Adalimumab for the treatment of active Crohn's disease

What is Crohn's disease?

Crohn's disease is a bowel disease in which the walls of the gastrointestinal tract become inflamed. Any part of the gastrointestinal tract can become affected, from the mouth to the anus. Symptoms can include abdominal pain, bloody diarrhea and weight loss. When people with Crohn's disease are experiencing symptoms, the disease is considered to be 'active'. When symptoms stop, the disease is considered to be in 'remission'.

What is adalimumab?

Adalimumab is a biologic drug that helps reduce inflammation and relieve pain in people suffering from inflammatory conditions such as Crohn's disease. Adalimumab works by binding to tumor necrosis factor-alpha and blocking the inflammatory effect, resulting in the reduction of pain in inflammation in people with Crohn's disease. For active Crohn's disease, adalimumab is usually injected under the skin at an initial dose of 160 mg followed by a dose of 80 mg two weeks later.

What did the researchers investigate

The researchers investigated whether adalimumab could bring people with moderate to severely active Crohn's disease into remission. They also looked at whether adalimumab could help with symptoms of Crohn's disease and whether it was associated with any harms (i.e. side effects). We looked at the medical literature up to 16 April 2019.

What did the researchers find?

The researchers found three studies with a total of 714 adult (> 18 years) participants. These participants all had moderate to severely active Crohn's disease. A total of 451 participants were treated with adalimumab and 268 were treated with a placebo (a fake medication). More participants who were treated with adalimumab achieved remission or improvement of their symptoms than those who were treated with placebo. The rates of side effects (adalimumab: 62%, placebo: 72%), serious side effects (adalimumab: 2%, placebo: 5%) and study withdrawal due to side effects (adalimumab: 1%, placebo: 3%) were lower in adalimumab participants than placebo participants. Commonly reported side effects included injection site reactions, abdominal pain, fatigue, worsening Crohn's disease and nausea.

Conclusions

High-certainty evidence suggests that treating participants with adalimumab is better than treating them with placebo for inducing remission and improving symptoms in people with moderate to severely active Crohn's disease. Side effects were lower in adalimumab participants compared to placebo. However, we are uncertain about the effect of adalimumab on side effects due to the low number of events, therefore, no firm conclusions can be drawn regarding the harms (side effects) of adalimumab in Crohn's disease. Futher studies are required to look at the long-term benefits and harms of using adalimumab in people with Crohn's disease.

Authors' conclusions: 

High-certainty evidence suggests that adalimumab is superior to placebo for induction of clinical remission and clinical response in people with moderate to severely active CD. Although the rates of AEs, SAEs and withdrawals due to AEs were lower in adalimumab participants compared to placebo, we are uncertain about the effect of adalimumab on AEs due to the low number of events. Therefore, no firm conclusions can be drawn regarding the safety of adalimumab in CD. Futher studies are required to look at the long-term effectiveness and safety of using adalimumab in participants with CD.

Read the full abstract...
Background: 

Adalimumab is an IgG1 monoclonal antibody that targets and blocks tumor necrosis factor-alpha, a pro-inflammatory cytokine involved in the pathogenesis of Crohn's disease (CD). A significant proportion of people with CD fail conventional therapy or therapy with biologics or develop significant adverse events. Adalimumab may be an effective alternative for these individuals.

Objectives: 

The objectives of this review were to assess the efficacy and safety of adalimumab for the induction of remission in CD.

Search strategy: 

We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register, ClinicalTrials.Gov and the World Health Organization trial registry (ICTRP) from inception to 16 April 2019. References and conference abstracts were searched to identify additional studies.

Selection criteria: 

Randomized controlled trials (RCTs) comparing any dose of adalimumab to placebo or an active comparator in participants with active CD were included.

Data collection and analysis: 

Two authors independently screened studies, extracted data and assessed bias using the Cochrane 'Risk of bias' tool. The primary outcome was the failure to achieve clinical remission, as defined by the original studies. Clinical remission was defined as a Crohn's Disease Activity Index (CDAI) score of less than 150 points. Secondary outcomes included failure to achieve clinical response (defined as a decrease in CDAI of > 100 points or > 70 points from baseline), failure to achieve endoscopic remission and response, failure to achieve histological remission and response, failure to achieve steroid withdrawal, adverse events (AEs) and serious adverse events (SAEs), withdrawal from study due to AEs and quality of life measured by a validated instrument. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes. Data were pooled for analysis if the participants, interventions, outcomes and time frame were similar. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence was assessed using GRADE.

Main results: 

Three placebo-controlled RCTs (714 adult participants) were included. The participants had moderate to severely active CD (CDAI 220 to 450). Two studies were rated as at low risk of bias and one study was rated as at unclear risk of bias. Seventy-six per cent (342/451) of adalimumab participants failed to achieve clinical remission at four weeks compared to 91% (240/263) of placebo participants (RR 0.85, 95% CI 0.79 to 0.90; high-certainty evidence). Forty-four per cent (197/451) of adalimumab participants compared to 66% (173/263) of placebo participants failed to achieve a 70-point clinical response at four weeks (RR 0.68, 95% CI 0.59 to 0.79; high-certainty evidence). At four weeks, 57% (257/451) of adalimumab participants failed to achieve a 100-point clinical response compared to 76% (199/263) of placebo participants (RR 0.77, 95% CI 0.69 to 0.86; high-certainty evidence). Sixty-two per cent (165/268) of adalimumab participants experienced an AE compared to 72% (188/263) of participants in the placebo group (RR 0.90, 95% CI 0.74 to 1.09; moderate-certainty evidence). Two percent (6/268) of adalimumab participants experienced a SAE compared to 5% (13/263) of participants in the placebo group (RR 0.44, 95% CI 0.17 to 1.15; low-certainty evidence). Lastly, 1% (3/268) of adalimumab participants withdrew due to AEs compared to 3% (8/268) of participants in the placebo group (RR 0.38, 95% CI 0.11 to 1.30; low-certainty evidence). Commonly reported adverse events included injection site reactions, abdominal pain, fatigue, worsening CD and nausea. Quality of life data did not allow for meta-analysis. Three studies reported better quality of life at four weeks with adalimumab (measured with either Inflammatory Bowel Disease Questionnaire or Short-Form 36; moderate-certainty evidence). Endoscopic remission and response, histologic remission and response, and steroid withdrawal were not reported in the included studies.

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