Acute Severe Ulcerative Colitis (ASUC)

1. Clinical Overview

Summary

Acute Severe Ulcerative Colitis (ASUC) is a medical emergency representing the most dangerous phenotype of inflammatory bowel disease. It is defined by the Truelove and Witts criteria (1955) as ≥6 bloody stools per day accompanied by systemic toxicity (tachycardia, fever, anaemia, or elevated inflammatory markers). Approximately 25% of patients with Ulcerative Colitis (UC) will require hospitalization for ASUC during their lifetime, and it carries a significant risk of colectomy (30–40% failure rate of intravenous steroids). [1]

The management of ASUC is a race against time. The "Three-Day Rule" is the cornerstone of modern care: failure to demonstrate a significant biological response to high-dose intravenous corticosteroids by Day 3 necessitates "rescue therapy" (Infliximab or Ciclosporin) or urgent surgery. Delayed decision-making beyond this window is the primary driver of perioperative mortality, which has historically been as high as 30% but has fallen to less than 1% in specialized centres. [2]

Key Facts

• The Diagnostic Standard: The Truelove & Witts criteria remain the gold standard after 70 years. The presence of ≥6 bloody stools/day + just one marker of toxicity (HR > 90, Temp > 37.8°C, Hb less than 105, ESR > 30/CRP > 30) defines the condition.
• The "Oxford Criteria" (Day 3): The most powerful predictor of outcomes. > 8 stools/day OR 3–8 stools + CRP > 45 mg/L on Day 3 predicts an 85% likelihood of colectomy.
• VTE Risk: Systemic inflammation makes ASUC a highly pro-thrombotic state. The risk of Pulmonary Embolism (PE) is 3-fold higher than in general medical admissions. Chemical thromboprophylaxis is mandatory, regardless of rectal bleeding.
• Toxic Megacolon: A surgical catastrophe where the inflammatory process paralyzes the colonic smooth muscle, leading to dilation (> 6cm) and impending perforation.
• Mortality: The mortality of elective colectomy is less than 1%, but this rises to > 20% if surgery is performed after perforation has occurred. Early surgical referral is life-saving.

Clinical Pearls

The "Loperamide" Warning: Never administer anti-motility agents (Codeine, Loperamide) to a patient with active colitis. By putting the bowel "to sleep" (ileus), you trap inflammatory toxins and gas, precipitating Toxic Megacolon.

The "Daily AXR" Pearl: A plain Abdominal X-ray is the most valuable daily monitoring tool. It allows you to track the transverse colon diameter (normal less than 6cm) and spot "mucosal islands"—edematous patches of mucosa that look like thumbprints. Loss of haustra and increasing diameter are warning signs of imminent perforation.

The "Surgical Handshake": The colorectal surgeon should meet the patient on Day 1, not Day 7. This psychological preparation is crucial for the patient ("We hope for the medicines to work, but we plan for safety") and prevents delays if emergency colectomy becomes necessary.

The "Hypokalemia" Trap: Excessive diarrhoea causes massive potassium loss. Hypokalemia causes smooth muscle paralysis, which worsens colonic dilatation. Aggressively replace K+ to keep it > 4.0 mmol/L to protect colonic tone.

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2. Epidemiology & Risk Factors

Incidence & Distribution

• Prevalence: ASUC accounts for 15-25% of all UC presentations.
• First Presentation: In 10-15% of cases, ASUC is the first manifestation of the disease (de novo presentation), often catching the patient completely off guard.
• Bimodal Age: Peaks at 15–30 years (aggressive disease) and 60–80 years (ischemic overlap, higher mortality).
• Geography: Highest incidence in Western Europe and North America, but rapidly rising in Asia and South America due to the "westernization" of diet and microbiome.

Risk Factors for Severity

Several factors predict a "severe" course requiring colectomy:

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3. Pathophysiology: The Perfect Storm

ASUC is not just "inflammation"; it is a cascading failure of the gut barrier, immune regulation, and neuromuscular control.

A. The Broken Barrier (Mucosal Layer)

• The Mucus Desert: The primary defect is the depletion of Goblet Cells and the loss of the MUC2 mucin layer. This "demilitarized zone" usually keeps bacteria away from the epithelium. In ASUC, it vanishes.
• Adherent Microbes: Commensal bacteria (usually benign) adhere directly to the epithelial cells, triggering TLR (Toll-Like Receptor) activation.
• Tight Junction Collapse: The intercellular "glue" (Occludin, Claudin-1, JAM-A) disintegrates. This increases paracellular permeability, allowing bacterial antigens to flood the lamina propria. "The dam breaks."

B. The Immunological Cascade (Lamina Propria)

Once the barrier is breached, the immune system launches a disproportionate attack.

1. Antigen Presentation: Dendritic cells sample the bacterial flood and migrate to lymph nodes, presenting antigens to naïve T-cells.
2. Atypical Th2 Response: Unlike Crohn's (Th1/Th17), UC is driven by an atypical Th2 response mediated by Natural Killer T-cells (NKT).
   • IL-13: The "Ulcerative" Cytokine. It induces epithelial cell apoptosis and impairs tight junction restitution.
   • IL-5: Recruits Eosinophils (often seen in crypt abscesses).
3. TNF-Alpha Explosion: Macrophages churn out Tumour Necrosis Factor alpha. This is the "Master Switch" that drives:
   • Vasodilation (Redness).
   • Endothelial adhesion molecule expression (Sticky vessels).
   • pain modulation.
   • Clinical Correlate: This is why Infliximab (Anti-TNF) is so effective as a rescue agent.

C. Leukocyte Trafficking (The Highway)

• The Problem: White blood cells need to get from the blood into the gut tissue.
• The Mechanism:
  • Gut blood vessels express an "address code" called MAdCAM-1.
  • Lymphocytes express a "key" called Alpha-4-Beta-7 Integrin.
  • When they lock, the lymphocyte exits the blood and destroys the gut.
  • Clinical Correlate: Vedolizumab blocks the $\alpha_4\beta_7$ integrin, preventing new soldiers from entering the battlefield.

D. Neuromuscular Paralysis (The Road to Megacolon)

Why does the colon dilate?

• Transmural Penetration: Usually, UC is mucosal. In severe disease, inflammation penetrates the muscularis propria.
• Nitric Oxide (NO): Inducible NO Synthase (iNOS) produces massive amounts of NO, a potent smooth muscle relaxant.
• The result: The colonic muscle paralysis. It stops contracting. Gas accumulates.
• LaPlace's Law: $Tension = Pressure \times Radius$. As the radius grows (dilatation), the wall tension increases exponentially until it exceeds the tensile strength of the tissue. Perforation ensues.

E. Microscopic Features: The Histopathology of ASUC

A biopsy in ASUC shows a "war zone":

• Crypt Abscesses: The hallmarks of activity. Neutrophils swarm into the crypt lumen, destroying the gland.
• Crypt Architecture Distortion: Glands are branched, forked, or atrophied. This proves chronicity (differentiating ASUC from acute self-limiting infection).
• Basal Plasmacytosis: Plasma cells accumulate at the crypt base. A highly specific sign of IBD.
• Mucin Depletion: The goblet cells are empty (exhausted).
• Paneth Cell Metaplasia: Paneth cells normally live in the small bowel. Finding them in the left colon is a sign of chronic repair/adaptation.

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4. Clinical Presentation

Defining specific Phenotypes

It is crucial to distinguish Severe from Fulminant colitis.

Symptoms Breakdown

1. Bloody Diarrhoea: The hallmark. In severe cases, patients may pass "pure blood and pus" with no recognizable faecal matter.
2. Nocturnal Symptoms: Waking at night to defecate is a highly specific sign of organic inflammation (vs IBS).
3. Tenesmus: A painful spasm of the anal sphincter with a feeling of incomplete evacuation, caused by rectal inflammation (Proctitis).
4. Urgency: The "stiff" rectum cannot stretch to accommodate stool, leading to incontinence.
5. Constitutional: Profound fatigue, anorexia, weight loss (catabolic state), and fevers.

Physical Signs

• General: Pale, dehydrated, febrile, tachycardia.
• Abdomen:
  • Tenderness: Usually follows the colonic outline (left iliac fossa, flank).
  • Distension: Danger Sign. Suggests gas trapping and megacolon.
  • Peritonism: Rebound tenderness or rigidity implies inflammation has reached the serosa or perforation has occurred.
• Nutritional: Muscle wasting, temporal wasting, peripheral oedema (hypoalbuminemia).
• Extra-Intestinal: Look for Erythema Nodosum (tender red shins), Pyoderma Gangrenosum (necrotic ulcers), or Episcleritis (red eye). Often these activity parallels the bowel disease.

Severity Scoring Systems

Standardized verification of "severity" is mandatory. Subjective assessment ("patient looks unwell") is unreliable.

1. Truelove and Witts Criteria (ASUC Definition)

The classic definition. Patient must have Diarrhoea ≥6/day PLUS ≥1 of the following:

2. The Mayo Score (Disease Activity Index)

Used in clinical trials and to monitor response. A score of 3-12 indicates active disease.

3. UCEIS (Ulcerative Colitis Endoscopic Index of Severity)

A more rigorous endoscopic tool than the Mayo score.

• Vascular Pattern (0-2): Normal -> Obliterated.
• Bleeding (0-3): None -> Spontaneous oozing.
• Erosions/Ulcers (0-3): None -> Deep ulceration.
• Total Score: 0-8. A score > 5 predicts a high risk of colectomy.

5. Investigations

1. Laboratory Assessment: The "Severity Panel"

A comprehensive blood panel is essential not just for diagnosis, but for risk stratification and preparing for potential rescue therapy or surgery.

Haematology

• Full Blood Count (FBC):
  • Anaemia: Hb less than 105 g/L is a component of the Truelove & Witts criteria. It usually signifies deep, extensive ulceration and chronic blood loss.
  • Leukocytosis: WCC > 12 x 10^9/L or rising counts can reflect severe systemic inflammation or developing complications like micro-perforation. Note that steroids will artificially raise the neutrophil count (demargination), so interpret with caution.
  • Platelets: Thrombocytosis is a marker of active inflammation.

Biochemistry

• C-Reactive Protein (CRP): The most critical biomarker in ASUC.
  • A CRP > 45 mg/L on Day 3 is the strongest predictor of steroid failure (Oxford Criteria).
  • Trend Analysis: The trajectory of CRP is more important than a single value. A failure of CRP to halve within 72 hours should trigger discussions about second-line therapy.
• Erythrocyte Sedimentation Rate (ESR): Included in the original Truelove criteria (> 30 mm/hr), but largely superseded by CRP due to its slower responsiveness.
• Albumin:
  • Hypoalbuminaemia (less than 30 g/L) is a powerful negative prognostic marker.
  • Mechanism: Correlates with the degree of protein-losing enteropathy.
  • Pharmacokinetic Impact: Low albumin (less than 30 g/L) accelerates the clearance of Infliximab, potentially leading to sub-therapeutic drug levels. This is the rationale for accelerated induction dosing (e.g., 10 mg/kg) in severe colitis.
• Urea & Electrolytes (U&Es):
  • Hypokalaemia: Must be aggressively corrected (target > 4.0 mmol/L). Low potassium impairs smooth muscle contractility, promoting colonic atony and precipitating Toxic Megacolon.
  • Magnesium: Baseline level required if considering Ciclosporin (which causes biomarkers wasting).
  • Creatinine: Assessment of renal function prior to potential nephrotoxic agents or contrast CT.

Microbiology (The "Infectious Mimic" Screen)

• Stool Culture: Standard MCS (Microscopy, Culture, Sensitivity) for Campylobacter, Salmonella, Shigella, E. coli O157.
• C. Difficile Toxin: A toxin EIAS (Enzyme Immunoassay) or PCR is MANDATORY. 20% of ASUC admissions have superadded C. diff.
• Parasitology: If relevant travel history (e.g., Entamoeba histolytica).

2. Emerging Prognostic Biomarkers

• Fecal Calprotectin (FCP):
  • Role: Although clinically obvious ASUC doesn't need FCP for diagnosis, baseline levels are often > 1000-2000 µg/g.
  • Utility: Failure of FCP to drop significantly by Day 3-5 predicts non-response to steroids.
• Oncostatin M (OSM): High mucosal levels of OSM are associated with resistance to Anti-TNF therapy (Infliximab).
• HLA-DQA1*05: A genetic variant carried by ~40% of Europeans.
  • Significance: Associated with a high risk of developing anti-drug antibodies (ADAs) to Infliximab/Adalimumab. Patients with this allele must be on combination therapy (with Azathioprine) to prevent immunogenicity. MANDATORY FOR ALL PATIENTS.

• Clostridioides difficile:
  • Toxin A/B and Glutamate Dehydrogenase (GDH).
  • Clinical Pearl: C. diff infection co-exists in up to 20% of ASUC flares and doubles the mortality risk. If positive, treat with oral Vancomycin or Fidaxomicin immediately alongside steroid therapy.
• Stool Culture: To exclude Campylobacter, Salmonella, Shigella, and E. coli O157.
• Cytomegalovirus (CMV):
  • Systemic viral load (CMV PCR in blood) is often checked but has low sensitivity for colonic disease.
  • Gold Standard: Tissue biopsy during sigmoidoscopy for Immunohistochemistry (IHC) or viral loops.

2. Imaging Strategies

Plain Abdominal Radiograph (AXR)

Every patient admitted with ASUC requires an admission AXR. It is the "stethoscope of the gastroenterologist" in this setting. Cheap, fast, and low radiation.

The "Dangerous Signs" Reporting Checklist:

1. Colonic Dilatation (The Megacolon Check):
   • Transverse Colon: > 6.0 cm. (The most mobile part, gas rises here).
   • Caecum: > 9.0 cm. (Thinnest wall, highest rupture risk).
   • Small Bowel: Presence of gas here implies "ileus" and correlates with extensive disease.
2. Mucosal Status (The Severity Check):
   • "Mucosal Islands": Small, polypoid-looking patches of residual mucosa floating in a sea of ulceration. Represent severe destruction.
   • "Thumbprinting": Thickened, oedematous haustral folds that look like thumb impressions. Indicates deep submucosal oedema.
   • "Lead Pipe" Appearance: Complete loss of haustra. The colon looks like a smooth featureless tube. Indicates chronic scarring (not acute risk, but confirms diagnosis).
3. Extent of Disease:
   • Faecal Loading: If you see hard stool in the ascending colon, the inflammation is likely distal to that point (active colitis causes rapid emptying, so stool stasis suggests healthy mucosa).
   • "Empty Colon": A completely gas-filled or empty colon from caecum to rectum suggests Pancolitis.
4. Perforation:
   • Rigler's Sign: Air on both sides of the bowel wall (wall becomes very distinct).
   • Football Sign: A large oval gas shadow (the whole peritoneal cavity).

Computed Tomography (CT)

A CT Abdomen/Pelvis with contrast is not routine but is the gold standard for complications.

• Indications:
  • Deterioration with toxic signs (Tachycardia/Hypotension) but non-diagnostic AXR.
  • Suspicion of Perforation (sealed or free).
  • Suspicion of Abscess (if fever persists despite steroids).
  • Evaluation of the Portal Vein (Pylephlebitis/Thrombosis).
• Protocol:
  • Intravenous Contrast: Essential (Portal venous phase).
  • Oral Prep: NEVER. Do not give oral contrast to a potential megacolon patient (risk of aspiration or worsening dilation).
• Key Findings:
  • Mural Hyperenhancement: Use "Target Sign" (Hyperenhancing mucosa + Oedematous submucosa).
  • Fat Stranding: Pericolonic inflammation.
  • Comb Sign: Engorged vasa recta supplying the inflamed bowel.

Intestinal Ultrasound (IUS) - The New Standard?

Bedside bowel ultrasound is emerging as a non-invasive monitoring tool.

• Findings: Bowel wall thickness > 4mm (> 3mm is abnormal), loss of stratification, and increased Doppler flow (Limberg score).
• Advantage: No radiation, repeatable daily. Can assess response to steroids (wall thickness decreases) without repeated scopes.

3. Endoscopic Assessment

Flexible Sigmoidoscopy (The "Gentle" Exam)

• Timing: Perform within 24 hours of admission.
• Technique:
  • No oral bowel prep (can trigger dilatation). Use a phosphate enema only if absolutely necessary.
  • Minimal Air Insufflation: Use CO2 if available. Over-distension can cause perforation in friable, inflamed bowel.
• Objectives:
  1. Confirm diagnosis (differentiate from ischaemic or infective colitis).
  2. Assess Severity (UCEIS or Mayo Score).
     • Deep ulceration predicts steroid failure.
  3. Biopsy for CMV: Take biopsies from the base of the deepest ulcers.

[!WARNING] Full Colonoscopy is CONTRAINDICATED In the acute severe setting, the risk of perforation with a full colonoscopy is unacceptably high. Do not attempt to visualize the caecum. assessing the rectum and sigmoid is sufficient to guide management.

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6. Differential Diagnosis: It's Not Always UC

Before committing to immunosuppression, one must rigorously exclude mimics. Treating infection with steroids can be fatal.

1. Infectious Colitis

The primary mimic.

• Clostridioides difficile:
  • Risk: Antibiotics, PPIs, Hospitalization.
  • Key Feature: Pseudomembranes on endoscopy.
  • Impact: Up to 20% co-infection rate.
• CMV Colitis:
  • Risk: Steroid refractory patients.
  • Features: Deep, punched-out ulcers on endoscopy. "Owl's Eye" inclusions on biopsy.
• Amoebic Colitis (Entamoeba histolytica):
  • History: Travel to endemic areas.
  • Diagnosis: Serology, stool ova/cysts (hot stool), flask-shaped ulcers.
• Bacterial Pathogens:
  • Campylobacter, Salmonella, Shigella, E. coli O157.
  • Usually acute onset, self-limiting.

2. Ischaemic Colitis

• Patient Profile: Elderly, vascular risk factors (AF, HTN).
• Distribution: "Watershed areas" (Splenic flexure, Rectosigmoid).
• Endoscopy: "Dusky" blue/black mucosa, sharp demarcation between healthy and ischaemic bowel.
• Rectal Sparing: The rectum has a dual blood supply and is rarely involved in ischaemia (unlike UC).

3. Crohn's Colitis

• Differentiation: Can be indistinguishable in acute severe setting ("Indeterminate Colitis").
• Features favoring Crohn's: Deep linear ulcers ("bear claw"), cobble-stoning, rectal sparing, peri-anal disease, granulomas on biopsy.

4. Other Mimics

• NSAID Colopathy: History of heavy NSAID use. diaphragm disease in right colon.
• Diverticulitis: Usually segmental (sigmoid), associated with diverticula.
• Radiation Proctitis: History of pelvic radiotherapy (Prostate/Cervical Ca).

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7. Complications: The "Deadly Trio"

In ASUC, three complications account for nearly all mortality. They must be actively hunted, not just passively observed.

1. Toxic Megacolon

• Definition: Non-obstructive colonic dilatation (> 6cm transverse colon) + Systemic Toxicity.
• Pathophysiology (The "Nitric Oxide" Theory):
  • Inflammation penetrates the muscularis propria.
  • Neutrophils release massive amounts of Nitric Oxide (NO).
  • NO is a potent smooth muscle relaxant.
  • Result: The colon loses tone and paralyses.
• The "LaPlace" Danger:
  • As the radius (r) increases, the wall tension (T) increases (Law of LaPlace: T ∝ P x r).
  • As the wall stretches, it becomes thinner.
  • Endgame: Ischaemia -> Perforation.
• Triggers:
  • Opioids (Codeine/Morphine).
  • Anticholinergics (Buscopan).
  • Hypokalaemia.
  • Barium enema / Colonoscopy (air insufflation).
• Management:
  • NBM: Bowel rest.
  • NG Tube: Decompression.
  • Rolling Maneuvers: Patient lies prone ("tummy") for 15 mins every 2 hours to help gas pass the transverse colon.
  • Surgery: If no improvement in 24 hours -> Colectomy.

2. Perforation

• The "Silent" Killer:
  • Patients on high-dose steroids often have masked signs.
  • They may have NO peritonism (guarding/rigidity).
  • The only sign might be Tachycardia (HR > 100) or a sudden drop in blood pressure.
• Diagnostic Clue: Loss of hepatic dullness on percussion (free air over liver).
• Action: Urgent CT and Laparotomy. Mortality is > 50% if missed.

3. Venous Thromboembolism (VTE)

• Risk: 3-8x higher than general population.
• Pathomechamism: The "Pro-thrombotic Storm".
  • Platelets: Thrombocytosis (reactive).
  • Fibrinogen: Elevated (acute phase reactant).
  • Antithrombin III: Lost in stool (protein-losing enteropathy).
• Clinical Pearl: A patient who suddenly becomes hypoxic or breathless has a PE until proven otherwise.
• Prophylaxis: Mandatory LMWH (e.g., Clexane 40mg). DO NOT withhold due to rectal bleeding. The risk of fatal PE outweighs the risk of mucosal ooze.

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7. Management: The Acute Severe Colitis Protocol

                          ACUTE SEVERE ULCERATIVE COLITIS (ASUC)
                          ======================================
                                         |
                                         v
                         ADMISSION (DAY 0): Truelove & Witts Met
                   (≥6 Bloody Stools + Systemic Toxicity: HR> 90, T> 37.8, Hbless than 105)
                                         |
            +----------------------------+-----------------------------+
            |                            |                             |
      IV STEROIDS                  VTE PROPHYLAXIS             STOOL CULTURES &
(Hydrocortisone 100mg QDS)       (LMWH Prophylactic)           C. DIFF TOXIN
            |                            |                             |
            +-------------+--------------+-----------------------------+
                          |
                          v
                 MONITORING PHASE (DAY 1 - 2)
           ----------------------------------------
           • Daily CRP, Stool Chart, Plain AXR
           • Flexible Sigmoidoscopy (Biopsy for CMV)
           • Nutrition: High protein, ensure K+ > 4.0
                          |
                          v
              THE "DAY 3" DECISION POINT (Oxford Criteria)
              --------------------------------------------
           Is CRP > 45 mg/L  OR  Stool Frequency > 8/day?
                          |
             +------------+-------------+
             |                          |
            NO                         YES (85% Risk of Colectomy)
     (Responding)                       |
             |                          |
             v                          v
    CONTINUE STEROIDS           INITIATE "RESCUE THERAPY"
    (Day 5: Switch to Oral)     -------------------------
             |                  1. INFLIXIMAB 5mg/kg (Consider 10mg/kg if Alb less than 30)
             v                  OR
     DISCHARGE PLAN             2. CICLOSPORIN 2mg/kg/day IV
             |                          |
    Reduce 5mg/week             Assess Response at Day 7 (Day 4 post-rescue)
                                        |
                            +-----------+-----------+
                            |                       |
                        RESPONSE                NO RESPONSE
                      (CRP less than 10)                     |
                            |                       v
                            |              EMERGENCY SURGERY
                    Maintenance Bio        (Subtotal Colectomy)

Management of ASUC is a high-stakes, time-critical exercise. Relentless monitoring and timely decision-making are more important than the choice of specific drug.

The "Three-Day Rule" (Traffic Light System)

1. Clinical Pharmacology: The ASUC Formulary

The management of ASUC relies on the precision delivery of potent immunomodulators. Understanding the pharmacokinetics, especially in the context of "protein-losing colopathy," is critical.

A. Intravenous Corticosteroids (Induction)

The "Anchor" of initial therapy.

• Mechanism:
  • Genomic: Binds cytosolic Glucocorticoid Receptor (GR), translocates to nucleus, inhibits NF-kB. Onset: 4-6 hours.
  • Non-Genomic: Stabilizes cell membranes, reduces capillary permeability. Onset: Minutes.
• Standard Regimens:
  • Hydrocortisone: 100 mg IV q6h (Standard UK Protocol).
  • Methylprednisolone: 60 mg IV OD (Preferred in cardiac/renal failure - less mineralocorticoid activity/fluid retention).
• The "Ceiling Effect": Evidence shows that doses > 400mg/day of Hydrocortisone do NOT increase efficacy but DO increase adverse events. Do not "push the dose" further.
• Management Support:
  • Gastric Protection: PPI cover is debatable but often given if additional risk factors present.
  • Diabetes: Aggressive glycaemic control is vital. Steroid-induced hyperglycaemia drives osmotic diuresis and dehydration.
  • Bone Health: Start Calcium/Vitamin D immediately if duration > 3 months anticipated.

B. Thrombo-prophylaxis (Mandatory)

• The Pathophysiology: ASUC is a "Thrombotic Storm".
  • Mechanism: Loss of Anti-Thrombin III (gut leak) + Activated Platelets + Acute Phase Response (Fibrinogen).
  • Risk: VTE rate is 8-fold higher than general population.
• Protocol:
  • Enoxaparin (Clexane): 40 mg SC OD (Prophylactic).
  • Weight Adjusted: Increase to 0.5 mg/kg BD if > 100kg.
  • Rectal Bleeding: NOT A CONTRAINDICATION. The risk of fatal PE > risk of exsanguination. Never withhold LMWH due to PR bleeding in colitis.

C. Infliximab (Anti-TNF Alpha)

"The Rescue Agent". A Chimeric monoclonal antibody (IgG1) against TNF-alpha.

• Indication: Steroid-refractory ASUC (Day 3 failure).
• The "Pharmacokinetic Failure" Concept:
  • ASUC patients lose protein through the gut ("Fecal Loss").
  • Standard doses (5mg/kg) may be washed out before they work.
  • Low Albumin (less than 30 g/L) is the single best predictor of rapid drug clearance.
• Dosing Protocol (Rescue):
  • Standard: 5 mg/kg IV infused over 2 hours.
  • Accelerated: 10 mg/kg IV stat (if Albumin less than 30 or CRP > 50).
  • Rapid Reload?: Some centres give a second dose at Day 4-5 if partial response.
• The Pre-Flight Checklist (The "Safety Stop"):
  • TB Screen: Chest X-ray (mandatory) + IGRA (T-spot) if time permits.
  • Viral Serology: Hep B Surface Ag, Hep C Ab, HIV, VZV IgG.
  • Heart Failure: Check Echocardiogram if history (Anti-TNF contraindicated in NYHA III/IV).
• Infusion Reaction Management:
  • Acute: Hypotension/Wheeze -> Stop infusion + IV Hydrocortisone + Chlorphenamine. Restart at 50% rate.
  • Delayed: Serum sickness (Joint pain/Rash) days later.

D. Ciclosporin (Calcineurin Inhibitor)

The "Old Guard" Rescue. Highly effective, fast, but narrow therapeutic window.

• Mechanism: Calcineurin inhibitor. Blocks IL-2 production. Stops T-cell clonal expansion.
• Dosing protocol:
  • IV Induction: 2 mg/kg/day continuous infusion.
  • Oral Switch: 4 mg/kg/day BD (once clinical response seen).
• Monitoring (The "Cyclo Chart"):
  • Trough Levels: Check Com (Aim 150-250 ng/mL).
  • Magnesium: Daily replacement (Hypomagnesemia precipitates seizures).
  • Cholesterol: Must be > 3.0 mmol/L (risk of seizures if low lipid binding).
  • Blood Pressure: Monitor for hypertension.
  • Renal Function: Monitor Creatinine (afferent arteriolar vasoconstriction).
• Prophylaxis: Co-trimoxazole (Septrin) often given for PCP prophylaxis (triple immunosuppression risk).

E. Tofacitinib (JAK Inhibitor)

The "New Challenger" for Rescue (Off-label in some regions, licensed in others).

• Mechanism: Pan-JAK inhibitor (JAK1/3). Blocks cytokine signaling (IL-2, 6, 15).
• Dose: 10 mg BD PO.
• Advantage: Oral. Fast onset (half-life 3 hours). No immunogenicity (it's a chemical, not a protein).
• VTE Risk Stratification:
  • FDA Warning: Increased risk of PE/DVT and Mortality in patients > 50 with cardiac risk factors.
  • Practical Rule: Avoid in patients > 65, Smokers, or history of DVT/PE.
• Lipid Profile: Causes dose-dependent increase in LDL (Check at 8 weeks).

F. Therapeutic Drug Monitoring (TDM)

• Concept: Measuring drug levels (trough concentrations) and anti-drug antibodies (ADAs) to guide dosing.
• Rationale: ASUC patients have a high inflammatory burden and lose protein (including antibodies) through the leaky gut ("fecal loss"). Standard doses of Infliximab may result in undetectable drug levels, leading to treatment failure.
• Target Levels:
  • Infliximab: Aim for trough levels > 3–7 µg/mL during maintenance. In ASUC, levels are often checked during induction (e.g., pre-second dose) to decide if accelerated dosing is needed. Some experts aim for > 15-20 µg/mL in the acute phase.
  • Adalimumab: Aim for > 7.5 µg/mL.
• Management of Low Levels:
  • Low Drug + No Antibodies: Dose optimization (increase dose or frequency).
  • Low Drug + High Antibodies: Immunogenicity failure. Switch class (e.g., to Vedolizumab or Tofacitinib) or add an immunomodulator (Thiopurine) to suppress antibodies (if using Infliximab).
  • Normal Drug + Active Disease: Mechanistic failure. Switch class (the drug is present but not working).

G. Biosimilars

• Definition: A biological medicine highly similar to another already approved biological medicine (the "reference medicine").
• Key Fact: They are functionally equivalent in terms of safety, purity, and potency. They are NOT "generic" drugs (which are identical chemical copies), but they are clinically interchangeable.
• Examples: CT-P13 (Infliximab biosimilar), ABP 501 (Adalimumab biosimilar).
• Impact: Significantly reduced cost, allowing lower thresholds for starting biologic therapy and wider access to combination therapy.
• Switching: Single-switch from originator to biosimilar is safe and effective. Multiple switching is generally avoided but evidence is growing.
• Status: Off-label for primary rescue in many regions, but gaining traction.
• Mechanism: Small molecule JAK1/3 inhibitor.
• High-Intensity Protocol: 10 mg BD x 3 days. Some studies explore higher "induction" doses in the acute setting.
• Utility: Useful in patients who have failed Anti-TNF and are steroid-refractory, offering an oral rescue option.

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2. Surgical Management: Technical Note

Surgery for ASUC is a "Damage Control" procedure. The priority is to remove the septic focal and allow the patient to recover, not to restore continuity.

The Procedure: Subtotal Colectomy + End Ileostomy

• Definition: Removal of the entire colon (cecum to rectosigmoid junction), leaving the rectum in situ and bringing the terminal ileum to the skin as an end ileostomy.
• Rationale: Removes the diseased organ (curing the colitis) while preserving the option for future restorative surgery (pouch) and avoiding the high risk of anastomotic leakage in an acutely ill, malnourished, steroid-loaded patient.

Step-by-Step Technical Guide for the Non-Surgeon

This is useful for explaining the procedure to patients ("We remove the sick colon but leave the rectum for now so you don't need a permanent bag").

1. Incision: Midline laparotomy (allows full access) or laparoscopic (preferred if stable and expertise available).
2. Mobilisation: The colon is mobilised from its attachments. Great care is taken at the Splenic Flexure to avoid splenic capsule tears (a common cause of catastrophic bleeding).
3. Vessel Ligation: The ileocolic, right colic, middle colic, and left colic vessels are ligated close to the bowel (preserving the mesentery) to minimise bleeding.
4. Transection: The ileum is transected 5-10cm proximal to the ileocaecal valve.
5. Rectal Stump Management (Critical):
   • The rectosigmoid is transected at the level of the sacral promontory.
   • Risk: "Rectal Stump Blowout". If the anal sphincter is tight and the stump involves active disease, mucus can build up, leading to pressure necrosis and pelvic sepsis.
   • Solution: Either bring the stump out as a Mucous Fistula (safest) or place a trans-anal catheter to decompress the rectum if stapled intraperitoneally.
6. Stoma Formation:
   • Site Marking: Crucial. Must be marked pre-operatively by Stoma Nurses (away from belt line/creases).
   • Spouting: The ileum is everted ("spouted") by 2-3cm. This ensures alkali effluent falls into the bag, not onto the skin (preventing chemical dermatitis).
7. Washout: Massive localized washout to reduce bacterial load.

Post-Operative Physiology & Care

• The "High Output" Phase: The colon normally absorbs 1-1.5L of water/day. Without it, the new stoma will output liquid chyme.
• Management:
  • Fluid Restriction: Paradoxically, restrict bacteria-free water (which flushes out electrolytes via osmosis).
  • Oral Rehydration Solution (St Mark's Solution): Contains Glucose + Sodium to drive the SGLT-1 pump and absorb water.
  • Loperamide: High doses (e.g., 4-8mg QDS) are often needed to slow transit.

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3. Nutritional Strategy in ASUC

"Bowel Rest" is a myth. The gut needs fuel to heal.

• Enteral Nutrition (EN): Preferred.
  • Maintains gut mucosal integrity (preventing villous atrophy).
  • Reduces bacterial translocation.
  • High protein targets (1.2–1.5 g/kg/day) to counteract catabolism.
• Parenteral Nutrition (TPN): Reserved for:
  • Toxic Megacolon (where oral intake is dangerous due to risk of perforation).
  • Prolonged post-operative ileus.
  • Intestinal failure (High output stoma).
• Specific Deficiencies:
  • Iron: IV Iron is standard (oral is poorly absorbed and pro-inflammatory).
  • Vitamin D: Supplement all patients on steroids.

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8. Complications: The "Big Four" and Beyond

The mortality of ASUC has fallen from > 30% to less than 1%, primarily due to the recognition and early management of complications. However, morbidity remains high.

1. Toxic Megacolon

A potentially fatal dilatation of the colon accompanied by systemic toxicity.

• Pathophysiology: Inflammation extends into the smooth muscle layer (muscularis propria), causing paralysis and dilatation. Nitric oxide acting as a local inhibitory neurotransmitter plays a key role.
• Definition (Jalan Criteria):
  • Radiographic evidence of colonic dilatation (> 6 cm transverse colon).
  • PLUS at least 3 of: Fever > 38°C, HR > 120, Neutrophilia > 10.5, Anaemia.
  • PLUS at least 1 of: Dehydration, Hypotension, Electrolyte disturbance, Altered mental status.
• Management Protocol:
  • "Drip and Suck": Wide-bore NGT for decompression, aggressive IV fluids, correction of electrolytes (especially Potassium and Magnesium).
  • Rolling Maneuvers: Asking the patient to roll into the prone position (knee-elbow) for 15 mins every 2 hours can help redistribute gas and decompress the colon.
  • Avoidance: Stop all anti-motility agents (opioids, anticholinergics).
  • Surgery: If no improvement within 24–48 hours, subtotal colectomy is mandatory to prevent perforation. Perforation carries a 40% mortality.

2. Colonic Perforation

The most feared complication.

• Risk Factors:
  • Full colonoscopy during active disease (air insufflation).
  • High-dose steroids (fragile tissue).
  • Deep ulceration on endoscopy.
  • Severe hypoalbuminaemia (less than 20 g/L).
• Clinical Signs: May be masked by steroids! Look for:
  • Loss of hepatic dullness on percussion.
  • Sudden worsening of tachycardia.
  • Unexplained hypotension.
  • Referred shoulder tip pain (diaphragmatic irritation).
• Management: Immediate resection (Hartmann's procedure).

3. Venous Thromboembolism (VTE)

• Epidemiology: IBD patients have a 3-fold increased risk of VTE compared to the general population; this rises to 8-fold during a flare.
• Mechanism (The Hypercoagulable State):
  • Increased pro-coagulant factors (Fibrinogen, Factor VIII, Platelets).
  • Decreased anti-coagulants (Antithrombin III is lost in stool).
  • Endothelial activation.
• Implication: Pulmonary Embolism is a leading cause of preventable death in IBD. Even if the patient is passing pure blood per rectum, therapeutic or high-dose prophylactic anticoagulation (LMWH) is mandatory.
• Post-Discharge: The risk remains elevated for weeks. Guidelines recommend 28 days of LMWH prophylaxis post-discharge.

4. Cytomegalovirus (CMV) Colitis

A critical "steroid-refractory" mimic.

• Pathophysiology: Reactivation of latent CMV in inflamed tissue, driven by immunosuppression (Steroids).
• Diagnosis:
  • Gold Standard: Immunohistochemistry (IHC) on colonic biopsies showing "Owl's Eye" inclusion bodies.
  • PCR: Tissue PCR is sensitive but low specificity (detects bystanders). Blood PCR is not sufficient to diagnose tissue colitis.
• Treatment Threshold:
  • If IHC positive (> 5 inclusions/field): Treat.
  • If steroid-refractory: Treat.
• Regimen:
  • IV Ganciclovir 5 mg/kg BD for 3-5 days, then switch to oral Valganciclovir 900 mg BD to complete 2-3 weeks.
  • NOTE: Ganciclovir is myelosuppressive. Monitor FBC closely if co-prescribed with Thiopurines (Risk of agranulocytosis).

5. Clostridioides Difficile Superinfection

• Incidence: Up to 20% of ASUC admissions.
• Impact: Doubles the colectomy risk and quadruples mortality.
• Management:
  • Oral Vancomycin 125 mg QDS or Fidaxomicin 200 mg BD.
  • Avoid Metronidazole (low efficacy in gut).
  • Contact precautions.

6. Extra-Intestinal Manifestations (EIMs)

These may flare concurrently with the bowel disease and complicate management.

• Dermatological:
  • Pyoderma Gangrenosum (PG): Deep, necrotic, ulcerating skin lesions, typically on the shins. Can occur at trauma sites ("Pathergy"). Response to anti-TNF therapy is usually good.
  • Erythema Nodosum (EN): Tender red nodules on shins. Mirrors bowel activity.
• Ocular: Anterior Uveitis / Episcleritis. Urgent ophthalmology review required if red eye/pain present (steroid eye drops may be needed).
• Hepatobiliary: Primary Sclerosing Cholangitis (PSC). Check ALP/GGT. Co-existent PSC increases the risk of colorectal cancer extended surveillance.
• Psychological: Acute Stress Reaction is common. The fear of colectomy and stoma is profound. Early involvement of IBD Nurse Specialists is crucial.

9. Evidence & Landmark Trials: The "Evidence Vault"

A deep dive into the pivotal studies that shape modern ASUC management. These are the trials that defined the "Three Day Rule" and the choice of rescue therapy.

1. The Steroid Era: The Original RCT

Truelove & Witts (1955)

• Study Title: Cortisone in Ulcerative Colitis
• Journal: British Medical Journal (BMJ)
• Objective: To determine if Cortisone is effective in active ulcerative colitis.
• Context: Before this trial, ASUC management was purely supportive (bed rest, raw eggs, psychotherapy). Mortality was appalling (> 30%).
• Design:
  • The first true RCT in gastroenterology (n=210).
  • Stratified into mild, moderate, severe.
  • Randomized to Oral/IM Cortisone vs Placebo.
• Key Findings:
  • Remission: 41% in Cortisone group vs 14% in Placebo.
  • Mortality: Dropped dramatically to 7% (from historical 30%+ in the placebo/historical controls).
  • Endoscopy: Significant improvement in the steroid group.
• Critical Appraisal:
  • Strengths: Established the Gold Standard. The definition of "Severe" used here (Truelove & Witts Criteria) has stood for 70 years.
  • Weaknesses: High doses by modern standards? No, actually similar. No maintenance phase included.
• Clinical Takeaway: Corticosteroids are the non-negotiable anchor of induction therapy. They save lives. [PMID: 13260656]

2. The Predictive Era: Knowing When to Stop

Travis et al. (1996) - The Oxford Criteria

• Study Title: Predicting Outcome in Severe UC
• Journal: Gut
• Objective: To identify early markers of steroid failure to avoid prolonged, futile immunosuppression ("The drift to death").
• Methodology: Prospective study of 51 severe attacks. Analyzed parameters on Day 3.
• Key Finding (The Rule of 8/45):
  • At Day 3 of IV steroids:
  • If Stool Frequency > 8/day OR CRP > 45 mg/L:
  • The likelihood of requiring colectomy is 85%.
• Implication:
  • This killed the practice of "giving it another few days."
  • If criteria are met on Day 3, you must plan for rescue therapy (Infliximab/Ciclosporin) or surgery immediately.
• Validation: Validated in multiple cohorts worldwide. It remains the bedrock of the "Day 3 Decision." [PMID: 8684129]

3. The Rescue Era: Infliximab vs Ciclosporin

CYSIF (2012) & CONSTRUCT (2016)

• The Question: Which rescue agent is better?
• CYSIF Trial:
  • Design: Open-label RCT (n=115) in Europe.
  • Arms: IV Ciclosporin (2mg/kg) vs Infliximab (5mg/kg).
  • Result: Failure rates were identical. Colectomy rates identical.
• CONSTRUCT Trial:
  • Design: Pragmatic RCT (n=270) in the UK.
  • Arms: Infliximab vs Ciclosporin.
  • Primary Endpoint: Quality of adjusted survival (QALYs).
  • Key Findings:
    1. Efficacy: No significant difference in colectomy-free survival at 3 months or 1 year. Both agents work equally well (approx 70-80% avoid immediate surgery).
    2. Safety: Similar severe adverse event rates.
    3. Cost: At the time, Infliximab was more expensive.
    4. Patient Preference: Patients preferred Infliximab (single infusion vs daily oral drugs + blood monitoring).
• Expert Consensus:
  • Infliximab is generally preferred for ease of use and easier transition to maintenance.
  • Ciclosporin is preferred if low albumin (causing fast Infliximab clearance) or if the patient has previously failed anti-TNF. [PMID: 27890736]

4. The Biologic Era: Head-to-Head

VARSITY (2019)

• Study Title: Vedolizumab versus Adalimumab for Ulcerative Colitis
• Journal: NEJM
• Design: Double-blind, double-dummy RCT (n=769).
• Context: The first trial to pit two biologics against each other directly.
• Key Findings:
  • Clinical Remission (Wk 52): Vedolizumab 31.3% vs Adalimumab 22.5% (p=0.006).
  • Mucosal Healing: Vedolizumab 39.7% vs Adalimumab 27.7%.
  • Steroid-Free Remission: Superior with Vedolizumab.
• Why did Adalimumab perform "poorly"?:
  • Dosing was standard (40mg eow). We now know standard dosing is often insufficient.
  • No dose escalation allowed in the design.
• Clinical Takeaway: For bio-naïve UC patients, Vedolizumab is statistically superior to Adalimumab for achieving deep remission. [PMID: 31553912]

5. The Small Molecule Era: JAK Inhibitors

OCTAVE Induction 1 & 2 (2017)

• Study Title: Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis
• Journal: NEJM
• Agent: Tofacitinib (Oral JAK1/3 inhibitor).
• Key Finding:
  • Highly effective vs placebo.
  • Speed of Onset: Significant symptom improvement seen within 3 days.
• Significance:
  • This "rapid onset" makes it the only oral agent that can logically compete with IV steroids/Infliximab in the acute setting (though strictly off-label for ASUC rescue).
• Safety Signal:
  • Higher rate of Herpes Zoster (Shingles) - 5%.
  • Venous Thromboembolism (VTE) signal seen in later safety studies (A3921133) at 10mg BD dose in older patients with CV risk factors. [PMID: 28467869]

6. The "Combination" Debate

UC-SUCCESS (2014)

• Design: Infliximab Monotherapy vs Azathioprine Monotherapy vs Combination.
• Finding: Combination therapy was significantly superior to either monotherapy for steroid-free remission at week 16.
  • Combo: 39.7%
  • Infliximab: 22.1%
  • Azathioprine: 23.7%
• Mechanism: Aza prevents the formation of Anti-Drug Antibodies (ADAs) against Infliximab, keeping drug levels high. [PMID: 24512909]

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9A. Advanced Pharmacology Profile

Understanding the "Why" and "How" of the drugs we use.

1. Corticosteroids (Hydrocortisone / Methylprednisolone)

• Mechanism:
  • Genomic: Bind to cytosolic Glucocorticoid Receptor (GR) -> Translocates to nucleus -> Inhibits transcription of pro-inflammatory genes (NF-kB pathway) -> Reduces IL-1, IL-6, TNF-alpha.
  • Non-Genomic: Stabilizes lysosomal membranes (rapid effect).
• Resistance: 30% of patients are "Steroid Refractory". Mechanism involves downregulation of GR-alpha expression (the "good" receptor) and upregulation of GR-beta (the dominant negative receptor).

2. Infliximab (Anti-TNF Alpha)

• Class: Chimeric (Mouse/Human) IgG1 Monoclonal Antibody.
• Mechanism:
  • Binds to both Soluble TNF-alpha (neutralizing circulating cytokine).
  • Binds to Transmembrane TNF-alpha on activated T-cells.
  • Result: Induces Apoptosis of the activated T-cells (cell suicide), effectively deleting the inflammatory clone.
• The "Albumin" Problem:
  • Infliximab acts like a protein.
  • If a patient has severe colitis, they leak protein (Albumin) into the gut.
  • They also leak Infliximab into the gut ("Fecal Loss").
  • Correlation: If Albumin less than 30, Infliximab half-life is drastically reduced. This is the rationale for Accelerated Dosing (10mg/kg) in severe cases.

3. Ciclosporin (Calcineurin Inhibitor)

• Mechanism:
  • Binds to Cyclophilin inside the T-cell.
  • This complex inhibits Calcineurin.
  • Calcineurin normally activates NF-AT (Nuclear Factor of Activated T-cells).
  • Result: Blocks IL-2 production. Without IL-2, T-cells cannot proliferate. It stops the "expansion" of the army.
• Key Advantage: Extremely short half-life (hours). If the patient gets septic or needs surgery, you stop the drug and it's gone. (Unlike Infliximab, which stays for weeks).

4. Tofacitinib (JAK Inhibitor)

• Class: Small Molecule (Oral).
• Mechanism:
  • Inhibits Janus Kinase (JAK) 1 and 3.
  • These kinases are attached to cytokine receptors (Pathways for IL-2, IL-6, IFN-gamma).
  • Blocks the STAT (Signal Transducer and Activator of Transcription) pathway.
  • "Broad Spectrum": Blocks multiple cytokines simultaneously.
• Why it works fast: It is a small chemical, not an antibody. It diffuses rapidly into inflamed tissue (hours, not days).

5. Vedolizumab (Integrin Antagonist)

• Class: Humanized IgG1 Monoclonal Antibody.
• Mechanism:
  • Binds specifically to Alpha-4-Beta-7 Integrin on lymphocytes.
  • This integrin is the "Key" that opens the "Door" (MAdCAM-1) to the gut.
  • Gut Selectivity: MAdCAM-1 is ONLY found in the gut. Therefore, Vedolizumab blocks white cells from entering the gut but DOES NOT block them from entering the lung or brain.
  • Safety: "Gut Selective Immunosuppression". Very low risk of systemic infection compared to Anti-TNF.

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9B. International Guidelines: ECCO vs ACG vs BSG

Different regions have slightly different flavors of management.

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10. Special Populations

1. Pregnancy

ASUC in pregnancy requires a "Standard of Care plus Safety" approach. Active disease is more dangerous to the fetus than most medications.

• Natural History: 1/3 improve, 1/3 stay same, 1/3 worsen during pregnancy. Relapse in 1st trimester predicts a tough course.
• Drug Safety (The PIANO Registry Data):
  • Steroids: Safe (Prednisolone > 90% metabolized by placenta).
  • Thiopurines: Safe.
  • Biologics (Anti-TNF/Vedo/Usteki): Safe. Cross placenta in T3. Stop at week 24-26 if in deep remission to reduce neonatal levels. If active, continue through delivery. Infant must avoid rotavirus (live) vaccine.
  • Small Molecules: CONTRAINDICATED. JAKs and S1P modulators are teratogenic.
• Delivery: Vaginal delivery is safe for most (unless active peri-anal disease, which is rare in UC). C-Section reserved for obstetric indications or active pouchitis/perineal involvement.

2. The Elderly (> 65 Years)

• The "Double Whammy":
  1. Immunosenescence: Higher risk of overwhelming sepsis on immunosuppression.
  2. Comorbidities: Heart failure (Anti-TNF contraindicated?), Renal failure (5-Aminosalicylates dosage?), Diabetes (Steroid destabilization).
• Management Nuance:
  • Lower Threshold for Surgery: An elective/semi-elective colectomy is often safer than prolonged, maximal immunosuppression in a frail 80-year-old.
  • VTE Prophylaxis: Aggressive. Risk of PE is highest in this cohort.

3. Paediatrics

• Scoring: Use the PUCAI (Paediatric Ulcerative Colitis Activity Index) instead of Truelove & Witts.
  • PUCAI > 65 indicates severe disease.
• Growth: Chronic inflammation causes permanent height stunting. "Mucosal Healing" is a non-negotiable target to preserve growth velocity.
• Management: Very similar to adults, but Infliximab often cleared faster (pharmacokinetics differ) - higher dosing per kg often required.

11. Maintenance Strategy & The Biological Library

The goal of acute management is to induce remission; the goal of maintenance is to prevent relapse, cancer, and surgery. The choice of maintenance agent depends heavily on what agent was used to induce remission (Rescue Therapy) or whether the patient was steroid-responsive.

1. Principles of Maintenance Selection

• Steroid-Responsive: Patients who responded to IV steroids should be discharged on a weaning course of oral prednisolone (usually 40mg, tapering by 5mg/week) PLUS a maintenance agent (usually Thiopurines or a Biologic if previously failed 5-ASAs). 5-ASA monotherapy is rarely sufficient for ASUC survivors.
• Infliximab-Responders: Should continue Infliximab standard induction (0, 2, 6 weeks) and then maintenance (q8 weeks).
• Ciclosporin-Responders: require a "bridge" to a maintenance agent (usually Thiopurines or Vedolizumab) because Ciclosporin acts fast but isn't safe for long-term use.

2. The Thiopurines (Azathioprine / Mercaptopurine)

Historically the backbone of maintenance, now often used in combination with Infliximab ("Combo-Therapy").

• Mechanism: Purine analogue; inhibits DNA synthesis in immune cells.
• Safety Prerequisite: Must check TPMT (Thiopurine Methyltransferase) and NUDT15 status before starting to avoid severe myelosuppression.
• Dosing:
  • Azathioprine: 2.0 - 2.5 mg/kg daily.
  • Mercaptopurine: 1.0 - 1.5 mg/kg daily.
• Key Side Effects: Pancreatitis (idiosyncratic), Bone Marrow Suppression (dose-dependent), Lymphoma (very low risk, Epstein-Barr Virus driven).

3. Anti-TNF Agents (Tumor Necrosis Factor)

The heavyweights for acute and severe disease.

• Infliximab (Remicade, Inflectra):
  • Route: IV infusion.
  • Role: Primary rescue therapy in ASUC.
  • Immunogenicity: High risk of anti-drug antibodies (ADAs). Best used with an immunomodulator (Mtx/Aza) to protect drug levels.
• Adalimumab (Humira):
  • Route: Subcutaneous injection.
  • Role: Maintenance preference for patient convenience; less effective as "rescue" in ASUC compared to IV Infliximab.
• Golimumab (Simponi):
  • Route: Subcutaneous.
  • Role: Option for moderate-severe UC.

4. Anti-Integrins (Gut-Selective)

• Vedolizumab (Entyvio):
  • Mechanism: Blocks alpha-4-beta-7 integrin, preventing lymphocyte trafficking specifically into the gut mucosa.
  • Safety: Excellent safety profile; no systemic immunosuppression (low infection risk).
  • Onset: Slow (10-14 weeks). NOT suitable for acute rescue. Excellent for maintenance after Ciclosporin bridge.

5. Anti-IL12/23 & Anti-IL23

• Ustekinumab (Stelara):
  • Mechanism: Blocks p40 subunit of IL-12 and IL-23.
  • Role: Effective in anti-TNF failures. Good safety profile.
• Mirikizumab / Risankizumab:
  • Mechanism: Selective p19 inhibition (pure IL-23 blockade).
  • Role: Newest class; very high efficacy and safety.

6. Small Molecules (JAK Inhibitors & S1P Modulators)

Oral options for rapid maintenance.

• Tofacitinib / Upadacitinib / Filgotinib:
  • Mechanism: JAK-STAT pathway inhibition.
  • Speed: Very fast onset (days).
  • Risk: VTE (Clots), Herpes Zoster (Shingles). Contraindicated in pregnancy.
• Ozanimod / Etrasimod:
  • Mechanism: S1P receptor modulation (sequesters lymphocytes in lymph nodes).
  • Role: Moderate-severe disease.

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12. Discharge Checklist

Discharge should only be considered when stool frequency is less than 4/day with no blood (or minimal) and CRP is normalising.

[!IMPORTANT] The Discharge Bundle Ensure every patient leaves with:

1. DVT Prophylaxis Plan: Extended prophylaxis (Clexane/Enoxaparin) for 28 days post-discharge is recommended by many guidelines due to persistent hypercoagulable state.
2. Bone Protection: Calcium + Vitamin D supplements if on prolonged steroids.
3. Vaccination Review: Pneumococcal and Influenza vaccines. Screen for Hepatitis B.
4. Steroid Taper Card: Clear written instructions on reducing prednisolone (do not stop abruptly).
5. Follow-up: Review in IBD clinic within 2-4 weeks.

Assessing Response & "Loss of Response"

Patients must understand "Red Flags" for seeking help immediately:

• Return of visible blood.
• Waking at night to open bowels (Nocturnal diarrhoea).
• Fever.

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13. Single Best Answer (SBA) Questions

Question 1

A 28-year-old male with known ulcerative colitis is admitted with 10 episodes of bloody diarrhoea per day, pulse 105 bpm, temp 38.1°C, CRP 85 mg/L. What is the appropriate first-line medical treatment?

• A) Oral Prednisolone 40 mg
• B) IV Hydrocortisone 100 mg QDS
• C) IV Infliximab 5 mg/kg
• D) Oral Mesalazine 4 g
• E) IV Ciclosporin 2 mg/kg

• Answer: B.
  • Explanation: This patient meets the Truelove & Witts criteria for Acute Severe Ulcerative Colitis (Bloody stool ≥6/day + Tachycardia + Fever + High CRP). The first-line "Anchor" therapy is high-dose Intravenous Corticosteroids (Hydrocortisone 100mg QDS or Methylprednisolone 60mg OD).
  • Why not A (Oral Pred)?: Oral absorption is unreliable in severe colitis due to gut oedema and rapid transit. Equivalent efficacy in mild-moderate disease, but not severe.
  • Why not C/E (Rescue)?: Rescue therapy is reserved for patients who fail to respond to IV steroids by Day 3. You must give steroids a chance first (approx. 60-70% will respond). Jumping to biologics first is incorrect unless there is a specific contraindication to steroids (rare).
  • Why not D (Mesalazine)?: 5-ASAs have no role in the acute severe flare. In fact, many guidelines suggest stopping them during the acute phase as they can contribute to nephrotoxicity if the patient is dehydrated.

Question 2

A patient has been on IV steroids for 72 hours. Stool frequency is 9/day and CRP is 50 mg/L. According to the Oxford Criteria, what is the approximate likelihood of requiring colectomy?

• A) 10%
• B) 30%
• C) 50%
• D) 85%
• E) 100%

• Answer: D.
  • Explanation: The Oxford Criteria (Travis et al., 1996) state that at Day 3, if Stool Frequency > 8/day OR CRP > 45 mg/L, the predictive value for colectomy is 85%.
  • Clinical Relevance: This high predictive value justifies the switch to "Rescue Therapy" (Infliximab/Ciclosporin) or Surgery at this time point. Waiting longer ("Day 4/5/6") only increases toxicity without changing the outcome.
  • Why not E?: It is not 100%. Some "slow responders" do exist, but the risk of waiting outweighs the benefit. The 85% is the threshold for action.

Question 3

Which medication is contraindicated in active severe colitis due to the risk of precipitating toxic megacolon?

• A) Heparin
• B) Paracetamol
• C) Codeine Phosphate
• D) Infliximab
• E) Prednisolone

• Answer: C.
  • Explanation: Anti-motility agents (Opioids like Codeine, Morphine, or Loperamide) paralyse the smooth muscle of the colon. In the context of severe inflammation (where neuromuscular tone is already compromised by Nitric Oxide), this precipitates colonic dilatation and Toxic Megacolon. Use simple analgesia (Paracetamol) only.
  • Why not A (Heparin)?: Heparin (LMWH) is mandatory for thrombosis prophylaxis. It does not significantly increase the risk of severe haemorrhage from the colitis.
  • Why not D (Infliximab)?: Infliximab treats the inflammation and reduces risk.

Question 4

A pregnant patient (28 weeks) with ASUC is failing steroids. Which statement regarding Infliximab is correct?

• A) It is absolutely contraindicated in pregnancy.
• B) It can be given, but the infant must not receive live vaccines for 6 months.
• C) It causes congenital malformations.
• D) It must be combined with Methotrexate.
• E) It requires immediate delivery of the fetus first.

• Answer: B.
  • Explanation: Infliximab is an IgG1 monoclonal antibody. It requires active transport across the placenta (via FcRn receptors), which occurs efficiently in the 3rd Trimester. It is safe for the mother to control the disease (active disease > risk of drug).
  • Vertical Transmission: Because it crosses, the infant will be born with therapeutic drug levels. This persists for months.
  • Implication: The infant is effectively immunosuppressed. Live vaccines (BCG, Rotavirus) given to an immunosuppressed infant can cause disseminated infection. Therefore, live vaccines are contraindicated for the first 6-12 months.
  • Why not A/C?: Not teratogenic.
  • Why not D?: Methotrexate is strictly teratogenic (Abortion agent). NEVER use in pregnancy.

Question 5

What is the diagnostic criteria for Toxic Megacolon on abdominal X-ray?

• A) Transverse colon > 3 cm
• B) Transverse colon > 6 cm
• C) Caecum > 6 cm
• D) Small bowel dilation > 3 cm
• E) Presence of free air

• Answer: B.
  • Explanation: Toxic Megacolon is defined as non-obstructive dilatation of the Transverse Colon > 6 cm (or Cecum > 9cm) AND signs of systemic toxicity.
  • Radiological Pearl: The transverse colon is the most anterior part of the colon in a supine patient, so gas rises into it, making it the most sensitive site to measure.
  • Why not E?: Free air indicates perforation. A patient can have megacolon without perforation (yet). Once verified, the management changes from "Medical Rescue" to "Emergency Laparotomy".

Question 6

A 68-year-old male with ASUC has failed steroids and Infliximab. He is stable but opening bowels 8 times a day with blood. What is the priority?

• A) Add Ciclosporin
• B) Add Tofacitinib
• C) Subtotal Colectomy
• D) Total Proctocolectomy
• E) Continue Infliximab for another week

• Answer: C.
  • Explanation: This is "Third-Line" or "Sequential" rescue. In an elderly patient (> 65), sequential rescue (A -> B -> C) carries a very high mortality risk due to opportunistic infection (approx 15-20% mortality).
  • Surgical Choice: He needs surgery. The safest operation is a Subtotal Colectomy (removing the diseased colon but leaving the rectum).
  • Why not D?: Total Proctocolectomy (removing rectum too) involves deep pelvic dissection. This is dangerous in an emergency (high blood loss, nerve injury risk). It is safer to leave the rectum and deal with it later when the patient is well.

Question 7

Which of the following is an extra-intestinal manifestation of UC that runs a course independent of the bowel activity?

• A) Erythema Nodosum
• B) Pyoderma Gangrenosum
• C) Episcleritis
• D) Primary Sclerosing Cholangitis
• E) Aphthous Stomatitis

• Answer: D.
  • Explanation: Primary Sclerosing Cholangitis (PSC) is a progressive fibrotic disease of the bile ducts. Its course operates independently of the colitis. Even if you remove the colon (colectomy), the PSC continues to progress (potentially to cirrhosis or cholangiocarcinoma).
  • Contrast:
    • Erythema Nodosum (A): Mirrors bowel activity (flares with the gut).
    • Episcleritis (C): Mirrors bowel activity.
    • Pyoderma Gangrenosum (B): Often mirrors, but can persist independently in some cases (less strictly linked than EN).

Question 8

What is the recommended VTE prophylaxis for a patient with ASUC and rectal bleeding?

• A) None
• B) Compression stockings only
• C) Low Molecular Weight Heparin (LMWH) at prophylactic dose
• D) Warfarin
• E) Aspirin

• Answer: C.
  • Explanation: ASUC is a massive pro-thrombotic state. The risk of Pulmonary Embolism (PE) is 3-8x higher than baseline.
  • Safety: Is it safe to anticoagulate a bleeding patient? Evidence shows that standard prophylactic LMWH does not increase the risk of severe haemorrhage or transfusion requirement significantly, but it DOES save lives from PE.
  • Guideline: Mandatory for ALL inpatients with ASUC unless there is a specific contraindication (e.g., active intracranial bleed).
  • Why not B?: Stockings alone are insufficient for this high-risk group.

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14. Clinical Case Scenarios

Case 1: The "Steroid Refractory" Young Male (Classic Rescue)

• Profile: 26-year-old male, known Pancolitis for 2 years (previously mild).
• Presentation: Admitted with 12 bloody stools/day, CRP 90 mg/L, Albumin 32 g/L, HR 110 bpm.
• Management Course:
  • Day 0: Started on IV Hydrocortisone 100mg QDS + LMWH + Stool Cultures sent. AXR shows no megacolon but mucosal islands.
  • Day 3 Review: Stools 9/day, CRP 55 mg/L.
  • Assessment: Meets Oxford Criteria (CRP > 45 + Stools > 8). Risk of colectomy 85%.
  • Decision: Discussed Infliximab vs Surgery. Patient chooses medical rescue.
  • Intervention: Infused Infliximab 5mg/kg (Induction Dose 1).
  • Day 7: Metabolic response. CRP 12 mg/L. Stools 3/day (no blood).
  • Discharge: Discharged on accelerated Infliximab schedule (0, 2, 6 weeks) + tapering steroids.

Case 2: The "Complicated" Elderly Patient (Surgical Rescue)

• Profile: 74-year-old female, new diagnosis of Left-sided colitis. Hx: Heart Failure (NYHA II) and previous DVT (on Warfarin).
• Presentation: Stools 8/day, CRP 60 mg/L, Hb 85 g/L.
• Management Course:
  • Day 0: IV Steroids started. Warfarin held -> IV Heparin bridge.
  • Day 3: No response. CRP 65 mg/L. Patient drowsy.
  • Decision Node: Rescue therapy options limited:
    • Infliximab: Relatively contraindicated (NYHA II Heart Failure - risk of exacerbation).
    • Tofacitinib: Contraindicated (Age > 65 + DVT History + Heart Failure).
    • Ciclosporin: High risk of nephrotoxicity/HTN.
  • Outcome: Proceeded to semi-elective Subtotal Colectomy.
  • Result: Histology confirmed deep ulceration (toxic megacolon averted). Stoma education provided. Discharged Day 10.

Case 3: The "Super-Responder" (JAK Inhibitor Rescue)

• Profile: 35-year-old female, failed Azathioprine and Adalimumab previously. Admitted with severe flare.
• Presentation: Stools 15/day, CRP 45.
• Management:
  • Day 0: IV Steroids.
  • Day 3: Partial response (CRP 30), but still bleeding 8x/day.
  • Decision: Failed Anti-TNF previously. Need different mechanism.
  • Intervention: Started Tofacitinib 10mg BD (High intensity).
  • Day 4: Dramatic improvement. Stools 4/day. "I slept through the night."
  • Mechanism: JAK inhibitors work within hours/days (small molecule) compared to weeks for some biologics.
  • Pearl: Tofacitinib is an excellent choice for Anti-TNF failures who need speed, provided VTE risk is managed.

Case 4: The Pregnant Flare

• Profile: 28-year-old female, 26 weeks pregnant. Discontinued Mesalazine because "worried about baby."
• Presentation: Severe flare. Stools 10/day, bleeding. Fetal movements normal.
• Management:
  • Multidisciplinary: Gastro + Obs + IBD Nurse.
  • Action: Restarted IV Hydrocortisone immediately. (Clarified: "Active disease is more dangerous to baby than steroids").
  • Rescue: Failed Day 3 criteria.
  • Choice: Infliximab chosen. Safe in pregnancy.
  • Plan: Continue Infliximab through third trimester. Baby to receive NO LIVE VACCINES (Rotavirus/BCG) for first 6 months.

Case 5: The "Double Trouble" (CMV + C. Diff)

• Profile: 50-year-old male, on Azathioprine. Flare not settling after 5 days of IV Steroids.
• Investigation:
  • Stool: C. Diff Toxin POSITIVE.
  • Biopsy: Flexi-sig biopsies show CMV inclusions (IHC positive).
  • Analysis: This is not "steroid failure"

• it is "steroid driven infection."

• Management:
  • Action: REDUCE steroids (don't stop abruptly, but taper).
  • Infection Control: Start Oral Vancomycin (for C. Diff) + IV Ganciclovir (for CMV).
  • Outcome: Gradual improvement over 10 days. Avoided colectomy.
  • Pearl: Always biopsy the refractory patient. "Steroids fuel the fire" in CMV.

15. Glossary of Advanced Terms

• Backwash Ileitis: Inflammation of the terminal ileum (TI) seen in 10-20% of patients with pancolitis. It is due to the reflux of cecal contents into the ileum through an incompetent ileocecal valve. Histologically distinct from Crohn's ileitis (no granulomas).
• Basal Plasmacytosis: The presence of plasma cells at the very bottom of the colonic crypts. A key histological sign that distinguishes chronic ulcerative colitis from acute infectious colitis.
• Calcineurin: An enzyme that activates T-cells. Inhibited by Ciclosporin and Tacrolimus.
• Crypt Abscess: A collection of neutrophils inside a colonic crypt (gland). A hallmark of active inflammation.
• Deep Remission: A treatment target comprising both Clinical Remission (no symptoms) AND Endoscopic Remission (mucosal healing).
• Indeterminate Colitis (IBD-U): A diagnosis used when distinct features of UC or Crohn's are absent, and the colitis cannot be definitively classified. Common in ASUC after colectomy (10-15%).
• JAK-STAT Pathway: A signaling pathway used by cytokines to activate immune cells. Blocked by Tofacitinib, Filgotinib, and Upadacitinib.
• Lead Pipe Colon: An appearance on barium enema or AXR where the colon looks like a rigid, featureless tube due to loss of haustra from chronic inflammation.
• MAdCAM-1: Mucosal Vascular Addressin Cell Adhesion Molecule 1. A gut-selective receptor on endothelial cells that attracts lymphocytes into the gut. Blocked by Vedolizumab.
• Mucosal Healing: Complete absence of visible ulceration or inflammation on endoscopy (Mayo Score 0 or 1). Associated with lower rates of surgery and cancer.
• Pouchitis: Inflammation of the ileal pouch reservoir created after colectomy. Symptoms include increased frequency, urgency, and bleeding. Treated with antibiotics (Ciprofloxacin/Metronidazole).
• Pseudopolyp: Islands of regenerating mucosa surrounded by ulceration. They are not pre-cancerous but are markers of previous severe inflammation.
• Toxic Megacolon: Non-obstructive dilatation of the colon (> 6cm) with signs of systemic toxicity. A surgical emergency.
• Truelove and Witts Criteria: The classic definition of ASUC: ≥6 bloody stools/day + Fever > 37.8, HR > 90, Hb less than 105, or ESR > 30.

15. Glossary of Advanced Terms

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16. The Discharge Bible: Patient Education Guide

Congratulations on making it through a severe flare. The acute danger has passed, but the work of recovery is just beginning. This guide (FAQ) will help you navigate the next 6 weeks.

Phase 1: The "Steroid Taper"

You are likely going home on Oral Prednisolone (starting at 30mg or 40mg).

• Active Weaning: You must reduce the dose by 5mg every week.
  • Week 1: 40mg
  • Week 2: 35mg
  • Week 3: 30mg... and so on.
• Why Taper?: Your own adrenal glands have gone to sleep while on high doses. If you stop suddenly, your blood pressure will crash (Adrenal Crisis).
• Side Effects: You might feel "wired", have trouble sleeping, or feel very hungry. This is normal. Take the tablets in the morning to save your sleep.

Phase 2: The "Safety Net" (Rescue)

If you received Infliximab (The Infusion):

• How it works: It is an antibody that mops up the inflammation.
• The Schedule: You usually get infusions at Week 0, Week 2, and Week 6.
• Long Term: If it works, you will likely stay on it (or a similar injection) long-term to prevent a future flare.
• Self-Monitoring: Watch for signs of infection (fever/cough). You are immunosuppressed. If you get a fever > 38°C, seek medical attention immediately.

Phase 3: Diet & Nutrition

• "What can I eat?":
  • Myth: "I must eat only plain toast."
  • Reality: You need PROTEIN. Your body has lost muscle mass fighting the inflammation. Eat chicken, fish, eggs, tofu.
  • Fibre: In the first 2 weeks, avoid "roughage" (nuts, seeds, sweetcorn, raw kale). These act like sandpaper on the healing ulcers. Cook your vegetables well.
  • Hydration: Drink 2-3 Litres of water. Your colon absorbs water; right now, it isn't doing its job well, so you are prone to dehydration.

Phase 4: Complication Watch (When to Call Us)

Do not wait for your scheduled appointment if you see the "Red Flags":

1. The "Rebound": If you were improving, but suddenly the bleeding returns.
2. The Fever: Any temperature > 37.8°C.
3. The Pain: Severe, constant tummy pain that stops you moving.
4. The Swelling: If one leg becomes swollen, red, and painful (DVT risk).

Frequently Asked Questions (FAQ)

Q: Will I get this again?

• A: Ulcerative Colitis is a lifelong condition. However, with the right "Maintenance Medication" (like Mesalazine or Biologics), we aim for "Deep Remission" where you have NO symptoms for years. The goal is a normal life.

Q: Can I take painkillers?

• A: Paracetamol is safe. Avoid Ibuprofen/Voltarol (NSAIDs) – they can trigger a flare. Avoid Codeine – it causes constipation and can be dangerous in colitis.

Q: What about my fertility?

• A: UC itself does not reduce fertility. In fact, active disease is the biggest risk to pregnancy. Getting the disease under control (even with biologics) is the best way to ensure a healthy future pregnancy.

Q: Did stress cause this?

• A: Stress doesn't cause UC (it's genetic/immune), but stress can trigger a flare. Managing stress is part of the treatment, but do not blame yourself. You didn't "think" yourself into a bloody flux.

Q: Do I need probiotics?

• A: There is no strong evidence that over-the-counter probiotics (like Yakult/Actimel) stop an acute severe flare. Save your money for good quality food. VSL#3 is a medical grade probiotic that has some evidence in pouchitis, but for acute UC, standard drugs are the key.

Q: Can I drink alcohol?

• A: In moderation, once you are well. During the taper phase, avoid it. Prednisolone + Alcohol allows for gastric irritation (ulcers in the stomach, not just the colon!).

The "New Normal" Checklist

Before you leave the ward, ensure you have:

• Your Steroid Taper Plan (Printed).
• Your Calcium/Vitamin D tablets.
• The "IBD Nurse Helpline" number.
• Your follow-up appointment (Booked for Week 2-4).

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17. Appendix A: Drug Administration Protocols

This section contains high-yield, specific administration guides for junior doctors and nurses.

Protocol 1: Intravenous Hydrocortisone (Acute Phase)

Indication: Acute Severe Ulcerative Colitis (Day 1-5).

• Dose: 100mg IV.
• Frequency: Four times daily (QDS). Total 400mg/24hr.
• Preparation:
  • Reconstitute 100mg powder with 2ml Water for Injections.
  • Give as a "slow bolus" over 1-2 minutes.
  • CAUTION: Rapid bolus can cause "groin burning" sensation (perineal irritation).
• Monitoring:
  • Glucose: Check Capillary Blood Glucose (CBG) QDS. If > 12mmol/L on two occasions, start variable rate insulin scale (VRII).
  • Potassium: Steroids cause renal potassium wasting. Maintain K+ > 4.0 mmol/L aggressively.
  • Gastric Protection: Routine PPI (Lansoprazole 30mg) is debated but often prescribed to prevent "Steroid Ulcers" in the stomach.

Protocol 2: Infliximab Infusion (Rescue Therapy)

Indication: Day 3 Rescue for steroid-refractory colitis.

• Dosing Weight: Use actual body weight.
• Standard Dose: 5mg/kg.
• Accelerated Dose: 10mg/kg (Use if Albumin less than 30 or CRP > 50).
• Preparation:
  • Each vial is 100mg.
  • Reconstitute with 10ml Sterile Water. Do NOT shake (it foams). Swirl gently.
  • Dilute in 250ml 0.9% Saline (Total volume 250ml).
  • Use an infusion set with a low-protein-binding filter (0.2 micron).
• Infusion Rate (Standard 2-Hour):
  • 0-15 mins: 10ml/hr
  • 15-30 mins: 20ml/hr
  • 30-60 mins: 40ml/hr
  • 60-90 mins: 80ml/hr
  • 90-120 mins: 150ml/hr -> Until finished.
• Pre-medication:
  • Chlorphenamine 10mg IV + Hydrocortisone 100mg IV is historical.
  • Modern practice: No pre-medication unless previous mild reaction.
• Anaphylaxis Drill:
  • Symptoms: Wheeze, hypotension, urticaria.
  • STOP infusion immediately.
  • Call for help. Administer IM Adrenaline (1:1000) 500mcg if airway compromised.

Protocol 3: Ciclosporin Infusion (Alternative Rescue)

Indication: Rescue therapy when Infliximab is contraindicated (e.g., TB history, Multiple Sclerosis).

• Dose: 2mg/kg/day IV.
• Key Requirement: MUST use a dedicated glass syringe or non-PVC giving set (leaches plastic).
• Magnesium Protocol:
  • Ciclosporin causes massive renal magnesium wasting.
  • Hypomagnesemia -> Seizures (Neurotoxicity).
  • Action: Prophylactic oral Magnesium aspartate or IV Magnesium sulfate replacement daily.
• Cholesterol Check:
  • Risk of seizures increases if Cholesterol less than 3.0 mmol/L.
  • Contraindication: Do not use Ciclosporin if Cholesterol is very low (malnutrition).

Protocol 4: LMWH Dosing (The "Clot Buster")

Indication: Mandatory VTE prophylaxis for ALL admissions.

• Renal Function Normal (eGFR > 30):
  • Standard Risk (less than 100kg): Enoxaparin 40mg SC OD.
  • High Risk (> 100kg): Enoxaparin 40mg SC BD (Twice daily).
• Renal Impairment (eGFR less than 30):
  • Reduce dose by 50% (e.g., 20mg SC OD).
• The "Bleeding" Conundrum:
  • Nurse: "Doctor, he is passing 500ml of blood per day, should I hold the blood thinner?"
  • Doctor (You): "NO. The bleeding is mucosal. He will not bleed to death from the heparin. He WILL die from a Pulmonary Embolism. Give the dose."

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Last Updated: 2026-01-05 | MedVellum Editorial Team