A 17-Year-Old Male Adolescent With Refractory Crohn’s Disease Managed With Upadacitinib and Risankizumab Combination Therapy: A Case Report and Review of Current Evidence

Introduction

Crohn’s disease (CD) is an autoimmune disease that exhibits progression in a relapsing-remitting pattern. Every part of the gastrointestinal tract is susceptible to being affected, with the terminal ileum and colon having the highest incidence of involvement [1]. In North America, the incidence of inflammatory bowel disease (IBD) varies, with ulcerative colitis affecting between 2.2 and 19.2 cases per 100 000 person-years, while CD ranges from 3.1 to 20.2 cases per 200 000 person-years [2]. The pathogenesis of CD involves immune activation, genetic predisposition, and microbiome alterations, leading to mucosal disruption [3]. The onset of CD is common at the age of 20 to 40 years, with a smaller incidence peak occurring between 50 and 60 years [1]. The most common presentation is with abdominal pain, fever, and signs of bowel obstruction or diarrhea, which may contain blood, mucus, or both [4].

There are no preset yardsticks for diagnosing CD. The diagnosis can be achieved as a collection of clinical evaluations. Some methods of diagnosis include endoscopy, microscopy, radiology-aided, and laboratory testing [5]. The progression of CD is categorized into remission, mild disease, moderate disease, and severe disease. The Crohn’s Disease Activity Index assesses activity, categorizing scores as follows: mild-moderate CD (150–220), moderate-severe CD (220–450), and severe/fulminant CD (above 450). Assessment is based on clinical measures, quality of life, complications, and treatment-related issues. For moderate-to-severe CD, advanced therapies such as biologics and small molecules are commonly used [6].

Early biologic treatment in pediatric and adult populations with CD can improve clinical outcomes [7]. Prolonged remission does not occur in all patients, and the high risk for surgery persists despite the use of biologic therapies. In such cases, therapeutic options are limited [8]. Indeed, half of individuals with CD require one or more surgical procedures throughout their lifetime. Such procedures include surgical drainage of abscesses, laparoscopic or open resection of affected bowel segments, and strictureplasty [9]. The surgical management of CD continues to be challenging and is determined by the site and severity of the condition [10].

In light of these challenges, alternative treatment strategies, such as the combination of biologics, have been proposed. This approach is considered for 2 categories of IBD: patients with well-managed luminal disease but who have uncontrolled extraintestinal symptoms, and patients with refractory and uncontrolled IBD [11].

Risankizumab is an interleukin (IL)-23 p19 inhibitor that has been approved by the US Food and Drug Administration (FDA), and is indicated in moderate-to-severe CD, plaque psoriasis, and psoriatic arthritis in adults [12]. Risankizumab showed effectiveness and safety both for induction and maintenance therapy in moderate-to-severe active CD in adults in the phase 3 ADVANCE and MOTIVATE induction trials, which included participants aged 16 to 80 years, with only 14 adolescents aged 16 to 17 involved in the trials, which limits the clear evidence available in this patient population [13]. In addition, upadacitinib is a selective Janus kinase (JAK) 1 inhibitor that was approved by the FDA and European Medicines Agency and is indicated in multiple autoimmune diseases, including non-radiographic axial spondyloarthritis, ulcerative colitis, and CD for adults and children above the age of 12 years [14]. Upadacitinib showed effectiveness and safety in a post hoc analysis of the U-EXCEL, U-EXCEED, and U-ENDURE phase 3 trials among patients with prior CD-related surgeries, compared with a placebo group [15]. In this report, we discuss the potential safety and efficacy of combining upadacitinib and risankizumab as a pharmacological intervention for refractory CD in an adolescent, with an emphasis on the case’s contribution to clinical practice. This report describes a 17-year-old male adolescent with refractory CD who achieved remission in terms of his symptoms, biochemical markers, and endoscopic findings through a combination of oral upadacitinib and subcutaneous risankizumab, thereby avoiding the need for surgical intervention.

Case Report

A 17-year-old male patient had a history of severe CD since the age of 10 years, with initial treatment of adalimumab and mesalamine. In December 2022, at the age of 14 years, he was referred to our hospital’s adult Gastroenterology Department where he reported 5 to 6 bowel movements daily, accompanied by occasional rectal bleeding. Upon examination, he had cachexia, with a hemoglobin level of 7 g/dL. Infectious workup was negative for Clostridium difficile and Cytomegalovirus colitis. Clinical remission was successfully achieved after administration of a tapering course of oral prednisolone (initially 40 mg). To maintain this remission, he was switched to infliximab (5 mg/kg). In February 2023, after receiving 2 doses, he relapsed shortly after stopping prednisolone, due to mechanistic failure of infliximab. He reported diarrhea more than 6 times daily, and his C-reactive protein (CRP) level was 75 mg/L. His infliximab level was therapeutic, with no anti-drug antibodies. Subsequent infectious workups remained negative. At that time, the patient underwent colonoscopy, which revealed severe ileocolonic CD. Induction therapy with ustekinumab 260 mg was given, clinical remission was achieved, and a maintenance regimen of ustekinumab 90 mg subcutaneously every 8 weeks was initiated. Upon follow-up, he reported occasional rectal bleeding, and his CRP level was 39 mg/L, which was decreased but still high. To enhance disease control, the maintenance dose frequency of ustekinumab was increased to 90 mg subcutaneously every 4 weeks, and he was scheduled for follow-up after 3 months. During this time, the patient maintained clinical remission for 9 months, his follow-up CRP level was 16 mg/L, and he was scheduled for follow-up gastroscopy and colonoscopy.

In February 2024, the patient’s body mass index was 17, and his hemoglobin level was 7.6 g/dL. He received intravenous (IV) iron therapy, and follow-up colonoscopy revealed multiple medium-sized deep ulcers with surrounding edema and erythema in the terminal ileum and cecum, with skip lesions (Figure 1A–1D). Biopsies revealed findings consistent with moderately active CD, thereby providing robust support for our diagnosis (Figure 2A–2D). Ustekinumab was stopped due to active endoscopic disease. At this stage, the Surgical Department reviewed the case and offered ileocolectomy with anastomosis; however, the patient and his parents refused the surgical intervention. Given the complexity of his case, various medical options for off-label use were discussed with both the patient and his parents. The patient was counseled regarding the use of upadacitinib, a selective JAK1 inhibitor approved by the FDA and European Medicines Agency and indicated in CD for adults and children above the age of 12 years. Written informed consent, which included the benefits and risks, was obtained from the patient and his parents. An induction course of upadacitinib 45 mg daily for 12 weeks was started after excluding contraindications to using upadacitinib. After 3 months, the fecal calprotectin level was 923 mcg/g, consistent with active disease, prompting an extension of the induction period to 24 weeks.

In August 2024, six months after starting upadacitinib, he was clinically well; however, his fecal calprotectin level was 500 mcg/g. Due to the partial response to upadacitinib, other salvage medical options were searched for as per the request of the patient and his parents. We opted to initiate advanced combination targeted therapy as an off-label treatment. Written informed consent was obtained from the patient and his parents. The choice of combining upadacitinib (selective JAK1 inhibitor) with risankizumab (interleukin-23 p19 inhibitor) was based on the different mechanism of inhibition targeted by these biologics and recent studies regarding the safety and effectiveness of both medications, which are further elaborated upon in the discussion section below. We kept the patient on oral upadacitinib 45 mg daily and a risankizumab induction dose of 600 mg IV at 0, 4, and 8 weeks, followed by 360 mg subcutaneously every 8 weeks. Upon follow-up after 8 weeks, the patient’s body mass index was 18, and his hemoglobin level was 14.4 g/L. The patient was symptom-free, with a CRP level decreased to 2.05 mg/L. He continued to be in clinical remission with normal CRP levels and fecal calprotectin within target (less than 150). At 9 months after being on advanced combination targeted therapy, his repeat colonoscopy showed quiescent disease, with a Simple Endoscopic Score for Crohn’s disease <4 (Figure 3A–3D). It is important to note that aside from close clinical monitoring and routine laboratory evaluations, no specific safety measures were implemented. During the therapy, no adverse effects were reported.

Discussion

This case report illustrates the potential of combining biologic therapies, specifically risankizumab and upadacitinib, as an effective treatment strategy for refractory CD in adolescents. It underscores the importance of exploring novel therapeutic combinations when conventional treatments fail, highlighting that using different mechanisms of action can lead to improved clinical outcomes and remission.

The treatment of moderate-to-severe CD usually requires advanced therapy, with anti-tumor necrosis factor (TNF) agents such as infliximab and adalimumab being commonly prescribed and licensed for adolescents with CD. Anti-TNF agents are the only biologics having FDA approval for treating CD in pediatric patients [16]. In cases of response failure to these agents, alternatives include vedolizumab, ustekinumab, and novel therapies such as risankizumab (interleukin-23 p19 inhibitor) and upadacitinib (selective JAK inhibitor) [17].

Risankizumab received FDA approval for treating moderate-to-severe active CD in adults [18]. In the phase 3 ADVANCE and MOTIVATE induction trials, which involved 1549 participants, risankizumab demonstrated superior outcomes compared with placebo, achieving remission rates of approximately 40% to 45% in treating CD in those with ineffective exposure to other biologics [13]. Additionally, the real-world GETAID study indicated that approximately 46% of patients who were refractory to anti-TNF, vedolizumab, and ustekinumab achieved steroid-free clinical remission after treatment with risankizumab [19]. The findings from the previous 2 studies differ from those of our case report, as they did not explore the use of risankizumab in combination therapy or in pediatric patients. However, in a preliminary report, risankizumab showed effectiveness in the treatment of pediatric CD, with no adverse effects related to the treatment, and a clinical remission rate of approximately 70% after 3 infusions. In the report, they included children below the age of 16 years treated with risankizumab [20]. This study aligns with our case report by supporting the safety and efficacy of risankizumab in pediatric patients.

Upadacitinib is the first FDA-approved oral medication for treating moderate and severe CD in adults. It showed effectiveness and safety in a post hoc analysis of the U-EXCEL, U-EXCEED, and U-ENDURE phase 3 trials among those with prior CD-related surgeries, compared with a placebo group [15]. In contrast to the present study, these trials did not consider a combination of biologics and did not include pediatric patients. An international multicenter retrospective study that did consider pediatric cases included a sample of 100 children, with a mean age of 15.4 years, and concluded upadacitinib was effective and safe in children aged below 16 years [21].

The management of refractory CD with a combination of medications is recognized for the potential to improve clinical outcomes. An experience from a tertiary care center reinforced that combining biologics with different mechanism of inhibition can be safe and effective in managing IBD [22]. A systematic review with meta-analysis demonstrated a clinical response of 78% and remission rate of 55% with the use of vedolizumab combined with anti-TNF agents [23]. Although the review did not specifically examine the combination of risankizumab and upadacitinib, the findings may support the use of dual biologics targeting different pathways to enhance clinical response and achieve remission.

In a descriptive case series, the therapeutic efficacy of combining upadacitinib with various biologics, including risankizumab and others, was evaluated in 27 patients with refractory CD aged 16 years and older. Notably, of the 17 patients treated with the combination of upadacitinib and risankizumab, a clinical response was observed in 9 patients by week 52±4 [24]. These findings align with those of our study in suggesting potential effectiveness of combining risankizumab and upadacitinib. While the study did not specify the exact combinations used in adolescent patients, the results of the study provide supporting evidence for the safety and clinical benefit of combining biologics, particularly in adult cohorts but potentially extending to adolescent populations.

Furthermore, a retrospective study from Taiwan included a combination therapy for refractory IBD, with the most frequently used regimen consisting of ustekinumab with upadacitinib. Remission rates were 50% at week 12 and 80% at week 24. Additionally, the sample size was small, involving only 16 patients, with a median age of 41.5 years [25]. This study differs from ours in its focus on the adult population and in the use of ustekinumab with upadacitinib. In contrast, risankizumab showed superior efficacy compared with ustekinumab in a head-to-head clinical trial involving adults who did not respond to anti-TNF therapy. The trial reported better remission at weeks 24 and 48 for risankizumab, as well as in endoscopic remission at week 48 [26]. This may support our approach of using risankizumab in combination with upadacitinib instead of ustekinumab with upadacitinib.

In the present case report, a novel approach using a combination regimen of risankizumab, (IL-23 p19 inhibitor) induction dose of 600 mg IV every 4 weeks and upadacitinib (selective JAK1 inhibitor) 45 mg daily oral administration was used in a 17-year-old male adolescent with severe colonic CD who did not respond to multiple therapies, highlighting a potential new approach when biologics and small molecules fail. Whereas using this combination may be a good option for refractory CD, it is essential to recognize that, although no adverse events were reported in our study, the confirmation of safety and efficacy in larger clinical trials is still important.

Conclusions

This report supports recent regulatory approvals, reports, and study findings that have shown the effectiveness of upadacitinib and risankizumab as second-line therapy in patients with refractory IBD.