Chapter 35A. Perspective on Inflammatory Bowel Disease

Fichera et al provide a comprehensive review of the surgical approach to Crohn's disease from indications for surgery to the surgical approaches to the management of the various patterns of disease.1 There are several areas that may benefit from expanded coverage so that the surgeon managing this difficult chronic disease can understand more regarding some of the current areas of controversy.

The onset of Crohn's disease has consistently been blamed on a yet to be identified alteration in mucosal immune response, possible in response to an altered susceptibility to luminal bacteria or other environmental exposures.2,3 Interestingly, there has been greater recognition of the consistent histopathologic changes of mucosal exudation, submucosal edema, and extensive dilation of lacteals seen in Crohn's disease lymphatics.4 These findings have correlated with animal models of lymphatic sclerosing agents leading to similar findings of inflammatory bowel disease. The inflammatory response was reduced with administration of cyclooxygenase (COX) inhibitors suggesting an arachidonic acid role. It is believed that the early lymphatic obstruction blocks the transfer of inflammatory cells to regional lymph nodes and the process of lymphoid neogenesis that produces lymphoid aggregates in the mesentery. Trapping the activated B lymphocytes in the region, coupled with an ongoing pattern of neoangiogenesis of lymphatics in the intestinal wall may be causally related to the development of the disease. Further credence is given to the theory because the virtual pathognomonic finding of fat wrapping is the result of cytokine and tumor necrosis factor (TNF) release from adjacent lymphatic tissue. These response leads to hypertrophy of fat cells in the mesentery that may be related to the common finding of thickened mesentery in patients with Crohn's disease. Although considerably more work is required to fully understand the interaction of abnormal lymph drainage and mucosal inflammation, it is intriguing to hypothesis that early resection of the draining mesentery might be an effective surgical strategy prior to the onset of chronic disease and extensive mesenteric involvement.

The availability of an increasing number of biologic agents capable of creating greater immunosuppression has led to the suggestion of a so called "top-down" strategy of more aggressive medical therapy at diagnosis. This is contradistinction to the more typical "bottom-up" approach of beginning with corticosteroids or even 5-aminosalicylic acid (5-ASA) preparations and escalating only after persistent symptoms. Markowitz et al reported an almost 90% remission rate in children using a strategy of corticosteroids and 6-mercaptopurine (6-MP) as induction therapy.5 Similar benefits have been described with the use of either certolizumab pegol therapy, where superior response was seen in patients with disease duration of shorter than 1 year compared to patients with longer than 5 years of disease (75 vs 52%).6 A prospective trial assessing patients naive to any immunomodulator reported both an improved clinical remission rate at 52 weeks (62 vs 42%) and longer time to relapse (329 vs 174 days) with a strategy of infliximab infusion and azathioprine/6-MP compared to corticosteroids and azathioprine.7 Infliximab was reserved for intractable disease that failed corticosteroids initially. Proponents of the top-down approach suggest that the benefit derives from management of a predominant Th1 immune response with excessive interferon-γ (IFN-γ) secretion. This response is lost with chronicity of disease accounting for a current management within a multidisciplinary approach because there still remains a 25–40% failure rate with the top-down management approach. In addition, the ACCENT-1 trial confirmed that scheduled long-term administration of infliximab was associated with a significant reduction in the development of anti-TNF antibodies compared to episodic therapy (1 vs 38%).7 This would indicate that selection of a top-down methodology could lead to expensive long-term therapy with these agents. Therefore, reassessment for medical failure may identify patients who would benefit from a surgical intervention prior to the onset of significant impact from poorly controlled inflammation, worsening nutritional onset, or masked complications from perforation. Surgical approaches may need to be modified for patients with recent exposure to anti-TNF agents, as suggested by the authors, and may require judicious use of diverting stomas to protect anastomoses in difficult cases.

The countervailing argument to aggressive early medical therapy is aggressive surgical therapy, primarily for ileocolic disease. There is limited data available comparing quality of life and cost-effectiveness for early surgery versus top-down medical therapy. Aratari et al reported on a retrospective analysis of patients and found that "early" operated patients had prolonged clinical remission.8 An interesting survey study demonstrated that gastroenterologists had a 2-fold higher desire to prevent an ileocolic resection compared to either colorectal surgeons or patients.9 These data support the same potential benefit of earlier intervention in localized Crohn's disease prior to the onset of a more problematic and difficult-to-manage inflammatory response. A current prospective randomized trial being performed in the Netherlands assessing the role of early resection of terminal ileal Crohn's disease should provide interesting data regarding risk of complications versus restoration of quality of life. The risk and timing of recurrent disease will also be an important outcome of the study. One could see an evolving strategy of early laparoscopic resection of localized terminal ileal disease with the aggressive top-down strategy reserved for early surgical recurrences or patients with multisegment disease.

As outlined by Fichera et al, surgical management is highly effective in managing complications of Crohn's disease, including obstruction, fistula, and perforation.1 Surgery is highly effective at restoring quality-of-life measures. However, current data suggest that 70–80% of patients will develop mucosal evidence of disease within 1 year postresection that is highly correlated with clinical recurrence. Approximately 25–30% of patients will develop significant recurrences requiring repeat surgical resection within 5 years and almost 70% of patients will need an additional surgical procedure by 10 years. Options for prophylaxis include probiotics. A variety of different bacteria have been assessed in probiotic formulae for Crohn's prophylaxis further complicating assessment. However, two recent meta-analyses failed to identify a benefit associated with probiotic whether it be clinical or endoscopic recurrence.10,11 Conversely, two limited trials suggested that nitroimidazole antibiotics may be beneficial in reducing clinical recurrence.12 These data are limited and would require confirmatory data prior to widespread adoption. Mesalamine is probably the best evaluated anti-inflammatory agent assessed as a postresection prophylactic strategy in Crohn's disease. The Cochrane meta-analysis reported a modest but significant benefit for this strategy with a risk ratio of 0.76 (0.62, 0.94).13 Azathioprine also enjoys a long history of evaluation and has demonstrated superiority over 5-ASA treatment albeit at an increased risk for adverse treatment events. Given these current data, a reasonable clinical strategy may be to withhold prophylaxis in patients with localized and fully resected disease and reserve prophylaxis for early recurrence or multiple prior resections. It would also be reasonable to consider prophylaxis when resection is combined with stricturoplasty.

The ongoing work in evaluating the immunologic components of Crohn's disease, and the related proteogenomic assessments may lead to a better understanding of the initial insult in patients with this complicated chronic disorder. The hope remains for refined and focused clinical strategies that minimize the impact of chronic illness and/or treatment-related morbidity while restoring quality of life. The authors are to be commended on an excellent clinical review of this broad topic.