Ulcerative colitis: an update

Key points

• Ulcerative colitis is common, and incidence and prevalence are increasing.

• Goals of treatment are to achieve prompt symptom amelioration and heal disease at the mucosal level, while restoring overall quality of life for the patient.

• Patient engagement in their care and monitoring (with symptoms in addition to objective markers of inflammation) are key to optimal management so that therapies can be escalated as necessary.

• 5-ASA drugs represent the main therapies for mild to moderately active UC, and optimising adherence is important.

• In UC patients with inadequate response to 5-ASA, immunosuppressive or biologic therapies are indicated, and choice is dependent on multiple factors, including patient choice.

• Surgical options for ulcerative colitis are important to discuss with patients and include restorative options such as an ileoanal pouch or, rarely, an ileorectal anastomosis or a permanent ileostomy.

• The future will see an array of new treatments with head-to-head trials allowing us to position treatments correctly.

Therapeutic goals and targets

In 2015, the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative made recommendations about therapeutic targets in IBD which were later updated in December 2020 in the SPIRIT consensus.^6,7 In summary, this consensus agreed that UC treatment goals should address a composite of clinical and endoscopic outcomes (potentially with use of surrogate measures of inflammation, such as faecal calprotectin), in addition to the ultimate goals of addressing impact on a patient’s life (health-related quality of life, disability and faecal incontinence), preventing disease extension, surgery, permanent stoma, and dysplasia or cancer.

Determining severity of disease presentation

Disease severity is measured by assessment of clinical and biochemical parameters, as showcased by the modified Truelove and Witts criteria (Table 2).⁴ Endoscopically, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is the only validated scoring system to assess severity, however, the Mayo score is commonly used in clinical practice due to its simplicity in application.^4,8

Medical therapy

5-aminosalicylic acid (5-ASA) drugs represent the standard therapy for patients with mild to moderate disease activity for induction and maintenance of UC. In patients with mild to moderate UC proctitis, 5-ASA suppositories are considered the first-line therapy, more so than oral 5-ASA monotherapy and rectal corticosteroids.⁴ In case of suboptimal response, addition of oral 5-ASA therapy should be the next step.⁴ If response remains incomplete, adding a corticosteroid suppository and/or optimising the oral 5-ASA dosing is recommended.⁴ UC patients with left-sided disease or extensive colitis should be offered dual therapy with oral 5-ASAs and topical 5-ASA.⁴ Oral 5-ASA doses of 2–3 g daily are sufficient in the induction of remission of most UC patients with mild to moderate activity.⁴ However, higher dosage (≥4 g daily) has been proven more effective in achieving clinical remission.⁴ 5-ASAs are well tolerated; renal impairment is a rare and an unpredictable adverse event, hence renal function should be checked regularly after 5-ASA initiation.⁴

Prednisolone should be restricted to patients with moderate to severe UC of any disease extent or those who are unresponsive to standard therapy. Alternatively, for cases of mild to moderate UC, a multi-matrix formulation of budesonide (budesonide multi-matrix system (MMX)) was shown superior to placebo at a daily dose of 9 mg over an 8-week course.⁴ Systemic adverse events of budesonide are considered fewer compared with conventional corticosteroids. Budesonide is not thought to induce adrenal suppression nor a significant reduction in bone mineral density.⁴

Thiopurines, such as azathioprine and mercaptopurine, have been used in maintenance of steroid-free remission. Thiopurines are associated with adverse events, with an estimated risk of 26% in a Spanish database study, including nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), pancreatitis (4%), non-melanoma skin cancers and lymphomas. Assessment of thiopurine methyltransferase (TPMT) status is recommended prior to thiopurine initiation, while measurements of thiopurine metabolites may be used in monitoring.⁴

Biologics have progressively changed the therapeutic landscape of UC (Fig 1). Choice of biologic agent depends on many factors, including route of administration, side effects, potential immunogenicity, speed of response to induction therapy, overall costs and availability of infusion facilities. Anti-tumour necrosis factor (TNF) drugs include intravenous infliximab originator and biosimilars, subcutaneous adalimumab originator and biosimilars, and subcutaneous golimumab. Primary response rates of infliximab in UC patients who failed standard therapy varied from 67% to 78% in real-world data.⁹ Anti-TNF agents are preferred in patients with extra-intestinal manifestations of IBD, such as type 1 IBD-associated arthropathy, ankylosing spondylitis and pyoderma gangrenosum.¹⁰ Formation of neutralising anti-drug antibodies is recognised as a reason for loss of response to anti-TNF drugs over time, which may be prevented by addition of an immunomodulator drug. Trials addressing combination therapy in UC have mostly studied the positive impact of combined infliximab and thiopurines; therefore, it is recommend that combination therapy with a thiopurine when infliximab is used as induction therapy for moderate to severe UC.⁴ Serum drug and anti-drug antibody levels should be measured in patients considered to have lost response to an anti-TNF drug in order to guide therapeutic decision making (dose escalation or switch to a different anti-TNF or biologic class). The use of anti-TNF drugs may increase two-fold the pooled infectious risks (including tuberculosis, herpes zoster, cytomegalovirus among others (risk ratio (RR) 2.05; 95% CI 1.1–3.85)), thus justifying a pre-biologics screen for tuberculosis, HIV, herpes zoster and hepatitis B and C.¹¹

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Fig 1.

Mechanisms of action for biologics and small molecules used in ulcerative colitis. α4β7 = alpha-4 beta-7 integrin; αeβ7 = alpha-e beta-7 integrin; IL = interleukin; Jak = Janus kinase; MAdCAM-1 = mucosal vascular addressing cell adhesion molecule-1; s1p1 = sphingosine-1-phosphate receptor; Stat = signal transducer and activator of transcription; TNF = tumour necrosis factor.

Vedolizumab inhibits α4β7 integrin, thus decreasing leukocyte migration from the circulation into the bowel wall. Such a gut-selective pathway may explain the relative long-term safety of the drug.¹² In the GEMINI 1 study, response rates at week 6 were 47.1% in the vedolizumab group and 25.5% in the placebo group (p<0.001). For those who went into the maintenance trial, 41.8% who received 8-weekly vedolizumab and 44.8% who received vedolizumab every 4 weeks were in clinical remission compared with 15.9% in the placebo group at week 52 (p<0.001).¹³ A head-to-head double-blind randomised controlled trial, the first to compare biologics in IBD between intravenous vedolizumab and subcutaneous adalimumab, showed higher rates of clinical remission and mucosal healing in the vedolizumab group at 52 weeks.¹⁴

Ustekinumab inhibits the p40 subunit of interleukins-12 and 23; in the UNIFI study, it was shown that 15.5% receiving ustekinumab achieved clinical remission at 8 weeks (p<0.01) compared with 5.3% receiving placebo. Of those who responded to induction, by week 44, 38.4% of those receiving ustekinumab every 12 weeks and 43.8% of those receiving ustekinumab every 8 weeks achieved clinical remission compared with 24% in the placebo group (p=0.002 and p<0.001, respectively).¹⁵ Clinical trial data suggest low rates of adverse events.¹⁶

Tofacitinib is an oral Janus kinase (JAK) inhibitor, which showed improvement in composite clinical/endoscopic outcomes in 16.6–18.5% of patients during the induction trials, compared with 3.6–8.2% of patients receiving placebo. At 1 year, remission was significantly higher in the treatment arms (34.3% in the 5 mg twice daily (BD) group and 40.6% in the 10 mg BD group), compared with 11.1% in the placebo group.¹⁷ Adverse events include a higher risk of herpes zoster infection, justifying adequate zoster vaccination, and increased risk of venous thromboembolism (VTE) reported on the 10 mg BD dosing.¹⁸ Higher doses should be avoided in patients considered at high risk of VTE.

Follow-up and monitoring

Patient understanding and engagement in their care is crucial. Clinical parameters should be re-assessed every 3 months during the active phase. Once symptoms have resolved, clinical reviews should be performed every 6–12 months. Colonoscopies should be performed every 1–5 years to investigate suspected flares and to ensure surveillance of colorectal dysplasia, preferably with dye-spray chromoendoscopy.⁸

Acute severe ulcerative colitis and surgical therapy including pouch implications

In the case of acute severe ulcerative colitis (according to the Truelove and Witts), the mainstay of treatment is intravenous steroids. For those not responding to intravenous steroids, a decision on day 3 is crucial using one of the various indices as a guide.⁴ In this situation, either ciclosporin or infliximab maybe used as rescue therapy, with studies showing that there is no difference in efficacy.¹⁹ Importantly, at the stage where rescue therapy is considered, it is imperative that surgical options are also explored.

The timing of surgical intervention in a patient with UC is multifactorial and needs to take into account disease severity and quality of life. In terms of acute severe ulcerative colitis that has not responded to medical therapy, a colectomy can be a life-saving procedure. For these patients who are offered surgery, a subtotal colectomy is the operation of choice. Surgical options include a permanent ileostomy, or restorative options to include the ileoanal pouch or, in some very selected cases, an ileorectal anastomosis. Importantly, when considering surgical options for patients with ulcerative colitis it is important to involve the multidisciplinary team to include surgeons, stoma nurses, pouch nurses and dietitians to counsel patients about expectations from the surgical options.

The future

There are a number of therapeutic targets being explored in the treatment of ulcerative colitis in various clinical phases to include sphingosine-1-phosphate receptor modulators (such as ozanimod and etrasimod), JAK inhibitors (such as upadacitinib), anti-leukocyte integrins (such as etrolizumab and abrilumab), monoclonal antibodies (such as mirikizumab) and faecal microbiota transplantation.²⁰ These potentially will offer new options for the medical treatment of ulcerative colitis, but currently remain at the clinical trial phase.

Head-to-head trials are likely to enable us to position biologics correctly. As we gain a better understanding of the biological mechanisms that drive UC, it may become possible to find the right drug for the right person at the right time, while also ensuring that the broader goals of the patient (impact on quality of life, psychological and dietary support) are addressed.