Tight Control Management in Perianal Crohn's Disease

Overview

Perianal Crohn's disease (pCD) affects around one-third of patients with Crohn's disease (CD) during their disease course. It represents a distinct disease phenotype and causes significant morbidity, often requiring multiple surgical interventions. However, treatment of pCD is still challenging and unsatisfactory. Only approximately one-third of pCD patients responded to biologic treatment. Overall, medical therapy with anti-TNF could only achieve prolonged remission in 30-40% of pCD cases. At the same time, surgical treatment could only lead to a favourable outcome in around 50% of patients with a higher recurrence rate in patients with complex than in simple fistulae. Recently, combination of optimal medical therapy with surgical therapy (drainage of sepsis and insertion of seton), with radiological guidance, has been suggested as the standard management so as to improve the outcomes of complex pCD. Magnetic resonance imaging (MRI) is considered to be the gold standard imaging technique for perianal CD. It can visualise the anal sphincter and the pelvic floor muscles, as well as the fistula tracts and abscesses. Previous studies using MRI to monitor treatment response to anti-TNF revealed that radiological healing lagged behind clinical remission by a median of 12 months and that long-term maintenance therapy is probably required to prevent recurrence despite a clinically healed external opening. Therefore, we hypothesize that serial monitoring with MRI is important. Recently, there has been some advance in the surgical treatment of perianal Crohn's disease. FiLaCTM uses a radial-emitting disposable laser fibre for endofistular therapy. Recent systemic review and meta-analysis showed that the primary success rate was 73.3% (11/15) in patients with perianal Crohn's fistula. There has been breakthrough in the management of luminal Crohn's disease. The CALM study has showed that timely escalation of anti-TNF on the basis of clinical symptoms combined with biomarkers in patients with luminal Crohn's disease resulted in better clinical and endoscopic outcomes than symptom-driven decision alone. It is unsure whether this approach is also applicable to patients with perianal Crohn's disease.

Perianal Crohn's disease (pCD) affects around one-third of patients with Crohn's disease (CD) during their disease course. It represents a distinct disease phenotype and causes significant morbidity, often requiring multiple surgical interventions. The presence of pCD causes significant burden to patients. The risk of developing perianal fistulae depends on disease location and is most commonly seen in colonic disease with rectal involvement. Perianal fistulae have been reported in 12% of subjects with small intestinal CD, 15% with ileocolonic CD, 41% with colonic CD without rectal involvement and 92% of those with colonic CD with rectal involvement. Persistently high CRP level \> 31 was recently found to be independently associated with subsequent development of perianal fistula in CD patients. Besides, male gender, those who have a younger age of onset of CD, non-Caucasians and Sephardic (as opposed to Ashkenazi) Jews are all at higher risk of developing pCD. However, treatment of pCD is still challenging and unsatisfactory. Antibiotics including metronidazole and ciprofloxacin, thiopurines and other immunomodulators failed to show radiological healing of anal fistulas. Approximately one-third of pCD patients responded to biologic treatment. The ACCENT II trial is the first double blind RCT that demonstrates the benefit of infliximab maintenance in fistulising Crohn's disease. At week 54, complete absence of draining fistulae was noted in 36% of patients in the infliximab maintenance group, compared to 19% in the placebo group. (p=0.009) There are also evidence that maintenance infliximab therapy could reduce hospitalisation, surgeries and procedures in fistulising Crohn's disease. In the CHARM study, 30% of patients with fistulae treated with adalimumab had complete fistulae closure, and this increased to 33% at 56 weeks compared with 13% in the placebo group. However, the risk of recurrence is high. Only 34% of patients remained free of relapse after one year of cessation. Up till now, there are still no clear predictors, which can predict the response to anti-TNF therapy except the presence of proctitis. Presence of proctitis has been shown to be a poor predictor of response to anti-TNF therapy. Recently, A.J. Yarur et al. reported that patients with pCD who achieved remission had higher infliximab trough level compared to those with active fistulae \[15.8 vs. 4.4 lg/mL, respectively (P \< 0.0001)\], and those who developed anti-infliximab antibodies had a lower chance of achieving fistula healing (OR: 0.04 \[95%CI: 0.005-0.3\], P \< 0.001). An infliximab level of ≥10.1 µg/mL is associated with fistula healing \[OR: 3.9 (95%CI: 1.34-11.8) P = 0.012\]. Another, retrospective study by Davidov et. al, showed that infliximab levels at week 2 and 6 were significantly associated with fistula response at week 14 and 30. Infliximab levels of 9.25µg/mL at week 2 and 7.25 µg/mL at week 6 could best predict response to treatment. Overall, medical therapy with anti-TNF could only achieve prolonged remission in 30-40% of pCD cases. At the same time, surgical treatment could only lead to a favourable outcome in around 50% of patients with a higher recurrence rate in patients with complex than in simple fistulae. Recently, combination of optimal medical therapy with surgical therapy (drainage of sepsis and insertion of seton), with radiological guidance, has been suggested as the standard management so as to improve the outcomes of complex pCD. An earlier study in 2003 revealed that the combination of seton placement and infliximab results in an earlier initial response (100% vs. 82.6%, p=0.014), lower recurrence rates (44% vs. 79%, p=0.001) and longer time to relapse (13.5 months vs. 3.6 months, p=0.0001) than infliximab alone. Further studies in Japan and France evaluating the efficacy of combination of seton insertion and infliximab also yielded positive results with higher chance of fistulae closure. A recent systemic review and meta-analysis of 24 studies by Yassin et al. revealed that combination therapy led to higher complete remission rate compared with single therapy (52% vs. 43%).33 Overall, long-term infliximab therapy with combined medical and surgical management produced clinical remission in 36-58%. Magnetic resonance imaging (MRI) is considered to be the gold standard imaging technique for perianal CD. It can visualise the anal sphincter and the pelvic floor muscles, as well as the fistula tracts and abscesses. Previous studies using MRI to monitor treatment response to anti-TNF revealed that radiological healing lagged behind clinical remission by a median of 12 months and that long-term maintenance therapy is probably required to prevent recurrence despite a clinically healed external opening. Therefore, investigators hypothesize that serial monitoring with MRI is important. Recently, there has been some advance in the surgical treatment of perianal Crohn's disease. FiLaCTM uses a radial-emitting disposable laser fibre for endofistular therapy. Recent systemic review and meta-analysis showed that the primary success rate was 73.3% (11/15) in patients with perianal Crohn's fistula. There has been breakthrough in the management of luminal Crohn's disease. The CALM study has showed that timely escalation of anti-TNF on the basis of clinical symptoms combined with biomarkers in patients with luminal Crohn's disease resulted in better clinical and endoscopic outcomes than symptom-driven decision alone. It is unsure whether this approach is also applicable to patients with perianal Crohn's disease. Therefore, investigators hypothesize that more proactive treatment with treating to target "Radiological healing on MRI" is associated with better outcome and the combination of examination under anesthesia with drainage of perianal abscess and together with FiLaCTM of the fistula will lead to better outcome.