Introduction

• The disease typically affects individuals in the second or third decade of life with hallmark clinical symptoms of bloody diarrhoea and rectal urgency with tenesmus.¹ The clinical course is marked by exacerbations and remissions, which may occur spontaneously or in response to treatment changes.¹
• The exact pathogenesis of UC is not well understood, but there are genetic factors attributed to the risk of developing the disease accompanied by epithelial barrier defects and environmental factors.¹ A number of environmental factors that increase the risk of developing UC have been identified:
  • A westernised lifestyle and diet, cessation of tobacco use, fatty diet, stress and high socioeconomic status are all associated with the development of inflammatory bowel disease (IBD).¹
• The diagnosis of UC is based on the clinical presentation and symptoms consistent with the disease and findings on colonoscopy or sigmoidoscopy showing continuous colonic inflammation starting in the rectum.¹ Pathologic findings of chronic colitis confirm the diagnosis.¹

Disease management

• Initial treatment is based upon disease severity and extent.¹ Patients can present with mild, moderate or severe disease and stratification based on clinical severity is used to guide management.¹
• The goals of treatment are induction of remission followed by maintenance of remission in conjunction with steroid-free treatments in the long-term management.¹
• Historically, the Truelove and Witts criteria have been used to stratify patients with mild, moderate or severe colitis:¹ See Table 1.¹
  • Patients categorised as having mild clinical disease have less than four stools per day with or without blood with no signs of systemic toxicity. Mild crampy abdominal pain and tenesmus are common clinical symptoms.¹
  • In moderate-to-severe disease, patients have abdominal pain, frequent loose bloody stools (typically more than four per day) and mild anaemia. They also have minimal signs of systemic toxicity such as low-grade fever.¹
  • Patients with severe or fulminant disease present with over six loose bloody stools with severe abdominal cramps and systemic toxicity such as fever or tachycardia. They also have manifestations such as anaemia or an elevated erythrocyte sedimentation rate (ESR)/ C-reactive protein (CRP).¹

Mild-to-moderate disease

5-Aminosalicylate

• There are multiple 5-aminosalicylate (5-ASA) compounds available e.g. mesalazine.¹ The dosing per pill is variable but, in general, these medications can be taken once or twice daily.¹
• The initial approach for mild-to-moderate disease is to start oral and topical 5-ASA:¹
  • Oral 5-ASA is started at a full-strength dose of 4.8 g/day for induction of remission.
  • Over time, this can be reduced to a maintenance dose of 2.4 g/day.
  • In patients who have not achieved remission on oral therapy, combining oral and rectal therapy (enema or suppository) is more effective in inducing remission.
• Patients with more limited disease of the rectum and/or sigmoid colon may be managed with topical treatments only.¹ However, if the patient fails to respond to topical therapy, then oral therapy should be added to the regimen.¹
• In general, 5-ASA starts working within 2-4 weeks and shows response in up to 80% of patients (when selected appropriately).¹ Once remission is achieved, patients are continued on the drug for maintenance therapy.¹ Given the safety of the drug and lack of any dose-dependent side effects, some practitioners opt to keep patients on the 4.8 g/day dose while others reduce the dose to 2.4 g/day when dosing for maintenance.¹ There are no data to support doses that are less than 2.4 g/day, and these doses should be avoided.¹

Moderate-to-severe disease

Corticosteroids

• Systemic corticosteroids are typically given first-line for induction of remission in cases of moderate-to-severe disease.¹ Oral steroids are used in most cases, but in up to 15% of patients, the disease may present as acute, severe ulcerative colitis requiring hospitalisation and intravenous steroids.¹
• Oral prednisone is usually the first choice of treatment at a dose of 40 to 60 mg daily.¹ Higher doses have not been shown to be more effective.¹ Intravenous methylprednisone is preferred in the hospitalised patient at a dose of 40 to 60 mg daily (e.g. 20 mg every 8 hours).¹
• Approximately two-thirds of patients respond to this treatment.¹ There are no specific recommendations for tapering the steroid dose, but it is advised to transition to an oral prednisone dose of 40 to 60 mg daily until significant clinical improvement occurs and then taper by 5 to 10 mg weekly until a dose of 20 mg is reached.¹ Thereafter, a tapering of 2.5 to 5 mg every week is advised.¹
• If there is no meaningful response to an intravenous steroid within 3 to 5 days, steroid-refractory disease should be considered and rescue therapy with other therapeutic agents - either infliximab or cyclosporine - should be initiated.¹
• Steroids are used in the acute inflammatory phase of the disease to assist with induction of remission but should always be bridged with a steroid-sparing agent for a goal of long-term steroid-free maintenance of remission.¹ Intravenous or oral steroids should not be used for long-term therapy as they are associated with a myriad of irreversible side effects such as weight gain, cataracts, osteoporosis, hypothalamic-pituitary-axis suppression and an immunocompromised state.¹
• Several classes of drugs can be used for maintenance of remission in moderate-to-severe disease, including thiopurines, anti-TNF agents, anti-integrins and Janus kinase inhibitors.¹

Thiopurines

• Thiopurines (azathioprine and 6-mercaptopurine) have a steroid-sparing effect and are used for maintenance of remission when steroids are withdrawn.¹ Thiopurines are slow-acting medications, and it can take 3 months before therapeutic concentrations are achieved.¹ As a result, a longer course of steroids is often required until the pharmacologic effect of the thiopurine occurs.¹

Anti-TNF agents

• Anti-TNF (tumour necrosis factor) agents such as infliximab, adalimumab and golimumab can be used for both induction and maintenance of remission.¹ They are most often used with corticosteroids to induce remission.¹ Anti-TNF agents can take up to 6 to 12 weeks to achieve initial response and mucosal healing.¹ All anti-TNF agents have risks of developing antibodies altering their efficacy.¹ Therefore, checking drug levels and levels of antibodies may allow tailoring of drug dosage or choice of medication to achieve a clinical response or remission.¹

Calcineurin inhibitors

• Cyclosporine has a role in induction of remission in severe-to-fulminant steroid-refractory colitis.¹ Transition to oral cyclosporine from a continuous infusion is typically performed after patients show response to intravenous cyclosporine.¹ When transitioning to oral cyclosporine, patients are also started on a long-term maintenance plan consisting of thiopurines or anti-integrins.¹ The oral cyclosporine is usually discontinued within 3 months.¹

Anti-integrins

• Integrins are proteins that regulate migration of leucocytes to the intestines.¹ Vedolizumab is a fully humanised recombinant monoclonal antibody that binds to alpha4-beta7 integrin and prevents migration of leucocytes to the gut.¹ Vedolizumab has been shown to be effective and is approved for use to induce and maintain remission in moderate-to-severe UC.¹ It is the first anti-integrin approved for use in UC.^1,2

Tofacitinib

• Tofacitinib is a Janus kinase inhibitor used for treatment of adult patients with moderate-to-severe UC.¹ Initial drug response can be seen in 6 weeks.¹ It has the advantage of oral dosing.¹

In summary¹

• The choice of medication for UC depends on the clinical stage of the disease.
• Contrary to the historical treatment paradigm of a bottom-up versus top-down strategy, the recommendation now is to treat the underlying severity of the disease with medications that are most appropriate for that level of disease severity.
• In cases of mild-to-moderate disease severity, mesalazine is preferred as it is the safest available drug for the management of UC.
• If the disease is not responding adequately to mesalazine or if the disease is categorised as moderate-to-severe, then immunosuppressants and biologics including anti-TNF, anti-integrin or a Janus kinase inhibitor should be considered.