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.

Authors' conclusions: 

Moderate-certainty evidence suggests that ustekinumab is probably effective for the maintenance of clinical remission and response in people with moderate to severe CD in remission without an increased risk of adverse events (high-certainty evidence) or serious adverse events (moderate-certainty evidence) relative to placebo. The effect of briakinumab on maintenance of clinical remission and response in people with moderate to severe Crohn's disease in remission was uncertain as the certainty of the evidence was low. The effect of briakinumab on adverse events and serious adverse events was also uncertain due to low-certainty evidence. Further studies are required to determine the long-term efficacy and safety of subcutaneous ustekinumab maintenance therapy in Crohn's disease and whether it should be used by itself or in combination with other agents. Future research comparing ustekinumab with other biologic medications will help to determine when treatment with ustekinumab in CD is most appropriate. Currently, there is an ongoing study that compares ustekinumab with adalimumab. This review will be updated when the results of this study become available. The manufacturers of briakinumab have stopped production of this medication, thus further studies of briakinumab are unlikely.

Read the full abstract...
Background: 

Ustekinumab and briakinumab are monoclonal antibodies that target the standard p40 subunit of cytokines interleukin-12 and interleukin-23 (IL-12/23p40), which are involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with Crohn's disease fail conventional therapy or therapy with biologics (e.g. infliximab) or develop significant adverse events. Anti-IL-12/23p40 antibodies such as ustekinumab may be an effective alternative for these individuals.

Objectives: 

The objectives of this review were to assess the efficacy and safety of anti-IL-12/23p40 antibodies for maintenance of remission in CD.

Search strategy: 

We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, Embase, and trials registers from inception to 17 September 2019. We searched references and conference abstracts for additional studies.

Selection criteria: 

We considered for inclusion randomized controlled trials in which monoclonal antibodies against IL-12/23p40 were compared to placebo or another active comparator in participants with quiescent CD.

Data collection and analysis: 

Two review authors independently screened studies for inclusion, extracted data, and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome measure was failure to maintain clinical remission, defined as a Crohn's disease activity index (CDAI) of < 150 points. Secondary outcomes included failure to maintain clinical response, adverse events (AE), serious adverse events (SAE), and withdrawals due to AEs. Clinical response was defined as a decrease in CDAI score of ≥ 100 points from baseline score. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each outcome. We analyzed all data on an intention-to-treat basis. We used GRADE to evaluate the overall certainty of the evidence supporting the outcomes.

Main results: 

Three randomized controlled trials (646 participants) met the inclusion criteria. Two trials assessed the efficacy of ustekinumab (542 participants), and one study assessed the efficacy of briakinumab (104 participants). We assessed all of the included studies as at low risk of bias.

One study (N = 145) compared subcutaneous ustekinumab (90 mg) administered at 8 and 16 weeks compared to placebo. Fifty-eight per cent (42/72) of ustekinumab participants failed to maintain clinical remission at 22 weeks compared to 73% (53/73) of placebo participants (RR 0.80, 95% CI 0.63 to 1.02; moderate-certainty evidence). Failure to maintain clinical response at 22 weeks was seen in 31% (22/72) of ustekinumab participants compared to 58% (42/73) of placebo participants (RR 0.53, 95% CI 0.36 to 0.79; moderate-certainty evidence). One study (N = 388) compared subcutaneous ustekinumab (90 mg) administered every 8 weeks or every 12 weeks to placebo for 44 weeks. Forty-nine per cent (126/257) of ustekinumab participants failed to maintain clinical remission at 44 weeks compared to 64% (84/131) of placebo participants (RR 0.76, 95% CI 0.64 to 0.91; moderate-certainty evidence). Forty-one per cent (106/257) of ustekinumab participants failed to maintain clinical response at 44 weeks compared to 56% (73/131) of placebo participants (RR 0.74, 95% CI 0.60 to 0.91; moderate-certainty evidence). Eighty per cent (267/335) of ustekinumab participants had an AE compared to 84% (173/206) of placebo participants (RR 0.94, 95% CI 0.87 to 1.03; high-certainty evidence). Commonly reported adverse events included infections, injection site reactions, CD event, abdominal pain, nausea, arthralgia, and headache. Eleven per cent of ustekinumab participants had an SAE compared to 16% (32/206) of placebo participants (RR 0.74, 95% CI 0.48 to 1.15; moderate-certainty evidence). SAEs included serious infections, malignant neoplasm, and basal cell carcinoma. Seven per cent (5/73) of ustekinumab participants withdrew from the study due to an AE compared to 1% (1/72) of placebo participants (RR 4.93, 95% CI 0.59 to 41.18; low-certainty evidence). Worsening CD was the most common reason for withdrawal due to an AE.

One study compared intravenous briakinumab (200 mg, 400 mg, or 700 mg) administered at weeks 12, 16, and 20 with placebo. Failure to maintain clinical remission at 24 weeks was seen in 51% (32/63) of briakinumab participants compared to 61% (22/36) of placebo participants (RR 0.84, 95% CI 0.58 to 1.20; low-certainty evidence). Failure to maintain clinical response at 24 weeks was seen in 33% (21/63) of briakinumab participants compared to 53% (19/36) of placebo participants (RR 0.64, 95% CI 0.40 to 1.02; low-certainty evidence). Sixty-six per cent (59/90) of briakinumab participants had an AE compared to 64% (9/14) of placebo participants (RR 1.02, 95% CI 0.67 to 1.55; low-certainty evidence). Common AEs included upper respiratory tract infection, nausea, abdominal pain, headache, and injection site reaction. Two per cent (2/90) of briakinumab participants had an SAE compared to 7% (1/14) of placebo participants (RR 0.31, 95% CI 0.03 to 3.21; low-certainty evidence). SAEs included small bowel obstruction, deep vein thrombosis, and respiratory distress. Withdrawal due to an AE was noted in 2% of briakinumab participants compared to 0% (0/14) of placebo participants (RR 0.82, 95% CI 0.04 to 16.34; low-certainty evidence). The AEs leading to study withdrawal were not described.

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