Advances, Challenges in Managing Acute Severe Ulcerative Colitis

Acute severe ulcerative colitis (ASUC) is a life-threatening condition requiring urgent medical intervention. Over the past decades, advances in corticosteroid therapy, biologics, small molecules, and predictive scoring systems have improved patient outcomes. However, challenges remain in optimizing medical therapy and reducing colectomy rates.

Predictors of Colectomy

Despite advancements in biologic therapy, colectomy rates within a year of medical salvage therapy remain high (30–50%). Response to corticosteroids within the first week of hospitalization is a key predictor of long-term colectomy risk. In the Oxford cohort study, patients achieving complete response (stool frequency ≤ 3/day, no blood) had a 5% colectomy rate, whereas incomplete responders had a 40% colectomy rate within 9 months.1

Additional predictors of colectomy include pre-admission immunomodulator use, which triples the risk of colectomy at 1 year. A combination of serum albumin ≤ 2.5 g/dL and band neutrophil count ≥ 13% at infliximab initiation had a 100% positive predictive value for 90-day colectomy.1

Scoring systems incorporating prior biologic exposure, age, and need for salvage therapy further refine risk stratification. Endoscopic severity also predicts colectomy risk, with a Mayo score of 3 associated with a 91% sensitivity for colectomy within a year. Biomarkers such as CRP/albumin ratio and CRP/lymphocyte ratio outperform traditional indices like the Mayo and Oxford scores in predicting colectomy.

Among clinical predictors, persistent hematochezia despite intravenous corticosteroid therapy is a concerning sign of steroid failure and often necessitates early consideration of salvage therapy.

Unresolved Challenges in ASUC Management

Several challenges remain unresolved in the management of ASUC.

Accelerated or Intensified Infliximab Dosing

An accelerated infliximab regimen (5 mg/kg at weeks 0, 2, and 6, with dose escalation to 10 mg/kg in select cases) has been explored. Observational studies show lower short-term colectomy rates with intensified dosing. However, meta-analyses reveal no significant difference in long-term colectomy rates or complications between standard and intensified regimens.

A recent Australian randomized trial found no difference in clinical response at day 7 between 10 mg/kg and 5 mg/kg dosing. Although intensified dosing may benefit select patients (e.g., those with serum albumin <25 g/L), further studies are needed to refine patient selection.1

Small Molecules as Rescue Therapy

Janus Kinase (JAK) inhibitors, such as tofacitinib and upadacitinib, have shown promise as alternative rescue therapies in steroid-refractory ASUC. In a phase 4 trial, 58.3% of patients receiving tofacitinib 10 mg twice daily achieved clinical response at day 7, with 45.8% remaining on therapy at 6 months.1

Concerns remain regarding thrombotic risks, particularly in patients over 50 with cardiovascular risk factors. While upadacitinib has shown efficacy in case series, large-scale trials are required to establish its role in ASUC management.

Biologics for Maintenance Following Cyclosporine Rescue

Patients achieving remission with cyclosporine require maintenance therapy, traditionally with azathioprine. In patients with prior azathioprine failure, biologics like vedolizumab have been proposed as alternatives. A systematic review showed a 65% colectomy-free survival rate with vedolizumab maintenance following cyclosporine induction. While promising, further studies are needed to confirm its safety and efficacy.

Metabolomic alterations in Ulcerative Colitis

A systematic analysis of metabolomics studies related to UC, mainly from ‘lipids and lipid-like molecules’ and ‘organic acids and derivatives’ superclasses reveal 101 metabolites consistently altered in multiple datasets within the same sample type and 78 metabolites common across different sample types. Of these, 62 metabolites exhibited consistent regulatory trends across various datasets or sample types. Pathway analysis revealed 22 significantly altered metabolic pathways, with 6 pathways being recurrently enriched across different sample types.2

Safety of Sequential Rescue Therapy

The practice of sequential rescue therapy—switching from infliximab to cyclosporine or vice versa—remains controversial. Studies report remission in 33-40% of patients, but significant adverse events, including severe infections and sepsis-related mortality, raise concerns. Given the unclear impact on long-term colectomy risk, sequential rescue therapy is not routinely recommended.

Unconventional Therapies

Non-traditional approaches, such as exclusive enteral nutrition (EEN) and hyperbaric oxygen therapy (HBOT), have shown potential.3 An open-label trial found lower steroid failure rates and reduced hospitalization in ASUC patients receiving EEN. HBOT, in a small study, improved remission rates and reduced colectomy risk. However, due to limited evidence, these therapies remain experimental.

Role of Bowel Ultrasound in ASUC

Bowel ultrasound is emerging as a non-invasive tool for assessing ASUC severity. Studies indicate that increased bowel wall thickness correlates with steroid failure. A thickness > 6 mm predicts the need for salvage therapy. While promising, ultrasound-based assessments require validation in larger cohorts.

Final notes

ASUC requires rapid recognition and multidisciplinary management. Corticosteroids remain the first-line therapy, with early identification of non-responders critical for guiding rescue therapy. While infliximab and cyclosporine remain standard salvage therapies, small molecules like tofacitinib and alternative biologics are emerging as potential options. Predictive scoring models and biomarkers aid in risk stratification, but require further validation.

The role of unconventional therapies and imaging techniques like bowel ultrasound is expanding, offering non-invasive monitoring tools. Future research should focus on personalized treatment strategies to optimize ASUC outcomes and reduce colectomy rates.

References

1. Vuyyuru, S. K., Nardone, O. M., & Jairath, V. (2024). Predicting outcome after acute severe ulcerative colitis: A contemporary review and areas for future research. Journal of Clinical Medicine, 13(15), 4509.
   https://pmc.ncbi.nlm.nih.gov/articles/PMC11312513/

2. Liu, M., Guo, S., & Wang, L. (2024). Systematic review of metabolomic alterations in ulcerative colitis: Unveiling key metabolic signatures and pathways. Therapeutic Advances in Gastroenterology, 17, 17562848241239580.
   https://pmc.ncbi.nlm.nih.gov/articles/PMC10981261/

3. Le Berre, C., Honap, S., & Peyrin-Biroulet, L. (2023). Ulcerative colitis. Lancet, 402(10401), 571–584. https://pubmed.ncbi.nlm.nih.gov/37573077/