Sirolimus (Rapamycin) Induced Mucosal Healing in Anti-Tumor Necrosis Factor Refractory Pediatric Ulcerative Colitis

“

TL;DR

This case report describes a 12-year-old boy with infliximab-refractory pediatric ulcerative colitis (PUC) who achieved sustained clinical remission and confirmed mucosal healing after treatment with sirolimus (rapamycin). Fecal calprotectin dropped from 7990 mcg/g to 51 mcg/g within 3.5 months, and follow-up colonoscopy at 8 months showed endoscopic and histologic healing. The findings suggest sirolimus may be a viable rescue therapy for anti-TNF refractory PUC, though larger studies are needed.

Full summary

4,046 CHARS

**Background:** Pediatric ulcerative colitis (PUC) is an aggressive disease, with approximately 6% of patients requiring colectomy within 1 year and 13% by 5 years of diagnosis. Current guidelines recommend infliximab (IFX) as the primary anti-TNF biologic for steroid-dependent or refractory moderate-to-severe disease, with colectomy considered after anti-TNF failure. Alternative rescue therapies include tacrolimus and cyclosporine, but sirolimus (rapamycin) has only been proposed in a small case series without endoscopic assessment of responders. This report describes the first documented case of sirolimus-induced mucosal healing in anti-TNF refractory PUC.

**Methods:** This is a single case report from a tertiary care center. The patient was a 12-year-old male with a maternal history of ulcerative colitis and a personal history of isolated left leg lymphangiectasia. He presented with 6 weeks of diarrhea and hematochezia and was diagnosed with moderately active pancolitis (Paris E4) by endoscopy. After initial steroid response followed by relapse during steroid wean, IFX was initiated 3 months after diagnosis. Despite intensification to every-4-week 7.5 mg/kg dosing and achieving a maintenance trough level of 5.4 mcg/mL, the patient could not achieve clinical remission, and fecal calprotectin (FC) remained above 900 mcg/g (normal <126 mcg/g). IFX was intensified to 10 mg/kg every 3 weeks, but 3 weeks after this dose, a moderate clinical flare occurred with FC rising to 7990 mcg/g. Colonoscopy 1 year into diagnosis showed moderate (Mayo 2) pancolitis. Sirolimus was chosen partly due to potential benefit for the patient's concurrent lymphangiectasia. He was started at 37.5 mcg/kg daily with a target trough level of 8–10 ng/mL. During dose adjustments, sirolimus levels ranged from 3.2 to 13.6 ng/mL.

**Key Results:** The patient achieved rapid clinical response within 5–6 days of sirolimus initiation and clinical remission by 2 months, with FC dropping to 205 mcg/g. He was maintained on 125 mcg/kg daily dosing, achieving trough levels between 7.7 and 9.7 ng/mL. By 3.5 months of treatment, FC had normalized to 51 mcg/g. A follow-up colonoscopy 8 months after starting sirolimus demonstrated mucosal healing by both endoscopy and histology. Histologic examination showed colonic mucosa with sparse crypt branching and no signs of active inflammation — a paucicellular lamina propria without increased neutrophils or eosinophils and no acute cryptitis. This contrasted sharply with the pre-sirolimus biopsy, which showed marked chronic active inflammation, crypt distortion, crypt loss, neutrophilic infiltration of crypt epithelium, and prominent eosinophils. After 14 months of treatment, FC remained low at 71 mcg/g. The patient gained weight and height and remained in clinical remission for over 17 months, even after drug levels were deliberately allowed to decline to 3 ng/mL at 100 mcg/kg dosing due to his good clinical condition. Liver function tests and lipid panels remained within normal limits throughout treatment. No adverse effects or events were noted. The patient's leg lymphangiectasia was unaffected by sirolimus.

**Clinical Implications:** This case demonstrates that sirolimus can induce both clinical remission and confirmed mucosal healing in anti-TNF refractory PUC, a population for whom colectomy is typically the next recommended step. The rapid response (within 5–6 days) and sustained remission (>17 months) are notable. The drug was well-tolerated with no observed adverse effects, though the authors acknowledge the need for long-term monitoring for potential side effects including hypertension, thromboembolism, headaches, hypertriglyceridemia, constipation, acne, bone marrow suppression, and lymphomas. The authors conclude that sirolimus should be positioned into the expanding treatment repertoire for PUC, though further clinical research is needed. Limitations include the single-patient, uncontrolled nature of this report and the lack of standardized dosing protocols.