Ulcerative colitis

• Bimodal – ages 15-30, 50-70
• Almost always rectal involvement and usually continuous disease unlike Crohn’s. No fistulae or strictures.
• Proctitis, left sided or extensive (20% risk of colectomy)
• The Montreal classification classifies extent and severity
• Severe flairs are admitted for steroid treatment
• The following relates to patients with known UC. For initial diagnosis – see Inflammatory Bowel Disease

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Initial assessment of a UC flair

• What to know (and what to document)
  • • When the UC was diagnosed
    • The extent of disease
    • The last colonoscopy (and histology)
    • Current treatment now, what has worked before
    • Number of previous admissions
    • Surgical history
• Use the Truelove and Witts Score to assess severity
  • • Severe is > 6 bloody stools (majority bloody, not all) a day plus any of:
      • • Tachycardia (>90)
        • Pyrexia (>37.8)
        • Large amount of blood in stool
        • Anaemia (Hb < 105)
        • ESR > 30 (the evidence is for ESR, but CRP often used as more pragmatic, sometimes cut off of 30, sometimes 12, sometimes 5)
    • Lower CRP has been suggested (eg in US guidelines) because the score was developed prior to lots of patients being on advanced therapies or steroids in the community
• Other non-scoring markers of severity
  • • Extent of inflammation on endoscopy (Mayo score 3)
    • Low albumin
    • Acute Kidney Injury
    • Electrolyte disturbance
    • High calprotectin >150
• Consider triggers – can include medications eg NSAIDs, antibiotics, infections, reduced adherence to treatment
• Consider important mimics
  • • Infections – viral, bacterial, parasitic (but especially acute CMV, C. Diff and amoebic colitis)
    • Ischaemic colitis
• Consider admission
  • • If severe flair – Always admit these for steroids
    • Admitting can be a grey area – for example if bowels open 5 times a day and CRP 20. Decide on a case by case basis

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Investigations

• Bloods
  • • Platelets, albumin, Hb and ESR – all important for assessing degree of inflammation
    • Also send bone profile, LFTs, CRP, haematinics, B12/folate, group and save
• Consider pre-biologic screen in severe flairs
  • • Lipids and magnesium (in case need ciclosporin later)
    • HIV test, Hep B and C, IGRA and CxR (in case needs infliximab)
    • EBV and TPMT (in case planning to use azathioprine)
    • Varicella IgG, CMV
• Stool culture (vital) – MC&S, C Diff, cysts/ova/parasites
• Faecal calprotectin – not particularly useful in a flair of known UC in hospital. See inflammatory bowel disease for tips on interpretation
• Consider AxR and erect CxR
  • • Xrays are often normal but can be worth checking
    • Typically stool is absent in areas of inflamed colon, so distal disease can appear as proximal constipation (give some laxatives or bowel prep for this, but this will make stool chart difficult to interpret)
    • AxR features may include
      • • Thickened colon
        • Free gas
        • Small bowel obstruction
        • Large bowel obstruction
        • Mucosal islands (poor prognostic sign, 50% need colectomy if these are present at day 2)
        • Thumbprinting
        • > 3 air filled loops
        • Lead piping
        • Toxic megacolon >5.5cm traverse colon or 9cm caecum. Risk is 10% in severe UC
    • Repeat AxR if initial bowel dilation or clinical change
• Consider CT – not routine but indicated if
  • • Suspected perforation or septic abscess
    • Palpable mass or possible collection clinically and very high CRP
    • If getting worse, especially if tachycardic (preferable to AxR)
    • If the patient needs a surgical review
    • If ischaemic colitis possible
• Flexi sigmoidoscopy
  • • Aim to do within 24 hours. Reality is 48-72 hours. Can sometimes wait until stool culture back
    • No bowel prep is required
    • When scoping, do the Mayo score or UCEIS score to assess severity of disease
      • • UCEIS score depends on vascular pattern, erosions, ulcers, bleeding. < 5 is reassuring, risk of colectomy low. Max of 8.
        • Mayo score is scored 0-3
    • Do biopsy for CMV colitis
      • • Do not check CMV serology, not useful
        • If biopsy positive, discuss with microbiology, may well not be very relevant, and rarely causes the severe ulceration
    • If very inflamed – might do a limited scope as high risk of perforation

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Acute management

• Aim of treatment if not just for symptoms but also to heal the ulcers
• Increasingly IBD is treated with strongest treatment up front instead of stepwise approach, but its managed on a case by case basis
• Outpatient management
  • • For mild or moderate flair and not admitting, can trial 5 ASA (eg mesalazine) for 4 weeks and review.
    • Check the patient is on oral and topical (enema) mesalazine / 5 ASA (eg Octasa, or Pentasa) at maximum dose
    • If mild to moderate proctitis (can present with constipation if painful to go) – might treat with 5ASA suppository first, then oral ASA, then topical prednisolone. But if severe – admit, straight for oral steroids.
    • Side effects of mesalazine include renal failure (0.1%) and transit diarrhoea (5%)
• Inpatient management of an acute severe flair
  • • Start stool chart – can ask patient to do so, provide a pen!
    • Chase results of stool cultures
    • Rehydrate and correct hypokalaemia promptly – it increases the risk of colonic dilatation, aim for K+>4. Also correct magnesium and phosphate.
    • IV steroids – don’t wait! More detail below.
    • Consider antibiotics – see below
    • VTE prophylaxis
      • • Even if PR bleeding (although consider more carefully if major bleed and Hb<70)
        • Consider extended VTE prophylaxis (4/52) even after discharge if they were very inflammatory
    • Refer to surgeons (if severe flair), gastroenterology and dietician
    • Order the flexi sigmoidoscopy – get it done in 72 hours at the latest, score with Mayo or UCEIS as above
    • Consider withholding 5-ASA if giving steroids – not wrong to continue, but they can cause diarrhoea which can mess up the scoring system, and probably don’t add much
    • PPI (and consider Adcal D3)
    • Low residue diet and keep up nutrition – no evidence for bowel rest
    • Assess refeeding risk if poor nutritional status
    • Keep Hb > 100 (some would say aim to normalise using IV iron at a later stage)
    • Analgesia – generally avoid NSAIDs and opiates. More detail below.
    • Avoid loperamide
    • Regular reassessment / daily bloods

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Analgesia

• Can try IV paracetamol and buscopan
• Can use Entonox if in extreme pain
• Discuss with pain team if struggling
• Generally avoid NSAIDs, loperamide, codeine / opiates, anticholinergics, antispasmodics
• Definitely avoid IV opiate infusions and tramadol
• A short course of NSAIDS is safer than opioids if pain is severe
• Sometimes give opioids at low dose but be cautious (try short acting oramorph at low dose for breakthrough pain). They increase the risk of megacolon

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Steroids

• In severe flairs – treat with 100mg hydrocortisone IV four times daily – do not give lower doses
• Alternative is 60mg of IV methylprednisolone once daily – some prefer this as less chance of missed doses
• If a patient has been taking oral prednisolone at home on advice of IBD team, switch to IV hydrocortisone if admitting
• Do not need to wait for stool cultures, scope or gastro review to start steroids. You can start treatment in ED. It’s not contraindicated if possible bacterial infection (just treat this too)
• Around 30% of patients will not respond to steroids alone in a severe flair (but continue steroids if starting a biologic – an overlap, not a switch)
• Failure to respond to steroids predicted by day 3 faecal calprotectin >1000 μg/g or high (>6) UCEIS score (odds ratio around 8)
• Monitor stool chart and CRP for response
• If a patient doesn’t end up needing rescue therapy, then generally give 3-5 days IV treatment, then oral prednisolone 40mg OD, reducing by 5mg every 7 days
• Council regarding steroid side effects – mood, infections, diebetes, weight gain, reflux
• Check CBGs and adjust diabetes treatment if diabetic
• Give PPI (omeprazole 20mg) and bone protection too (Adcal D3, 2 capsules once daily)
• Consider a biologic in the future if repeated steroid courses required

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Infections and antibiotics

• Antibiotics
  • • Not usually required (though if first presentation and unclear diagnosis, consider them)
    • Check trust policy for GI infection. Some give metronidazole on its own as routine
    • Always give antibiotics if toxic megacolon, perforation, high risk of infectious colitis
• Clostridium difficile
  • • If suspected, can treat
    • If confirmed C. Diff – give the IV hydrocortisone with oral vancomycin (no need to stop steroids)
    • Increased incidence of C. Diff in UC patients and usual risk factors (old age and previous antibiotics) often not present
    • It carries an increased mortality
• If unsure if infection or flair
  • • Unlikely to cause harm by giving steroids – but be careful if very high fevers, travel history or recent antibiotics
    • Infections can cause flairs and flairs can lead to infections. 20% of flairs are related to infection (hence always send cultures and a C Diff test)
    • You can treat both concurrently with antibiotics and steroids
    • Having a concurrent infection means the chance of responding to usual UC treatment is halved
• Dysentery
  • • Steroids can be very harmful in amoebic dysentery
    • Consider oral metronidazole if patient comes from an endemic country
• If sepsis develops on immunosuppression – discuss with microbiology

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Complications

• Perforation
• Toxic megacolon
  • • Occurs in around 3% of severe flairs of UC
    • 20% mortality if it perforates
    • Not just dilated bowel
      • • Check the Jalan criteria
        • Transverse colon >6cm, fever, tachycardia, anaemia, leucocytosis, sometimes hypotension, electrolyte imbalance, altered mentation
• Colectomy
  • • Risk is 15% in 3 months for acute severe UC, and falling (was >80% before steroids, and 30% afterwards but before rescue therapy)
    • Risk is determined by severity of disease (at the time of UC diagnosis, and acutely) and therapeutic response
• VTE
  • • Risk associated with severity of disease (severity of flair and severity of chronic UC)
    • Higher risk if on steroids or JAK inhibitors (and maybe avoid the latter if previous VTE or high risk), or post-operatively
    • Risk of VTE in IBD patients with flair out of hospital is 3 x higher
    • Risk of VTE in a non-flair but hospitalised IBD patient is 16 x higher
    • Risk of VTE in a UC flair in hospital is 27 x higher
    • Risk of VTE in IBD-related surgery is around 40 x higher
• Clostridium difficile
  • • Patients with UC 5-10 times more liekly to develop C Diff (due to gut dysbiosis and medications)
    • Treat with vancomycin or fidaxomicin
    • See clostridium difficile
• CMV colitis
  • • Treat with valacyclovir (if non-systemic) or gangiclovir
• Death
  • • Higher risk if C. diff positive, comorbid or older age
    • 1% mortality for acute severe UC

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Regular inpatient assessment

• Regularly re-examine abdomen
• Daily bloods
  • • A CRP > 30 is concerning
    • A CRP < 30 is not entirely reassuring (bloods can be close to normal in flairs even when severe)
    • Check electrolytes – Aim for K+> 4. Replace magnesium and phosphate if low (IV as oral could worsen diarrhoea)
• If high swinging fevers – check CMV PCR
• Discuss with surgeons early if
  • • Signs of perforation / sepsis
    • Massive haemorrhage requiring > 6 units
    • Toxic megacolon
    • Deterioration despite treatment (as per the Travis Criteria – see below)
    • Severe pain
    • Oedema with hypoalbuminaemia
    • Long standing intractable colitis in patients who have cycled through various treatments before without surgery
    • Psoas abscess – pain on flexing hip, neurological symptoms, problems walking. Can be due to immunosuppression, TB or a fistula

• At day 3 (72 hours) 
  • • Assess response to treatment using The Travis Criteria
    • After 3 days of IV steroids, if stool frequency > 8/day, or 3-8x / day and CRP>45, 85% chance that further steroids won’t be enough and will need colectomy (unless rescue therapy initiated)
    • Risk of treatment failure is 62% if bowels opening > 9x day, or albumin < 30, or heart rate > 90
    • Poor signs also include mucosal islands on AxR and colonic diameter > 5.5cm
    • Risk of surgical complications rise if you delay this assessment
    • If >8 bowel movements/day, or 3-8 AND CRP >45: discuss with surgeons
      • • Although it’s very rare these days to have colectomy before rescue therapy unless complications
        • If no colectomy planned – continue IV steroids, and initiate 2^nd line therapy of infliximab or ciclosporin (see below)
    • If < 4 bowel movements per day for 2 days AND no rectal bleeding
      • • Switch to oral prednisolone 40mg once daily, commence a thiopurine if not already on it, restart 5-ASA if withheld
        • Consider discharge home if no worse after 24 hours oral treatment
    • If 4-7 bowel movements/day or <8 AND rectal bleeding
      • • Continue IV steroids for 4 additional days (if meets criteria above within next 4 days, can do the oral switch and discharge planning, if not: start 2^nd line treatment, maybe at day 7)
    • Can give rescue treatment even if immunosuppressive screen not back, but you do need the stool culture result
    • Steroid response can also be predicted by ADMIT-ASC score
      • • Based on CRP>100, albumin <25, UCEIS score
        • If 0, response rate is 100%, if 1 = 70%, if 2 = 40%, if 3 = 17%, if 4 = 0%
        • ASUC score is an alternative (omits CRP)

• At day 7
  • • If not winning – re-review for colectomy or repeat infliximab/accelerated dosing
    • If < 4 bowel movements for 2 days and no rectal bleeding – step down to oral treatment
    • Do not give IV steroids for more than 10 days – if medical therapy failing, they need an operation, otherwise mortality rises significantly

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Discharge

• Consider if
  • • If stool frequency < 4 with no blood at day 3, normal albumin and no colonic dilatation
    • However, if stool frequency >3 and still blood present at day 7 – 60% positive predictive value of needing colectomy
    • If going home after infliximab, complete loading and commence maintenance
    • If on ciclosporin – discharge on oral treatment twice daily, and check trough levels
• All acute severe flairs will also go home with
  • • An advanced therapy – azathioprine or mercaptopurine
    • Mesalazine
    • Weaning course of steroids (usually >20mg prednisolone daily to begin with)
    • PPI (sometimes) and Adcal D3
    • +/- septrin (PCP prophyalxis). Indicated if on triple immunosuppression and if on >20mg prednisolone

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Rescue / salvage therapy and immunosuppression / biologics

• Continue steroids, plus add either infliximab or ciclosporin
• Infliximab vs ciclosporin
  • • Equivalent response rates / efficacy, similar rate of side effects.
    • Don’t give both!
    • If one fails, occasionally the other is tried, but only is specialist centres due to the risk involved
• Infliximab
  • • Contraindicated if previous TB or very high risk of TB, although can be given if patient being successfully treated for TB previously
    • Before starting – do biologic screen (see investigations above for details)
    • It’s infused over 1-2 hours (5mg/kg)
    • Can take up to 14 weeks to know if patient has responded, but they can work very fast
    • It can be used long term, useful if patient already on thiopurines (ie they have failed) and can escalate the dose
    • Hypoalbuminaemia can reduce the therapeutic response (therefore consider other agents if albumin <20)
    • It is lost in the stools, so severe diarrhoea will also reduce its effect
    • Repeat infusion in 2 and 6 weeks, then every 8 weeks
    • Can do accelerated dosing – 2 x 5mg/kg in first 7 days (not much evidence of benefit, though this is under review)
    • Subcutaneous preparation now available – every 2 weeks, fixed dosing
    • On a Friday, ask if Infliximab is ready/available in case of steroid failure over the weekend
    • Live vaccines contraindicated
    • Side effects include – increased risk of some cancers (eg lymphomas, melanomas), lupus-like illness / arthropathies, rashes (psoriasis), demyelination, infections like TB
• Ciclosporin
  • • Ciclosporin has various side effects and the infusions / drug levels can be a complicated, so probably 2^nd line option
    • But… short half-life and cheap, and used preferentially if risk of TB
    • Check blood pressure, magnesium and lipids first – can’t be used if low Magnesium, high cholesterol (seizure risk), marked hypertension
    • Once on it, steroids can be tapered soon afterwards
    • > 75% respond
    • Dosing is 2mg/kg/day as four back to back continuous infusions per 24 hours for 7 days (ie an infusion every 6 hours – there is a risk of delayed treatment if infusion finishes and is not replaced overnight)
    • Then at day 7 (if patient responding) switch to oral ciclosporin 6-8mg/kg every 24 hours (twice daily dosing) for 3-4 months and start azathioprine
    • Measure levels alternate days. Target 150-250 ng/ml
    • In general it’s a bridge to immunosuppression with other medications (azathioprine or a newer biologic), and shouldn’t usually be used for maintenance > 6 months
    • Side effects include paraesthesia (51%), hypertension (43%) hypomagnesaemia (42%), CKD (23%), infections (20%), seizures (3%), thrombophlebitis
• Tofacitinib as rescue also under review
  • • Some very promising data coming in regarding early use.
    • Latest guidance suggests consider in highly selected patients
    • Effective dose however is higher than approved for use in Europe
• Azathioprine
  • • Very long half-life and takes 4-6 weeks to work.
    • Check TPMT first (which helps gauge risk of neutropenia) and do a viral screen (HIV, EBV, CMV, hepatitis). Withhold if acute EBV (treat with antivirals first)
    • If deranged liver function can check MEMP:TGN ratio. If high, treat with allopurinol and reduce azathioprine dose
    • Risks
      • • Skin cancer and warts. Use high factor sunscreen
        • Acute pancreatitis in first 3 months
        • Lymphoma 0.1%
        • Chicken pox reactivation
        • 10-15% do not tolerate
        • 1-2% have a serious complication
        • Only 0.1% have irreversible long term complication
    • Explain risk of treatment to patient, also explain risks of losing their colon
• Special considerations
  • • In liver disease
      • • Withhold biologic/immunosuppression if ALT >200, or acute rise in bilirubin to >50
        • Do urgent CLD screen and US liver / biliary tree
        • Keep on steroids only
    • If already on infliximab / biologic
      • • Try ciclosporin as a bridge to another biologic like vedolizumab (which takes longer to work)
    • If neutrophils <1 or lymphocytes < 0.5 – often withhold biologics until this recovers

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Surgery

• Surgeons should review daily if patient on rescue therapy with regular abdominal xrays
• If rescue therapy fails – surgery (but this isn’t really a ‘failure’ – it sorts out the problem, and there’s no other option. It also reduces chance of cancer)
• Lifetime colectomy risk in UC is 25%
• Risk of colectomy on first presentation has gone from 20% to 5% with modern treatments
• Usual surgery is subtotal colectomy and ileostomy, with stoma, and preservation of the rectum
• Then either
  • • IPAA (ileal-pouch anal anastomosis)
      • • Operation for pouch (join small bowel to rectum), then close stoma a little after that
        • Best option for younger patients
        • Pouchitis / proctititis, fistulae is a risk, and still need bowel surveillance
    • Proctectomy – ileostomy/stoma for life
• Timing – usually if no response to rescue therapy within 7 days, or with a deterioration before that time

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Chronic UC / maintenance treatment (in the community)

• Treat with 5ASAs
  • • Mesalazine or sulfasalazine if mild-moderate, once daily
    • Rectal ASA first (especially if rectal disease), then orally if no remission in 4 weeks. Most on both though, especially if extensive/severe disease
    • Side effects include nephrotoxicity (1.5%) – monitor renal function
    • Consider adding oral ASA and/or increasing the dose (eg from 2.4g to 4.8g)
• Consider adding oral steroids to control disease not controlled with 5ASA (oral budesonide, oral beclomethasone or oral prednisolone 40mg OD, reduce by 5mg/week and give calcium/Vitamin D and PPI alongside)
• If failed ASA therapy or > 2 flairs in last 6 months – will require disease modifier, ie. Azathioprine
• Check trend in faecal calprotectin
• Check levels of Humira (Adalimumab) or infliximab
  • • Former any time, latter trough level
    • Check for antibodies against humira
    • Usually check Humira levels at 14 weeks
• Sometimes consider faecal transplant
• Biologics for chronic active UC – usually started after 3 months of steroids and azathioprine if not working well enough
  • • Adalimumab – anti-TNF, subcutaneous every 2 weeks, good evidence
    • Vedolizumab
      • • Expensive, gut specific, good for older frail patients
        • 2 monthly. Can be given subcutaneously
        • Less effective if used after an anti-TNF. More effective than adalimumab.
    • Ustekinumab – anti-interleukin
    • Tofacitinib
      • • JAK inhibitor, oral, daily
        • Good maintenance drug
        • 10% have serious adverse reaction, 40% have some adverse reaction (including herpes zoster, lipid abnormalities, skin reactions, headaches, infections)
        • Probably more effective than vedolizumab
    • Golimumab
    • Etanercept
    • Certolizumab
• Patients can be primary or secondary non-responders (in this case, might try another biologic)
• Upcoming drugs – S1P modulators (-imods), cytokine inhibitors, integrin blockers, signalling inhibitors

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Pitfalls in management of UC

• Getting overly concerned with detailed management and forgetting to do the basics right. See ‘acute management’ above for the key stuff
• Unnecessary radiation/scans
• Not diagnosing infection
• Inappropriate steroids – careful starting steroids if no known IBD diagnosis (often avoid doing so). Should always have stool cultures and scope first
• Withholding treatment of a flair until cultures or gastro review
• Not starting rescue therapy when steroids aren’t working
• Delay in surgical intervention – decision/review at day 3, not day 7