S4944 When the Scope Is Silent: Biopsy-Negative Perianal Fistulizing Crohn’s Disease Requiring Biologic Reinitiation

Introduction: Fistulizing Crohn’s disease (CD) carries significant morbidity, often requiring long-term biologic therapy. A subset of patients presents with discordant disease phenotypes—minimal mucosal inflammation but clinically active perianal disease—complicating diagnosis and therapeutic decisions. Case Description/Methods: A 24-year-old man with previously diagnosed CD presented with ongoing perianal fistula symptoms, pressure-like abdominal pain, and odynophagia to solids. He had previously been on infliximab and methotrexate but had self-discontinued therapy years earlier. He reported daily dark green stools without hematochezia or steatorrhea. Physical exam revealed indwelling perianal setons. Recent esophagogastroduodenoscopy showed mild gastric erythema with normal duodenal biopsies. Colonoscopy revealed a patent ileocolonic anastomosis and an inflammatory polyp without mucosal ulcerations. SES-CD was 0. Histologic samples from the ileum, colon, and rectum were all normal. Magnetic resonance imaging enterography showed a small posterior perirectal fluid collection within the levator ani, consistent with chronic fistulizing disease. He denied systemic symptoms. Lab testing showed normal liver enzymes, complete blood count, and negative infectious workup including C. difficile and QuantiFERON®-TB Gold. Despite normal endoscopic and histologic findings, his persistent symptoms, imaging, and perianal exam supported active fistulizing disease. After confirming normal thiopurine methyltransferase activity, methotrexate 25 mg IM weekly and infliximab 5 mg/kg were initiated. Trough levels and clinical response will guide future dose optimization. Discussion: This case illustrates a key diagnostic dilemma in perianal CD: the absence of luminal inflammation does not preclude active perianal disease. Reliance solely on endoscopy or histology may delay treatment. Radiologic correlation and physical exam remain essential for disease assessment. Anti-tumor necrosis factor therapy remains the mainstay for fistulizing disease and may be warranted even in the absence of endoscopic activity. Perianal fistulizing CD can persist with normal biopsies and endoscopic scores. Clinicians must integrate clinical, radiographic, and surgical findings to guide therapy. This case reinforces the need for individualized, multidisciplinary management in patients with complex CD phenotypes.