Anti‐IL‐12/23p40 antibodies for maintenance of remission in | Figure 1

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Anti‐IL‐12/23p40 antibodies for maintenance of remission in Crohn's disease

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Ustekinumab and briakinumab for the treatment of inactive Crohn's disease

What is Crohn's disease?

Crohn's disease is a long‐term (chronic) inflammatory bowel disease that can affect any part of the gastrointestinal tract from the mouth to the anus. Common symptoms include abdominal pain, diarrhea, and weight loss. Crohn's disease is usually managed through medical and surgical therapies. When a person with Crohn's disease is experiencing symptoms, the disease is ‘active’. When symptoms of Crohn's disease disappear, the disease is said to be in remission.

What are ustekinumab and briakinumab?

Ustekinumab and briakinumab are biologic medications, which suppress the immune system and reduce the inflammation associated with Crohn's disease. They can be injected under the skin using a syringe (subcutaneous) or directly infused into a vein (intravenous). Many people with Crohn's disease fail conventional therapy with steroids or therapy with biologics (e.g. infliximab) or develop significant side effects. A drug such as ustekinumab may be an effective alternative for these individuals.

What did the research investigate?

The researchers investigated whether ustekinumab or briakinumab helps maintain remission in people with Crohn's disease and whether these medications have harmful effects (side effects). The researchers searched the medical literature up to 17 September 2019.

What did the researchers find?

The researchers identified 3 studies (646 participants) that compared ustekinumab (2 studies, 542 participants) or briakinumab (1 study, 104 participants) to a placebo (a fake medicine). The treatment effect of ustekinumab was examined in one study after 22 weeks and another study after 44 weeks. The study of briakinumab examined the treatment effect after 24 weeks. All studies were of high methodological quality.

Moderate‐certainty evidence suggests that ustekinumab is more effective than placebo at maintaining remission and reducing symptoms of Crohn's disease at 22 and 44 weeks. The rates of side effects (ustekinumab: 80%; placebo: 84%) and serious side effects (ustekinumab: 11%; placebo: 16%) were lower in ustekinumab participants than in placebo participants. High‐certainty evidence suggests there is no increased risk of side effects with ustekinumab compared to placebo. Commonly reported side effects included infections, injection site reactions, Crohn's disease event (e.g. disease worsening), abdominal pain, nausea, arthralgia (i.e. joint pain), and headache. Moderate‐certainty evidence suggests there is no increased risk of serious side effects with ustekinumab compared to placebo. Serious side effects included serious infections, malignant neoplasm (i.e. a cancerous tumor), and basal cell carcinoma (i.e. skin cancer). In one study, more ustekinumab participants (7%) withdrew from the study due to a side effect than placebo participants (1%). However, the certainty of the evidence was low. The most common side effect leading to study withdrawal was worsening Crohn's disease.

Fifty‐one per cent (32/63) of briakinumab participants relapsed at 24 weeks compared to 61% (22/36) of placebo participants (low‐certainty evidence). The proportion of participants without a reduction in Crohn's disease symptoms at 24 weeks was 33% (21/63) in the briakinumab group compared to 53% (19/36) in the placebo group (low‐certainty evidence). The rates of side effects (briakinumab: 66%; placebo: 64%; low‐certainty evidence) and study withdrawal due to side effects (briakinumab: 2%; placebo: 0%; low‐certainty evidence) were comparable in briakinumab and placebo participants. Commonly reported side effects included upper respiratory tract infection, nausea, abdominal pain, headache, and injection site reaction. The rate of serious side effects was lower in briakinumab participants (2%) compared to placebo participants (7%) (low‐certainty evidence). Serious side effects included small bowel obstruction, deep vein thrombosis, and respiratory distress.

Conclusions

Moderate‐certainty evidence suggests that ustekinumab is probably effective for the maintenance of clinical remission and response in people with moderate to severe Crohn's disease in remission without an increased risk of side effects (high‐certainty evidence) or serious side effects (moderate‐certainty evidence). Further studies are required to determine the long‐term benefits and harms of subcutaneous ustekinumab maintenance therapy in Crohn's disease and whether it should be used alone or in combination with other agents. Future research comparing ustekinumab with other biologic medications will help to determine when treatment with ustekinumab in Crohn's disease is most appropriate. Currently, there is an ongoing study that compares ustekinumab with adalimumab (another type of biologic medication). The manufacturers of briakinumab have stopped production of this medication, thus further studies of briakinumab are unlikely.

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\ \ Cochrane Review; six studies (326 participants).\ Background\ Immunosuppressant drugs (e.g. azathioprine, 6-mercaptopurine and methotrexate) and biologic medications (e.g. infliximab, adalimumab, vedolizumab and ustekinumab) are commonly used alone or in combination to treat Crohn's disease. While effective for initially controlling disease (i.e. inducing remission), there are safety and cost concerns regarding the long-term use of these drugs for the prevention of relapse in people with Crohn's disease in remission.\ Conclusions\ The effects of withdrawal of immunosuppressant therapy in people with Crohn's disease in remission are uncertain. Low quality evidence suggests that continuing azathioprine monotherapy may be superior to withdrawal of azathioprine for avoiding clinical relapse in people with Crohn's disease in remission. Low quality evidence suggests that stopping the immunosuppressive after combination therapy does not seem to impact on the risk of relapsing.\ It is unclear whether the withdrawal of azathioprine, initially administered alone or in combination, impacts on the development of Crohn's disease-related complications, side effects, serious side effects, or withdrawal from the studies due to side effects. More research is needed.](https://app.figure1.com/case-detail/69c7e124-85d9-456a-b1a4-64175631cdd9)

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  1. Probiotics may improve induction of clinical remission when compared to placebo.\
  2. It is unclear whether probiotics lead to a difference in adverse events (minor and serious) when compared to placebo.\
  3. There is limited evidence to determine whether probiotics offer better disease improvement when compared to placebo.\
  4. There may be little or no difference in the induction of remission with probiotics when compared to 5‐ASA (low‐certainty evidence).\
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