Crohn's disease (CD)

What changes during this transition

Crohn's disease is a transmural inflammatory bowel disease distinct from ulcerative colitis on multiple axes that matter editorially. UC inflammation is mucosal, continuous, and confined to the colon; CD inflammation is full-thickness through the bowel wall, skip-lesion (discontinuous), and can involve any segment of the GI tract from mouth to anus — though ileal predominance defines the typical phenotype (Montreal L1 terminal ileum ~40%, L3 ileocolonic ~30%, L2 colonic ~20%, L4 upper GI). Disease behavior at diagnosis or over time is stratified by Montreal classification: B1 inflammatory (non-stricturing/non-penetrating), B2 stricturing (fibrostenotic), B3 penetrating/fistulizing. The perianal disease subset (perianal fistulas, abscesses) is independently tracked and frequently determines therapeutic strategy. Genetic risk is genuinely Crohn's-distinct. NOD2/CARD15 was the first IBD susceptibility gene identified (Hugot 2001, Ogura 2001) — homozygotes or compound heterozygotes for the three common loss-of-function variants (R702W, G908R, 3020insC) have several-fold increased CD risk, particularly ileal stricturing phenotype. ATG16L1 (T300A variant) drives Paneth-cell autophagy defects affecting antimicrobial peptide secretion. IRGM variants further implicate autophagy and bacterial handling. Together these genes point CD pathophysiology toward defective bacterial sensing and clearance at the epithelial-microbial interface — biology that no peptide in the Juno library engages. Standard-of-care has been reshaped substantially in the 2022-2024 window. Risankizumab (Skyrizi, anti-IL-23 p19, FDA-approved for CD June 2022 via ADVANCE / MOTIVATE induction + FORTIFY maintenance) was the first selective IL-23 inhibitor approved in CD. Upadacitinib (Rinvoq, JAK1 inhibitor, FDA-approved for CD May 2023 via U-EXCEL / U-EXCEED induction + U-ENDURE maintenance) brought JAK inhibition into the CD ladder with the ORAL Surveillance black-box context applying. Guselkumab (Tremfya, anti-IL-23 p19, FDA-approved for CD April 2024 via GRAVITI / GALAXI) became the second selective IL-23 inhibitor in CD. Combined with the older ladder — anti-TNF (infliximab, adalimumab, certolizumab pegol), vedolizumab (Entyvio, gut-selective α4β7 anti-integrin), and ustekinumab (Stelara, anti-IL-12/23 — biosimilars now entering the market) — Crohn's now has more therapeutic mechanism diversity than at any prior point. Conventional therapy remains in the protocol. Corticosteroids (oral prednisone or pulse methylprednisolone for severe flare; budesonide for ileal/right-colon disease) cover induction. Thiopurines (azathioprine, 6-mercaptopurine) and methotrexate cover maintenance, with TPMT and NUDT15 genotype testing required before thiopurine initiation to avoid catastrophic myelosuppression in deficient patients. The 5-ASAs that anchor UC therapy are not effective in CD (this is a genuine UC-CD distinction). Pediatric induction in particular has a non-pharmaceutical evidence-based first-line: exclusive enteral nutrition (EEN) for 6-8 weeks produces mucosal healing rates comparable to corticosteroids per ECCO and ESPGHAN pediatric guidelines, without the steroid side-effect burden. Perianal fistulizing CD has its own evidence-driven pathway. The combined-modality approach pairs anti-TNF (infliximab is the most-evidenced) with surgical seton placement and, where available, Cx601 (darvadstrocel, brand Alofisel — allogeneic adipose-derived mesenchymal stem cells, EU approved after the ADMIRE-CD Phase 3 trial, NOT US approved). This is an evidence-based stem-cell therapy for a Crohn's complication — and notably not a peptide. Surgical decision-making is part of the CD framework in a way that distinguishes it from UC. Stricturoplasty for fibrostenotic disease, ileocecal resection for terminal ileal disease that has failed medical therapy, perianal abscess drainage, and fistula surgery are integrated into the long-term management plan. Postoperative recurrence prevention with anti-TNF or other biologics is standard. ECCO 2024, ACG 2018, and AGA 2021 guidelines are the cross-jurisdictional anchors; the Crohn's & Colitis Foundation (CCFA) is the major US patient organization. Where Juno's library fits — narrowly and with deliberate non-elevation. None of the candidate peptides has CD-specific human evidence. BPC-157 is the most-pitched compound in the Crohn's community and the editorial obligation is to address that directly: the Sikiric Croatia rodent corpus is colitis-model and acute-injury work, the Pliva PL-14736 Phase 2 was in ulcerative colitis (not Crohn's), the Phase 2 efficacy results were never published, and even a positive UC readout would not propagate to CD per Rule 6. KPV has the cleanest mechanism story (PepT1-mediated NF-kB suppression, Dalmasso 2008 Gastroenterology) but the published work is generic mouse colitis-model, not Crohn's transmural disease — and the epithelial PepT1 mechanism does not engage the transmural and serosal involvement that defines CD pathology. Thymosin alpha-1 is directionally OPPOSED to CD biology (Th1/Th17-driven disease, biologic ladder SUPPRESSES IL-12/IL-23, TA-1 augments T-cell maturation and Th1 polarization — concrete theoretical flare risk). Larazotide has Phase 3 celiac data with mixed primary-endpoint history but zero CD-specific evidence; per Rule 6 celiac evidence does not propagate to CD. TB-500's angiogenic and tissue-remodeling mechanism is theoretically the wrong direction in stricturing (B2) and penetrating/fistulizing (B3) phenotypes, and the studied perianal-fistula intervention is Cx601 / darvadstrocel / Alofisel — not a peptide. The honest editorial frame: gastroenterology coordination, full Montreal classification (B1/B2/B3, L1/L2/L3/L4, perianal), NOD2/ATG16L1 genetic context where available, the modern biologic ladder (anti-TNF + vedolizumab + ustekinumab + risankizumab Skyrizi 2022 + guselkumab Tremfya 2024 + upadacitinib Rinvoq 2023), TPMT/NUDT15 testing before thiopurines, EEN as evidence-based pediatric induction, Cx601 (EU) for perianal fistulizing subset, and ECCO 2024 + ACG 2018 + AGA 2021 + CCFA resources drive outcomes.