Ulcerative colitis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

UC can be classified by both severity and extent.[4] Treatment is guided by both factors.

The treatment goal for patients with active UC is to achieve remission (endoscopic and clinical) by demonstrating complete mucosal healing.[23]

The severity of UC is defined as:[4]

Mild: passage of ≤4 stools per day (with or without blood), absence of any systemic illness, and normal levels of inflammatory markers (erythrocyte sedimentation rate [ESR]). C-reactive protein (CRP) ≥12 mg/L has been suggested as a sensitive cut-off that might be considered as an alternative to ESR for determining UC severity.[31]
Moderate: passage of >4 stools per day but with minimal signs of systemic toxicity
Severe: passage of ≥6 bloody stools daily, pulse rate of at least 90 beats per minute (bpm), temperature of at least 37.5ºC (99.5ºF), haemoglobin level of <105 g/L (<10.5 g/dL), and ESR of at least 30 mm/hour.

Fulminant disease correlates with >10 bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement, and colonic dilation (expansion).[23]

The American Gastroenterological Association (AGA) considers patients as having moderate-to-severe UC if they:[44]

are dependent on or refractory to corticosteroids
have severe endoscopic disease activity (presence of ulcers), or
are at high risk of colectomy.

The extent of UC is defined as follows:[4]

Proctitis: disease limited to the rectum, often extending 15 to 20 cm proximal to the anal verge and distal to the rectosigmoid junction
Left-sided colitis (also called distal UC): disease that extends beyond the sigmoid colon and as far proximally as the splenic flexure or 60 cm from the anal verge
Extensive colitis (also called pancolitis): disease extending proximal to the splenic flexure.

Treatment selection should be based on inflammatory activity and disease prognosis, i.e., patients with factors that impact on disease prognosis (previous hospitalisation or steroid dependence) with mild UC, should be considered for treatments typically recommended for patients with moderate to severely active disease.[23]

Acute severe ulcerative colitis (ASUC)

ASUC is defined as adults with ≥6 bloody stools per day and systemic toxicity with at least one of:[44][45]

temperature >37.8ºC (>100.0ºF)
pulse >90 bpm
haemoglobin <105 g/L (<10.5 g/dL)
Elevated inflammatory markers; ESR >30 mm/h or CRP >30 mg/L. CRP ≥12 mg/L has been suggested as a sensitive cut-off for determining UC severity.[31]

These patients should be admitted to hospital for assessment and intensive management.[45] Patients may be haemodynamically unstable on admission, and need supportive measures such as blood transfusion, fluids, and electrolyte replacement.[45] Prophylactic low molecular weight heparin to prevent venous thromboembolism is recommended.[23][45]

Patients presenting with possible ASUC should have urgent inpatient assessment and blood tests (full blood count, CRP, urea and electrolytes, liver function tests, and serum magnesium level), stool culture, Clostridium difficile assay, radiological imaging (abdominal x-ray or computed tomography), and flexible sigmoidoscopy.[23]

ASUC: initial treatment

A high-dose intravenous corticosteroid such as methylprednisolone or hydrocortisone is recommended first line to induce remission in patients with ASUC.[23][44][45][46]

If patients have concomitant C difficile infection, treatment with oral vancomycin is recommended in preference to metronidazole.[23] See Clostridium difficile-associated disease.

ASUC: rescue therapy

If patients do not respond adequately to intravenous corticosteroid treatment within 3-5 days, rescue therapy with either intravenous infliximab or ciclosporin should be added to the corticosteroid.[23][44][45][46] Although evidence indicates comparable efficacy, the adverse effect profile of ciclosporin is less favourable than that of infliximab.[47][48]

There is growing interest in accelerated infliximab induction for ASUC.[23] The British Society of Gastroenterology recommends that patients treated with infliximab who have not responded to the first infusion sufficiently after 3-5 days should be treated with an accelerated induction regimen (i.e., an early repeat infusion), particularly in those with a low albumin (below 35 g/L [3.5 g/dL]) after colorectal surgical review to determine whether emergency colectomy is required.[33][45]

US guidance does not currently recommend accelerated infliximab induction for patients with ASUC.[23]

ASUC: surgery

The absolute indications for colectomy for patients with ASUC are complications such as toxic megacolon, perforation, uncontrolled severe haematochezia, or multiorgan dysfunction.[23][45][46]

Delay in surgery is associated with an increased risk of surgical complications.[23]

Moderate-to-severe ulcerative colitis

Recommended treatments to induce remission in patients with moderate-to-severe disease include systemic corticosteroids, thiopurines (e.g., azathioprine, mercaptopurine), methotrexate, tumour necrosis factor (TNF)-alpha inhibitors (e.g., infliximab, adalimumab, golimumab), selective adhesion-molecule inhibitors (e.g., vedolizumab), interleukin-12/23 inhibitors (e.g., ustekinumab, mirikizumab), sphingosine 1-phosphate (S1P) receptor modulators (e.g., etrasimod, ozanimod), and Janus kinase (JAK) inhibitors (e.g., tofacitinib, upadacitinib), either alone or in combination.[23][45][46][49][50] AGA guidance focuses on immunosuppressants, biologicals, and small molecules for induction and maintenance of remission.[44]

For patients with moderate-to-severe UC who respond to treatment with TNF-alpha inhibitors, but lose response, serum drug levels, and antibodies (if there is not a therapeutic level) should be measured to assess the reason for the loss of response.[23]

Corticosteroids

Oral corticosteroids can be used to induce remission in patients with moderate-to-severe UC of any extent and have typically been first-line induction treatments in moderate-to-severe disease.[23][24]
In patients with moderately active UC, oral budesonide multi-matrix system (MMX), a locally acting corticosteroid, can be considered before the use of systemic therapy.[23]

Biological and targeted disease-modifying therapies

In patients with moderate-to-severe UC, early use of biological treatment with or without immunosuppressant therapy, rather than gradual step-up treatment after aminosalicylate failure, is suggested.[44] However, patients with less severe disease may prefer gradual step-up therapy.[44]
Combination treatment with a TNF-alpha inhibitor, vedolizumab, or ustekinumab plus a thiopurine or methotrexate is suggested rather than biological monotherapy.[44][45] Monotherapy with a TNF-alpha inhibitor, vedolizumab, ustekinumab, or tofacitinib is preferred to monotherapy with a thiopurine.[44]
Upadacitinib, mirikizumab, and S1P receptor modulators are now also approved for use in these patients, but American Gastroenterological Association guidelines do not currently recommend their use.

Patients with less severe disease may prefer to begin with TNF-alpha inhibitor monotherapy, but this increases the risk of drug antibody formation.[44]

Adalimumab

Recommended for inducing and sustaining clinical remission in adult patients with moderate-to-severe active UC who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or mercaptopurine.[23][44]
Meta-analyses report that adalimumab is more effective than placebo with respect to inducing clinical response, clinical remission, and mucosal healing.[51][52]
Adalimumab may also be used as an alternative to infliximab for maintenance therapy.[44]

Golimumab

Recommended for inducing and sustaining clinical remission in adult patients with moderate-to-severe active UC who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine, or mercaptopurine.[23][44]
Golimumab has been shown to induce clinical remission and mucosal healing in patients with moderate-to-severe active UC with a similar safety profile to other TNF-alpha inhibitors.[53][54]

Infliximab

Effective as long-term maintenance therapy for UC and it should be considered as an alternative to induce and maintain disease remission.[55][56] When infliximab is used as induction therapy for patients with moderate to severely active UC, combination therapy with azathioprine is recommended.[23][45] In patients with moderate-to-severe UC who are naive to biological agents, the AGA suggests using infliximab rather than adalimumab for induction of remission.[44]

Vedolizumab, a monoclonal antibody against alpha-4-beta-7 integrin (selective adhesion-molecule inhibitor), is approved to treat moderate to severely active UC. It has been shown to be more effective than placebo as induction and maintenance therapy for UC.[57][58]

One Cochrane review found vedolizumab to be more effective than placebo for inducing clinical remission, clinical response, and endoscopic remission in patients with moderate-to-severe active UC, and for preventing relapse in patients with quiescent UC.[59] In another systematic review and meta-analysis, vedolizumab efficacy for the induction and maintenance of mucosal healing in UC was similar to that of TNF-alpha inhibitors.[60] Network meta-analysis suggested that vedolizumab may lead to a more sustained clinical response than other biological agents approved for UC.[51] Vedolizumab appears to have a favourable safety profile.[61]
The AGA recommends vedolizumab, in preference to adalimumab, for the treatment of patients with moderate-to-severe UC who are naive to biological agents for induction of remission.[44] The American College of Gastroenterology (ACG) recommends vedolizumab for induction of remission for patients who have previously failed TNF-alpha inhibitor therapy.[23]
The AGA suggests vedolizumab in combination with a thiopurine or methotrexate, rather than thiopurine monotherapy.[44]

Ustekinumab, a monoclonal antibody targeting interleukin (IL)-12 and IL-23, is approved for the treatment of adults with moderate to severely active UC.

The AGA recommends ustekinumab rather than vedolizumab or adalimumab for induction of remission in patients with moderate-to-severe UC who have previously been exposed to infliximab, particularly those with primary non-response.[44] Patients with less severe disease may prefer vedolizumab as a potentially safer alternative.[44]
The AGA suggests that ustekinumab is given in combination with a thiopurine or methotrexate rather than thiopurine monotherapy.[44]
The interim results of a phase 3 study of ustekinumab in biologic-naive and biologic-experienced adults with moderate to severely active UC indicate that ustekinumab is more effective than placebo for inducing and maintaining remission. Significantly more patients treated with ustekinumab achieved endoscopic improvement and mucosal healing.[62][63]

Mirikizumab, a monoclonal antibody targeting IL-23, is approved for the treatment of adults with moderately to severely active UC. It is the only treatment that selectively targets the p19 subunit of IL-23, which plays a role in inflammation related to UC.

In two phase 3, randomised, doouble-blind, placebo controlled trials it was found that mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active UC.[50]
US guidelines do not currently include recommendations on mirikizumab as it is a relatively new treatment. In the UK, National Institute for Health and Care Excellence (NICE) recommends mirikizumab as an option for adults with moderately to severely active UC when conventional or biological treatments, especially TNF-alpha inhibitors, cannot be tolerated or are not working well enough.[64]

Immunosuppressants

A thiopurine (e.g., azathioprine, mercaptopurine) or methotrexate in combination with vedolizumab or ustekinumab is recommended for induction of remission in patients with moderate-to-severe UC.[23][44][45] Monotherapy with either a thiopurine or methotrexate is not recommended for induction therapy.[23]
Dose-dependent adverse effects of methotrexate include bone marrow suppression, particularly leukopenia, which can develop suddenly and have an unpredictable course; liver injury; and infections.[65] Other adverse effects (not dose-dependent) include pancreatitis, headache, fatigue, anorexia, weight loss, stomatitis, alopecia, arthralgia, muscular weakness, and rash.[65]
Thiopurines are associated with a small but statistically significant increased risk for lymphoma among adults with inflammatory bowel disease compared with patients not receiving thiopurine.[66] Persistent use of thiopurines is also is associated with an increased risk of non-melanoma skin cancer; therefore, patients should be educated in primary skin cancer prevention (e.g., reduced ultraviolet exposure).[67]
Azathioprine may be considered in pregnancy, but should only be initiated under consultant guidance.[68][69]
Azathioprine and mercaptopurine doses should be lowered in patients with heterozygous thiopurine methyltransferase variant genotype.[70]
Allopurinol should be avoided (or patients monitored closely), as it inhibits the breakdown of azathioprine and increases the risk of myelosuppression.[71] However, adjunctive treatment with low-dose allopurinol, in addition to a 25% to 50% thiopurine dose reduction, is required for select patients in whom thiopurine is preferentially metabolised via the hepatotoxic methylmercaptopurine pathway.[72][73][74]

S1P receptor modulators (e.g., ozanimod, etrasimod) are approved for the treatment of adults with moderately to severely active UC. These drugs are contraindicated in patients with recent (in the last 6 months) myocardial infarction, unstable angina, stroke, transient ischaemic attack, or heart failure.[25] They are also contraindicated in patients with a history or presence of second- or third-degree atrioventricular block, sick sinus syndrome, or sino-atrial block (unless the patient has a functioning pacemaker).

Ozanimod

One pivotal phase 3 randomised controlled trials (RCTs) evaluating ozanimod as an induction and maintenance therapy versus placebo in adult patients with moderately to severely active UC found that during the induction at week 10 (ozanimod n=429 vs. placebo n=216), 18% of patients receiving ozanimod achieved clinical remission (primary end point) compared with 6% of patients in the placebo group. During maintenance at week 52 (ozanimod n=230 vs. placebo n=227), 37% of patients receiving ozanimod maintained clinical remission compared with 19% of patients in the placebo group (clinical remission is defined as: rectal bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a decrease from baseline in the stool frequency subscore of ≥1 point), and endoscopy subscore = 0 or 1 without friability). The study met secondary end points such as clinical response (defined as as a reduction from baseline in the 3-component Mayo score of ≥ 2 points and ≥35%, and a reduction from baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1) and endoscopic improvement (defined as a Mayo endoscopy subscore of 0 or 1 without friability) for both induction and maintenance.[75]
US guidelines do not currently include recommendations on ozanimod as it is a relatively new treatment. In the UK, NICE recommends ozanimod for treating moderately to severely active UC in adults, only if conventional treatment cannot be tolerated or is not working well enough and infliximab is not suitable, or biological treatment cannot be tolerated or is not working well enough.[49]

Etrasimod

The safety and efficacy of etrasimod in patients with moderately to severely active UC has been demonstrated in two RCTs.[76][77]
US guidelines do not currently include recommendations on ozanimod as it is a relatively new treatment. In the UK, NICE recommends etrasimod for treating moderately to severely active UC in patients aged ≥16 years when conventional or biological treatments cannot be tolerated, or the condition has not responded well enough, or lost response to treatment.[78]

JAK inhibitors are approved for the treatment of adults with moderately to severely active UC.

Tofacitinib

Phase 3 RCTs have demonstrated that tofacitinib is superior to placebo for the induction and maintenance of remission of moderate to severely active UC (Mayo score 6-12) in patients previously treated with conventional therapy or a TNF-alpha inhibitor.[79] [ ] Network meta-analyses have shown that tofacitinib is non-inferior to TNF-alpha inhibitors in biologic-naive patients, and suggest that it is the most effective second-line agent in patients with previous biological failure.[80][81] In the UK, NICE recommends tofacitinib for treating moderately to severely active UC in adults when conventional therapy or a biological agent cannot be tolerated or the disease has responded inadequately or lost response to treatment.[82]

Upadacitinib

Data from three phase 3 RCTs show clinical remission at 8 weeks (primary end point) with upadacitinib (26% and 34%) compared with placebo (5% and 4%, respectively) and at 52 weeks (42% or 52%, depending on the dose of upadacitinib compared with placebo 12%).[83][84]
One recent systematic review suggested that upadacitinib was the best performing agent for the induction of clinical remission compared with other biologicals and small molecule drugs; however, it was also the worst performing agent in terms of adverse effects.[85]
In the UK, NICE recommends upadacitinib for treating moderately to severe active UC in adults, where conventional or biological treatment cannot be tolerated or if they have not responded well enough or stopped responding to these treatments.[83]

Safety concerns with JAK inhibitors

The US Food and Drug Administration (FDA) has issued a warning about an increased risk of serious cardiovascular events, malignancy, thrombosis, and death with JAK inhibitors.[86] This follows final results from a large randomised safety clinical trial which compared tofacitinib with TNF-alpha inhibitors in patients with rheumatoid arthritis. The study found an increased risk of blood clots and death with the lower dose of tofacitinib (5 mg twice daily); this serious event had previously been reported only with the higher dose (10 mg twice daily - the induction dose for UC) in the preliminary analysis.[87]

The FDA advises clinicians to:[86]

Reserve JAK inhibitors for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors
Consider the patient’s individual benefit-risk profile when deciding to prescribe or continue treatment with these medications, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy (other than a successfully treated non-melanoma skin cancer).

The European Medicines Agency (EMA) also recommends measures to minimise the risk of serious adverse effects with JAK inhibitors in patients who are >65 years old, patients who are current or past smokers, patients with other cardiovascular risk factors, and patients with other malignancy risk factors. The EMA advises that JAK inhibitors should only be used to treat moderate or severe UC in these patient groups if no suitable treatment alternative is available.[88]

In addition the EMA recommends that:[88]

JAK inhibitors should be used with caution in patients at high risk of blood clots (other than those listed above)
The dose should be reduced in patients who are at risk of venous thromboembolism, major cardiovascular problems, or cancer, where possible.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) supports these recommendations, and also advises patients taking JAK inhibitors to carry out periodic skin examinations, due to an increased risk of non-melanoma skin cancer associated with these medications.[89]

Guidelines recommend tofacitinib for induction of remission in patients with moderate-to-severe UC who have previously been exposed to infliximab, particularly those with primary non-response, or those who are intolerant to TNF-alpha inhibitor therapy.[23][44] Upadacitinib is now also approved for use in these patients, but American Gastroenterological Association guidelines do not currently recommend its use.

Patients with less severe disease, who place higher value on the potential safety of medications, and a lower value on the relative efficacy of medications, may reasonably choose vedolizumab as an alternative.[44]

Therapeutic drug monitoring

To optimise drug concentration and clinical improvement for patients with UC being treated with immunosuppressants and/or biologicals, therapeutic drug monitoring (TDM) is becoming more frequently used to check drug trough concentration, and assess for the presence of anti-drug antibodies.[90][91][92] BMJ Rapid Recommendations: proactive therapeutic drug monitoring of biologic drugs in adult patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis: a clinical practice guideline Opens in new window

TDM can be performed at any point during induction or maintenance therapy, and is conditionally recommended by the AGA to guide treatment changes for patients with inflammatory bowel disease.[90][93]

Surgery

Any patients with severe intractable symptoms or intolerable adverse effects from medication should be considered for colectomy.[23][44][45][46]

One systematic review of outcomes and postoperative complications following colectomy for patients with UC suggests that early and late complications arise in about one third of patients undergoing surgery for UC.[94] While colorectal surgical procedures are recommended for a specific group of patients, the postoperative complications associated with these procedures should not be underestimated.[94]

Mild ulcerative colitis

Treatment to induce remission in patients with mild disease is topical (rectal) or oral aminosalicylates (also known as 5-aminosalicylates or 5-ASA drugs), or a combination of both.[7][45][46] Corticosteroids may also be added to aminosalicylate therapy.[45][46] Aminosalicylates include mesalazine, sulfasalazine, balsalazide, and olsalazine. Mesalazine is the only aminosalicylate available as a topical formulation.

An oral aminosalicylate is not as effective as topical; if used, initial treatment of mild UC is with a low-dose oral aminosalicylate.[23][46] Once-daily dosing of oral aminosalicylates is recommended, but more frequent doses can be used based on patient preference to optimise adherence.[23]

Proctitis

First-line treatment for proctitis

First-line treatment to induce remission for patients with mildly active ulcerative proctitis is rectal aminosalicylate.[23][45]

A rectal aminosalicylate is recommended over a rectal corticosteroid.[23][45]

Left-sided colitis

First-line treatment for left-sided colitis

First-line treatment for the induction of remission in patients with left-sided colitis is a rectal aminosalicylate (in preference to a rectal corticosteroid) combined with oral aminosalicylate.[7][23][45][46]

Alternative treatment for left-sided colitis

For patients with mildly active left-sided UC who are intolerant or non-responsive to an oral and rectal aminosalicylate, the addition of oral budesonide MMX is recommended for induction of remission.[7][23][45][46]

Second-generation corticosteroids, such as budesonide MMX, are starting to emerge as a primary treatment option in mild-to-moderate UC.[45][95][96] They are associated with significantly fewer corticosteroid-related adverse events than conventional corticosteroids.[97] MMX technology may facilitate adherence by reducing the pill burden.[98]

Extensive UC

First-line treatment for extensive UC

The ACG suggests that an oral aminosalicylate is the preferred treatment.[23]

Alternative treatment for extensive UC

In patients with mild UC refractory to optimised oral and rectal aminosalicylate therapy, the addition of either oral prednisolone or budesonide MMX is recommended.[23][24][33][45]

Maintenance of remission

The goal of maintenance therapy is to maintain corticosteroid-free clinical and endoscopic remission; systemic corticosteroids are not recommended for maintenance of remission of UC of any severity.[23][45]

Acute severe UC

Patients with ASUC who achieve remission with infliximab treatment should continue treatment with infliximab for maintenance of remission.[23] However, if patients with ASUC achieve remission with ciclosporin, a thiopurine is suggested for maintenance of remission.[23] Allopurinol should be avoided (or patients monitored closely) in patients taking thiopurines, as it inhibits the breakdown of azathioprine and increases the risk of myelosuppression.[71] However, adjunctive treatment with low-dose allopurinol, in addition to a 25% to 50% thiopurine dose reduction, is required for select patients in whom thiopurine is preferentially metabolised via the hepatotoxic methylmercaptopurine pathway.[72][73][74]

Moderate-to-severe UC

The AGA guidelines on treatments for moderate-to-severe UC do not present separate recommendations for induction and maintenance of remission.[44] It is assumed that if a drug (excluding corticosteroids and ciclosporin) is effective for induction of remission, it will be continued for maintenance of remission unless otherwise specified.[44][45]

Some exceptions and additional considerations include:

Patients with previous moderate-to-severe UC who have achieved remission with TNF-alpha inhibitors and/or immunosuppressants, or JAK inhibitors, should not be given concomitant aminosalicylates for maintenance of remission.[23][44]
For patients with previously moderate-to-severe UC who achieve remission with corticosteroid induction, a thiopurine is suggested for maintenance of remission in preference to no treatment.[44]
Methotrexate monotherapy is not recommended for maintenance of remission.[23][44]

Mild UC

The large majority of patients with mild UC who achieve remission with aminosalicylate therapy continue with aminosalicylate treatment to maintain remission.[23][45]

Patients on maintenance therapy with a high-dose aminosalicylate, who require two or more courses of corticosteroids in 12 months, or who become corticosteroid dependent or refractory, require treatment escalation to a thiopurine, a TNF-alpha inhibitor, vedolizumab, or tofacitinib.[33][45] The treatment choice should be determined by clinical factors and patient preference.[33][45]

Proctitis

In patients with mildly active ulcerative proctitis, rectal aminosalicylate is recommended to maintain remission.[23][45]

Left-sided or extensive UC

In patients with mildly active left-sided or extensive UC, an oral aminosalicylate is recommended to maintain remission.[7][23][45][46]

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