Question: A 46-year-old woman with a medical history of psoriatic arthritis, antiphospholipid syndrome, and previous pulmonary embolism on warfarin was admitted with a 2-week history of progressive right upper quadrant pain, frequent nonbloody diarrhea, tenesmus, and nonbloody emesis. Her immunosuppressant therapy included certolizumab for the past 5 years and leflunomide for the past 17 months. She denied use of other medications. She has no personal or family history of inflammatory bowel disease. Initial laboratory evaluation (reference ranges in parenthesis) was significant for a mild leukocytosis of 12.6/L × 109/L (3.4–9.6 × 109/L), lipase of 476 U/L (12–61 U/L), C-reactive protein of 50.8 mg/L (≤8.0 mg/L), and a supratherapeutic international normalized ratio of 3.9 (0.9–1.1). Gastrointestinal pathogen panel including Clostridioides difficile was negative. Ultrasound examination of the right upper quadrant revealed cholelithiasis without cholecystitis and a poorly visualized common bile duct. Computed tomography imaging with contrast showed no evidence of pancreatitis and revealed mild wall thickening with mucosal hyperenhancement, consistent with ileocolitis. The patient underwent colonoscopy, which was notable for circumferential, contiguous inflammation throughout the colon, but a normal terminal ileum. Inflammation was described as mild with erythema, decrease in vascular pattern, and mild friability depicted in the sigmoid (Figure A). Cold forceps biopsy was performed from the terminal ileum and revealed surface erosion and increased lamina propria inflammation. The descending colon was also biopsied as shown in Figure B, demonstrating surface erosion, crypt abscess (arrowhead) and destruction, and increased lamina propria inflammation. No evidence of chronicity was noted. What is the most likely etiology of the patient’s colitis? Look on page 2035 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. Colonic biopsy was negative for cytomegalovirus immunostaining and also lacked the chronic inflammation classically seen in inflammatory bowel disease. Symptoms persisted despite a 3-day course of high-dose intravenous steroids. The decision was made to stop leflunomide, the disease-modifying antirheumatologic drug, owing to select case reports documenting rare leflunomide-induced colitis.1Verschueren P. Vandooren A.K. Westhovens R. Debilitating diarrhea and weight loss due to colitis in two RA patients treated with leflunomide.Clin Rheumatol. 2005; 24: 87-90Crossref PubMed Scopus (21) Google Scholar,2Kwok A.M.F. Morosin T. Leflunomide-induced colitis in association with enterocutaneous fistula in an immunosuppressed patient with renal transplant and rheumatoid arthritis.Clin J Gastroenterol. 2019; 12: 310-315Crossref PubMed Scopus (5) Google Scholar Symptoms improved within 2 weeks of drug cessation, with a decrease of stool frequency to 2 formed bowel movements daily, resolution of abdominal pain, and improvement of erythema on repeat flexible sigmoidoscopy. Current prescribing information for leflunomide includes diarrhea and abdominal pain as side effects but, as seen in our patient, these symptoms may be dramatic and severe. Although the immunosuppressive properties of leflunomide as a pyrimidine synthesis inhibitor have been well-studied, the mechanism by which it induces colitis is not well understood.1Verschueren P. Vandooren A.K. Westhovens R. Debilitating diarrhea and weight loss due to colitis in two RA patients treated with leflunomide.Clin Rheumatol. 2005; 24: 87-90Crossref PubMed Scopus (21) Google Scholar Diagnostic challenges to leflunomide-induced colitis not only include its rarity, but also its late onset after medication initiation. In previously documented cases, symptoms of weight loss and diarrhea began 18–24 months after initiation of the drug—a similar timeline to our patient.1Verschueren P. Vandooren A.K. Westhovens R. Debilitating diarrhea and weight loss due to colitis in two RA patients treated with leflunomide.Clin Rheumatol. 2005; 24: 87-90Crossref PubMed Scopus (21) Google Scholar Additionally, patients with rheumatologic diseases are often on other medications with adverse gastrointestinal effects, including biologics, steroids, nonsteroidal anti-inflammatory drugs, and other immunomodulators, making a medication history pivotal for appropriate management. Moreover, there are no specific endoscopic or histologic findings that distinguish this disease from other causes of colitis, with previous reports describing a wide range of histologic changes. As such, the current mainstay for diagnosis appears to also be its treatment: symptomatic improvement after medication cessation.1Verschueren P. Vandooren A.K. Westhovens R. Debilitating diarrhea and weight loss due to colitis in two RA patients treated with leflunomide.Clin Rheumatol. 2005; 24: 87-90Crossref PubMed Scopus (21) Google Scholar, 2Kwok A.M.F. Morosin T. Leflunomide-induced colitis in association with enterocutaneous fistula in an immunosuppressed patient with renal transplant and rheumatoid arthritis.Clin J Gastroenterol. 2019; 12: 310-315Crossref PubMed Scopus (5) Google Scholar, 3Gunendo Z. Benli E. Gogus F. et al.Long term use of leflunomide as a cause of severe diarrhea?.Turk J Rheumatol. 2010; 25: 41-43Crossref Scopus (5) Google Scholar This case demonstrates an example of leflunomide-induced colitis which should be considered in patients who present with symptoms of abdominal pain and diarrhea in the setting of leflunomide use, even months to years after medication initiation.
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Apr 24, 2024
Dunja Putniković + 11
Open Access