Mycophenolate-Induced Colitis

Mycophenolate induced colitis is colonic mucosal injury caused by mycophenolate mofetil or mycophenolate sodium (mycophenolic acid), mimicking inflammatory bowel disease, graft-versus-host disease and cytomegalovirus colitis. It occurs in transplant recipients and patients with autoimmune disease.

Diarrhoea occurs in 12% to 36% of patients on mycophenolate, most often within the first months but sometimes years later; histologically proven colitis is less common.

Risk factors are higher doses, renal impairment, concurrent tacrolimus, high mycophenolic acid exposure, infection and older age.

Pathophysiology.

Mycophenolic acid inhibits inosine monophosphate dehydrogenase, depleting guanosine nucleotides and impairing epithelial regeneration, with mucosal apoptosis and crypt injury. Enterohepatic recirculation of the glucuronide metabolite increases colonic exposure.

Watery or bloody diarrhoea, abdominal pain, nausea, weight loss and dehydration. Features improve after dose reduction.

Red flags.

• Severe dehydration or renal impairment.
• Fever with bleeding.
• Toxic dilatation.

Exclude infection with stool culture, Clostridioides difficile and parasites, and cytomegalovirus on biopsy or by blood PCR. Colonoscopy shows erythema, erosions, ulcers or a normal mucosa; ileal involvement is common. Biopsies show crypt apoptosis, crypt distortion and villous blunting resembling graft-versus-host disease or inflammatory bowel disease, with relatively sparse neutrophils. A test period of dose reduction or withdrawal that settles symptoms supports the diagnosis. Measure mycophenolic acid exposure when available.

Differential diagnosis.

• Cytomegalovirus colitis.
• Graft-versus-host disease.
• Clostridioides difficile colitis.
• Inflammatory bowel disease.
• Other drug effect (tacrolimus, antibiotics, magnesium).
• Lymphoproliferative disease.

Reduce exposure with the transplant team, since immunosuppression must be maintained.

• Mycophenolate mofetil dose reduction: reduce by 25% to 50% (for example from 1 g to 500 mg twice daily), or divide into 3 or 4 smaller doses; continue at the lowest effective dose; maximum 3 g daily in specialist use; monitor mycophenolic acid exposure (target area under the curve 30 to 60 mg·h/L in kidney transplantation), blood counts and graft function; reduce in severe renal impairment (creatinine clearance under 25 mL/min), at a maximum of 1 g twice daily.
• Mycophenolate sodium (enteric coated alternative): 720 mg orally twice daily; ongoing; maximum 1,440 mg daily in usual dosing; monitor symptoms and counts; same renal limits.
• Alternative immunosuppression such as azathioprine (1 to 2 mg/kg orally once daily; maximum 3 mg/kg daily; monitor blood counts and liver enzymes; check thiopurine methyltransferase first; reduce in renal impairment and with allopurinol) when symptoms persist.
• Loperamide: 4 mg orally initially, then 2 mg after each loose stool; maximum 16 mg daily; monitor QTc and for ileus; avoid in infective colitis.

Correct fluid and electrolyte losses. Rechallenge is possible after resolution at a lower dose.

Monitoring. Stool frequency, renal function, drug levels and counts weekly during dose changes; repeat endoscopy if no response in 2 to 4 weeks.

Referral and escalation. Transplant physician and gastroenterology; biopsy review by a gastrointestinal pathologist.