Colonoscopy-based prophylactic therapy for postoperative Crohn’s disease

What is Crohn's disease?

Crohn's disease (CD) is a chronic inflammatory disorder that can affect any segment of the gastrointestinal tract. Symptoms include abdominal pain, non‐bloody diarrhoea and weight loss. CD is characterised by periods of clinical relapse when people experience symptoms and periods of clinical remission when the symptoms stop. Despite the available therapies, about half of patients require surgery and resection of the affected segment within 10 years of diagnosis. This surgery is highly effective, however, the majority require a second surgery after 10 years.

What is colonoscopy?

Colonoscopy is a procedure whereby a physician inserts a viewing tube (colonoscope) into the rectum for the purpose of inspecting the colon.

What did the researchers investigate?

Most patients that experience a clinical relapse of CD have inflammation of the intestinal mucosa weeks or months before starting with symptoms. This asymptomatic inflammation can be detected by colonoscopy and it is usually called endoscopic recurrence. The researchers investigated whether the initiation or intensification of prophylactic-therapy guided by the detection of endoscopic recurrence may improve the prognosis of postoperative CD.

What are the issues related to start prophylactic-therapy in asymptomatic patients?

The drugs usually used as prophylactic-therapy in CD are 5-aminosalicylates, antibiotics, thiopurines, methotrexate and/or anti-tumour necrosis factor antibody (anti-TNFα) drugs. The main issues related to these drugs are costs and adverse effects. The most frequent adverse events are alopecia, gastrointestinal intolerance, infections, sensory symptoms, lupus, vasculitis, leukopenia, pancreatitis, skin lesions and less frequently skin and haematological cancer.

How was this study performed?

A systematic review of the current literature was performed to assess the efficacy of prophylactic-therapy guided by colonoscopy in reducing the postoperative recurrence of CD. An electronic search of several databases was performed and studies that met our inclusion criteria were selected for further evaluation.

What did the researchers find?

The researchers identified three strategies of management of CD after surgery: prophylactic-therapy guided by clinical symptoms, prophylactic-therapy guided by colonoscopy and full-treatment immediately after surgery.

Five studies compared prophylactic-therapy guided by colonoscopy versus prophylactic-therapy guided by clinical symptoms. In these studies, all patients received the same prophylactic therapy immediately after surgery. In the colonoscopy-based management group, therapy was intensified in the case of asymptomatic mucosal inflammation, and in the control group, therapy was intensified only in case of clinical symptoms. According to these studies, intensification of therapy guided by colonoscopy may reduce postoperative clinical recurrence and endoscopic recurrence when compared to intensification guided by symptoms. Data from the study with the highest methodological quality showed that 378 patients in the colonoscopy-guided management group experience clinical recurrence compared to 462 patients in the group where the management was guided by symptoms, assuming 18 months of follow-up and a population of 1000 patients underwent intestinal resection due to CD in each group. At 18 months the benefit is greater in terms of endoscopic recurrence, which is a good predictor of clinical recurrence. Studies of lower methodological quality but longer follow-up also supported the benefit in terms of clinical recurrence. Additionally, there may be little or no difference in the risk of adverse events in colonoscopy-guided management compared to intensification guided by symptoms. We are uncertain whether intensification of prophylactic therapy guided by colonoscopy compared to therapy guided by symptoms impacts surgical recurrence as the certainty of the evidence is very low.

Three studies compared prophylactic-therapy guided by colonoscopy versus full-treatment immediately after surgery. In the colonoscopy-based management group, the therapy was delayed up to the detection of asymptomatic mucosal inflammation, while in the other group the drugs were started immediately after surgery. Unfortunately, these studies had many limitations, hence the certainty of the evidence was judged as very low. Considering this, we are uncertain about the effect of initiation of therapy guided by colonoscopy on postoperative recurrence and adverse effects when compared to therapy immediately after surgery.

Conclusions

Prophylactic-therapy guided by colonoscopy may decrease the risk of clinical and endoscopic recurrence compared to prophylactic-therapy guided by symptoms with little or no difference the risk of adverse events. We are uncertain whether initiation of therapy guided by colonoscopy compared to initiation immediately after surgery impacts postoperative recurrence and adverse events.

Authors' conclusions: 

Intensification of prophylactic-therapy guided by colonoscopy may reduce clinical and endoscopic postoperative recurrence of CD compared to intensification guided by symptoms, and there may be little or no difference in adverse effects. We are uncertain whether initiation of therapy guided by colonoscopy impacts postoperative recurrence and adverse events when compared to initiation immediately after surgery, as the certainty of the evidence is very low. Further studies are necessary to improve the certainty of the evidence of this review.

Read the full abstract...
Background: 

About half of patients with Crohn's disease (CD) require surgery within 10 years of diagnosis. Resection of the affected segment is highly effective, however the majority of patients experience clinical recurrence after surgery. Most of these patients have asymptomatic endoscopic recurrence weeks or months before starting with symptoms. This inflammation can be detected by colonoscopy and is a good predictor of poor prognosis.Therapy guided by colonoscopy could tailor the management and improve the prognosis of postoperative CD.

Objectives: 

To assess the effects of prophylactic therapy guided by colonoscopy in reducing the postoperative recurrence of CD in adults.

Search strategy: 

The following electronic databases were searched up to 17 December 2019: MEDLINE, Embase, CENTRAL, Clinical Trials.gov, WHO Trial Registry and Cochrane IBD specialized register. Reference lists of included articles, as well as conference proceedings were handsearched.

Selection criteria: 

Randomised controlled trials (RCTs), quasi-RCTs and cohort studies comparing colonoscopy-guided management versus management non-guided by colonoscopy.

Data collection and analysis: 

Two review authors independently considered studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using both the Cochrane 'Risk of bias' tool for RCTs and Newcastle-Ottawa scale (NOS) for cohort studies. The primary outcome was clinical recurrence. Secondary outcomes included: endoscopic, surgical recurrence and adverse events. We calculated the risk ratio (RR) for each dichotomous outcome and extracted the hazard ratio (HR) for time-to-event outcomes. All estimates were reported with their corresponding 95% confidence interval (CI). Data were analysed on an intention-to-treat (ITT) basis. The overall quality of the evidence was evaluated using GRADE criteria.

Main results: 

Two RCTs (237 participants) and five cohort studies (794 participants) met the inclusion criteria. Meta-analysis was not conducted as the studies were highly heterogeneous. We included two comparisons.

Intensification of prophylactic-therapy guided by colonoscopy versus intensification guided by clinical recurrence

One unblinded RCT and four retrospective cohort studies addressed this comparison. All participants received the same prophylactic therapy immediately after surgery. In the colonoscopy-based management group the therapy was intensified in case of endoscopic recurrence; in the control group the therapy was intensified only in case of symptoms.

In the RCT, clinical recurrence (defined as Crohn's Disease Activity Index (CDAI) > 150 points) in the colonoscopy-based management group was 37.7% (46/122) compared to 46.1% (21/52) in the control group at 18 months' follow up (RR 0.82, 95% CI: 0.56 to 1.18, 174 participants, low-certainty evidence). There may be a reduction in endoscopic recurrence at 18 months with colonoscopy-based management (RR 0.73, 95% CI 0.56 to 0.95, 1 RCT, 174 participants, low-certainty evidence). The certainty of the evidence for surgical recurrence was very low, due to only four cohort studies with inconsistent results reporting this outcome.

Adverse events at 18 months were similar in both groups, with 82% in the intervention group (100/122) and 86.5% in the control group (45/52) (RR 0.95, 95% CI:0.83 to 1.08, 1 RCT, 174 participants, low-certainty of evidence).The most common adverse events reported were alopecia, wound infection, sensory symptoms, systemic lupus, vasculitis and severe injection site reaction. Perforations or haemorrhages secondary to colonoscopy were not reported.

Initiation of prophylactic-therapy guided by colonoscopy versus initiation immediately after surgery

An unblinded RCT and two retrospective cohort studies addressed this comparison. The control group received prophylactic therapy immediately after surgery, and in the colonoscopy-based management group the therapy was delayed up to detection of endoscopic recurrence.

The effects on clinical and endoscopic recurrence are uncertain (clinical recurrence until week 102: RR 1.16, 95% CI 0.73 to 1.84; endoscopic recurrence at week 102: RR 1.16, 95% CI 0.73 to 1.84; 1 RCT, 63 participants, very low-certainty evidence). Results from one cohort study were similarly uncertain (median follow-up 32 months, 199 participants). The effects on surgical recurrence at a median follow-up of 50 to 55 months were also uncertain in one cohort study (RR 0.79, 95% CI 0.38 to 1.62, 133 participants, very low-certainty evidence).

There were fewer adverse events with colonoscopy-based management (54.8% (17/31)) compared with the control group (93.8% (30/32)) but the evidence is very uncertain (RR 0.58, 95% CI 0.42 to 0.82; 1 RCT, 63 participants). Common adverse events were infections, gastrointestinal intolerance, leukopenia, pancreatitis and skin lesions. Perforations or haemorrhages secondary to colonoscopy were not reported.

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