Real-world inflammatory bowel disease-modification outcomes: A narrative review

Table 1 Outcome measures recommended by the selecting therapeutic targets in inflammatory bowel disease II and standard protocol items: Recommendations for interventional trials consensus for use in inflammatory bowel disease-modification trials

Regulatory endpoints: STRIDE II	Disease modification endpoints: SPIRIT
Intermediate targets	Outcome measures
	Midterm complications
Clinical response [at least 50% decrease in PRO2 (CD: Abdominal pain and stool frequency; UC: Rectal bleeding and stool frequency)]	Bowel damage in patients with CD (Lemann Index; 12-24 months)
Clinical remission [CD: PRO2 (abdominal pain ≤ 1 and stool frequency ≤ 3) or HBI < 5; UC: PRO2 (rectal bleeding = 0 and stool frequency = 0) or partial Mayo < 3 and no sub-score > 1]	IBD-related surgery [any colectomy (UC), any CD-related surgery, endoscopic balloon dilation, perianal surgery (CD); 24-36 months]
Normalization of C-reactive protein (values under the upper limit of normal) and fecal calprotectin (to 100-250 μg/g)	IBD-related hospitalizations (composite of number of hospitalizations and cumulative length of hospital stay; 12-24 months)
Long-term targets	Disease extension in UC (excluding patients with pancolitis) (macroscopic proximal disease extension; 2-5 years after diagnosis)
Restoration of normal growth in children	Extraintestinal manifestations (12-36 months)
Endoscopic healing (CD: SES-CD < 3 points or absence of ulcerations; UC: Mayo endoscopic sub-score = 0 points or UCEIS ≤ 1 point)	Permanent stoma
Absence of disability and normalization of HRQoL	Short-bowel syndrome (small-bowel length < 200 cm)
Adjunctive targets to endoscopic remission	Long-term complications
Histological remission	Dysplasia or cancer (5 years)
Transmural healing	Mortality (both IBD-related and non-IBD related mortality; 5 years)
	Impact on patient’s life
	Health-related quality of life (tool: Composite of IBDQ-36 and SF-36; every 6-12 months)
	Disability (IBD Disability Index; every 6-12 months)
	Fecal incontinence (excluding patients with isolated liminal ileal CD) (Cleveland score or Jorge-Wexner score; every 6-12 months)

STRIDE: Selecting therapeutic targets in inflammatory bowel disease; SPIRIT: Standard protocol items: Recommendations for interventional trials; PRO2: Patient-reported outcomes 2; CD: Crohn’s disease; UC: Ulcerative colitis; HBI: Harvey-Bradshaw index; SES-CD: Simple endoscopic score for Crohn’s disease; UCEIS: Ulcerative colitis endoscopic index of severity; HRQoL: Health-related quality of life; IBD: Inflammatory bowel disease; IBDQ-36: 36-Item Inflammatory Bowel Disease Questionnaire; SF-36: 36-Item Short-Form Health Survey.

Table 2 Studies using standard protocol items: Recommendations for interventional trials disease-modification endpoints found in initial literature search[16-34,37,39,41-49,51-54,56,75]

Ref.	Treatment	Patient population	Endpoints	Key results
Midterm complications
IBD-related hospitalizations
D’Amico et al[17]	Not restricted (included infliximab, adalimumab, vedolizumab)	All patients with UC (n = 156); LOT not mentioned	IBD-related hospitalizations (median follow-up, 30.5 months)	Significantly more patients with histological disease activity were hospitalized than those with histological remission (36.0% vs 7.1%)
Ferrante et al[18]	Golimumab	Patients with UC (n = 109); biologic naive (n = 83) and biologic experienced (second-line biologic; n = 26)	UC-related hospitalizations (54 weeks)	UC-related hospitalizations (through week 54): 3.7% (4/109). Missing information: 61.5% (67/109)
Meyer et al[75]	Vedolizumab vs ustekinumab	Patients with UC (n = 218); anti-TNF experienced	IBD-related hospitalizations (52 weeks)	At week 52, there were no differences between vedolizumab and ustekinumab for hospitalization (9.0% vs 12.1%; OR = 1.44; 95%CI: 0.48-4.37; P = 0.52)
Adimadhyam et al[27]	Vedolizumab vs tofacitinib	Patients with UC (n = 956); anti-TNF experienced	All-cause hospitalizations	All-cause hospitalization was similar between tofacitinib and vedolizumab cohorts (adjusted HR = 1.23; 95%CI: 0.83-1.84)
Greener et al[22]	Adalimumab	Patients with CD (n = 79); anti-TNF experienced	IBD-related hospitalizations	Of 79 patients included, patients receiving higher maintenance doses of adalimumab (40 mg weekly, ≥ 80 mg every other week; n = 39) had a numerically lower number of IBD-related hospitalizations (21% vs 38%, P = 0.08) than those receiving a standard maintenance regimen of adalimumab (40 mg every other week; n = 40)
Narula et al[23]	Adalimumab	Patients with CD (n = 117); anti-TNF experienced	IBD-related hospitalizations	Patients receiving higher maintenance doses of adalimumab (40 mg weekly, ≥ 80 mg every other week; n = 40) had a numerically lower number of IBD-related hospitalizations [8/40 (20%) vs 28/77 (36.3%), P = 0.09] than those receiving a standard maintenance regimen of adalimumab (40 mg every other week; n = 77)
Kappelman et al[29]	Vedolizumab vs ustekinumab	Patients with CD (n = 1375); anti-TNF experienced	IBD-related hospitalizations with surgery and hospitalizations without surgery (52 weeks)	885 new users of ustekinumab had fewer nonsurgical CD hospitalizations than 490 new users of vedolizumab [adjusted HR = 0.58 (0.40-0.83)]. There was a numerical trend toward fewer surgical CD hospitalizations [adjusted HR = 0.83 (0.57-1.22)]
Dulai et al[34]	Vedolizumab, anti-TNFs	Patients with CD (n = 1803); biologic naive and anti-TNF experienced	CD-related hospitalizations and surgery (12 months)	Patients were stratified into high, intermediate, and low probabilities of response in the Optum dataset (n = 358) and high and low probabilities of response in the Truven dataset (n = 1445). In the Optum dataset, rates of hospitalization were 2-4 times lower for vedolizumab-treated patients with a high probability of response vs those with a low probability of response (hospitalization, 19.0% vs 48.1%, P < 0.001). In the Truven dataset, a significantly lower proportion of the high probability of response group experienced a CD-related hospitalization (14.4% vs 19.6%, P = 0.011) during the 12 months after vedolizumab initiation
Narula et al[24]	Adalimumab	Patients with CD (n = 61); biologic naive	CD-related hospitalizations	At week 48, 11/61 (18.0%) patients had a CD-related hospitalization. Of the 11 patients with CD-related hospitalizations, 8 patients had 1 CD-related hospitalization and 3 patients had 2 CD-related hospitalizations
Lenti et al[28]	Vedolizumab vs ustekinumab	Patients with CD (n = 400); anti-TNF experienced	IBD-related hospitalizations (52 weeks)	There was a significant risk difference between ustekinumab (n = 282) and vedolizumab (n = 118) in the unmatched cohort (risk difference, 12; 95%CI: 3-20; P = 0.01), which was no longer significant in the matched population (risk difference, 9; 95%CI: -4 to 22; P = 0.20)
Singh et al[31]	Vedolizumab, ustekinumab, or TNF-α antagonists	Patients with CD (n = 2965); anti-TNF experienced	All-cause hospitalizations	No difference in the risk of hospitalization between ustekinumab vs TNF-α antagonists (HR = 0.99; 95%CI: 0.89-1.21), ustekinumab vs vedolizumab (HR = 0.76; 95%CI: 0.54-1.07), or vedolizumab vs TNF-α antagonists (HR = 1.32; 95%CI: 0.98-1.77)
Abraham et al[25]	Infliximab-dyyb	Patients with IBD (n = 115); biologic naive (n = 39) and biologic experienced (n = 76)	IBD-related hospitalizations (12 months)	In the overall population, IBD-related hospitalizations were recorded in 9.6% (n = 11/115) of patients at baseline and 1.2% (n = 1/84) within the 12-month observation period. Of biologic-naive patients, this was 6 (15.4%) and 0 (0%) at baseline and 12 months, respectively. No patients who switched from infliximab to the infliximab biosimilar had an IBD-related hospitalization
Alharbi et al[26]	Infliximab	Patients with IBD (n = 86; UC, n = 24; CD, n = 62); received ≤ 2 biologic agents	Hospitalizations	Over 2 years, the mean number of hospitalization days was 1.1 days for patients with CD and was 0.7 days for patients with UC
Rundquist et al[32]	Vedolizumab vs anti-TNF-α	Patients with IBD (n = 400; CD, n = 198; UC, n = 202); anti-TNF experienced (second-line biological)	IBD-related hospitalizations (12 months)	After propensity score matching, vedolizumab-treated patients with UC had significantly lower drug survival without IBD-related hospitalization after a 12-month follow-up compared with anti-TNF-treated patients (82% vs 93%, P = 0.02). There were no significant differences between treatments for drug survival without IBD hospitalization in patients with CD (88% vs 82%, P = 0.24)
Surgery
D’Amico et al[17]	Not restricted (included infliximab, adalimumab, vedolizumab)	All patients with UC (n = 156); LOT not mentioned	IBD-related surgery (median follow-up, 30.5 months)	Surgery, n = 16; hospitalized, n = 44; mean (SD) hospitalization duration of 8.97 (8.55) days. 16 patients with histological disease activity at baseline underwent surgery compared with no patients in the histological remission group (14% vs 0%)
Panés et al[19]	Infliximab, conventional therapy	Patients with UC (n = 2239); LOT not mentioned	Surgery (colectomy) (5-year follow-up)	During 5 years of follow-up, 271 patients had colectomy: 174/1059 (16.4%) in the infliximab group and 48/1180 (4.1%) in the conventional therapy group
Meyer et al[75]	Vedolizumab vs ustekinumab	Patients with UC (n = 218); anti-TNF experienced	IBD-related surgery (52 weeks)	At week 52, there were no differences between vedolizumab and ustekinumab UC-related surgery (8.8% vs 12.3%; OR = 2.42; 95%CI: 0.77-7.59; P = 0.13) outcomes
Adimadhyam et al[27]	Vedolizumab vs tofacitinib	Patients with UC (n = 956); anti-TNF experienced	Surgery (colectomy)	There were no significant differences between the secondary outcome of colectomy between new users of tofacitinib (n = 234) and new users of vedolizumab (n = 722) for the secondary outcome of colectomy (incidence rate per 1000 person-years: Tofacitinib, 97.17; Vedolizumab, 59.25; Adjusted HR = 1.79; 95%CI: 0.93-3.44)
Hirai et al[20]	Adalimumab, infliximab, or ustekinumab	Patients with CD (n = 1346); biologic naive (first-line biologic treatment)	Surgery any time after biologic introduction; time to first surgery	292/1346 (21.7%) patients had a surgery any time after biologic initiation. The mean (SD) time from biologic introduction to first surgery was 21.8 (20.8) months
Greener et al[22]	Adalimumab	Patients with CD (n = 79); anti-TNF experienced	IBD-related surgery	Patients receiving the standard maintenance doses (40 mg every other week; n = 40) had a higher risk of surgery than those receiving higher maintenance doses (40 mg weekly, ≥ 80 mg every other week; n = 39) of adalimumab (18% vs 3%, P = 0.03)
Narula et al[23]	Adalimumab	Patients with CD (n = 117); anti-TNF experienced	Surgery	There was no difference between patients receiving higher maintenance doses of adalimumab (40 mg weekly, ≥ 80 mg every other week; n = 40) and those receiving a standard maintenance regimen of adalimumab (40 mg every other week; n = 77) in the number of surgeries [4/77 (5.1%) vs 1/40 (2.5%), P = 0.65]
Vu et al[30]	Vedolizumab or ustekinumab	Patients with CD (n = 1122); biologic naive	IBD-related surgery	After 1-year of follow-up, there was a significantly lower rate of CD-related surgeries in vedolizumab-treated (n = 578) vs ustekinumab-treated (n = 544) patients (7.7% vs 11.6%; HR = 0.67; 95%CI: 0.44-0.99; P = 0.047)
Dulai et al[34]	Vedolizumab, anti-TNFs	Patients with CD (n = 1803); biologic naive and anti-TNF experienced	CD-related surgery (12 months)	Patients were stratified into high, intermediate, and low probabilities of response in the Optum dataset (n = 358) and high and low probabilities of response in the Truven dataset (n = 1445). In the Optum dataset, rates of surgery were 2-4 times lower for vedolizumab-treated patients with a high probability of response vs those with a low probability of response (8.4% vs 44.4%, P < 0.001). In the Truven dataset, a significantly lower proportion of the high probability of response group experienced a CD-related surgery (13.5% vs 23.3%, P < 0.001) during the 12 months after vedolizumab initiation
Narula et al[24]	Adalimumab	Patients with CD (n = 61); biologic naive	CD-related surgery	At week 48, 7/61 (11.5%) had a CD-related surgery
Singh et al[31]	Vedolizumab, ustekinumab, or TNF-α antagonists	Patients with CD (n = 2965); anti-TNF experienced	IBD-related surgery	There were no differences in the 1-year risk of IBD-related surgery for the comparisons of ustekinumab and vedolizumab [propensity score-matched cohort HR = 1.42 (0.54-3.72)], vedolizumab and anti-TNF antagonists [propensity score matched cohort HR = 0.63 (0.27-1.47)], or ustekinumab and anti-TNF antagonists [propensity score matched cohort HR = 1.08 (0.69-1.70)]
Bressler et al[33]	Vedolizumab and anti-TNF-α	Patients with IBD (n = 1095; CD, n = 491; UC, n = 604); biologic naive	IBD-related surgery	There was no difference in disease-related surgeries between vedolizumab and anti-TNF cohorts in patients with CD (incidence rate, 0.7 vs 1.5 per 100 years). Only 1 patient with UC had a colectomy (anti-TNF group)
Rundquist et al[32]	Vedolizumab vs anti-TNF-α	Patients with IBD (n = 400; CD, n = 198; UC, n = 202); anti-TNF experienced (second-line biological)	IBD-related surgery (12 months)	After propensity score matching, there were no significant differences between vedolizumab and anti-TNF treatments for drug survival without IBD-related surgery in patients with UC (93% vs 97%, P = 0.21) or CD (89% vs 82%, P = 0.17)
Clinical relapse
Park et al[21]	Ustekinumab	Patients with CD (n = 99); anti-TNF experienced	Clinical relapse assessed via treatment failure, defined as the need for additional corticosteroid use, withdrawal of ustekinumab, need for CD-related surgery, or CD-related hospitalization	11/99 (11.1%) patients needed a CD-related surgery and 22/99 (22.2%) patients needed a CD-related hospitalization
EIMs
Eder et al[41]	Vedolizumab	Patients with UC (n = 100); biologic naive (n = 55) and biologic experienced (n = 45)	EIMs	EIMs were reported in 13/100 (13.0%) patients with UC at baseline, and 12/91 (13.2%), 3/62 (4.8%), and 3/61 (4.9%) at weeks 14, 54, and 80, respectively. The most frequently reported extraintestinal symptom was arthralgia (n = 11 at week 14 vs n = 3 at week 54)
Straatmijer et al[39]	Ustekinumab	Patients with CD (n = 252); LOT not mentioned	EIMs (2 years)	59/252 patients with CD who were treated with ustekinumab had EIMs at baseline. All patients with uveitis, aphthous, stomatitis, and pyoderma gangrenosum achieved EIM remission and 1 of the 2 patients with erythema nodosum achieved EIM remission during the 2-year follow-up period
Ferretti et al[42]	Vedolizumab vs non-gut-selective biologics	Patients with IBD (n = 1182); LOT not mentioned	EIMs (3-4 years)	224 patients with new or preexisting EIMs were included, who received ongoing biologic for a median of 3 (vedolizumab) and 4 (non-gut-selective agents) years. Patients treated with vedolizumab experienced a slightly higher rate of clinical worsening than those treated with non-gut-selective therapies (15.5% vs 7.3%, P = 0.08)
Livne-Margolin et al[43]	Vedolizumab vs ustekinumab	Patients with IBD (n = 111); LOT not mentioned	EIMs	Clinical response of EIM at week 52 was achieved in 36% (18/50) of ustekinumab-treated patients and 34% (19/54) of vedolizumab-treated patients (P = 0.9)
Kopylov et al[44]	Vedolizumab	Patients with IBD (n = 99; CD, n = 55; UC, n = 44); LOT not mentioned	EIMs (12 months)	In patients with moderately to severely active IBD, within 12 months of vedolizumab initiation 25.3% of patients reported resolution of all EIMs, and 49.5% reported improvement of EIMs
Long-term complications
Death
D’Amico et al[17]	Various (included infliximab, adalimumab, vedolizumab)	Patients with UC (n = 156); LOT not mentioned	Deaths (median follow-up, 30.5 months)	No deaths occurred
Macaluso et al[47]	Adalimumab biosimilar	All patients with IBD (n = 559); biologic naive and biologic experienced	Deaths	No deaths occurred
Cancer
Singh et al[45]	Vedolizumab vs TNF-α antagonists	Patients with IBD (n = 5566); biologic naive	Cancer	There were no differences in the risk of incident malignancy between patients treated with vedolizumab (n = 759) vs those treated with TNF-α antagonists (n = 4807) (incidence rate, 9.0 vs 11.6 per 1000 patient-years; incidence rate ratio, 1.28; 95%CI: 0.61-2.45)
Macaluso et al[47]	Adalimumab biosimilar	All patients with IBD (n = 559); biologic naive and biologic experienced	Neoplasia	No neoplasia occurred
Vedamurthy et al[46]	Vedolizumab and anti-TNF-α	Patients with IBD (n = 463); LOT not mentioned	New or recurrent cancer (median follow-up, 6.2 years)	Incidence rates of new or recurrent cancer following an index cancer diagnosis were 22, 4.2, and 5.6 per 1000 person-years in the vedolizumab, anti-TNF, and no immunosuppression groups, respectively. Neither vedolizumab [HR = 0.72 (0.38-1.36)] nor anti-TNF therapy [HR = 1.03 (0.65-1.64)] had an increased risk of new or recurrent cancer compared with no immunosuppression
Impact on patient’s life
IBDQ
Gatopoulou et al[49]	Golimumab	Patients with UC (n = 81); anti-TNF naive	IBDQ-32 remission (12 months), IBDQ response (6 and 12 months)	IBDQ-32 remission was achieved by 76.9% of patients at 12 months of treatment. The proportion of patients achieving IBDQ-32 response at 6 months and 12 months was 73.0% (46/63) and 75.0% (39/52), respectively
Karami et al[51]	Adalimumab vs infliximab	Patients with UC (n = 238); LOT not mentioned	IBDQ-9	Mean (SD) IBDQ-9 scores were similar between the adalimumab [37.42 (10.72); n = 160] and infliximab [36.61 (11.12); n = 78] treatment groups
Mendonça et al[53]	Various	Patients with IBD (n = 56); LOT not mentioned	IBDQ-32 (cross-sectional)	Total IBDQ-32 scores were significantly lower in females than in males. The difference in IBDQ-32 scores between males and females was larger in patients with CD than in those with UC
Alharbi et al[26]	Infliximab	Patients with IBD (n = 86; CD, n = 62; UC, n = 24); received ≤ 2 biologic agents	IBDQ	This study was terminated early due to low patient numbers. The mean (SD) change from baseline to 3 months in IBDQ score was 11.3 (39.6) points
IBD-DI
Ruiz-Casas et al[56]	Various	Patients with UC (n = 2966); LOT not mentioned	IBD-DI (12 months); IBD-Control Questionnaire	The IBD-DI score was 30.6 in patients with moderate or severe UC (n = 1000) and 22.3 in patients with moderate or severe UC who achieved mild UC or remission status 12 months before the index date (n = 647). The IBD-Control score (United Kingdom only) was a mean 7.2 overall and was similar between cohorts (7.1 vs 7.3)
SIBDQ
Bamias et al[48]	Vedolizumab	Patients with UC (n = 96); LOT not mentioned	SIBDQ (weeks 14 and 54)	Vedolizumab-treated patients with UC reported significant improvements in SIBDQ scores from baseline (mean score, 44.9) to weeks 14 (mean score, 55.2; P < 0.001) and 54 (mean score, 56.5; P < 0.001)
Matsuoka et al[52]	Vedolizumab	Patients with UC (safety, n = 268); anti-TNF experienced	SIBDQ (54 weeks)	There was an increase in mean (SD) SIBDQ score from 44.2 (11.89) at baseline (n = 223) to 53.3 (11.05) after vedolizumab induction (n = 210), with a mean (SD) change (n = 204) of 8.9 (12.53)
Abraham et al[25]	Infliximab-dyyb	Patients with IBD (n = 115; CD, n = 67; UC, n = 48); biologic naive (n = 39) and biologic experienced (n = 76)	SIBDQ (12 months)	There were significant improvements in SIBDQ scores from baseline to 12 months in patients with CD and patients with UC who were treated with infliximab-dyyb (all P < 0.05)
SF-36
Bellone et al[54]	Vedolizumab and infliximab	Patients with IBD (n = 50); LOT not mentioned	SF-36 (14 weeks)	There was a significant improvement from baseline to 14 weeks of treatment in all domains of the SF-36

TNF: Tumor necrosis factor; IBD: Inflammatory bowel disease; EIM: Extraintestinal manifestation; IBD-DI: Inflammatory Bowel Disease Disability Index; IBDQ: Inflammatory Bowel Disease Questionnaire; SIBDQ: Short Inflammatory Bowel Disease Questionnaire; SF-36: 36-Item Short-Form Health Survey; CD: Crohn’s disease; UC: Ulcerative colitis; LOT: Line of therapy; IBDQ-32: 32-Item Inflammatory Bowel Disease Questionnaire; IBDQ-9: 9-Item Inflammatory Bowel Disease Questionnaire; CI: Confidence interval; HR: Hazard ratio; OR: Odds ratio.

Table 3 Summary of differences between standard protocol items: Recommendations for interventional trials disease-modification endpoints and endpoints used in real-world studies

SPIRIT endpoints		Measure	Timeframe	Number of publications using SPIRIT definition	Number of publications using alternative definition	Difference from SPIRIT
Midterm	Bowel damage in patients with CD	Lemann Index	12-24 months	0	0
	IBD-related surgery	Any colectomy (UC), any CD-related surgery, endoscopic balloon dilation, perianal surgery (CD)	24-36 months	8	5	Different timeframes used
	IBD-related hospitalizations	Composite of number of hospitalizations and cumulative length of hospital stay	12-24 months	0	14	No length of stay reported
	Disease extension in UC1	Macroscopic proximal disease extension	2-5 years after diagnosis	0	0
	Extraintestinal manifestations		12-36 months	5	0
	Permanent stoma			0	0
	Short-bowel syndrome	Small-bowel length < 200 cm		0	0
Long-term	Dysplasia or cancer		5 years	0	3	No 5 year follow up
	Mortality	IBD and non IBD related	5 years	0	2	No 5 year follow up
Impact of patients’ life	Health-related quality of life	Composite of IBDQ-36 and SF-36	Every 6-12 months	0	8	Shorter forms and no composite use
	Disability	IBD Disability Index	Every 6-12 months	1	0
	Fecal incontinence2	Cleveland score or Jorge-Wexner score	Every 6-12 months	0	0

¹Excluding patients with pancolitis.

²Excluding patients with isolated liminal ileal Crohn’s disease.

SPIRIT: Standard protocol items: Recommendations for interventional trials; CD: Crohn’s disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis. IBDQ: Inflammatory Bowel Disease Questionnaire; SF-36: 36-Item Short-Form Health Survey.