Abstract
Background
Older adults with ulcerative colitis (UC) are often undertreated with advanced therapies due to safety concerns. We evaluated whether outcomes differ by age in randomized trials.
Methods
Post hoc analysis of 2841 participants from 13 UC induction trials of biologics and JAK inhibitors compared efficacy (patient-reported outcomes 2 response/remission, clinical remission, endoscopic improvement) and safety between patients ≥60 years of age vs <60 years of age.
Results
Efficacy and safety outcomes were similar across age groups, with minor therapy-specific variation. Hospitalization was numerically higher in older adults.
Conclusions
Advanced therapies show comparable efficacy and safety in UC regardless of age.
Keywords: ulcerative colitis, inflammatory bowel disease, PRO-2 response, PRO-2 remission, clinical remission
Introduction
Concerns about risks of adverse events (AEs) in older adults with ulcerative colitis (UC) can lead to undertreatment with advanced therapies.1 However, it is unclear if these concerns are justified or if efficacy and safety differs by age. In this post hoc analysis of clinical trial data from 2841 UC patients treated with advanced therapies, patient-reported clinical outcomes and AEs were consistent between patients ≥60 years of age and <60 years of age.
Methods
We compared response and remission rates at postinduction time points across eight advanced therapies for UC: adalimumab, golimumab, infliximab, mirikizumab, ustekinumab, vedolizumab, tofacitinib, and upadacitinib using data from ACT 1 (NCT00036439), ACT 2 (NCT00096655), ULTRA-1 (NCT00385736), ULTRA-2 (NCT00408629), GEMINI-1 (NCT00783718), VARSITY (NCT02497469), PURSUIT (NCT00488631), UNIFI (NCT02407236), LUCENT-1 (NCT03518086), LUCENT-2 (NCT03524092), OCTAVE (NCT01465763), U-ACHIEVE (NCT02819635), and U-ACCOMPLISH (NCT03653026).2–11 Analyses were restricted to active-treatment arms only. GEMINI-1, VARSITY, and LUCENT 1/2 had an upper age limit of 80 years of age, while U-ACHIEVE and U-ACCOMPLISH had a limit of 75 years of age. Data were accessed via Vivli Inc. (protocol #: 00010940) and Yale Open Data Access project (protocol #: 2024-0748) and obtained by permission from Pfizer, AbbVie, Eli Lily, Takeda, and Janssen Inc.
Efficacy outcomes were compared in those ≥60 years of age vs <60 years of age and included postinduction 2-item patient-reported outcome (PRO-2 Patient Report Outcomes) response (defined as ≥50% reduction in stool frequency score [SFS] and rectal bleeding score [RBS] from baseline), PRO-2 remission (defined as SFS and RBS scores of 0), clinical remission (defined as modified Mayo score ≤2 with SFS ≤1, RBS of 0, and Mayo endoscopic subscore [MES] ≤1), and endoscopic improvement (EI), defined as MES ≤1. Postinduction time points occurred at week 6 for golimumab and vedolizumab; week 8 for adalimumab, infliximab, tofacitinib, ustekinumab and upadacitinib; and week 12 for mirikizumab. Safety outcomes included hospitalization, infections, and infusion/injection site reactions.
Results
Similar rates of PRO-2 response, remission, clinical remission, and EI were observed (Table 1). Postinduction PRO-2 response was achieved in 54.6% of older vs 53.8% of younger patients (P = .781). Clinical remission (22.7% vs 25.3%; P = .401), PRO-2 remission (21.7% vs 20.7%; P = .844), and EI (39.1% vs 37.2%; P = .429) were also similar.
Table 1.
Efficacy outcomes among UC participants based on age.
| PRO-2 response at postinduction a | PRO-2 remission at postinduction a | Clinical remission at postinduction a | Endoscopic improvement at postinduction a | |||||
|---|---|---|---|---|---|---|---|---|
| Therapy | <60 y (n = 2489) | ≥60 y (n = 352) | <60 y (n = 2489) | ≥60 y (n = 352) | <60 y (n = 2489) | ≥60 y (n = 352) | <60 y (n = 2489) | ≥60 y (n = 352) |
| Total (n = 2841) | 1338/2489 (53.8) | 192/352 (54.6) | 540/2489 (21.7) | 73/352 (20.7) | 629/2489 (25.3) | 80/352 (22.7) | 973/2489 (39.1) | 131/352 (37.2) |
| Adalimumab (n = 130) | 40/121 (33.1) | 5/9 (55.6) | 8/121 (6.6) | 1/9 (11.1) | 25/121 (20.7) | 2/9 (15.4) | 34/121 (28.1) | 3/9 (33.3) |
| Golimumab (n = 149) | 45/136 (33.1) | 5/13 (38.5) | 14/136 (10.3) | 3/13 (23.1) | 16/136 (11.8) | 2/13 (15.4) | 36/136 (36.8) | 4/13 (30.4) |
| Infliximab (n = 241) | 157/210 (74.8) | 18/31 (58.1) | 52/210 (24.8) | 6/31 (19.4) | 100/210 (47.6) | 12/31 (38.7) | 111/210 (52.9) | 16/31 (53.1) |
| Mirikizumab (n = 980) | 446/845 (52.8) | 69/135 (51.1) | 152/845 (18.0) | 20/135 (14.8) | 197/845 (23.3) | 25/135 (18.5) | 324/845 (38.3) | 45/135 (33.5) |
| Ustekinumab (n = 322) | 131/282 (46.5) | 16/40 (40.0) | 60/282 (21.3) | 3/40 (7.5) | 52/282 (18.4) | 6/40 (15.0) | 94/282 (33.4) | 12/40 (30.0) |
| Vedolizumab (n = 122) | 74/111 (66.7) | 5/11 (45.5) | 41/111 (36.9) | 3/11 (27.3) | 39/111 (35.1) | 3/11 (27.3) | 56/111 (50.1) | 4/11 (40.5) |
| Tofacitinib (n = 429) | 166/385 (43.1) | 22/44 (50.0) | 166/385 (43.1) | 22/44 (50.0) | 79/385 (20.5) | 10/44 (22.7) | 137/385 (35.5) | 17/44 (37.7) |
| Upadacitinib (n = 468) | 279/399 (69.9) | 52/69 (75.4) | 47/399 (11.8) | 15/69 (21.7) | 121/399 (30.3) | 20/69 (29.0) | 181/399 (45.3) | 30/69 (44.0) |
| P value (total <60 y vs ≥60 y) | .781 | .844 | .401 | .429 | ||||
Values are n/n (%). PRO-2 response: ≥50% reduction in stool frequency score and rectal bleeding score. Clinical remission: modified Mayo score ≤2 with stool frequency score ≤1, rectal bleeding score of 0 and Mayo endoscopic subscore ≤1. PRO-2 remission: stool frequency and rectal bleeding scores of 0. Endoscopic improvement: Mayo endoscopic subscore ≤1.
Abbreviation: PRO-2, 2-item patient-reported outcome.
aPostinduction time points: adalimumab (week 8), golimumab and vedolizumab (week 6), infliximab, tofacitinib, ustekinumab and upadacitinib (week 8), and mirikizumab (week 12).
These trends persisted across individual agents, with several therapies, particularly infliximab and upadacitinib, showing high rates of postinduction PRO-2 response in both groups (eg, infliximab: 58.1% in ≥60 years of age vs 74.8% in <60 years of age; upadacitinib: 75.4% vs 69.9%). Golimumab and ustekinumab had modestly lower postinduction response and remission rates overall, with comparable age-specific patterns. Mirikizumab, a newer IL-23 antagonist, showed similar PRO-2 response rates (51.1% vs 52.8%). Consistent efficacy across both groups was also seen with both JAK inhibitors, upadacitinib and tofacitinib. Significant differences were observed for PRO-2 response using infliximab (74.8% vs 58.1%; P = .014). Higher rates were observed for PRO-2 response in younger vs older adults using vedolizumab (66.7% vs 45.5%; P = .026) and for PRO-2 remission with ustekinumab (21.3% vs 7.5%; P = .011). No differences in EI were observed across individual therapies.
Safety outcomes were also similar by age (Table S1). Rates of hospitalization were 11.1% in ≥60 years of age vs 7.4% in <60 years of age (P = .475). Infection rates were similar (9.9% in ≥60 years of age vs 9.8% in <60 years of age; P = .320), and infusion/injection site reactions were rare and not significantly different (0.3% vs 0.8%; P = .845). These results held across individual agents, although older infliximab-treated patients had the highest hospitalization rate (32.3% [n = 10 of 31]). Five of these 10 older patients hospitalized while on infliximab were hospitalized due to refractory disease requiring colectomy compared with 10 of 26 patients <60 years of age. While safety outcomes were similar by age across all individual agents, mirikizumab, vedolizumab, and ustekinumab showed particularly low absolute AE rates.
Discussion
These findings suggest that age alone should not limit using effective therapies. Older patients respond to advanced therapies similarly to younger patients, and AEs occurred at a similar rate as younger patients. Unsurprisingly, efficacy is similar between older and younger participants, as pharmacokinetic studies show no meaningful differences in biologic clearance by age.12,13 However, safety concerns often drive clinical hesitation for use of advanced therapies in elder patients.14 This analysis revealed that AE rates were similar, suggesting that older patients can be safely managed on advanced therapies. The highest hospitalization rates were observed in older infliximab-treated patients (32.3%). While this group demonstrated high rates of PRO-2 response, the high hospitalization rate highlights a discordance between short-term symptomatic response and downstream outcomes. This could reflect more severe disease, but lack of other therapeutic options at the time the ACT-2 trial may contribute, given that half of those hospitalizations were for colectomy. These findings should be interpreted with caution given the small sample size of the older infliximab cohort (n = 31).
These findings raise the possibility that AEs often attributed to age may instead reflect inadequate disease control. Uncontrolled inflammation in UC is itself a potent driver of complications. Prior studies have shown that delayed or underdosed treatment may paradoxically increase the risk of AEs, particularly in older adults with inflammatory burden and comorbidities.14 Thus, the key to reducing complications may not be avoiding therapy, but rather using it effectively to induce remission.
This study is strengthened by its large sample size, broad inclusion of therapeutic classes, and granular safety data. This analysis is limited by not controlling for disease severity, prior biologic exposure, comorbidities, or frailty indices. This may influence outcomes independently of age as older adults naturally have a higher comorbidity burden. Our analysis included a small sample of participants >60 years of age, particularly for safety outcomes. Regarding generalizability, clinical trial participants represent a selected population of older adults and may not fully reflect the frailer patients often encountered in routine clinical practice. However, there are limited data for patients at more advanced ages (>70 years). Nonetheless, our findings are consistent with real-world data suggesting that poor outcomes in older UC patients are associated with uncontrolled disease, rather than age. Future studies should evaluate predictors of response and safety outcomes.
In summary, we observed that efficacy and safety outcomes were similar between older and younger patients across multiple classes of therapy. These results support the safety and efficacy of advanced therapies in older patients.
Supplementary Material
Contributor Information
Emily C L Wong, Division of Gastroenterology, Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.
John K Marshall, Division of Gastroenterology, Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.
Christopher Ma, Division of Gastroenterology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, ON, Canada.
Vipul Jairath, Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada.
Walter Reinisch, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Neeraj Narula, Division of Gastroenterology, Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.
Author contributions
E.C.L.W.—study concept and design; acquisition and compilation of data; statistical analysis; drafting of the manuscript; J.K.M.–study concept and design; data interpretation; drafting of the manuscript; C.M.—study concept and design; acquisition and compilation of data; statistical analysis; drafting of the manuscript; V.J.–study concept and design; data interpretation; drafting of the manuscript; W.R.—study concept and design; acquisition and compilation of data; data interpretation; drafting of the manuscript; N.N.—study concept and design; acquisition and compilation of data; statistical analysis; data interpretation; drafting of the manuscript.
Supplementary material
Supplementary data is available at Inflammatory Bowel Diseases online.
Funding
None declared.
Conflicts of interest
N.N. holds a McMaster University AFP Clinician Researcher Award; has received honoraria from Janssen, AbbVie, Takeda, Pfizer, Sandoz, Novartis, Iterative Health, Innomar Strategies, Fresinius Kabi, Amgen, Organon, Eli Lilly, and Ferring. J.K.M. has received consulting and/or speaking fees from AbbVie, Alimentiv, Amgen, AstraZeneca, Bausch Health, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, Lilly, Lupin, Organon, Paladin, Pfizer, Pharmascience, Qu Biologics, Roche, Sandoz, SCOPE, Takeda, Teva, and Viatris. C.M. has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc., Bristol Myers Squibb, Celltrion, Domain Therapeutics, Eupraxia, Eli Lilly, Ferring, Forte Biosciences, Fresenius Kabi, Gilead, Janssen, McKesson, Mirador Therapeutics, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, and Tillotts Pharma; speaker fees from AbbVie, Amgen, AVIR Pharma Inc., Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Merck, Organon, Pendopharm, Pfizer, Sanofi, Takeda, and Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Eli Lilly, Ferring, and Pfizer. W.R. has served as a speaker for AbbVie, Celltrion, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Sobi, and Takeda; has served as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Microbiotica, Pfizer, and Takeda; has served on the advisory board for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, and Pfizer; and has received research funding from AbbVie, Janssen, Sandoz, Sanofi, and Takeda. V.J. has received consulting/advisory board fees from AbbVie, Alimentiv Inc., Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso, Takeda, TD Securities, Teva, Topivert, Ventyx, and Vividion; speaker fees from, AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. All other authors disclose no conflicts.
Data availability
This publication is based on research using data from data contributors AbbVie, Eli Lilly, Pfizer, and Takeda that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and Vivli, Eli Lilly, AbbVie, Pfizer, and Takeda are not in any way responsible for, the contents of this publication. This study, carried out under YODA Project #2024-0748, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research & Development, L.L.C. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, L.L.C.
Ethical approval
The Hamilton Integrated Research Ethics Board determined that a local ethics review was not necessary as previously deidentified data were used, therefore no informed consent was required.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
This publication is based on research using data from data contributors AbbVie, Eli Lilly, Pfizer, and Takeda that has been made available through Vivli, Inc. Vivli has not contributed to or approved, and Vivli, Eli Lilly, AbbVie, Pfizer, and Takeda are not in any way responsible for, the contents of this publication. This study, carried out under YODA Project #2024-0748, used data obtained from the Yale University Open Data Access Project, which has an agreement with Janssen Research & Development, L.L.C. The interpretation and reporting of research using this data are solely the responsibility of the authors and does not necessarily represent the official views of the Yale University Open Data Access Project or Janssen Research & Development, L.L.C.