: To identify the signatures of the circulating blood microbiome associated with hepatocellular carcinoma, response to treatment and disease prognosis.
Methods: This study conducted a post-hoc analysis of the SORAMIC clinical trial utilizing peripheral blood plasma samples. For this analysis, blood plasma samples from a cohort of 71 patients with HCC were examined (25 treated with Sorafenib and 46 with SIRT/Sorafenib). Peripheral blood samples were collected at two time points: baseline (prior to the initiation of anti-tumor therapy) with all 71 patients included, and post-therapy (7 to 9 weeks after treatment) with 39 patients included. Additionally, peripheral blood samples were obtained from 52 control subjects, who were endoscopically diagnosed with colonic diverticulosis, to compare against the patient group. The composition of the circulating blood microbiome was assessed through 16S rRNA gene sequencing, targeting the V1-V2 hypervariable regions. Subsequent analyses focused on identifying associations with potential novel biomarkers for diagnosis, prognosis, and response to treatment.

Results

Patients with HCC had significantly diminished α-diversity of the circulating blood microbiome as compared to controls. Significant differences were also observed in between microbial communities of these two cohorts based on Bray-Curtis dissimilarity index. Patients with HCC had significantly higher levels of Proteobacteria and Bacteroidetes and lower levels of Firmicutes and Campylobacterota. Differential abundance analysis revealed that families of Gordoniaceae, Cryomorphaceae, Burkholderiaceae, Comamonadaceae, Enterobacteriaceae were significantly enriched in patients with HCC. At the genus level, patients with HCC had higher levels of Gordonia, Fluviicola, Burholderia, Limnohabitans and Escherichia/Shigella and lower levels of Corynebacterium. HCC patients, who responded to treatment with SIRT/Sorafenib showed an increase in blood bacterial diversity, enrichment of families Burkholderiales incertae sedis, Arcobacteraceae, Peptostreptococcaceae, Moraxellaceae, genera Sphaerotilus, Aliacrobacter, Rhodoluna, Giesbergeria, Microbacterium, Romboutsia, Arcicella, Pseudorhodoferax and depletion in families Gordoniaceae, Cryomorphaceae and genera Cloacibacterium, Gordonia, Limnohabitans, Fluviicola after the treatment. Levels of Acinetobacter, Enhydrobacter and Micrococcus in the blood before the HCC treatment were associated with patient prognosis.

Conclusion

Patients with HCC exhibit a unique circulating blood microbiome profile characterized by reduced bacterial diversity. Response to treatment is linked to an increase in α-diversity and changes in the circulating microbiome profile. Specific members of the circulating microbiome show potential prognostic capabilities, suggesting their utility as biomarkers for predicting disease progression and treatment outcomes in HCC.

Introduction

Dietary fatty acids impact the fatty acid profile of cell membranes and act as a source of fatty acids for many key physiological pathways. Overconsumption of n-6 polyunsaturated fatty acids (PUFAs) with low intake of n-3 PUFAs is associated with the pathogenesis of inflammatory-driven diet-related chronic diseases, including CD. Derivatives of n-6 PUFAs, such as arachidonic acid (AA) are involved in the proinflammatory cascade, whereas the n-3 PUFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) maintain anti-inflammatory homeostasis. Considering that fatty acids in the cell membrane may be relevant to inflammation, we examined how changing the fatty acid composition of the diet would alter the erythrocyte cell membrane's (EM) fatty acid profile in adult patients with mild-moderate luminal CD following the CD Therapeutic Dietary Intervention (CD-TDI).

Aims & Methods

This is a sub-study (n=24, 46% female, median age 43(31-54)) of an ongoing RCT designed to determine the effectiveness of the CD-TDI to induce clinical and biomarker remission in patients with CD. We examined how the fatty acid profile of the EM changes in adults with mild-moderate luminal CD (n=13) that follow the CD-TDI or their habitual diet (HD) (n=11) for 13 weeks. The CD-TDI is a whole-food diet which incorporates principles of the Mediterranean diet, with one strategy being to shift the fatty acid profile by limiting dietary sources of n-6 PUFA, increasing dietary sources of n-3 PUFA and monounsaturated fatty acids (MUFA). The HD did not change their dietary intake. Blood samples were collected at Week 0 (W0) and Week 13 (W13) and analyzed for EM fatty acid composition. Fatty acids were extracted using a combined extraction and methylation protocol with direct-injection gas chromatography to quantify long-chain fatty acids from the EM. Dietary intake was evaluated using the ASA 24-hour Dietary Assessment Tool^®.

Results

Diet analysis comparing intakes from W0 to W13 revealed a significant reduction in AA intake (p=0.05) with a trend for increased intake of n-3 PUFA from DHA (p=0.07). The HD group had a significantly higher intake of AA (p=0.03), with no other dietary changes in fatty acid intakes observed within or between groups. In the EM of the CD-TDI group, within-group differences at W13 showed a lower percentage of arachidonic acid (n-6 PUFA) (0.3±0.3% vs. 0.1±0.1%, p=0.03), a significant increase in oleic acid (MUFA) (12±2.3% vs 13±2.2% p=0.02) and a trend for higher DHA (n-3 PUFA) (2.9±0.9% vs. 3.4±0.9%; p=0.08). No significant differences within groups were observed in the HD at W0 and W13. Between-group differences at W13 demonstrated that the CD-TDI group had a significantly higher mean percentage of total EM n-3 PUFAs than the HD (4.4% vs. 3.2%; p=0.005). At week 13 a higher EM PUFA balance (EPA+DHA/n-6 PUFA) was observed between groups (CDI:15±3.1% vs HD:11±2.1%; p=0.002). PUFA balance was inversely correlated to the change in the intestinal biomarker fecal calprotectin at W13 in the CDI-group (r2=0.634; p=0.03).

Conclusion

The CD-TDI altered the fatty acid profile of the EM in patients with mild-moderately active CD. Within the EM, the CD-TDI group demonstrated significant reductions in the proinflammatory mediatory AA while increasing oleic acid, total n-3 PUFA, leading to a higher PUFA balance which correlated with intestinal biomarkers of mucosal inflammation. More research is needed to fully understand the relationship between EM and gut inflammation to determine the underlying mechanisms involved.

Introduction

The randomized controlled OPTIC trial reported that optimised mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at one year in ulcerative colitis (UC) patients failing 5-aminosalicylates after receiving induction treatment with corticosteroids.

Aims & Methods

We aimed to assess cost-effectiveness and cost-utility of therapeutic drug monitoring (TDM)-guided mercaptopurine treatment in UC. Data were collected during the OPTIC trial to perform a health economic evaluation for mercaptopurine treatment versus placebo in UC patients. The economic evaluation was performed from a health care and societal perspective using a cost-effectiveness and cost-utility analysis with a time horizon of one year. Volumes and costs of in-hospital care, out-of-hospital care, out-of-pocket expenses and productivity loss were assessed. Main outcomes were the costs per patient who achieved combined corticosteroid-free clinical remission and endoscopic improvement at one year and the costs per quality-adjusted life-year (QALY).

Results

In total, 59 patients were randomized to the intervention (n = 29) and control (n = 30) group. Patients on mercaptopurine treatment showed a non-significant gain in QALYs of 0.047 (-0.024 to 0.117) (P=0.184) corrected for baseline health utility. Non-significant differences in costs were €63 (-€1267 to €1434; P=0.927) in favour of placebo from a health care perspective and -€742 (-€3683 to €2016; P=0.644) in favour of mercaptopurine from a societal perspective, including patients’ out-of-pocket expenses and employers’ productivity loss. The probability of optimised mercaptopurine treatment being cost-effective was 0.80 at a willingness to pay per additional QALY of €20,000.

Conclusion

Optimised mercaptopurine treatment in UC patients failing 5-aminosalicylates is a cost-effective strategy from a societal perspective.

References

1. de Boer NKH, Peyrin-Biroulet L, Jharap B, et al. Thiopurines in inflammatory bowel disease: new findings and perspectives. J Crohns Colitis 2018;12:610–20.
2. Löwenberg, M., Volkers, A., van Gennep, S., Mookhoek, A., Montazeri, N., Clasquin, E., Duijvestein, M., van Bodegraven, A., Rietdijk, S., Jansen, J., van Asseldonk, D., van der Zanden, E., Dijkgraaf, M., West, R., de Boer, N., & D'Haens, G. (2023). Mercaptopurine for the Treatment of Ulcerative Colitis: A Randomized Placebo-Controlled Trial. Journal of Crohn's & Colitis, 17(7), 1055–1065.

Disclosure

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