Regulation of Mucosal Healing in Inflammatory Bowel Disease

Induction of mucosal healing in inflammatory bowel disease (IBD) is associated with reduced hospitalizations, surgeries, and reduced cancer risk. However, previous studies have shown that 54-69% of ulcerative colitis (UC) patients fail to heal ulcers after several weeks of treatment, and roughly half do not maintain remission at one year. The single most important factor in preventing severe medical consequences, like colon removal surgery or cancer, is treatment to completely heal the top layer of the intestine as quickly as possible. Healing is a complex process and the dysfunction observed in colitis can only be fully understood by comparison to healing in non-IBD patients.

This is a prospective trial involving three groups of patients: 1) IBD patients with active disease, newly treated with anti-TNF therapy (biologic failure or naïve); 2) non-IBD patients with rheumatoid/psoriatic arthritis who are receiving anti-TNF therapy, and 3) healthy control patients. Biopsies will be collected at baseline during standard of care endoscopy and at a follow-up research endoscopy.

This study will probe mechanisms of ulcer healing by analyzing gene expression patterns and mitochondrial function.

• Serial Biopsy (Procedure): During the initial colonoscopy, 16-20 biopsies will be collected in addition to standard of care biopsies, and biopsy sites will be tattoed. Patients will return for a follow-up colonoscopy 4-35 days later. An additional 16-20 biopsies will be collected in a "biopsy of the biopsy" approach.

Primary outcomes

• Change in Relative Ratio of Mitochondrial DNA to Nuclear DNA [35 days]: Change in relative ratio of mitochondrial DNA to nuclear DNA in epithelial cells collected from biopsies taken during the initial colonoscopy and at the follow-up colonoscopy.
• Fold Change in Expression Levels of cMyc [Baseline and 35 days]: Fold change in expression levels of cMyc (mRNA) will be measured in epithelial cells collected from biopsies taken during the initial colonoscopy and at the follow-up colonoscopy.
• Fold Change in Expression Levels of PGC-1 Alpha [Baseline and 35 days]: Fold change in expression of PGC-1 alpha (mRNA) will be measured in epithelial cells collected from biopsies taken during the initial colonoscopy and at the follow-up colonoscopy.
• Change in Expression Levels of Ki67 [35 days]: Change in Ki67 alpha (mRNA) expression will be measured by immunohistochemistry in epithelial cells collected from biopsies taken during the initial colonoscopy and at the follow-up colonoscopy.
• Number of Visible Ulcers [1 day (at follow-up visit)]: The number of visible ulcers will be assessed during the follow-up endoscopy for healthy patients and rheumatoid/psoriatic arthritis patients only.

Secondary outcomes

• Change in Full Mayo Score [Baseline and 35 days]: Change in Full Mayo Score, a measure of inflammatory bowel disease activity, from baseline to 35 days. The Full Mayo Score ranges from 0-12, with higher scores indicating worse disease activity. The score is calculated by summing the four components of the Mayo Score: stool frequency, rectal bleeding, endoscopic findings, and physician's global assessment.
• Change in Segmental SES-CD Score [35 days]: The Simple Endoscopic Score (SES) will be calculated at baseline and follow-up in patients with Crohn's disease (CD) only. The SES-CD score incorporates ulcer size, narrowing, and the area affected by disease or ulceration. Scores range from 0-12; lower scores indicate remission while higher scores indicate severe endoscopic activity.

Other outcomes

• Fecal Calprotectin Levels [35 days]: Levels of fecal calprotectin (ug/g) will be measured from stool samples collected from patients at any time during the study protocol.

Sex: All, ages: 18 Years to 90 Years, accepts healthy volunteers

Inclusion Criteria (Group 1):

* Diagnosed ulcerative colitis or Crohn's disease
* Biologic failure or naive to biologic treatment
* Eligible to be treated with anti-TNF therapy

Inclusion Criteria (Group 2):

* Diagnosed rheumatoid or psoriatic arthritis
* Receiving anti-TNF antibody therapy at the time of enrollment

Inclusion Criteria (Group 3):

* Endoscopically unremarkable colonic mucosa
* Absence of inflammatory bowel disease

Exclusion Criteria:

* Classified in an anesthesia risk group, ASA Class =4
* History of bleeding diathesis or coagulopathy
* Stroke or transient neurological attack with the last 6 months
* Pregnant
* Receiving anticoagulants or anti-platelet medications other than low-dose aspirin
* Receiving steroid therapy or metformin
* HIV positive
* Incarceration
* History of total proctocolectomy
* History of system chemotherapy within 18 months
* Uncontrolled intercurrent illness

Participant flow

Outcome results

• Change in Relative Ratio of Mitochondrial DNA to Nuclear DNA (Primary), Mean, Relative Ratio of mtDNA to nucDNA: Healthy Controls 1218.374 +/- 148.83; Inflammatory Bowel Disease 394.98 +/- 39.22; Rheumatoid/Psoriatic Arthritis
• Fold Change in Expression Levels of cMyc (Primary), Mean, Relative Fold Change: Healthy Controls 2.41 +/- 0.24; Inflammatory Bowel Disease 1.09 +/- 0.225; Rheumatoid/Psoriatic Arthritis
• Fold Change in Expression Levels of PGC-1 Alpha (Primary), Mean, Relative Fold Change: Healthy Controls 0.96 +/- 0.02; Inflammatory Bowel Disease 0.315 +/- 0.05; Rheumatoid/Psoriatic Arthritis
• Change in Expression Levels of Ki67 (Primary), Mean, Ki67+Cells/Crypt: Healthy Controls 35.8 +/- 2.878; Inflammatory Bowel Disease 17 +/- 0.997; Rheumatoid/Psoriatic Arthritis
• Number of Visible Ulcers (Primary)
• Change in Full Mayo Score (Secondary), Mean, score on a scale: Healthy Controls ; Inflammatory Bowel Disease 5 +/- 0.726; Rheumatoid/Psoriatic Arthritis
• Change in Segmental SES-CD Score (Secondary), Mean, score on a scale: Healthy Controls ; Inflammatory Bowel Disease 8.2 +/- 2.28; Rheumatoid/Psoriatic Arthritis
• Fecal Calprotectin Levels (Other pre specified), Mean, ug/Kg: Healthy Controls 151.2 +/- 31.93; Inflammatory Bowel Disease 1203.57 +/- 305.898; Rheumatoid/Psoriatic Arthritis

Adverse events

Time frame: 30 Days

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2025-10-02)

• Terrence Barrett, MD, Principal investigator, University of Kentucky

NIH grants: R01DK095662