Crohn’s disease is a type of inflammatory bowel disease (IBD) that causes chronic and progressive inflammation of the gastrointestinal tract (GIT). It can affect any part of the GIT from the mouth to the anus, but most often affects the ileum and the beginning of the colon, leading to symptoms such as diarrhoea, abdominal pain, fatigue and weight loss. The exact cause of Crohn’s disease is not well understood, but it is believed that a combination of a genetic predisposition, environmental exposure and infectious factors may all contribute to a subsequent dysregulated immune response, leading to chronic inflammation.
There is currently no known cure for Crohn’s disease and the main goals of treatment are to relieve symptoms, improve quality of life, induce and maintain remission of the disease, heal the mucosa, and prevent complications and nutritional deficiencies. Thus, management is lifelong and multimodal, involving pharmacotherapy, dietary modifications, nutritional supplementation and sometimes surgery.
Pharmacotherapy for Crohn’s disease has changed, developed, and emerged over the years as more is understood about the disease, and improved diagnostic tools have been developed. Traditionally, a “step-up” approach was adopted for the treatment of IBD inflammation, where a milder class of medications were tried first, such as 5-aminosalicylates, before progressing to stronger medications if required. Severe disease states warranted the use of corticosteroids before surgery was considered, and immunomodulators and/or biological therapies were only considered as a last resort.
The newer approach to treating IBD is a “top-down” approach, whereby more aggressive therapy with biological drugs is started first, sometimes in combination with immunosuppressants and then following a plan for maintenance therapy once remission is achieved. In using more aggressive therapies earlier on, more complete remission with mucosal healing is more likely to be achieved, and the natural course of the disease can change, lessening the number of flare-ups and preventing long-term complications.
Treatments are also individualised for the patient based on the severity of the disease, location of the inflammation, the patient’s prognosis, response to previous treatment and presence of comorbidities, and often a combination of therapies are required to increase the effectiveness of the treatment.
The main classes of drug treatments available for Crohn’s disease in Australia include aminosalicylates, corticosteroids, immunomodulators, thiopurines, and biological immunotherapy agents. Antibiotics may also be used for associated complications, such as simple perianal fistulas, and enteral nutritional therapy is used in certain circumstances.
Vedolizumab and ustekinumab are relatively newer biological drugs used for inducing and maintaining remission in moderate to severe Crohn’s disease if there is inadequate response or failed response to conventional or conventional or TNF-alpha antagonist therapies (other biological agents). These potent monoclonal antibodies target proteins that may cause the inflammation associated with Crohn’s disease symptoms. However, their use has often been limited due to high costs, primary non-responders, secondary loss of response in some people, restricted routes of administration and adverse effects. Clinical pre-screening is essential prior to a patient commencing a biological agent, to assess historic risk of exposure to tuberculosis or viral infections, and immunisation status.
Vedolizumab is considered a “gut selective” integrin blocker, binding to alpha 4-beta7-integrin which is present on the surface of leukocytes, including T-lymphocytes. It reduces inflammation in the GIT by inhibiting the adhesion of T-lymphocytes to gastrointestinal tissues. It may cause fewer side effects than anti-TNF drugs due to only targeting the gut rather than the whole body. Vedolizumab is given with an induction treatment when the patient is acutely unwell, followed by maintenance treatment. The induction schedule for adults over 18 years old is 300mg IV infusion at weeks 0, 2 and 6. If there is no response after three doses, then the patient may benefit from a dose at week 10 as well. The maintenance schedule for adults over 18 years old is 300mg IV infusion at week 14, then every eight weeks. If subcutaneous (SC) maintenance treatment is to be used, then the IV dose at week six can be replaced with the first SC dose, and the maintenance schedule for adults over 18 years old is 108mg SC every two weeks. Vedolizumab is stopped if there is no clinical response by week 14, and if there is a loss of response to vedolizumab, 300mg is often given every four weeks instead.
Ustekinumab is a human IgG1k monoclonal antibody that inhibits the activity of the cytokines interleukin-12 and -23, which are involved in inflammatory and immune responses and are found to be elevated in Crohn’s disease. An induction treatment is also followed by maintenance treatment every eight weeks. A single IV infusion is given a week 0. For patients less than 55kg: IV 260mg is used. For patients between 55-85kg: IV 390mg is used. And for patients greater than 85kg: IV 520mg is used. A maintenance dose of SC 90mg is used at week eight and then once every eight weeks. If the response is adequate, then reducing the frequency of dosing to every 12 weeks is considered. If there is no clinical response by week 16, then ustekinumab should be stopped.
Side effects of both vedolizumab and ustekinumab include opportunistic infections, infusion reactions (e.g. pain, erythema, nausea, fever, dyspnoea, urticaria), reactivation of latent infections (e.g. tuberculosis) and potentially increased risk of malignancy and lymphoma.
As there is generally a lack of comparative studies between the biological therapies, treatment initiation is often based upon the clinician’s preference and familiarity, the disease severity, patient characteristics, and the price and availability of the drug.
References:
- Australian Medicines Handbook [Internet]. Adelaide: AMH; c2022. Crohn’s Disease [cited 2023 Jan 14].
- Crohn’s and Colitis Australia [Internet]. Camberwell, Victoria: Australian Crohn’s and Colitis Association; 2023. About Crohn’s Disease; 2023 [cited 2023 Jan 14].
- Im JP, Ye BD, Kim YS, Kim JS. Changing treatment paradigms for the management of inflammatory bowel disease. Korean J Intern Med [Internet]. 2018 Jan [cited 2023 Jan 14]; 33(1): 28-35.
- Morrison G. Update in Inflammatory Bowel Disease. AFP [Internet]. 2009 Dec [cited 2023 Jan 14]; 38 (12): 1.
- NPS Medicine Wise. Ustekinumab (Stelara) PBS listed for severe Crohn’s disease. Australia: NPS Medicine Wise; 2017.
- NPS Medicine Wise. Vedolizumab for inflammatory bowel disease. Aust Prescr [Internet]. 2015 [cited 2023 Jan 14]; 38: 224-5.
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