Crohn’s disease (CD) is a chronic recurrent inflammatory disease of the gastrointestinal tract with a high surgical rate despite clinical treatment with drugs such as 5-aminosalicylic acid (5-ASA), glucocorticoids, immunosuppressive agents, and biologic agents such as anti-tumor necrosis factor monoclonal antibody (infliximab). Foreign reports indicate that 50-80% of CD patients require surgical treatment, especially those with severe combined complications (e.g., fistula, stenosis, abscess, perforation) and those for whom medical treatment is ineffective, and most recur after surgical treatment and require re-surgical treatment. The rate of surgery is not high in China because patients and physicians do not pay enough attention to the disease. The literature reports that endoscopic examination 1 year after surgery revealed recurrence of intestinal mucosal inflammation in 28%-73% of patients and recurrence of clinical symptoms in close to 50% of patients. Therefore, it is particularly important for postoperative recurrence prevention and clinical management.
Recurrence after CD surgery includes clinical, endoscopic, histological and imaging recurrences. Clinical recurrence refers to the recurrence of clinical symptoms, abdominal pain, diarrhea, and disruption of daily life with a CD activity index (CDAI) >200. Histological recurrence refers to inflammatory changes in the intestinal mucosa, glandular structural changes, intestinal epithelial cell hyperplasia, necrosis or detachment, leukocyte infiltration and ulcer formation. Endoscopic recurrence mainly refers to inflammatory changes in the anastomosis and proximal intestinal mucosa found by endoscopy when there is no clinical appearance, and the diagnosis is usually confirmed by endoscopic review 6 months after surgery.
I. Mechanism and causative factors of postoperative recurrence
The mechanism of postoperative recurrence is still unclear, but it has been found that bacterial antigens in the intestinal stool are important triggering factors, and Rutgeerts et al. found that if ileal resection combined with small bowel fistula kept stool from passing through the ileo-colonic anastomosis, the mucosal inflammation of the anastomosis and ileum would not recur; however, if stool continued to pass through the anastomosis, the mucosal inflammation recurred, and the recurrence was mostly at the small bowel end of the anastomosis. It was found that intermuscular plexus inflammation in the proximal intestinal mucosa of the anastomosis often accompanies postoperative recurrence, the cause of which remains unclear.
The main triggers of postoperative recurrence of CD are.
1, smoking: smoking significantly increases postoperative recurrence, and the recurrence rate is higher for heavy smokers. One study showed that the recurrence rate of smokers 5 years after surgery was 36%, while that of non-smokers was only 20%.
Disease-related factors: patient’s age, disease duration, presence of intestinal stricture and penetrating inflammation, extent and severity of lesions, ileo-colonic anastomosis, especially penetrating lesions (perforation, abscess, fistula).
3. Surgical-related factors: end-lateral anastomosis, side-to-side anastomosis over end-to-end anastomosis, extent of surgery, complications and the presence of intra-mucosal non-caseating granulomas and blood transfusion. Other studies have found that bleeding, obstruction, and the presence of postoperative anastomotic fistula are associated with recurrence, but this is not supported by others. In conclusion, smoking and the presence of combined perforating lesions are the most important factors for postoperative recurrence.
II. Diagnosis of postoperative recurrence
Endoscopy, histopathology and imaging are often used clinically to determine postoperative recurrence of CD, but there are still differences between these findings and the occurrence of the disease. While serological indicators such as CRP, anti-neutrophil cytoplasmic antibodies (pANCA), anti-brewery yeast antibodies (ASCA) and fecal calprotectin or lactoferrin have poor clinical value.Rutgeerts et al. proposed to determine postoperative recurrence by endoscopy based on the grading of inflammation of the intestinal mucosa at the endoscopic anastomosis or the upper end of the anastomosis. Specifically, inflammation grade i-0: normal mucosa without inflammation and ulceration; grade i-1: ≤5 ulcer foci; grade i-2: >5 ulcer foci with normal mucosa between ulcers; grade i-3; (small) intestinal scattered aphthous ulcers and mucosal inflammatory lesions; grade i-4: diffuse mucosal inflammation with large ulcers, nodular inflammatory hyperplasia, or intestinal strictures. Clinical observation showed that 80%-85% of patients with endoscopic mucosal grading of i-0 or i-1 had no clinical symptom recurrence within 3 years, and the recurrence rate was <5%; while those with mucosal inflammation grading of i-2, i-3, and i-4 had clinical symptom recurrence rates of 15%, 40%, and 90% within 3 years, respectively. The recurrence of endoscopic mucosal inflammation preceded the recurrence of clinical symptoms, and mucosal inflammation at grade i-2 suggested aggravation of the disease; those at grades i-3 and i-4 suggested critical condition and worse prognosis. Therefore, the more severe the grade of mucosal inflammation found by endoscopy, the more severe the disease is, and usually endoscopic grade of mucosal inflammation; i-2 is considered as recurrence of CD after surgery. Due to the importance of endoscopy, endoscopy is usually performed at 6 months after surgery. Colonoscopy and small bowel microscopy are superior and allow the removal of intestinal mucosal tissue for pathological analysis. Capsule endoscopy can also observe mucosal edema, ulcers and strictures, and is more suitable for inflammatory lesions high in the upper ileum, but should be contraindicated in cases of intestinal strictures.
III. Treatment of postoperative recurrence
There are still no standardized treatment guidelines for the clinical treatment of postoperative recurrence of CD. In addition to preoperative nutritional support therapy and perioperative symptomatic treatment, gastroenterology and surgery specialists should discuss the medical records together to develop a reasonable surgical resection plan according to the patient’s condition, and postoperative patients should be instructed to quit smoking and enhance nutritional support therapy.
1. 5-ASA: The use of 5-ASA drugs to prophylactically reduce postoperative recurrence of CD remains controversial. Previous clinical analysis found that postoperative oral 5-ASA can reduce the postoperative recurrence rate of CD and the degree of intestinal mucosal inflammation, but a clinical meta-analysis of a large number of cases from Italy found that 5-ASA could only reduce endoscopic recurrence in 18% of patients. Based on the limited role of 5-ASA, prophylactic treatment is not needed for some asymptomatic low-risk patients. European IBD consensus guidelines recommend >2g/d of 5-ASA prophylaxis to reduce postoperative recurrence of CD.
2, glucocorticoids: Clinical studies have shown that glucocorticoids may be effective in some patients and can alleviate the anastomosis and proximal mucosal inflammatory response, but the clinical efficacy remains to be seen because of the serious side effects associated with long-term use, but they are ineffective in preventing postoperative recurrence of CD.
3. Antibiotics: The literature reports that the use of metronidazole (20 mg/kg/d) started within 7 days after surgery for 3 months significantly reduced postoperative endoscopic recurrence of CD. Other studies have found that the clinical recurrence rate of CD was also significantly reduced after 1 year of postoperative treatment with ornidazole (1 g/d). Although there is a trend toward lower clinical recurrence of CD with these drugs, their clinical use is limited by the serious complications associated with long-term use.
4. Immunosuppressants: Azathioprine/6-mercaptopurine (AZA/6-MP) can effectively treat CD, control symptoms, maintain remission, and effectively control postoperative recurrence of CD. Treatment with AZA (2-2.5 mg/kg) was started 2-4 weeks after surgery, and the endoscopic recurrence rate was found to be 34.3% after 3 months of colonoscopy compared with 52.6% in the control group; endoscopic recurrence was found to be 43.7% after 1 year of treatment compared with 69% in the control group, and the endoscopic mucosal inflammation grade was also significantly reduced after AZA treatment. Clinical studies have found that the 5-year survival rate was also significantly prolonged in those who maintained AZA therapy for more than 3 years after surgery. In contrast, methotrexate (MTX) was rarely reported in the clinical treatment of postoperative recurrence of CD.
5, probiotics: Although studies have found that bacterial antigens in stool play an important role in postoperative recurrence of CD, and that postoperative recurrence is mostly in the anastomotic and proximal small intestine regions where bacterial concentrations are high, clinical studies have found that the efficacy of probiotic therapy on postoperative recurrence of CD is still uncertain.
6, biological immunotherapy: recently reported intravenous treatment with infliximab (5mg/kg) after 2-4 weeks after surgery, once each at weeks 0, 2 and 6, and then once at an interval of 8 weeks, the endoscopic observation after 1 year found that the recurrence rate of mucosal inflammation was 9.1%, which was significantly lower than that of the control group 84.6%, and the endoscopic mucosal inflammation grade was also significantly lower; histopathological examination found The histopathological examination revealed that the recurrence rate of inflammation was 27%, which was significantly lower than 85% in the control group; while the remission rate of clinical symptoms was 90.9%, which was significantly higher than 15.4% in the control group; and the CDAI score was also at a lower level. Therefore, anti-TNF monoclonal antibody plays an extremely important role in controlling clinical symptoms, maintaining remission and preventing postoperative recurrence in CD patients.
IV. Clinical management plan after CD surgery
For patients treated with the first surgery, if they are only low-risk patients with intestinal stenosis and no smoking, there is generally no need for drug treatment after surgery, and colonoscopy will be repeated after 6-12 months. For high-risk patients with a history of smoking, combined intestinal perforation, lesions involving the ileum-colon, and resection >10 cm, postoperative prophylaxis with 5-ASA (3-4 g/d) is used, and colonoscopy is repeated after 6-12 months; if no recurrence of inflammation is detected, annual endoscopy follow-up is performed and no treatment is required; if recurrence of intestinal mucosal inflammation is detected, oral AZA (2.0-2.5 mg/kg/d) or 6-MP (1.0-1.5 mg/kg/d) for long-term maintenance treatment with annual colonoscopy follow-up. For patients treated by surgery again, smoking cessation, treatment with AZA (2.0-2.5mg/kg/d) or 6-MP (1.0-1.5mg/kg/d), recurrent colonoscopy in 6-12 months, if no recurrence, continued maintenance treatment and annual colonoscopy follow-up are recommended; if endoscopic recurrence, treatment with infliximab is recommended.