Letter to the Editor: Can upadacitinib dose escalation redefine treatment strategies in refractory inflammatory bowel disease?

Abstract

Despite major advances in inflammatory bowel disease (IBD) therapeutics, secondary loss of response remains a persistent clinical challenge. Upadacitinib, a selective Janus kinase-1 inhibitor, has demonstrated efficacy in both ulcerative colitis and Crohn’s disease; however, real-world patients frequently experience declining response during maintenance therapy. In this editorial, we discuss the findings of Ellington et al, who evaluated upadacitinib dose re-escalation to 45 mg daily in patients with refractory IBD and secondary loss of response. In their retrospective single-center cohort study involving 56 heavily treatment-experienced patients, dose escalation was associated with significant improvement in abdominal pain, hematochezia, urgency, and diarrhea, along with reduced corticosteroid exposure and favorable treatment durability. Objective inflammatory markers and endoscopic outcomes improved numerically but did not achieve statistical significance. These findings highlight the growing importance of individualized therapeutic optimization in IBD management while also underscoring the need for careful patient selection, long-term safety monitoring, and prospective comparative studies. Although current evidence remains preliminary, upadacitinib dose escalation may represent a pragmatic rescue strategy for selected patients with refractory disease.

Key Words: Inflammatory bowel disease; Upadacitinib; Dose escalation; Janus kinase inhibitors; Treatment resistance; Personalized medicine; Ulcerative colitis; Crohn’s disease

Core Tip: Upadacitinib dose escalation may provide symptomatic benefit and reduce corticosteroid dependence in selected patients with refractory inflammatory bowel disease who experience secondary loss of response. The findings of Ellington et al support a more flexible and individualized approach to therapeutic optimization while emphasizing the need for careful safety monitoring and prospective validation.

TO THE EDITOR

Despite major therapeutic advances in inflammatory bowel disease (IBD), secondary loss of response remains a major clinical challenge. Even with anti-tumor necrosis factor agents, anti-integrins, interleukin inhibitors, and small molecules, many patients eventually require treatment modification due to declining efficacy[1,2]. Strategies to overcome secondary loss of response include dose intensification, therapeutic optimization, and switching to alternative mechanisms of action.

In the issue of the World Journal of Gastrointestinal Pharmacology and Therapeutics, Ellington et al[3] evaluate an increasingly relevant but insufficiently studied strategy: Upadacitinib dose re-escalation in refractory IBD. Their study raises an important clinical question: Should fixed maintenance dosing remain the standard approach in a disease characterized by dynamic and heterogeneous inflammatory activity?

Upadacitinib is a selective Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe ulcerative colitis and Crohn’s disease. As a rapidly acting oral small molecule, it has emerged as an important therapeutic option for patients with treatment-refractory disease[4]. Unlike biologic therapies, JAK inhibitors are not limited by immunogenicity and possess relatively rapid pharmacokinetic activity, making flexible dose adjustment more feasible. This pharmacologic profile provides a rationale for temporary or sustained dose intensification in patients with partial response or secondary loss of response.

This editorial examines whether upadacitinib dose escalation represents a clinically meaningful rescue strategy for selected patients with refractory IBD and how these findings contribute to broader discussions regarding individualized therapeutic optimization.

UPADACITINIB DOSE ESCALATION IN REFRACTORY IBD

Ellington et al[3] conducted a single-center retrospective cohort study including 56 patients with IBD, comprising 38 patients with Crohn’s disease and 18 with ulcerative colitis. Importantly, the cohort represented a highly treatment-experienced population, with a mean prior biologic exposure of 2.49 agents. Patients underwent re-escalation to upadacitinib 45 mg daily following secondary loss of response on maintenance dosing or prolonged induction therapy beyond standard labeling recommendations.

The study demonstrated meaningful symptomatic improvement after dose escalation. Among 49 patients with paired symptom data, abdominal pain decreased from 57.1% to 28.6% (P = 0.003), hematochezia from 49.0% to 20.4% (P = 0.004), urgency from 45.0% to 16.3% (P = 0.003), and diarrhea from 55.1% to 36.7% (P = 0.049). Corticosteroid use also declined significantly from 50% to 32% following escalation (P = 0.031). Additionally, the proportion of patients experiencing at least one IBD-related hospitalization or emergency department visit decreased from 32% to 20%, although statistical significance was not reached.

Perhaps most importantly, 50 of 56 patients (89.3%) remained on escalated upadacitinib dosing at follow-up, suggesting reasonable treatment durability in a highly treatment-experienced population[3].

These findings are clinically relevant because they reflect real-world therapeutic dilemmas encountered in daily practice. Clinical trial populations are highly selected and protocol-driven, whereas patients managed in routine care frequently exhibit multidrug exposure, fluctuating inflammatory burden, and incomplete or transient response to therapy.

BIOLOGICAL RATIONALE FOR JAK INHIBITOR DOSE ESCALATION

Unlike biologic therapies, JAK inhibitors possess pharmacologic characteristics that may make dose adjustment strategies more feasible in clinical practice. Upadacitinib is a rapidly acting oral small molecule with relatively short half-life and predictable pharmacokinetics[4]. In contrast to monoclonal antibody therapies, JAK inhibitors are not limited by immunogenicity or anti-drug antibody formation, which are major contributors to secondary loss of response with biologic agents. Consequently, therapeutic response may potentially be recaptured through dose intensification without the concern of neutralizing antibody development[5]. Additionally, the rapid onset of action associated with JAK inhibition allows clinicians to assess treatment response within shorter timeframes, thereby facilitating more flexible and adaptive therapeutic optimization strategies in selected patients with refractory IBD[6].

These pharmacologic properties provide a biologic rationale for evaluating temporary or sustained re-escalation strategies in patients who lose response during maintenance therapy.

SYMPTOMATIC VS OBJECTIVE DISEASE CONTROL

One of the most important observations from the Ellington et al[3] study is the discordance between symptomatic and objective disease improvement. While clinical symptoms improved significantly, reductions in inflammatory biomarkers and endoscopic scores were numerically favorable but did not achieve statistical significance.

Median fecal calprotectin decreased from 276 μg/g to 146 μg/g, while C-reactive protein and erythrocyte sedimentation rate also demonstrated numerical improvement after escalation. Similarly, Mayo endoscopic subscores in ulcerative colitis improved directionally, whereas Simple Endoscopic Score for Crohn’s Disease scores in Crohn’s disease remained relatively stable[3]. However, interpretation was limited by small paired sample sizes and retrospective data collection.

This discrepancy between subjective improvement and objective inflammatory control reflects a broader challenge in IBD management. Symptoms remain clinically meaningful and strongly influence quality of life and healthcare utilization, yet they are imperfect surrogates for mucosal inflammation. Conversely, biomarkers and endoscopy provide objective evidence of disease activity but may not always correlate with patient-reported symptoms or may be unavailable at standardized intervals in real-world practice.

The study therefore raises an important clinical question: Should symptomatic improvement alone justify ongoing dose escalation when objective disease markers remain less convincing? At present, the answer is uncertain.

SAFETY CONSIDERATIONS

Safety remains a major concern when considering prolonged high-dose JAK inhibitor therapy. Upadacitinib carries class-wide boxed warnings for serious infections, malignancy, venous thromboembolism, and major adverse cardiovascular events[5].

In the Ellington et al[3] cohort, no major new laboratory safety signals were identified during follow-up. However, one patient discontinued therapy after developing colorectal cancer, while additional discontinuations occurred because of allergic reaction and skin infection. Although causality cannot be established in a retrospective study, these findings reinforce the importance of careful patient selection and ongoing monitoring.

Importantly, the study was not powered to detect rare adverse events. The relatively short follow-up duration and limited sample size restrict conclusions regarding long-term safety. Questions regarding cumulative risk associated with sustained 45 mg dosing remain unanswered, particularly in elderly patients or individuals with cardiovascular comorbidities.

The economic implications of prolonged high-dose therapy also remain uncertain. Although reduced corticosteroid use and fewer healthcare encounters may potentially offset costs, formal cost-effectiveness analyses are currently lacking.

DOSE ESCALATION VERSUS THERAPEUTIC SWITCHING

An important unresolved question is whether dose escalation should be preferred over therapeutic switching. In patients with partial response or secondary loss of response, dose intensification may preserve therapeutic benefit while avoiding the risks associated with transitioning to another advanced therapy. This may be particularly relevant in heavily treatment-experienced patients, such as the cohort studied by Ellington et al[3].

Conversely, patients with primary non-response, progressive objective inflammation, or severe structural disease may derive greater benefit from switching to an alternative mechanism of action. Current treat-to-target recommendations emphasize optimization of therapy before abandoning a therapeutic class, but specific guidance regarding upadacitinib dose escalation remains limited due to insufficient prospective evidence[7-11].

At present, comparative data evaluating upadacitinib dose escalation against therapeutic switching strategies are lacking. Future studies directly comparing these approaches would substantially improve clinical decision-making.

PERSONALIZED TREATMENT STRATEGIES IN IBD

The broader implication of the Ellington et al[3] study extends beyond upadacitinib itself. The findings reflect the ongoing shift toward individualized therapeutic optimization in IBD management.

Historically, treatment algorithms have relied upon fixed induction and maintenance dosing schedules derived from population-based clinical trial data. However, real-world disease behavior is far more heterogeneous. Patients differ in inflammatory burden, prior treatment exposure, pharmacodynamic response, comorbidities, and therapeutic goals[12].

Dose intensification has long been established for biologic therapies such as anti-TNF agents, vedolizumab, and ustekinumab. The extension of this principle to small molecules such as JAK inhibitors represents a logical evolution in treatment strategy. Rather than viewing maintenance dosing as static, clinicians may increasingly need to consider therapy as adaptable according to disease behavior and response patterns[13].

Nevertheless, caution is warranted. The generalizability of the Ellington cohort remains uncertain because most patients were heavily treatment-experienced and managed at a tertiary referral center. Whether similar benefits would be observed in biologic-naïve populations, elderly individuals, or patients with substantial comorbidities remains unclear.

CONCLUSION

Current evidence suggests that upadacitinib dose escalation may represent a useful rescue strategy for carefully selected patients with refractory IBD who experience secondary loss of response. The study by Ellington et al[3] demonstrates meaningful symptomatic improvement, reduced corticosteroid exposure, and favorable treatment durability in a highly treatment-experienced cohort.

However, objective inflammatory outcomes remain less convincing, and important questions regarding long-term safety, optimal duration of escalation, patient selection, and comparative effectiveness remain unresolved. Therefore, dose escalation should currently be viewed as a selective and individualized management strategy rather than a definitive change in standard treatment algorithms.

The principal contribution of the Ellington et al[3] study is not simply demonstrating symptomatic improvement with higher-dose upadacitinib, but highlighting the potential role of flexible therapeutic optimization in refractory IBD. As IBD management continues to evolve, the future may depend not only on discovering new therapies, but also on using existing therapies more intelligently and adaptively.