Dual-Targeted Therapy With Upadacitinib and Ustekinumab in Pediatric Refractory Perianal Crohn's Disease

ABSTRACT

Perianal Crohn’s disease (pCD) is a challenging manifestation of CD. We present the case of a 17-year-old adolescent girl with severe, refractory pCD, complicated by a rectovaginal fistula, who failed multiple lines of therapy and required a temporary ileostomy. While on upadacitinib (UPA) monotherapy, she experienced a flare with magnetic resonance imaging (MRI)-confirmed perianal abscesses. The addition of ustekinumab (UST) to UPA resulted in marked improvement in clinical symptoms and radiographic resolution of perianal disease on follow-up MRI. No adverse events occurred. This case highlights dual UPA/UST therapy as a promising strategy for severe, refractory pCD in an adolescent.

INTRODUCTION

Perianal Crohn's disease (pCD) is a complex and debilitating manifestation of Crohn's disease (CD) that is difficult to manage, particularly when complicated by fistulae. Tumor necrosis factor (TNF) antagonists are first-line for fistulizing disease; however, pCD often persists despite improvement in luminal disease.¹ Patients who develop intolerance or primary nonresponse face significant therapeutic challenges. Although monotherapy with biologics or small molecules has been the traditional approach, emerging evidence suggests that combination-targeted therapy may benefit highly refractory disease.^2–4 Dual immunosuppressive treatment strategies are increasing, particularly for patients with early-onset or treatment-resistant phenotypes. We report a case of an adolescent patient with severe, refractory pCD who showed marked clinical, biochemical, and radiographic improvement with the addition of ustekinumab (UST) to ongoing upadacitinib (UPA).

CASE REPORT

A 17-year-old adolescent girl with ileocolonic CD, diagnosed at age 6 years, presented with a history of severe perianal disease, refractory to multiple therapies (Figure 1). Her early disease course was complicated by recurrent perirectal abscesses at ages 8 and 9, metastatic CD involving the vulva, and development of a rectovaginal fistula at age 9.

Figure 1.

Longitudinal course of inflammatory bowel disease demonstrating therapeutic interventions, key disease events, and corresponding C-reactive protein levels. Periods of disease flare, remission, surgical diversion, and treatment escalation are annotated. Timeline not to scale. IFX, infliximab; pCD, perianal Crohn’s disease; TNF, tumor necrosis factor; UST, ustekinumab.

At age 11, an initial trial of infliximab (IFX level 14 mcg/mL) and methotrexate was discontinued due to poor response and a severe anti-TNF-induced psoriasiform rash. On colonoscopy at the time, the perianal examination revealed an anal fissure and rash. The entire examined colon appeared normal; however, purulent discharge was noted in the distal rectum and anal canal. She subsequently failed multiple therapies, including UST, vedolizumab, tacrolimus, and interleukin (IL)-1 blockade with anakinra followed by canakinumab, without durable clinical improvement. Her endoscopic biopsies showed an atypical immune-mediated process with lymphocytic predominance on histology. A recurrent perianal abscess required examination under anesthesia with incision and drainage and placement of draining setons, followed by intravenous (IV) piperacillin–tazobactam for 1 week and oral ciprofloxacin and metronidazole for 4 weeks.

Owing to several prolonged hospitalizations for active perianal disease despite medical and surgical management, a diverting ileostomy was created at age 12 to divert the fecal stream away from the affected bowel and promote healing of the perianal and rectovaginal fistulae. Following this, she was transitioned to combination sirolimus and UST. A pelvic magnetic resonance imaging (MRI) at age 13 noted complex branching fistulae with bilateral labial openings. Endoscopic evaluation at that time showed pseudopolypoid, ulcerated, and vascular-pattern-decreased mucosa in the entire examined colon, with severe open fistulas and open wounds of the perianal area. She later achieved relative disease control on combination sirolimus (4 mg daily, goal 8–10 ng/mL) and UST (90 mg every 4 weeks), allowing for successful ileostomy reversal at age 17.

Postreversal, she experienced a prolonged hospitalization for disease flare, failing prednisone and sirolimus, both of which were discontinued. The patient presented with a C-reactive protein of 181 mg/L, fecal calprotectin of 891 mcg/g, and a sirolimus level of 13.8 ng/mL. UPA 45 mg daily was initiated at age 17, with a slow initial clinical response. Colonoscopy revealed congested mucosa in the rectum and sigmoid colon of moderate severity.

At age 17, she required a 3-week hospitalization for severe abdominal pain and diarrhea following a norovirus infection. A pelvic MRI (Figure 2) confirmed extensive active perianal inflammation, including a sinus tract extending from the perianal soft tissues into the right majora with associated fluid and edema, and 2 small irregular enhancing outpouchings consistent with perianal abscesses. The abscesses were too small to be managed surgically, so antibiotic therapy was repeated with IV piperacillin-tazobactam, followed by oral ciprofloxacin and metronidazole before escalation of biologic therapy. Given the partial response to UPA and prior history of response to UST, UST IV 390 mg loading dose followed by 90 mg subcutaneous every 6 weeks was reintroduced as combination therapy.

Figure 2.

Pelvic MRI axial view (baseline, precombination therapy). A sinus tract can be seen extending into the right labia majora (image on right) and small perianal abscesses (image on left). MRI, magnetic resonance imaging.

However, at age 18, she experienced a brief, insurance-related lapse in access to UST. She quickly presented with 12 bowel movements per day and required a 6-day hospital admission. Her symptoms responded briefly to IV methylprednisolone. UST was reapproved and restarted shortly after discharge. A follow-up pelvic MRI (Figure 3) obtained during the admission for her flare confirmed significant interval response with substantial reduction of the perianal and labial edema and no discrete abscesses seen. A concurrent magnetic resonance enterography showed stable to marginally decreased mural enhancement.

Figure 3.

Pelvic MRI axial view (postcombination therapy). Significant therapeutic response, with substantial diminution of perianal and labial edema and fluid (image on right), and resolution of discrete abscesses (image on left). IFX, infliximab; MRI, magnetic resonance imaging; pCD, perianal Crohn's disease; UST, ustekinumab; UPA, upadacitinib.

Following reinitiation of UST, she was asymptomatic from a gastrointestinal perspective. At follow-up, her perianal lesions had healed, with closed left labial, right perilabial, and posterior sacral fistulae. Her C-reactive protein normalized, and the erythrocyte sedimentation rate decreased from 120 to 41 mm/hr. Her bloodwork was notable for persistent iron-deficiency anemia (hemoglobin 9.9 g/dL, median corpuscular volume 78.4 fL). She did not experience any adverse events on this combination therapy.

DISCUSSION

pCD represents a severe and debilitating phenotype of CD, affecting up to 40% of patients.⁵ It is characterized by a high burden of disease and significantly affects quality of life. While anti-TNF agents, specifically infliximab, remain the only biologics with dedicated randomized controlled trial evidence for pCD, long-term efficacy is often limited. Furthermore, adjunctive therapies such as antibiotics often provide only temporary symptomatic relief rather than sustained fistula healing. Consequently, patients who exhaust these standard options face a “therapeutic ceiling” where single-agent strategies frequently prove insufficient to achieve lasting improvement.⁶

For patients refractory to anti-TNF agents, data regarding alternative therapies are largely derived from subgroup analyses, post hoc analyses, and real-world studies rather than dedicated randomized trials in pCD. UST has demonstrated modest efficacy in perianal fistulizing CD, with a systematic review showing clinical response in 44% of patients within 6 months and 53.9% of patients at 12 months; however, fistula remission rates remain low and variably reported.⁷ Similarly, emerging data for UPA are promising, with a post hoc analysis of 3 phase 3 clinical trials demonstrating resolution of drainage of perianal fistulas in 44.7% of patients receiving UPA 45 mg compared with 5.6% receiving placebo at the end of induction.⁸ Despite these advances, the complexity of refractory pCD often necessitates a multimodal approach, as a large proportion of patients are unable to achieve remission with monotherapy.^1,4,6

This case highlights the successful application of dual targeted therapy, combining UPA and UST, for severe, refractory pCD. The rationale for this combination lies in targeting complementary inflammatory pathways: UST inhibits IL-12/23, while UPA provides inhibition of Janus kinase (JAK)-1-mediated signaling. The synergy of targeting 2 distinct immune pathways may overcome the limitations of monotherapy to achieve transmural healing.^2–4 Despite the potential benefits, significant practical barriers exist. High cost, limited insurance coverage, and the need for frequent monitoring can interrupt access and compromise outcomes. This was evident in our patient, who experienced an acute flare requiring hospitalization after a brief insurance-related lapse in UST therapy, which resolved upon reinitiation of the dual regimen.

Although combined UST and UPA therapy has been described in pediatric and young adult patients with refractory inflammatory bowel disease, this case represents one of the first detailed case reports describing the clinical, biochemical, and radiographic evolution of refractory pCD in an adolescent treated with this combination.^3,9,10 This supports consideration of this approach in carefully selected individuals who have exhausted standard therapy. Prospective studies are needed to better define the safety, efficacy, and optimal positioning of dual targeted therapy in the management of complex pCD.

DISCLOSURES

Author contributions: N. Sathe, M. Kline, A. Kellar, D. Choi, and R. Gokhale contributed to the design of the manuscript, wrote and revised the manuscript, and gave final approval and are accountable for the information presented.

Financial disclosure: D. Choi has served on the speaker bureau for Janssen Pharmaceuticals, Abbvie, and Eli Lilly; has served as a consultant to Bristol Myers Squibb (September 18, 2024), Abbvie, Eli Lilly, Janssen Pharmaceuticals, and Pfizer; and has received manuscript support for Takeda. The authors report no relevant financial conflicts of interest.

Informed consent was obtained for this case report.

ABBREVIATIONS:

CD

Crohn's disease

pCD

perianal Crohn's disease

UPA

upadacitinib

UST

ustekinumab