Preclinical Disease Detection of Inflammatory Bowel Disease

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Recent articles indicate the possibility of preclinical disease detection of inflammatory bowel disease; perhaps this is analagous to the “precrime’ detection in The Minority Report which allowed the police to arrest people before they committed their crime.

D Bergemalm et al. Gastroenterol 2021; 161: 1526-1539. Open Access: Systemic Inflammation in Preclinical Ulcerative Colitis

In this study from Sweden, the authors used biobanked plasma samples from 72 individuals with ulcerative colitis (UC) and matched healthy controls (n=140). Then the findings were validated in an inception cohort (n=101 with UC and 50 healthy controls. In addition, a cohort of heathy twin siblings of patients with UC (n=41) were matched with healthy controls (n=37).

Key findings:

  • Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls
  • MMP10, CXCL9, CXCL11, and MCP1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings. This up-regulation is triggered by exposure to genetic and early environmental factors.

The discussion elaborates on the role of these proteins.

  • “MMP10 is classified as a stromelysin. Upregulated levels of stromelysin have been detected in inflamed segments of the colon from patients with ulcerative colitis….The observed preclinical upregulation of MMP10 [thought to promote wound healing] in plasma might indicate that endogenous pathways for wound healing are up-regulated several years before clinically overt ulcerative colitis to counteract disease progression and maintain mucosal homeostasis”
  • “Eotaxin (CCL11) is a potent chemoattractant of monocytes…eosinophilic-driven inflammation represents an early element in the pathogenesis of ulcerative colitis”
  • “CXCL9 and CXCL11 has been observed previously in inflamed colonic tissue specimens and blood from patients with ulcerative colitis… Both chemokines are regulated by IFN-gamma and attract CXCR3-positive CD4þ T cells and natural killer cells to the inflammatory site”

My take: This study shows up-regulation of 6 plasma proteins indicating activation of both pro-inflammatory and tissue-repairing pathways several years before clinically overt UC. It offers hope of intervention to prevent the development of UC.

Related study: S-H Lee et al. Gastroenterol 2021; 161: 1540-1551. Open Access: Anti-Microbial Antibody Response is Associated With Future Onset of Crohn’s Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk

In this study, the authors measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS).

Key finding:

“High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4–12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Liver Shorts: Autoimmune Liver Disease/HLA profiles, Saroglitazar for fatty liver, and Liver Transplantation Survivorship

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Y Ma et al. Hepatology 2021; 74: 2032-2046. Open Access: Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry

The main reason I had to highlight this article is the study period was 42 years!!! (1977-2019, n=236 children). Key findings: “Unique HLA profiles are seen in each subgroup of juvenile AILD:  DRB1*03 for AIH-1, DRB1*03 plus DRB1*07 for AIH-2, and DRB1*13 for ASC. DRB1*03 and the A1-B8-DR3 haplotype are disease-predisposing genes for all three subgroups. The influence of HLA class II genes on disease severity is strong, DRB1*03 homozygosity and possession of DRB1*13 being associated to histologically more advanced disease from onset, while DRB1*07 is linked to the least optimal response to immunosuppression”

S Gawrieh et al. Hepatology 2021; 74 1809-1824. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial

The “EVIDENCES IV study was a multicenter, randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of saroglitazar.” n=106. Key findings:

  • For ALT: mean percent change from baseline at week 16 was −25.5% (5.8), −27.7% (5.9), and −45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all)
  • Compared with placebo, saroglitazar 4 mg improved liver fat content on MRI PDFF (4.1% [5.9] vs. −19.7% [5.6]), adiponectin (−0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment–insulin resistance (−1.3 [1.8] vs. −6.3 [1.7]), and triglycerides (−5.3 mg/dL [10.7] vs. −68.7 mg/dL [10.3]) (P < 0.05 for all)
  • Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27)

My take: This study shows the potential of one agent for pharmacologic therapy for NAFLD/MAFLD.

SR Lieber et al. Liver Transplantation 2021; 27: 1454-1467. What Survivorship Means to Liver Transplant Recipients: Qualitative Groundwork for a Survivorship Conceptual Model

“A majority of LT recipients (75%) identified themselves as survivors. Integral to the definition of survivorship was overcoming hardship (including experiences on the waiting list) and the unique experience of being given a “second chance” at life. Motivations to survive included a new chance at life (55%), family (40%), spirituality/faith (30%), and fear of rejection (15%)”

Sucralfate Might Help With Wound Healing

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HB Zheng et al. JPGN Reports: 2021; 2 (3) p e111. Open Access: Effective Use of Topical Sucralfate in the Conservative Management of Expanded Gastrostomy Tract Reduction

This case report describes a 10 yo with multiple medical problems with an expanding G-tube site with mucosal prolapse “where the G-tube balloon easily fell out of her gastrocutaneous fistula.”

The site was treated with three modalities, though the authors attribute the improvement to the use of sucralfate:

  • Nasojejunal feedings
  • Removal of Gastrostomy tube for 5 days
  • Sucralfate: “1 gram tablet, ½ tablet crushed sprinkled around the ostomy site 3 times a day. Powder was used to fill in the defect and any residual powder medication was gently cleaned off before the next application”
  • Images showing improvement noted below

The authors provide pathophysiological reasons for sucralfate’s effectiveness:

This image has an empty alt attribute; its file name is image-70.png
Treatment with sucralfate helped reduce the 2 cm x 1.5 cm site (Panel A)
over 5 days to Panel B and over 4 weeks to Panel C

Next-Generation Treatment for H Pylori

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KG Hulten, et al. Gastroenterol 2021; 11: 1433-1442. Open Access: Comparison of Culture With Antibiogram to Next-Generation Sequencing Using Bacterial Isolates and Formalin-Fixed, Paraffin-Embedded Gastric Biopsies

Background: “The general unavailability of culture-based susceptibility testing for H pylori has resulted in the almost universal reliance on hopeful (empiric) therapy and a high proportion of treatment failures.” Besides the lack of availability of culture-based susceptibility testing, the global increase in prevalence of antimicrobial resistance contributes to the poor cure rates obtained with empiric use of the currently most popular triple therapies for H pylori infection.

Methods: H pylori isolates (n=170) (clinical isolates and formalin-fixed, paraffin-embedded) were tested for susceptibility to amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifabutin using agar dilution and NGS targeted to 23S rRNA, gyrA, 16S rRNA, pbp1, rpoB and rdxA. Agreement was quantified using κ statistics.

Key findings:

  • Agreement between agar dilution and NGS from culture isolates was very good for clarithromycin (κ = 0.90012), good for levofloxacin (κ = 0.78161) and fair for metronidazole (κ = 0.55880), and amoxicillin (κ = 0.21400)
  • Comparison of NGS from tissue blocks and agar dilution from isolates from the same stomachs demonstrated good accuracy to predict resistance for clarithromycin (94.1%), amoxicillin (95.9%), metronidazole (77%), levofloxacin (87.7%), and tetracycline (98.2%)

Associated editorial: F Megraud et al. Gastroenterol 2021; 11: 1367-1369. Open Access: Molecular Diagnosis for Helicobacter pylori . . . at Last

Excerpts from editorial:

  • “By targeting all of the genes responsible for antibiotic resistance, it is possible to obtain genotypic susceptibility data for all of the antibiotics of potential use, without the need to perform” culture and antibiotic susceptibility testing
  • “Hulten et al show not only that they obtained comparable results with the reference method (phenotypic) for most of the antibiotics, but also that NGS can also be performed on both culture isolates and stored histologic preparations. This result is important because it avoids the need for extra biopsies and culture”
  • “NGS could also be applied on stools. In this particular environment where H pylori DNA is found in a low amount, excellent DNA extraction methods are mandatory and progress is being made in this field”

My take: NGS can bring H pylori treatment to a new era (like almost all other infections). “Molecular methods can potentially augment or even replace the current in vitro methods for susceptibility testing, which are cumbersome, technically challenging, and time-consuming.”

Related blog posts:

Outcomes of SARS-CoV-2 with Chronic Liver Disease

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J Ge et al. Gastroenterol 2021; 161: 1487-1501. Full text-open access: Outcomes of SARS-CoV-2 Infection in Patients With Chronic Liver Disease and Cirrhosis: A National COVID Cohort Collaborative Study

Key finding:
“In this study of approximately 221,000 nationally representative, diverse, and sex-balanced patients with CLD; we found SARS-CoV-2 infection in patients with cirrhosis was associated with 2.38 times mortality hazard, and the presence of cirrhosis among patients with CLD infected with SARS-CoV-2 was associated with 3.31 times mortality hazard”

Related blog post: Aspen Webinar 2021 Part 1 COVID-19 and the Liver

The Really Simplified Endoscopy Scoring

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A recent article on simplifying the “simple” endoscopic assessment for Crohn’s disease reminded me of a scene from “There’s Something About Mary” (see below) where one of the characters plans to market a 7 minute abs video to replace the 8 minute abs video craze.

The article describes replacing the current “SES-CD” (or Simple Endoscopic Score for Crohn’s disease) with SEMA-CD (or Simplified Endoscopic Mucosal Assessment for Crohn’s disease).

YouTube: 7-minute abs Scene (from There’s Something About Mary)

J Adler et al. Inflamm Bowel Dis 2021; 27: 1585-1592. Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn’s Disease: The SEMA-CD

The SEMA-CD was scored by assigning a numerical value ranging from 0 (remission) to 4 (severe disease) for each bowel region (ileum and colon). The colon score was multiplied by the number of involved colonic segments and then added to the ileum score. “For example, if overall the colon was felt to have moderate involvement, and only the ascending and transverse colon had mucosal abnormalities, then a score of 3 for moderate disease would be multiplied by a total of 2 segments for a total [colon] score of 6.”

Key finding:

  • While there was excellent correlation between SES-CD and SEMA-CD, SEMA-CD was much easier as it required one scoring for the entire colon rather than evaluation of each segment

The authors note that clinical assessment is inadequate to monitor CD. CDAI (PCDAI) are poor surrogates for mucosal improvement…”30-68% of patients in clinical remission have evidence of mucosal inflammation on colonoscopy….Patients whose disease is managed based on clinical information alone are more likely to have disease complications, need more surgeries, or lose response to medications.”

My take: The SEMA-CD appears to be much easier than the SES-CD and thus more likely to be useful in clinical practice (& research), especially as it becomes incorporated into routine endoscopy software. If the SEMA-CD is widely adopted, we will need to be on the lookout for the ‘6 minute ab’ version.

Related blog post: Pediatric Adoption of ‘Treat to Target’ & Difficulty ‘Unlearning’

Thanks to Jeremy Adler for sharing this figure

Infection or Flareup in IBD: GI PCR Panel Helps

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S Hong et al. Inflamm Bowel Dis 2021; 27: 1634-1640. Comparative Evaluation of Conventional Stool Testing and Multiplex Molecular Panel in Outpatients With Relapse of Inflammatory Bowel Disease

In this retrospective cohort study with 268 adult patients with inflammatory bowel disease, the authors compared the use of a GI PCR panel with 22 analytes (BioFire) and C diff testing to ‘conventional’ stool testing (culture, O&P and C diff). Key findings:

  • Pathogens were more frequently identified on GI PCR (26 vs 5%; P < 0.01)
  • GI PCR was associated with less escalation in IBD therapy (16 vs 29%; P < 0.01) and fewer posttest endoscopies (10% vs 18%; P = 0.04), with no differences in IBD outcomes
  • Those with recent travel had a higher pathogen detection rate: 38% vs 14%; P<0.01
  • In the GI PCR group, the most common pathogens were E coli species 22 (including 12 Enteropathogenic E coli), Campylobacter 10, Multiple pathogens 7, Norovirus 6, Yersinia 3, C diff 3,

The authors note that the group who underwent GI PCR panel testing were more likely to present with severe symptoms (eg. fever, rectal bleeding) as well as a history of recent travel. Even when controlling for symptoms and biomarkers of inflammation, GI PCR testing was still associated with lower likelihood of escalating IBD therapies.

My take: This study indicates that identification of an infectious pathogen which is more likely with a GI PCR panel helps avoid escalation of IBD therapy and need for endoscopy in the outpatient setting.

Related blog post: Molecular Panels for Identifying Etiology with Acute GI Symptoms