The study, conducted by researchers at Pfizer Japan, IQVIA Solutions Japan, and Pfizer Inc., built a hybrid model combining a decision tree for the initial induction phase with a Markov framework for maintenance and all subsequent lines of therapy. Patients who failed their first advanced therapy were assumed to switch to an alternative agent, then to a basket of remaining drugs, and eventually to best supportive care if they continued to lose response. The simulated population mirrored Japanese trial participants newly starting advanced therapy, with a mean age of 42.4 years and a mean body weight of 59.7 kilograms. Efficacy and safety inputs came from a Bayesian network meta-analysis covering ten advanced therapies, supplemented with Japan-specific costs drawn from a nationwide claims database and adjusted to 2025 price levels.

The economics were evaluated from the perspective of the Japanese payer, with both costs and quality-adjusted life years discounted at an annual rate of 2.0 percent, in line with national health technology assessment guidelines. The willingness-to-pay threshold was set at JPY 7,500,000 per QALY, roughly USD 49,547, the benchmark used in Japan’s system for designated intractable diseases, a category to which ulcerative colitis belongs. Only serious infections were modelled as adverse events, a choice consistent with previous economic evaluations in this therapeutic area, because they drive the greatest costs and quality-of-life impairment while safety profiles across the drug classes remain broadly similar.

The central result was striking in its clarity. Among all 79 sequences evaluated, starting with etrasimod and following with upadacitinib produced the greatest lifetime health benefit, a total of 17.801 quality-adjusted life years. Four strategies anchored the efficiency frontier, the curve tracing the most efficient options at each cost level: infliximab followed by ustekinumab, infliximab followed by etrasimod, infliximab followed by upadacitinib, and etrasimod followed by upadacitinib. Each successive step along the frontier bought more health at an incremental cost-effectiveness ratio comfortably below the Japanese threshold, culminating in etrasimod followed by upadacitinib at JPY 6,684,442 per QALY, which remained cost-effective and delivered the most value overall.

The mechanistic logic behind the winning sequence is instructive. The network meta-analysis showed that upadacitinib, an oral JAK inhibitor, achieved the highest remission and response rates among patients who had already been exposed to advanced therapy, making it a particularly powerful second-line option. Etrasimod, which traps lymphocytes in lymph nodes by modulating the S1P receptor on their surface and thereby blunts intestinal inflammation while preserving systemic immune surveillance, showed favorable efficacy and safety across multiple endpoints in treatment-naïve patients. Pairing the two oral agents in that order therefore maximized cumulative quality-adjusted survival, and etrasimod outperformed ozanimod, its identically priced oral counterpart, on maintenance response, remission, and serious infection rates in the comparative evidence underpinning the model.

Sensitivity analyses revealed where the conclusion could shift. When infliximab and adalimumab biosimilars were introduced into the model, the picture changed materially. Because biosimilar infliximab costs JPY 13,860 per 100-milligram vial compared with JPY 35,981 for the originator, a first-line biosimilar infliximab sequence followed by upadacitinib became the most cost-effective strategy, pushing the etrasimod-upadacitinib combination above the threshold. Yet the authors caution that real-world biosimilar uptake in Japanese ulcerative colitis remains around 20 percent, and a survey found that 85 percent of Japanese inflammatory bowel disease patients were unaware biosimilars even existed. Under Japan’s high-cost medical expense benefit program, out-of-pocket costs are so constrained that patients have little financial incentive to switch.

Other scenario analyses tested alternative assumptions about disease progression and treatment intensity. Allowing dose escalation of tofacitinib, upadacitinib, and ustekinumab during maintenance left etrasimod followed by upadacitinib as the most cost-effective sequence, though with a narrower margin. Assuming patients never transitioned from later-line therapy to best supportive care shifted the optimal sequence to etrasimod followed by ustekinumab. Applying higher colectomy rates, informed by Japanese national database studies, moved infliximab followed by upadacitinib to the top. The fragility of the base-case result was further underlined by the one-way sensitivity analysis, in which placebo-arm maintenance parameters and infliximab’s relative efficacy had the largest influence on the incremental net monetary benefit.

The study carries important caveats that temper any temptation to treat its ranking as clinical gospel. Efficacy estimates derive from a network meta-analysis of trials published through November 2022, and such analyses for ulcerative colitis are known to suffer from heterogeneity in prior biologic exposure, baseline disease activity, and outcome definitions. Real-world evidence, which now exists for several of the agents, was excluded because of incomparability across studies. Serious infections were the only adverse event modelled, leaving unquantified risks such as major cardiovascular events, venous thromboembolism, herpes zoster, and malignancy, factors that matter greatly in real treatment choices. Utility values came largely from non-Japanese populations, and the transition rate from late-line therapy to best supportive care was borrowed from a United States claims database.

There is also the question of who conducted the analysis. All clinical authors are Pfizer employees or contractors funded by Pfizer Japan, and the company financed the research and publication. The acknowledged conflicts do not invalidate the mathematics, but they do mean the framing of etrasimod, a Pfizer drug, as the preferred starting point deserves independent scrutiny, particularly given how sensitive the results were to pricing assumptions around cheaper biosimilars.

For clinicians and policymakers, the study’s value lies less in crowning a single winner than in demonstrating that sequencing choices carry quantifiable economic and health consequences over a lifetime of disease. The authors themselves stress that the findings should complement, not dictate, clinical judgement, alongside patient age, comorbidities, pregnancy plans, and personal preference. As Japan’s ulcerative colitis population grows, having expanded roughly 1.4-fold over eight years, and as real-world data accumulate on the newer oral agents, future updates of this model will be needed to confirm whether the etrasimod-then-upadacitinib pathway truly delivers the best value in everyday practice rather than in simulation.

Subject of Research: Cost-effectiveness modeling of advanced therapy sequences for moderately to severely active ulcerative colitis in Japan

Article Title: Comparative Cost-Effectiveness of Advanced Treatment Sequences for Moderately to Severely Active Ulcerative Colitis in Japan

Article References: Kamei, K., Enami, M., Matsuda, H., Yamagami, K., Dai, Y., Hoshi, M., Law, E. H., & Yuasa, A. (2026). Comparative Cost-Effectiveness of Advanced Treatment Sequences for Moderately to Severely Active Ulcerative Colitis in Japan. Advances in Therapy. https://doi.org/10.1007/s12325-026-03757-3

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03757-3

Keywords: ulcerative colitis, cost-effectiveness, etrasimod, upadacitinib, infliximab, S1P receptor modulators, JAK inhibitors, network meta-analysis, QALY, Japan, biosimilars, treatment sequencing