Long-Term Outcomes After Ustekinumab Dose Intensification for Inflammatory Bowel Diseases

Introduction

In the United States, standard dosing of ustekinumab for Crohn’s disease (CD) and ulcerative colitis (UC) consists of a weight-based intravenous (IV) induction dose followed by 90-mg subcutaneous injections every 8 weeks. The best therapeutic strategy after suboptimal clinical response or loss of response (LOR) to standard ustekinumab dosing is not known. Limited data support the use of therapeutic drug monitoring of serum ustekinumab trough concentrations to guide dose adjustments.^1,2 Therefore, empiric dose intensification to every 4 weeks or every 6 weeks after LOR is a common approach, which appears to be effective at recapturing clinical response in both CD and UC.^3–5

Studies that have evaluated the efficacy of ustekinumab dose intensification for inflammatory bowel diseases (IBDs) have primarily reported outcomes within 16 weeks.^3,4,6,7 The long-term durability and effectiveness of dose intensification in real-world settings is unknown. We therefore performed a retrospective cohort study to determine clinical and endoscopic outcomes up to 2 years after ustekinumab dose intensification for IBD.

Methods

Study Design

This was a retrospective cohort study of adults undergoing dose intensification of ustekinumab from 90 mg every 8 weeks to 90 mg every 4 weeks or every 6 weeks for the treatment of CD or UC (International Classification of Diseases–Tenth Revision Clinical Modification codes 50x and 51x, respectively) at Brigham and Women’s Hospital (Boston, MA, USA), Massachusetts General Hospital (Boston, MA, USA), and affiliated hospitals between January 1, 2016, and April 1, 2021. Dose intensification decisions were at the discretion of the ordering provider for either suboptimal response or LOR to standard ustekinumab dosing. Patients were excluded if they received an IV reinduction dose of ustekinumab within 8 weeks prior to dose intensification or if they were primarily treated with ustekinumab for pouchitis or non-IBD indications. Patients treated with ustekinumab for CD of the pouch were not excluded. Electronic health records were manually reviewed for clinical, laboratory, and endoscopic data through April 1, 2022. Clinical disease activity was documented in gastroenterology clinic notes using the Harvey-Bradshaw Index (HBI) for CD and the Simple Clinical Colitis Activity Index (SCCAI) for UC.

Independent Variables

Baseline independent variables at the time of dose intensification include dose interval (every 4 weeks or every 6 weeks), age, sex, race, ethnicity, disease duration, substance use (cigarette smoking, cannabis, opioids), concomitant medications (oral corticosteroids, immunomodulators), prior biologic exposures, extraintestinal manifestations, disease location and behavior (CD only), active perianal disease (based on most recent imaging or exam), last Mayo endoscopic subscore and disease extent (UC only), prior bowel resection, and the most recent laboratory markers and disease activity scores within 3 months (serum albumin, C-reactive protein, HBI, and SCCAI). Ustekinumab trough concentrations were not reported due to availability in <10% of the cohort.

Outcomes

The primary outcome was corticosteroid-free clinical remission at 24 ± 2 months (CFCR-24), defined as HBI <5 or SCCAI ≤2 (or per provider global assessment if scores were not documented) with no use of oral or intravenous corticosteroids within 30 days preceding assessment. The secondary outcome was CFCR at 12 ± 2 months (CFCR-12). Patients who discontinued ustekinumab due to lack of efficacy prior to these endpoints were considered treatment failures. Additional outcomes over all available follow-up included endoscopic response and remission (using the latest available procedure during follow-up while on ustekinumab), bowel resection surgery (includes total proctocolectomy), ustekinumab discontinuation, and adverse events requiring treatment discontinuation. Endoscopic response was defined as reduction in the Simple Endoscopic Score for CD by >50% or Mayo endoscopic subscore for UC by ≥1 point or per endoscopist assessment when compared with the most recent preintensification assessment. Endoscopic remission was defined as Simple Endoscopic Score for CD ≤4 or Mayo endoscopic subscore ≤1 or per endoscopist assessment.

Statistical Analysis

Continuous data were reported as means ± SD or median (interquartile range [IQR]) depending on normality. Logistic regression of the following baseline covariates was performed to identify factors associated with CFCR-24 for CD: dose interval frequency (every 4 weeks vs every 6 weeks), age, female sex, Caucasian race, current cannabis use, current opioid use, current oral corticosteroid use, current immunomodulator uses, small bowel involvement, penetrating disease, perianal disease, extraintestinal manifestation, prior bowel resection surgery, >1 prior anti-tumor necrosis factor α exposures, prior anti-integrin exposure, last C-reactive protein, last serum albumin, and last HBI. Variables with P < .10 on univariable analysis were included in a multivariable model in which P < .05 was considered significant. Owing to few outcomes, logistic regression was not performed for UC. STATA/SE 17.0 (StataCorp, College Station, TX, USA) was used for all statistical analyses.

Ethical Considerations

This study was approved by the institutional review board of Brigham and Women’s Hospital.

Results

A total of 123 patients with CD and 40 patients with UC underwent ustekinumab dose intensification. Median available follow-up was 1024 days (IQR, 708-1295 days; 321 patient-years) for CD and 481 days (IQR, 205-653 days; 58 patient-years) for UC. Median disease duration at time of dose intensification was 13.7 (IQR, 8.6-20.6) years for CD and 9.0 (IQR, 4.6-14.9) years for UC. The majority of patients received every 4 weeks dosing (52.8% CD, 65.0% UC), and the majority were women (56.9% CD, 52.0% UC) and Caucasian (89.4% CD, 88.0% UC). All patients were previously exposed to anti-tumor necrosis factor α agents and many were previously exposed to vedolizumab (47.2% CD, 75.0% UC). Other baseline characteristics are listed in Table 1.

Table 1.

Baseline characteristics at the time of ustekinumab dose intensification

Characteristic	Crohn’s Disease (n = 123)	Ulcerative Colitis (n = 40)
Days from induction to dose intensification	307 (168-557)	157 (88-279)
Disease duration, y	13.7 (8.6-20.6)	9.0 (4.6-14.9)
Dose interval frequency
Every 4 wk	65 (52.8)	26 (65.0)
Every 6 wk	58 (47.2)	14 (35.0)
Age, y	39 (31-49)	36 (30-57)
Female	70 (56.9)	21 (52.0)
Race/ethnicity
Caucasian non-Hispanic	110 (89.4)	35 (88.0)
Black non-Hispanic	3 (2.4)	3 (8.0)
Asian non-Hispanic	2 (1.6)	2 (5.0)
Hispanic	1 (0.8)	0 (0.0)
Other or unknown	7 (5.7)	0 (0.0)
Current smoking	13 (10.6)	1 (.0)
Current cannabis	26 (21.1)	7 (18.0)
Current opioids	38 (30.9)	1 (2.0)
Current oral corticosteroids	28 (22.8)	12 (55.0)
Current immunomodulator	39 (31.7)	15 (38.0)
Small bowel involvement	94 (76.4)	n/a
Penetrating disease	68 (55.3)	n/a
Perianal disease	51 (41.5)	n/a
Montreal extent >E1 (proctitis)	n/a	33 (82.0)
Mayo endoscopic subscore 3 (severe)	n/a	15 (38.0)
Extraintestinal manifestation	63 (51.2)	20 (50.0)
Prior bowel surgery	77 (62.6)	0 (0.0)
Prior anti-TNF exposure	123 (100.0)	40 (100.0)
>1 prior anti-TNF exposure	92 (74.8)	18 (45.0)
Prior anti-integrin exposure	58 (47.2)	30 (75.0)
C-reactive protein, mg/L	6.8 (3.2-16.3)	3.5 (1.6-7.6)
Albumin, g/dL	4.1 (3.8-4.3)	4.2 (3.9-4.5)
HBI	6 (3.5-9)	n/a
SCCAI	n/a	4 (3-8.5)

Values are median (interquartile range) or n (%).

Abbreviations: HBI, Harvey-Bradshaw Index; SCCAI, Simple Clinical Colitis Activity Index; TNF, tumor necrosis factor.

Clinical and endoscopic outcomes are summarized in Figure 1. CFCR-24 was observed in 63 (60.6%) of 104 CD patients and 6 (40.0%) of 15 UC patients with sufficient documentation at 24 months. CFCR-12 was observed in 67 (57.3%) of 117 CD patients and 21 (52.5%) of 40 UC patients with sufficient documentation at 12 months. Among 58 CD patients in CFCR-12 with documented assessments at 24 months, 49 (84.5%) of 58 remained in CFCR at 24 months. Among 6 UC patients in CFCR-12 with documented assessments at 24 months, 5 (83.3%) of 6 remained in CFCR at 24 months.

Figure 1.

Outcomes after ustekinumab dose intensification. CFCR, corticosteroid-free clinical remission.

Endoscopic response among patients with available data was observed in 49 (59.0%) of 83 CD patients after a median of 400 (IQR, 212-632) days and 13 (59.1%) of 22 UC patients after a median of 314 (IQR, 194-449) days post–dose intensification. Endoscopic remission was observed in 36 (43.4%) of 83 CD patients and 12 (54.5%) of 22 UC patients. Bowel resection surgery occurred in 11 (8.9%) of 123 CD patients and 1 (2.5%) of 40 UC patients over all available follow-up. Ustekinumab was discontinued among 24 (19.5%) of 123 CD patients and 12 (30.0%) of 40 UC patients over all available follow-up. The primary documented reasons for discontinuation were LOR (70.8% CD, 100.0% UC), adverse events (12.5% CD, 0.0% UC), and self-discontinuation or change in insurance coverage (16.7% CD, 0% UC). Adverse events leading to treatment discontinuation for the CD cohort (n = 3/123) included arthralgia, abdominal wall abscess, and excessive drowsiness with weight gain.

After multivariable logistic regression, history of bowel resection surgery (odds ratio, 0.27; 95% confidence interval, 0.10-0.73) and HBI at time of dose intensification (odds ratio, 0.84; 95% confidence interval, 0.75-0.94) were negatively associated with CFCR-24 among patients with CD.

Discussion

In this retrospective cohort study, we observed that >50% of all CD and UC patients were in CFCR at 12 months after ustekinumab dose intensification, and at 24 months, ≥40% were in CFCR. Greater than 80% of both CD and UC patients who were in CFCR-12 remained in CFCR-24 and <30% of all IBD patients discontinued ustekinumab during 379 patient-years of follow-up. Additionally, 43% of CD patients and 55% of UC patients with endoscopic data were able to achieve endoscopic remission. These data support the long-term effectiveness of ustekinumab after empiric dose intensification. While we were unable to identify factors associated with CFCR in UC, we observed that a history of prior bowel resection surgery and higher baseline HBI were negatively associated with achieving CFCR-24 after dose intensification for CD, which may help identify individuals who are better suited for alternative therapies.

Two recent meta-analyses have reported outcomes after ustekinumab dose intensification in cohort studies in IBD; however, the majority of clinical assessments included were performed 16 weeks or sooner after dose intensification.^3,5 To our knowledge, this is the first study to report clinical and endoscopic outcomes up to 24 months after ustekinumab dose intensification for IBD, which will allow providers to inform patients regarding the durability of this treatment strategy.

The study has several strengths, including the availability of granular data such as disease activity scores and endoscopy reports to evaluate the performance of ustekinumab. We utilized a stringent definition of CFCR, requiring that patients did not use corticosteroids within 30 days preceding clinical assessment. We were also able to investigate specific reasons for treatment discontinuation and significant adverse events, which were uncommon over 379 patient-years of follow-up. Limitations include the retrospective design and limited sample that precluded subgroup analyses. While we identified only 15 UC patients with 24 months of follow-up after dose intensification, we provided remission outcomes at 12 months for 40 UC patients, which have not been previously reported.

In summary, ustekinumab dose intensification appears to be effective at both achieving and maintaining CFCR for IBD. Prospective research is needed to compare the relative cost-effectiveness and durability of specific ustekinumab optimization strategies, including every 4 weeks dosing, every 6 weeks dosing, and IV reinduction.

Author Contribution

R.S.D.: study concept and design, acquisition of data, statistical analysis, analysis and interpretation of data, drafting of manuscript. J.C.P.: acquisition of data. J.R.A.: study concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, study supervision

Funding

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007533-35 to R.S.D.) and the Frederick Makrauer IBD Fund (to R.S.D.).

Conflicts of Interest

J.R.A. has served as a consultant for Takeda, Janssen, Pfizer, Pandion, Servatus, Finch Therapeutics, Iterative Scopes, and Artugen; and received grant support from Merck. R.S.D. has served as a consultant for Centaur Labs and received grant support from Pfizer. J.C.P. has no financial or personal conflicts of interest to disclose.

Writing assistance: none