Clinical Case Summary

Pyoderma Gangrenosum (PG) is a rare ulcerative neutrophilic dermatosis, usually associated with Inflammatory Bowel Disease (IBD) (1). Treatment is challenging, often involving a variety of immunosuppressive therapies. The introduction of anti-tumor necrosis factor alpha (anti TNFα) drug is a current treatment option for IBD patients with dermatological manifestations (2,3). We report the case of a 46 years-old-man diagnosed with ileal Crohn Disease (CD) and simultaneous PG multifocal lesions located on the cheek, abdomen, back of the feet and hands bilaterally. The patient received oral corticosteroids, mesalazine and azathioprine for 11 years, with partial skin improvement; then, when he was 57 -year-old, he referred to our Gastroenterology Unit. Physical examination showed extensive inflammatory erytematous plaque and violaceous vesicles of various sizes located on the cheeks, abdomen, back of the feet and hands bilaterally with functional impairment of limbs. Some of the lesions had undergone central necrosis and ulceration (Fig 1). Colonoscopy showed mild ileal CD confirmed to biopsies. Laboratory tests showed anemia, leukocytosis, and increased inflammatory markers; quantiferon test was negative. The patient received Infliximab (IFX) 5 mg/kg; after the induction phase, he showed partial lesions improvement. At week 12 his skin was completely healed except the abdominal wall. Optimization of IFX treatment every 6 weeks achieved complete healing in the abdominal, hands, cheeks and feet lesions (Fig2). We tried, unsuccessfully, to extend the drug-free time at 8 weeks, because the patient showed early PG reactivation marks (Fig3). After 8 years, both intestinal and cutaneous manifestations maintained long term healing. Our case report suggest that: I) IFX optimization therapy is effective and safe in the long-term treatment of CD associated multifocal PG; II) IFX was well tolerated with no adverse events; III) no intestinal disease recurrence occurred.

References

1 Vavricka SR, Brun L, Ballabeni P, Pittet V, Prinz Vavricka BM, Zeitz J, Rogler G, Schoepfer AM. Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort. Am J Gastroenterol. 2011 Jan;106(1):110-9. doi: 10.1038/ajg.2010.343. Epub 2010 Aug 31. PMID: 20808297.
2 Zippi M, Pica R, De Nitto D, Paoluzi P. Biological therapy for dermatological manifestations of inflammatory bowel disease. World J Clin Cases. 2013 May 16;1(2):74-8. doi: 10.12998/wjcc.v1.i2.74. PMID: 24303470; PMCID: PMC3845939.
3 Al Ghazal P, Dissemond J. Therapy of pyoderma gangrenosum in Germany: results of a survey among wound experts. J Dtsch Dermatol Ges. 2015 Apr;13(4):317-24. doi: 10.1111/ddg.12585. Epub 2015 Mar 11. PMID: 25761564.

Introduction

Tumor necrosis factor-like ligand 1A (TL1A) has been implicated in numerous immune-mediated and fibrotic diseases, such as inflammatory bowel disease (IBD) and asthma, making it an ideal target for therapeutic intervention. TEV-48574 is a human IgG1 monoclonal antibody with a novel mechanism of action that preferentially inhibits binding of TL1A to the Death Receptor 3 (DR3), involved in proinflammatory signaling, with a greater potency compared to the Decoy Receptor (DcR3), which could preserve the natural homeostatic mechanism. TEV-48574 has been shown to reduce fibrosis, inflammation, and mortality in animal models of IBD and asthma.¹ A phase 1 first-in-human (FIH) study, comprised of a single ascending dose (SAD) and a multiple ascending dose (MAD) phase, assessed safety, tolerability, immunogenicity, pharmacodynamic and pharmacokinetics of TEV-48574 amongst healthy participants and those with asthma. It has also been assessed in a phase 2A uncontrolled T2 low/non T2 asthma proof-of-concept (POC) study, where results from an interim analysis met predefined futility criteria leading to early termination. TEV-48574 is in clinical development as a potential treatment for ulcerative colitis and Crohn’s disease. This analysis aims to evaluate target engagement; free TL1A levels were measured in phase 1 and phase 2A TEV-48574 studies.

Aims & Methods

Free TL1A levels were measured using a ligand binding assay in the FIH and POC studies. In the FIH SAD phase, healthy participants were administered TEV-48574 as a single dose (1-1000 mg) or placebo by subcutaneous (SC) route. In the FIH MAD phase, mild asthmatic patients were randomized to active (up to 2300 mg) or placebo SC treatment. The phase 2A POC study was a 16-week randomized, double-blind, parallel-group trial to evaluate the efficacy, tolerability, and safety of a single dose regimen of TEV-48574 compared to placebo.

Results

In the FIH study, following SAD and MAD administration, while unchanged in the placebo group, free TL1A levels showed a rapid reduction at the first analyzed time point (1 hour after dose) in the active treatment groups. The free TL1A levels in the MAD phase of the FIH study remained suppressed up to day 92 (63 days after last dose, pooled result for doses), despite extremely low remaining TEV-48574 concentrations. In the POC study, TEV-48574 resulted in reduction of free TL1A levels, sustained up to ~10 weeks after the last dose. An analysis of patients who received all doses showed a persistent pharmacodynamic effect, demonstrated by continued suppression of free TL1A despite decreasing concentrations of TEV-48574 after the last dose on day 98.

Conclusion

Target engagement was shown by a rapid and sustained TEV-48574-mediated suppression of free TL1A that persisted longer than the drug exposure. Given that TL1A has been implicated in the pathogenesis of immune-mediated and fibrotic diseases, such as IBD¹, the data herein support further development of TEV-48574 in patients with ulcerative colitis and Crohn’s disease.

References

1. Clarke AW, et al. mAbs. 2018;10:4664-77.

Disclosure

All other authors are employees of Teva Pharmaceuticals. TEV-48574 is being developed in a partnership between Teva and Sanofi.

Introduction

Patients with decompensated cirrhosis have high mortality rates. Several prognostic scores have been developed, based on clinical and laboratory parameters, to assess the prognosis of patients with cirrhosis. However, to date, there is no consensus on the best prognostic model. The MELD 3.0 score was recently published with the aim of refining the MELD score to contemporary data.

Aims & Methods

The objective of this study was to evaluate and compare models based on the hepatic severity index to investigate their predictive performance in mortality.
A retrospective cohort study was conducted, including consecutively admitted patients to a Gastroenterology Department for first admission due to decompensated cirrhosis. MELD, MELD-Na, MELD 3.0, and Child-Pugh scores were calculated upon admission. Mortality at 6 weeks and 180 days was the main outcome studied.

Results

109 patients admitted for the first episode of decompensated cirrhosis were included, 82.6% with alcoholic aetiology. Mean age was 61.8 ±10.8 years, 73.4% were men and 26.6% were women. Of the included patients, 11% died within the first 6 weeks and 25.7% died within the first 180 days after admission.
All models showed good accuracy in predicting mortality at 6 weeks and 180 days, with slight superiority of the MELD 3.0 score (AUC 0.693, 95% CI 0.598-0.778 at 6 weeks; AUC 0.712, 95% CI 0.617-0.795 at 180 days), although statistically significant differences between the different prognostic models were not observed.

Conclusion

The use of models based on hepatic severity indices accurately predicts the risk of mortality at 6 weeks and 180 days in patients with decompensated cirrhosis. The new MELD 3.0 score showed superior predictive performance in mortality, although without statistically significant differences.

Introduction

Lymphangiectasia and lymphangiectic cysts result from dilated intestinal lacteals due to disordered drainage. This can result in leakage of lymph into the lumen with resultant hypoproteinaemia, hypogammaglobulinaemia, hypoalbuminaemia and a lymphopenia (1,2). This is most clinically apparent in those with widespread severe change, such as congenitally anomalous drainage or secondary causes including, infections, lymphoma/malignancy, inflammation or radiotherapy (1,3,4). This can result in malabsorption or widespread failure of lymphatic drainage.
It is unclear whether subtle incidental lymphangiectasia without clinical malabsorption are significant. Subtle, incidentally noted changes including scattered pinpoint white spots, prominent villi with white tips and small focal macules or nodules (5) are an increasingly common finding. With increased use of high-definition capsule technology, more subtle changes are increasingly recognised. Older studies show these are common, with follow up and fat absorption studies concluding that incidentally noted dilated lacteals, without clinical malabsorption likely did not require follow up (5–7).

Aims & Methods

We aim to assess whether the incidental, and “clinically insignificant”, lymphangiectasia seen on capsule endoscopy are associated with changes in protein, albumin, cholesterol, triglyceride, calcium or lymphocyte levels. The hypothesis being that more subtle lymphatic anomaly will result in a more subtle biochemical picture.
Values are stated as means (+/- SD) with P values calculated using two tailed t-test or Chi square, <0.05 taken as significant.

Results

21 patients with lymphangiectasia noted to be the only, or main, finding on capsule endoscopy were retrospectively reviewed. 21 age and gender matched controls (61.9% male, aged 52 (+/-15) years) with normal capsule and colonoscopies were extracted for comparison. Comorbidities and blood results were recorded for each.
Two patients with clinically significant widespread lymphatic changes secondary to systemic disease (disseminated mycobacterial infection and end stage cirrhosis both with lymphatic obstruction) were excluded. The remaining patients had either incidental scattered white tipped villi, discrete nodules/polyps of dilated white villi, or discrete chylous cysts (or a combination of these).

Conclusion

This study would suggest that those with lymphangiectasia have lower protein, albumin, calcium, cholesterol, and triglyceride levels (protein, albumin and triglycerides reaching statistical significance). There is a paucity of recent research in this field and the historical assumption that incidentally noted lymphangiectasia are meaningless may not be entirely accurate. Correlation does not equal causation as these markers are dependent on a huge number of factors. This is a small patient group, and a larger study would be required to further explore this. Selectively blocking small bowel lymphatics may represent a potential therapeutic target and further research in this field could have a range of clinical implications.

References

1. Freeman HJ, Nimmo M. Intestinal lymphangiectasia in adults. World J Gastrointest Oncol. 2011;3(2):19.
2. Hu D, Cui X, Ren W, Zhang J, Guan X, Jiang X. A case of primary intestinal lymphangiectasia with non-Hodgkin lymphoma. BMC Gastroenterol. 2021 Dec;21(1):461.
3. Iwamuro M, Tanaka T, Kanzaki H, Kawano S, Kawahara Y, Iwasaki Y, et al. Deterioration of duodenal lymphangiectasia after radiotherapy for gastric MALT lymphoma. ecancermedicalscience [Internet]. 2017 Jul 11 [cited 2023 Apr 1];11. Available from: http://www.ecancer.org/journal/11/full/752-deterioration-of-duodenal-lymphangiectasia-after-radiotherapy-for-gastric-malt-lymphoma.php
4. Taveira F, Magalh�es JP, Brito D. Duodenal Lymphangiectasias - The first sign of Pancreatic Adenocarcinoma. Rev Esp Enfermedades Dig [Internet]. 2021 [cited 2023 Apr 1]; Available from: https://online.reed.es/fichaArticulo.aspx?iarf=732799150340-589162820258
5. Kim J, Bak Y, Kim J, Seol S, Shin B, Kim H. Clinical significance of duodenal lymphangiectasia incidentally found during routine upper gastrointestinal endoscopy. Endoscopy. 2009 Jun;41(06):510–5.
6. Patel AS, DeRidder PH. Endoscopic appearance and significance of functional lymphangiectasia of the duodenal mucosa. Gastrointest Endosc. 1990 Jul;36(4):376–8.
7. Barnes RE, DeRidder PH. Fat absorption in patients with functional intestinal lymphangiectasia and lymphangiectic cysts. Am J Gastroenterol. 1993 Jun;88(6):887–90.

Introduction

ESSENCE (NCT04822181) is an ongoing 247-week Phase 3, randomised, placebo-controlled trial evaluating the effect of the glucagon-like peptide-1 analogue, semaglutide 2.4 mg subcutaneous once weekly (OW) in participants with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH). We report the baseline characteristics of the randomised participants.

Aims & Methods

Following a 14-week screening phase, 800 participants (part 1) of 1200 planned (part 2) with MASH and fibrosis stages 2/3 (F2/F3) were randomised 2:1 to receive semaglutide 2.4 mg subcutaneous OW or placebo OW added to standard of care. In part 1, the two primary endpoints at 72 weeks are resolution of steatohepatitis and no worsening of liver fibrosis, and improvement in liver fibrosis and no worsening of steatohepatitis. Based on a central pathologist evaluation, inclusion criteria were histological presence of steatohepatitis stages F2/F3 per the Nonalcoholic Steatohepatitis Clinical Research Network classification, and a non-alcoholic fatty liver disease activity score (NAS) of ≥ 4, with a score of ≥ 1 in steatosis, lobular inflammation and hepatocyte ballooning.

Results

800 participants (250 F2; 550 F3) were randomised. Mean (SD) age was 56 (11.6) years; 57.1% were female; ≥ 99% had ≥ 1 cardiometabolic risk factor(s) in accordance with the metabolic dysfunction-associated steatotic liver disease (MASLD) definition. Mean (SD) NAS was 5.05 (0.95), and higher in F3 versus F2 (5.11 [0.95] vs 4.92 [0.93], respectively). Notably, participants with a higher NAS had more cardiometabolic risk factors for MASLD (52.9% with NAS ≥ 5 vs 45.3% with NAS 4). Similarly, a greater proportion of participants with F3 had all five cardiometabolic risk factors versus F2 (52.9% vs 44.8%, respectively). Although cardiometabolic comorbidities were highly prevalent, 44.5% of participants did not have type 2 diabetes (T2D), and 27.3% did not have obesity. Normal liver transaminases were observed in 26.3% of participants (28% F2; 26% F3). Mean (SD) FibroScan liver stiffness was 12.8 (6.9) kPa, and values of < 8 kPa were observed in 15.3% of participants. Mean (SD) controlled attenuation parameter value was 329 (46) dB/m; mean (SD) enhanced liver fibrosis (ELF) score was 10.0 (1.0), and 43.5% of participants had an ELF score of < 9.8. Overall, 8.8% and 9.0% of participants with/without T2D did not meet any of the following non-invasive criteria: Fibrosis-4 index ≥ 1.3, vibration-controlled transient elastography ≥ 8.1, or ELF ≥ 9.8, and more participants with F2 (14.7–16.4%) did not meet these criteria versus F3 (4.5–6.7%).

Conclusion

The ESSENCE baseline population includes participants with significant fibrosis (F2 and F3) and approximately 91% of the trial population had ≥ 1 positive diagnostic non-invasive test. Cardiometabolic risk factors were found in ≥ 99% of participants, and in increased numbers in those with higher NAS and fibrosis stages.
This is an encore of an abstract that will be presented for the first time at the European Association for the Study of the Liver (EASL) Congress, 5–8 June 2024, Milan, Italy.

Disclosure

The ESSENCE trial is funded by Novo Nordisk A/S.
PNN: reports grants from Novo Nordisk, and has received consulting fees from Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol Myers Squibb (BMS), Pfizer, Sun Pharma, Madrigal and GSK. PNN also reports honoraria as a speaker for Novo Nordisk and AiCME; support for attending meetings for Novo Nordisk; and participation on an advisory board for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, Madrigal and GSK.
EB: served as a consultant or advisory board member for Boehringer Ingelheim, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento, and as a speaker for Gilead, Intercept, Merck, Novo Nordisk and Pfizer. EB has also received a research grant from Gilead for fatty liver research.
VR: received consulting fees from Novo Nordisk, Sagimet, Madrigal, Enyo, Poxel, Northsea, Intercept and ProSciento, and research grants (to institution) from Gilead and Intercept.
MER: consults for Boehringer Ingelheim, CytoDyn, GSK, Novo Nordisk, HistoIndex, Intercept, Madrigal, NGM Bio and Sonic Incytes.
MR: reports grants from Boehringer Ingelheim and Novo Nordisk, and has received fees for consulting or participation in advisory boards for Boehringer Ingelheim, Echosens, Eli Lilly and Novo Nordisk. MR also reports honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Madrigal.
AJS: consults for and advises Avant Santé and AstraZeneca. AJS also consults for and has received grants from Akero, BMS, Intercept, Eli Lilly, Madrigal and Novo Nordisk. AJS consults for and owns stock in Rivus, and also consults for AGED Diagnostics, Albireo, Alnylam, Altimmune, Boehringer Ingelheim, 89Bio, Echosens, Genentech, Gilead, GSK, HistoIndex, Mallinckrodt, Merck, NGM Bio, Novartis, PathAI, Pfizer, Poxel, Regeneron, Salix, Siemens, Surrozen, Takeda, Terns and Zydus. AJS owns stock in Durect, Exalenz, Genfit, Indalo, Inversago and Tiziana, and has received royalties from Elsevier and Wolters Kluwer.
KAE, IK, LHØ, DV and JZ: employees and stockholders of Novo Nordisk A/S.

Introduction

Increased intestinal permeability, or leaky gut, is a condition where the gut's epithelial barrier is compromised, allowing bacteria and toxins to enter the blood stream. In liver cirrhosis, this can exacerbate liver damage and accelerate disease progression by perpetuating inflammation and immune system activation. Accurate assessment of this dysfunction is critical to the management of cirrhotic patients, but traditional methods such as serum markers and indirect assays often lack specificity and sensitivity.
Confocal laser endomicroscopy (CLE) is an advanced imaging technique that provides real-time, high-resolution visualisation of the gastrointestinal tract at the cellular and subcellular levels. CLE is used to diagnose leaky gut by directly observing disruptions in the intestinal mucosa. It integrates a confocal microscope within an endoscope, enabling in vivo histology-like imaging during routine endoscopic examinations.

Aims & Methods

We aimed to use confocal laser microendoscopy (CLE) in the diagnosis of intestinal barrier dysfunction by direct observation of the intestinal mucosa, in patients with liver cirrhosis. CLE (Cellvizio, Mauna Kea Technologies) was performed in the second part of the duodenum following intravenous administration of 2.5 – 5 mg of fluorescein in 58 patients with liver cirrhosis of various aetiologies. These patients were undergoing routine endoscopic surveillance or therapeutic intervention for oesophageal varices. The study cohort consisted of 39 men (61.9%) and 19 women (30.2%), with a mean age of 53.9 ± 14.0 years. We collected and analysed the most recent results of hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and fibrosis index for liver fibrosis (Fib-4). A Watson score of 1 indicates normal barrier function, while a Watson score of 2 indicates impaired barrier function. Data are given as mean± standard deviation, statistical analysis included Chi-square tests and Student’s t-tests, with a significance level set at p<0.05. NS=not significant.

Results

We observed a gradation of intestinal barrier dysfunction that correlated with the severity of liver cirrhosis. Specifically, of the 35 patients with Child-Pugh A cirrhosis, 18 (51.4%) had a Watson score of 2. In the group of 14 patients with Child-Pugh B cirrhosis, 9 (64.3%) had a Watson score of 2 and of the 9 patients with Child-Pugh C cirrhosis, 8 (88.9%) had a Watson score of 2, further underscoring the trend of increasing intestinal barrier dysfunction with increasing liver disease severity (p<0.05). In contrast, no significant differences in hepatic venous pressure gradient (HVPG) were observed between patients with Watson score 1 (16.8 ± 6.2 mmHg) and Watson score 2 (17.2 ± 6.2 mmHg, p NS). Similarly, liver stiffness measurements (LSM) showed no statistical difference between patients with Watson score 1 (39.0+/-23.7 kPa) and those with score 2 (40.2 ± 22.9 kPa) (p NS)=. Similarly, Fib-4 was 4.5 +/-3.1 in patients with Watson score 1 and 5.7+/-3.6 in patients with Watson 2 (p NS).

Conclusion

The findings suggest an association between the severity of liver cirrhosis and impaired intestinal barrier function as assessed by CLE. This impairment does not correlate with changes in haemodynamic parameters or liver fibrosis. The CLE promises to provide accurate and immediate diagnostic data and to improve our understanding of the pathophysiological changes in the gut associated with liver cirrhosis. Further research is needed to explore the mechanisms linking the severity of cirrhosis to intestinal barrier dysfunction and its clinical implications.

Disclosure

No conflict of interest to declare