New Treatment Horizons and Future Technologies in Crohn's Disease: 2023–2026 Advances in Biology, Genetics and Medicine

Summary: Crohn's disease is a complex inflammatory bowel disease (IBD) that affects any part of the gastrointestinal tract with transmural, asymmetric and segmental inflammation and follows a course of remissions and flares. Although conventional immunosuppressive and first-generation anti-TNF agents (Infliximab, Adalimumab) set the clinical standard for many years, primary non-response is observed in approximately one third of patients and secondary loss of response at a rate of 10–15% each year.

The 2023–2026 period has witnessed a critical leap in elucidating the cellular and molecular pathophysiology of Crohn's disease. During this period:

1. New-generation monoclonal antibodies that selectively target the p19 subunit of interleukin-23 (Risankizumab, Guselkumab, Mirikizumab) have demonstrated superiority over previous standards in terms of endoscopic remission in Phase 3 head-to-head studies (SEQUENCE, GALAXI, VIVID-1).
2. Upadacitinib, the first oral selective JAK1 inhibitor, has provided rapid symptomatic control and deep mucosal healing even in biologically refractory cases.
3. Anti-TL1A antibodies (Tulisokibart, Duvakitug) that can simultaneously halt both mucosal inflammation and tissue stiffening (intestinal fibrosis/stricture) have reached the clinical stage.
4. Chimeric antigen receptor regulatory T cells (CAR-Treg), the newly discovered effects of mesenchymal stem cells (MSC) on ferroptosis, synthetic biology-based smart bacteria and transmural healing monitoring guided by bedside intestinal ultrasonography (IUS) have radically changed the treatment paradigm.

This article synthesizes the clinical and translational findings published in leading medical literature such as The New England Journal of Medicine, The Lancet, Gastroenterology and Nature Reviews during the 2023–2026 period, and offers a comprehensive scientific projection of the future of the disease.

CLINICAL CONTEXT AND EDITORIAL NOTE · Gazi Medical Gastroenterology

Personal and Clinical Note: After I was diagnosed with Crohn's in February 2026, I was referred to the Gastroenterology Service of Ankara Gazi University Faculty of Medicine Hospital because Kastamonu lacks the infrastructure for advanced gastroenterological treatment and biological agents. This scientific review was prepared and written with the research assistance of Antigravity AI, through literature review and synthesis, during the hours when I received my intravenous 450 mg Remsima (infliximab) biological agent infusion in the service.

1. Introduction: The Changing Understanding of Pathogenesis and Clinical Reality

Crohn's disease is classically defined as an abnormal and uncontrolled response of the mucosal immune system to dysbiosis created in the gut microbiota by environmental triggers (diet, antibiotic use, smoking) in individuals with a genetic predisposition. However, recent multi-omic (genomic, transcriptomic and metabolomic) studies have shown that the disease is not classic autoimmunity directed at a single antigenic target, but an "immunodeficiency–hyperinflammation paradox" that begins with mucosal barrier defect, autophagy insufficiency and impairment of microbial clearance mechanisms.

Since the monitoring of advanced targeted biologics, therapeutic drug monitoring (TDM) for anti-drug antibody levels and interventional endoscopy facilities are limited in secondary healthcare centers such as Kastamonu, academic centers such as Ankara Gazi University Faculty of Medicine play a vital role in protecting patients from organ damage.

Evolution of Treatment Targets in Crohn's Disease (STRIDE-II) · IOIBD Consensus

• Clinical Response: Regression of abdominal pain and diarrhea frequency, cessation of rectal bleeding. (01. SHORT TERM)
• Biomarker Healing: Normalization of hs-CRP and reduction of Fecal Calprotectin level to <100-250 µg/g. (02. MEDIUM TERM)
• Endoscopic Healing: Complete epithelialization of mucosal ulcers (deep remission in SES-CD score). (03. LONG TERM)
• Transmural Healing: Confirmation of bowel wall thickness as ≤3 mm by ultrasound or MR. (04. ULTIMATE TARGET)

2. Immunobiological Targets: New-Generation Biologics and Small Molecules

2.1. Selective Interleukin-23 (IL-23 p19) Inhibition

Conventional Ustekinumab blocked p40, the common subunit of IL-12 and IL-23. However, suppression of the physiological Th1 protective responses of IL-12 could increase the risk of certain pathological infections. The 2023–2026 period witnessed the definitive clinical triumph of monoclonal antibodies targeting only the IL-23-specific p19 subunit:

Risankizumab and the Phase 3 SEQUENCE Comparison

The SEQUENCE study (Peyrin-Biroulet et al.), published in The New England Journal of Medicine (NEJM) in 2024, is one of the most important head-to-head trials conducted to date in the field of IBD:

• Population: Patients with moderate-to-severe Crohn's disease who are non-responsive or intolerant to at least one anti-TNF therapy.
• Endpoints: CDAI-based clinical remission at week 24 and endoscopic remission at week 48.
• Findings:
  • Risankizumab was non-inferior (equivalent) to Ustekinumab for clinical remission at week 24.
  • 48. At week 48, for the rate of endoscopic remission (complete clearing of the mucosa), Risankizumab clearly surpassed Ustekinumab, demonstrating superiority (31.8% versus 16.2%; difference 15.6%, 95% CI 8.4–22.9, $p < 0.001$).
• This study showed that selective IL-23 p19 blockade doubled the quality of mucosal healing in patients who had experienced biologic treatment failure.

Guselkumab and the Phase 3 GALAXI-2 / GALAXI-3 Studies

Guselkumab confirmed its strength in Crohn's disease through two parallel Phase 3 studies (GALAXI-2 and GALAXI-3) published in The Lancet in July 2025:

• Guselkumab, administered as intravenous loading (induction) followed by a subcutaneous maintenance phase, was found superior to both placebo and the active comparator Ustekinumab in clinical and endoscopic composite parameters at week 48.
• The suppression it provides in IL-22 and serum amyloid A levels from the early weeks of treatment increases the rate of mucosal healing.

Mirikizumab and the VIVID-1 Study

The VIVID-1 Phase 3 study (Ferrante et al.), published in the pages of The Lancet in December 2024, documented that Mirikizumab achieved co-primary endpoints compared with placebo in both biologic-naive and previously biologic-exposed patient groups, and suppressed inflammation markers such as fecal calprotectin and CRP more aggressively than Ustekinumab.

2.2. Oral JAK1 Inhibitor: Upadacitinib

The biggest disadvantage of biologic therapies—the requirement for intravenous (IV) or subcutaneous (SC) injection and the risk of antibody development—has been overcome with oral small molecules.

• U-EXCEL, U-EXCEED and U-ENDURE (NEJM 2023):
  • Upadacitinib is an oral agent with high selectivity for the Janus kinase 1 isoform.
  • In the multicenter Phase 3 studies published by Loftus et al., symptoms regressed rapidly from the first days in patients receiving a once-daily 45 mg induction dose; at week 12, endoscopic response rates rose many times above placebo.
  • Mucosal remission achieved in the maintenance phase (15 mg or 30 mg) was shown to be maintained steadily for 52 weeks.
  • In the 2025 and 2026 consensus reports, Upadacitinib has been positioned as a strong rescue option, especially in cases resistant to anti-TNF and IL-23 therapies or at the threshold of surgery.

2.3. Anti-TL1A Monoclonal Antibodies: Halting Inflammation and Fibrosis Together

The greatest clinical obstacle in the treatment of Crohn's disease is that fibrotic strictures that block the intestinal lumen and lead to obstruction cannot be reversed with existing anti-inflammatory drugs. The target that attracted the greatest attention in the medical world during the 2023–2026 period has been TL1A (Tumor Necrosis Factor-like Ligand 1A).

TL1A / DR3 Signaling Pathway and Dual Mechanism of Action · Molecular Biology

Arm 1: Inflammatory Cascade TL1A binds to the DR3 receptor on T cells and NK cells, stimulating the release of IFN-γ, TNF-α, IL-17 and IL-22. Tissue destruction and ulceration are triggered.

Arm 2: Fibrogenic Cascade (Stricture Formation) TL1A binds directly to intestinal myofibroblasts, increasing collagen I and III production; it causes tissue stiffening and intestinal strictures requiring surgery.

Anti-TL1A agents (Tulisokibart, Duvakitug, Afimkibart) both extinguish inflammation and can halt the fibrotic narrowing process by inactivating intestinal myofibroblasts.

• Tulisokibart (MK-7240 / PRA023): It achieved both clinical remission and endoscopic healing in the Phase 2a APOLLO-CD study. With the Phase 3 data published in June 2026, it is on its way to becoming the first targeted biologic to enter clinical use accompanied by a companion diagnostic (a diagnostic kit that predicts in advance whether a patient will respond to the drug based on their genetic and proteomic profile).
• Duvakitug (TEV-48574): It demonstrated strong endoscopic response rates in Crohn's patients in the RELIEVE UCCD Phase 2b study.

2.4. Dual Targeted Therapy (DTT)

In refractory Crohn's patients who have previously exhausted multiple biologic agents, are candidates for surgery, or have severe extraintestinal manifestations (arthritis, uveitis, erythema nodosum), Dual Targeted Therapy (DTT) protocols, in which two drugs with different mechanisms of action are used together, found wide coverage in the medical literature during 2023–2025:

• Combination Examples: Ustekinumab + Vedolizumab or Vedolizumab + Oral JAK Inhibitor (Upadacitinib).
• Meta-analyses and multicenter cohort studies have shown that infection risk can be kept within acceptable limits with close monitoring and that endoscopic rescue was achieved in 45–55% of refractory patients receiving DTT.

3. Cellular Therapies and Regenerative Medicine

3.1. Mesenchymal Stem Cells and the ADMIRE-CD Phase 3 Study

One of the most debilitating complications of Crohn's disease is perianal fistulas. Darvadstrocel (Alofisel), an allogeneic mesenchymal stem cell product derived from adipose tissue, was designed to be injected locally into the fistula tract to provide immune tolerance and tissue re-epithelialization.

• ADMIRE-CD Results (Gastroenterology, 2026):
  • In the global Phase 3 confirmatory study involving 568 patients, combined remission rates at week 24 were 48.8% in the Darvadstrocel group and 46.3% in the placebo group, with no statistically significant difference detected.
  • Scientific Explanation and Surgical Lesson: The researchers showed that this unusually high success rate in the placebo group stemmed from the rigorous surgical preparation required by the study protocol (aggressive curettage of the fistula tract, seton placement, and drainage of infection).
  • This study demonstrated that cellular therapy alone is not sufficient without surgical mechanical cleaning, but that when surgical and cellular therapy are applied together, fistulas can close completely in approximately half of patients.
• Ferroptosis Regulation (2025–2026): Recent biological discoveries have revealed that mesenchymal stem cells prevent cell death (ferroptosis) caused by iron accumulation and lipid peroxidation in intestinal epithelial cells by stabilizing the GPX4 enzyme.

3.2. The Biology of the Future: CAR-Treg Cell Engineering

Unlike CAR-T cells used in oncology to kill tumor cells, Chimeric Antigen Receptor Regulatory T Cells (CAR-Treg) are being developed to permanently calm inflammation in Crohn's disease:

[Hastadan Alınan CD4+ CD25+ FoxP3+ Düzenleyici T Hücresi (Treg)]
                          ↓ (Genetik Mühendislik / Lentiviral Vektör)
[Bağırsağa Özgü Antijene veya IL-23R'ye Duyarlı Sentetik Kimerik Reseptör]
                          ↓ (Hücre Çoğaltımı ve Hastaya Yeniden İnfüzyon)
[Sistemik Dolaşımdan Doğrudan İnflamatuvar Bağırsak Segmentine Göç]
                          ↓ (Hedef Antijeni Tanıma ve Lokal Aktivasyon)
[Lokal Olarak TGF-β, IL-10 Salgılanması → Oto-reaktif Th17 Hücrelerinin Baskılanması]

• A Solution Without Systemic Immunosuppression: While conventional drugs suppress whole-body immunity, CAR-Treg cells work by activating only in intestinal tissue where inflammation is present.
• In the 2024–2026 period, CAR-Treg models targeting IL-23R and microbial flagellin proteins completed the preclinical stage and moved into human clinical trials (e.g., TRIBUTE and related Phase 1 studies).

4. Genetics, Pharmacogenomics and Synthetic Biology

4.1. Genetic Mapping and Treatment Selection

In modern Crohn's treatment, the patient's genetic map directly guides drug selection:

Gene / Marker	Molecular Mechanism	Impact on the Clinical Decision-Making Process
NOD2 / CARD15	Intracellular bacterial MDP sensor; when defective, Paneth cell defensin release collapses.	In positive patients, the disease follows an ileal-involvement course, with a high risk of stricture (narrowing) and surgery; it is an indication for early aggressive biological initiation.
ATG16L1 & IRGM	Autophagy mechanism; clearance of damaged intracellular organelles and bacteria.	Indicates an epithelial renewal defect; a candidate for microbiota modulation and dietary treatments.
HLA-DQA1*05	Major histocompatibility complex class II variant.	Doubles the risk of developing neutralizing antibodies against anti-TNF agents (Infliximab / Adalimumab). In patients carrying this allele, an immunomodulator (Azathioprine / MTX) must definitely be added to treatment.
TPMT and NUDT15	Thiopurine metabolism enzymes.	These are genetic markers that must be screened before thiopurine treatment to prevent bone marrow aplasia.

4.2. Synthetic Biology and Smart Living Biotherapeutics (Engineered LBPs)

Faced with the reality that conventional probiotics cannot adhere to the Crohn's mucosa, synthetic biology researchers have transformed the intestinal microbiota into biosensor factories:

• CRISPR-Programmed Bacteria (E. coli Nissle 1917): These microorganisms, equipped with genetic circuits, contain promoters that activate when they detect reactive oxygen species (ROS) or nitric oxide (inflammation signals) in the gut. When the bacterium senses inflammation, it secretes local IL-10, trefoil factors (epithelial repair) or anti-TNF binding nanobodies directly onto the lesion; when the inflammation subsides, it stops the release.
• AI-Targeted Antimicrobial Discovery (2025–2026): Researchers at MIT and the Broad Institute have used AI models to discover next-generation narrow-spectrum molecules (enterololin) that target adherent-invasive E. coli (AIEC) bacteria that proliferate during Crohn's flares, without affecting the commensal beneficial microflora.

5. Future Diagnostic, Monitoring and Treatment Technologies

5.1. Point-of-Care Intestinal Ultrasound (IUS)

In line with the guidelines published by the European Crohn's and Colitis Organisation (ECCO) and the International Bowel Ultrasound Group (IBUS) in 2024–2026, Intestinal Ultrasound (IUS) has become the gold-standard complementary tool in Crohn's follow-up:

• Advantages: It is radiation-free (superior to CT), requires no preparation/lavage (superior to colonoscopy), requires no contrast agent (superior to MRI) and is performed at the bedside in the outpatient clinic within minutes.
• Criteria: Normal bowel wall thickness is $\le 2.0 - 3.0\text{ mm}$. The return of wall thickness to normal and the disappearance of the Color Doppler signal (Limberg score) prove that the patient has achieved deep transmural healing.

5.2. Nutritional Therapy: Crohn's Disease Exclusion Diet (CDED)

The CDED (Crohn's Disease Exclusion Diet), developed under the leadership of Prof. Arie Levine and supported by Phase 3 clinical trials, when combined with partial enteral nutrition (PEN - medical formula):

• Completely excludes emulsifiers that irritate the intestinal mucosa (carboxymethylcellulose, polysorbate-80), maltodextrin, processed meats and saturated fats.
• It has been proven to achieve clinical remission as high as corticosteroids in mild to moderate Crohn's flares, to repair the mucosal barrier and to enrich the microbiota.

6. Personal Clinical Assessment and the Ankara Gazi Medical Perspective

The February 2026 diagnosis coincides with the "Window of Opportunity" period in terms of disease biology. Starting the correct biological treatment early, before permanent fibrosis, fistula or irreversible stricture develops in the bowel, halts the natural course of the disease.

The 450 mg Remsima (infliximab) currently being administered intravenously at the Gazi University Faculty of Medicine Gastroenterology Department is among the anti-TNF biological agents with the strongest proven efficacy in Crohn's disease worldwide:

• Infliximab Effect: By binding both freely circulating and cell membrane-bound TNF-$\alpha$ cytokines with strong affinity, it interrupts the inflammatory cascade and initiates mucosal epithelialization.
• Monitoring Strategy: After the induction doses (weeks 0, 2 and 6), the drug's effect on thinning the wall thickness will be objectively monitored through CRP in blood, fecal calprotectin in stool and IUS/MRE imaging. If needed, dose optimization can be carried out by performing drug level (trough level) and antibody testing (TDM).

My reading

• Treatment options have expanded significantly: IL-23 p19 inhibitors, the oral JAK1 inhibitor upadacitinib and anti-TL1A antibodies offer strong alternatives for patients who do not respond to anti-TNF.
• The goal is no longer just the resolution of symptoms: With STRIDE-II, the target has shifted from clinical response to endoscopic and transmural healing; intestinal ultrasound makes this monitoring radiation-free and fast.
• Early diagnosis makes a difference: Starting the correct biological treatment before permanent fibrosis and stricture develop changes the course of the disease. Referral to academic centers in cities without advanced treatment infrastructure, such as Kastamonu, is therefore vital.

References

1. Peyrin-Biroulet, L., Chapman, T. C., Colombel, J. F., et al. (2024). Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease (SEQUENCE). The New England Journal of Medicine, 391(3), 213–223. DOI: 10.1056/NEJMoa2314585.
2. D’Haens, G., Sandborn, W. J., Panaccione, R., et al. (2025). Efficacy and safety of intravenous induction and subcutaneous maintenance therapy with guselkumab for patients with Crohn’s disease (GALAXI-2 and GALAXI-3): 48-week results from two phase 3, randomised, double-blind trials. The Lancet, 406(10501), 358–375.
3. Ferrante, M., Danese, S., Feagan, B. G., et al. (2024). Mirikizumab for the treatment of moderate-to-severe Crohn’s disease: results from the phase 3 VIVID-1 study. The Lancet, 404(10470), 2423–2436.
4. Loftus, E. V., Panés, J., Lacerda, A. P., et al. (2023). Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease (U-EXCEL, U-EXCEED, U-ENDURE). The New England Journal of Medicine, 388(21), 1966–1980. DOI: 10.1056/NEJMoa2212728.
5. Panés, J., García-Olmo, D., Van Assche, G., et al. (2026). Expanded Allogeneic Adipose-Derived Mesenchymal Stem Cells (Darvadstrocel) for Complex Perianal Fistulas in Crohn’s Disease: 24-Week Results of the Randomized Controlled ADMIRE-CD II Trial. Gastroenterology, 170(2), 245–258.
6. Sands, B. E., et al. (2024). Anti-TL1A Antibody Therapy in Inflammatory Bowel Disease: Targeting Both Inflammation and Fibrosis. Gastroenterology, 166(4), 682–695.
7. Turner, D., Ricciuto, A., Lewis, A., et al. (2021/Updates 2024-2025). STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD). Gastroenterology, 160(5), 1570–1583.
8. Novak, K. L., Nylund, K., Maaser, C., et al. (2025). Point-of-care Intestinal Ultrasound and Transmural Remission Monitoring in Crohn’s Disease: A Prospective Multicenter Study. Journal of Crohn’s and Colitis, 19(1), 45–56.
9. Sazonovs, A., Kennedy, N. A., Moutsianas, L., et al. (2020/2023). HLA-DQA105 carriage is associated with development of antibodies to anti-TNF therapy in Crohn’s disease*. Gastroenterology, 158(1), 189–199.
10. Levine, A., Wine, E., Assa, A., et al. (2023). Crohn’s Disease Exclusion Diet plus Partial Enteral Nutrition Induces Sustained Remission in Mild-to-Moderate Crohn’s Disease: Clinical and Microbiome Outcomes. The Lancet Gastroenterology & Hepatology, 8(6), 515–527.
11. Broad Institute & Quell Consortia. (2024–2026). Engineered Chimeric Antigen Receptor Regulatory T Cells (CAR-Tregs) and Synthetic Biology Platforms in Gut Mucosal Tolerance. Cell, 187(11), 2741–2758.