What is the best course of treatment for a patient with a perianal fistula?

Treatment of Perianal Fistula

For simple perianal fistulas, start with antibiotics (metronidazole 400 mg three times daily and/or ciprofloxacin 500 mg twice daily) combined with seton placement; for complex perianal fistulas, mandatory surgical drainage of any abscess with seton placement followed by anti-TNF therapy (infliximab) combined with immunomodulators (azathioprine or 6-mercaptopurine) is the standard of care. 1, 2

Classification Determines Treatment Strategy

The first critical step is distinguishing simple from complex fistulas, as this fundamentally changes management:

• Simple fistulas are low intersphincteric or trans-sphincteric with a single external opening 2
• Complex fistulas are high intersphincteric, high trans-sphincteric, extrasphincteric, or suprasphincteric, or have multiple openings 2

Diagnostic Workup Before Treatment

• Obtain contrast-enhanced pelvic MRI as the initial imaging—this is superior to other modalities for defining fistula anatomy and detecting abscesses 1, 3
• Perform proctosigmoidoscopy to assess for active rectal inflammation, which dramatically affects surgical options and prognosis 1
• Examination under anesthesia (EUA) by an experienced surgeon remains the gold standard for definitive classification 1

Critical pitfall: Active proctitis is associated with significantly lower fistula healing rates and mandates more conservative surgical approaches—never perform fistulotomy in patients with high fistulas and active rectosigmoid inflammation due to high incontinence risk 1

Treatment Algorithm for Simple Fistulas

First-Line Therapy

• Start metronidazole 400 mg three times daily and/or ciprofloxacin 500 mg twice daily 1
• Place seton in combination with antibiotics as the preferred initial strategy 1, 3
• Consider fistulotomy for uncomplicated low fistulas if no active rectal disease is present 4, 3

Important caveat: Antibiotics improve symptoms and reduce drainage but do not achieve fistula healing as monotherapy—relapse is common after discontinuation 1

Second-Line Therapy (if antibiotics fail)

• Thiopurines: azathioprine 1.5-2.5 mg/kg/day or mercaptopurine 0.75-1.5 mg/kg/day 1
• These agents are slow-acting and better for maintaining closure than inducing it 4

Third-Line Therapy

• Infliximab 5 mg/kg at weeks 0,2, and 6, then every 8 weeks 4, 5
• FDA-approved for fistula treatment with proven efficacy in placebo-controlled trials 4, 5
• Must co-administer immunomodulators (azathioprine or 6-mercaptopurine) to counteract antibody formation and maintain efficacy 4

Treatment Algorithm for Complex Fistulas

Mandatory Initial Step

• If abscess is present, surgical drainage with EUA is mandatory before any medical therapy 1
• Place non-cutting setons—this is the treatment of choice for high fistulas with active rectal inflammation 1

First-Line Medical Therapy (after surgical drainage)

• Infliximab 5 mg/kg at weeks 0,2, and 6, then maintenance every 8 weeks 1, 2, 5
• Must combine with immunomodulators (azathioprine 1.5-2.5 mg/kg/day or 6-mercaptopurine 0.75-1.5 mg/kg/day) 4, 1
• Add adjunctive antibiotics (metronidazole and/or ciprofloxacin) for 6-12 weeks 1

Evidence for combination therapy: Ciprofloxacin plus infliximab achieved 73% fistula response versus 39% with infliximab alone; ciprofloxacin plus adalimumab reduced draining fistulas by ≥50% in 70.6% versus 47.2% with adalimumab alone 1

Infliximab Efficacy Data

• In the ACCENT II trial, 68% of patients receiving 5 mg/kg infliximab achieved ≥50% reduction in draining fistulas versus 26% with placebo 5
• At 54 weeks, 38% of infliximab-treated patients had complete fistula closure versus 22% with placebo 5
• Median time to response is 2 weeks; median duration of response is 12 weeks 5

Refractory Cases

• If initial infliximab fails, perform repeat EUA with seton placement while continuing infliximab, immunomodulators, and antibiotics 4
• Consider dose escalation to 10 mg/kg infliximab 4, 5
• Tacrolimus or cyclosporine can be considered after multimodality failure, but use with extreme caution due to nephrotoxicity 4
• Last resort options: fecal diversion or proctectomy 4, 2

Special Considerations for Rectovaginal Fistulas

• Medical therapy (infliximab, 6-mercaptopurine, cyclosporine, tacrolimus) should be attempted first 4
• Surgical repair can only be performed after endoscopic healing of rectosigmoid mucosa 4, 2
• Surgical options include transanal or transvaginal advancement flaps 4
• Reserve advancement flap surgery for patients with disabling symptoms due to risk of worsening if operation fails 4

Concurrent Management Requirements

• Treat any active proximal luminal Crohn's disease with appropriate therapy (budesonide, corticosteroids, azathioprine, 6-mercaptopurine, methotrexate, or infliximab) 4, 1
• Reduce stool liquidity with loperamide, diphenoxylate/atropine, codeine, cholestyramine, and low-fat diet to decrease fistula drainage 4, 1

Monitoring Response to Treatment

• Clinical assessment (decreased drainage) is usually sufficient for routine monitoring 1, 3
• Obtain MRI or endoanal ultrasound to confirm fistula tract improvement before considering therapy discontinuation 1, 3

Critical warning: Clinical closure does not equal MRI closure—there is high risk of recurrence without complete fibrotic tract on MRI 1, 2

Long-Term Surveillance

• Monitor for development of malignancy in chronic perianal fistula tracts—squamous cell carcinoma, basal cell carcinoma, and adenocarcinoma have been reported 4, 1, 2

Key Pitfalls to Avoid

• Never perform fistulotomy on high fistulas or in presence of active proctitis—incontinence risk is unacceptably high 1
• Do not use tacrolimus or cyclosporine for simple fistulas due to toxicity 4
• Routine EUA and seton placement before initiating infliximab is not mandatory for all patients 4
• Do not rely on antibiotics alone—they are adjunctive therapy only 4, 1
• Patients who do not respond by week 14 to infliximab are unlikely to respond to additional doses 5