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

The research team drew on a prospectively maintained institutional database at Hyogo Medical University, where 1,440 patients with Crohn’s disease underwent intestinal surgery during the study window. Of these, 422 adults required at least one stoma for a Crohn’s-related indication, meaning that nearly three in ten surgical patients—29.3 percent—faced diversion at some point in their disease course. The cohort reflected the notoriously aggressive biology of the disease: the median age at Crohn’s diagnosis was just 21 years, disease at diagnosis was classified as penetrating or stricturing in the vast majority of cases under the Montreal classification, and 321 patients—76.1 percent—had anorectal lesions such as perianal fistulas, abscesses, or strictures. This high rate of anorectal involvement, which reaches nearly 49 percent in some Japanese prospective cohorts compared with 4 to 14 percent in Western series, is a defining feature of Crohn’s disease in Asian populations and shapes much of what the study found.

At the initial operation, three quarters of the patients received what surgeons hoped would be a temporary stoma, while a quarter underwent permanent diversion, typically in conjunction with abdominoperineal resection—the removal of the anus, rectum, and sphincter complex. Among the temporary stomas, small-intestinal stomas predominated, accounting for 86 percent of initial diversions, while permanent stomas were more evenly split between small-intestinal and colonic origins. The reasons behind temporary diversion proved to be the study’s most consequential variable. Progression of anorectal lesions drove stoma creation in 224 patients, or 71.1 percent of the temporary group. Poor intestinal conditions—severe malnutrition, complicated abscesses or perforations, or bowel-wall edema so pronounced that a safe anastomosis was deemed impossible—accounted for 23.8 percent. Anastomotic leakage necessitated diversion in just 4.4 percent of cases, and two patients were diverted for rare causes, including fistulas arising from an ileal pouch in individuals initially misclassified as having ulcerative colitis.

When the researchers traced each indication forward through time, a stark divergence emerged. Among patients diverted because of refractory anorectal disease, 87 percent ultimately ended up with a permanent stoma over long-term follow-up. Only 19 percent of this group ever achieved stoma closure at all, and even among those successes, five patients later required abdominoperineal resection and eight needed re-creation of a stoma. By contrast, patients diverted because of poor intestinal conditions fared far better: 61 percent achieved closure, and bowel continuity was maintained in 56 percent of the entire group. Those diverted for anastomotic leakage occupied an intermediate position, with 57 percent achieving closure and 43 percent ultimately keeping their continuity intact. The message for clinical practice is unambiguous—a stoma created to rest an inflamed but structurally salvageable bowel behaves very differently from one created to sidestep a fistulizing, destroyed perineum.

The overall numbers tell a similarly granular story. Of the 315 patients with temporary stomas, 98—31 percent—achieved closure, but 13 percent of those later required re-creation, and among patients whose re-created stomas again failed, only one ever achieved a second durable closure. Over the long run, 92 of the 315 temporarily diverted patients, or 29.2 percent, ended with abdominoperineal resection, and a further 133 lived with stomas that were never closed. Stoma-related complications requiring reoperation arose in 23 patients, and the investigators noted that the most common problem—stenosis adjacent to the stoma, seen in 19 cases—was attributed to Crohn’s disease lesions at the stoma site rather than to technical failure of the stoma itself, a distinction that underscores how the underlying inflammation pursues patients even after diversion.

Quantifying the population-level burden, the team used Kaplan–Meier analysis from the time of Crohn’s diagnosis. Stoma-free survival—freedom from any diversion, temporary or permanent—was 94.9 percent at five years, 88.4 percent at ten years, 81.5 percent at fifteen years, and 75.4 percent at twenty years. Freedom from permanent stoma was considerably higher among the full cohort of 1,440 surgical patients: 98.2 percent at five years, 94.8 percent at ten years, 89.5 percent at fifteen years, and 82.7 percent at twenty years. These cumulative figures, the authors note, exceed some previously published rates, likely because the study defined permanent stomas as those unclosed for more than 24 months and focused on surgically treated patients with a heavy load of anorectal disease followed for decades rather than years.

One of the study’s most provocative findings concerns the era in which patients were treated. Infliximab, the first anti-tumor necrosis factor biologic approved for Crohn’s disease in Japan, entered routine clinical practice in the mid-2000s, and the researchers used 2005 as a cutoff to compare outcomes before and after the biologics era. Permanent stoma-free survival was significantly better in the later group: twenty-year rates reached 86.5 percent in the biologic era versus 79.3 percent before it, a statistically significant difference with a p-value of 0.032. This suggests that the arrival of potent immunologic therapies has meaningfully reduced the long-term risk of losing the rectum and sphincters. Yet the data also temper enthusiasm. Population-based studies cited by the authors show that the early risk of stoma creation after diagnosis has not substantially declined despite wider biologic use, and in this surgically referred cohort, patients with advanced anorectal damage continued to progress to permanent diversion at high rates. Biologics, in other words, appear to change the trajectory of earlier disease but cannot reverse irreversible perineal destruction.

The study also casts light on a less-discussed hazard: malignancy arising in diseased or diverted bowel. Thirteen percent of the cohort developed cancer related to anorectal disease, and the investigators identified two cases of cancer developing in diverted or excluded rectal segments after stoma creation—a scenario that arises because the excluded rectum escapes routine endoscopic surveillance. Surveillance for Crohn’s-associated cancer remains fraught, the authors point out, since strictures and pain often make endoscopy technically difficult, and standardized screening programs comparable to those established for ulcerative colitis simply do not exist for Crohn’s disease. They argue that patients with anorectal disease need regular perianal examination, evaluation under anesthesia when necessary, and continued monitoring of diverted rectal segments, ideally within a framework of close collaboration between gastroenterologists and colorectal surgeons.

The authors acknowledge the limitations inherent in their design: the analysis was retrospective and single-center, conducted at a tertiary inflammatory bowel disease referral center likely enriched with severe and refractory cases; management evolved dramatically across the 43-year study period; and the precise onset of anorectal disease could not always be established, particularly in patients referred from elsewhere. Median follow-up, however, was an extraordinary 19.5 years, with observations extending to 50 years, giving the study a temporal depth that few cohorts in inflammatory bowel disease can match. Within those constraints, the conclusions are clear and clinically actionable. Temporary diversion for Crohn’s disease is far more likely to become permanent when created for anorectal disease than for mechanical reasons such as leakage or poor bowel condition, a reality that should shape preoperative counseling and the timing of closure attempts. For patients and clinicians alike, the findings reinforce that aggressive, early, and coordinated control of perianal inflammation—combining surgical drainage techniques such as seton placement with immunomodulators, biologics, and antibiotics before irreversible damage accumulates—remains the best defense against a lifetime with a permanent stoma.

Subject of Research: Long-term outcomes of stoma creation in patients with Crohn's disease

Article Title: Long‐Term Outcomes After Stoma Creation in Crohn's Disease: A Retrospective Cohort Study of 422 Patients

Article References: Nagano, K., Kuwahara, R., Tomoo, Y., Kusunoki, K., Horio, Y., Kimura, K., Kataoka, K., Ikeda, M., Uchino, M., & Ikeuchi, H. (2026). Long‐Term Outcomes After Stoma Creation in Crohn's Disease: A Retrospective Cohort Study of 422 Patients. Annals of Gastroenterological Surgery, 10(5), 1463-1469. https://doi.org/10.1002/ags3.70219

Image Credits: AI Generated

DOI: 10.1002/ags3.70219

Keywords: Crohn's disease, stoma creation, anorectal disease, abdominoperineal resection, inflammatory bowel disease, biologic therapy, infliximab, stoma closure, permanent stoma, perianal fistula, retrospective cohort study, colorectal surgery