Intravenous Ustekinumab Reinduction Is Effective in Prior Biologic Failure Crohn’s Disease Patients Already on Every-4-Week Dosing

Ustekinumab (UST) targets the common subunit (p40) of interleukins-12/23,1Benson J.M. Peritt D. Scallion B.J. et al.Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treament of immune-mediated disorders.MAbs. 2011; 3: 535-545Crossref PubMed Scopus (171) Google Scholar,2Singh S. Fumery M. Sandborn W.J. et al.Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn’s disease.Aliment Pharmacol Ther. 2018; 48: 394-409Crossref PubMed Scopus (102) Google Scholar approved for intravenous (IV) induction of remission in moderate-to-severe Crohn’s disease (CD), followed by subcutaneous (SC) doses for maintenance of remission.3Sandborn W.J. Feagan B.G. Fedorak R.N. et al.A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease.Gastroenterology. 2008; 135: 1130-1141Abstract Full Text Full Text PDF PubMed Scopus (616) Google Scholar,4Feagan B.G. Sandborn W.J. Gasink C. et al.Ustekinumab as induction and maintenance therapy for Crohn’s disease.N Engl J Med. 2016; 375: 1946-1960Crossref PubMed Scopus (951) Google Scholar The role of IV reinduction of UST in patients already on every-4-week (Q4) maintenance with partial response or loss of response (LOR) is unclear.5Battat R. Kopylov U. Bessissow T. et al.Association between ustekinumab trough concentrations and clinical, biomarker, and endoscopic outcomes in patients with Crohn’s disease.Clin Gastroenterol Hepatol. 2017; 15: 1427-1434.e2Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar The aim was to assess response and remission rates for UST IV reinduction in patients with CD with partial response or LOR who already were on Q4 SC dosing and had failed prior biological therapies. Retrospective and prospective cohort study of real-world effectiveness outcomes in patients with moderate-to-severe CD who were already on Q4 SC maintenance dosing of UST, with partial response or LOR based on clinical, endoscopic and imaging, or biochemical criteria, in a tertiary Canadian inflammatory bowel disease center. We assessed response and remission after IV reinduction using the same criteria, and safety outcomes. The definitions were the following: A.Before reinduction: (1) remission: no abdominal pain, ≤2 bowel movements (BM)/d, absence of blood with defecation, and stable or no weight loss; (2) mild activity: mild-to-moderate abdominal pain, ≤4 BM/d, occasional blood with defecation, and objective weight loss; (3) moderate-to-severe activity: moderate-to-severe abdominal pain, >4 BM/d, bloody defecation with most BM, and objective weight loss.6Brahmania M. Bernstein C. Physician global assessments or blood tests do not predict mucosal disease activity in ulcerative colitis.Can J Gastroenterol Hepatol. 2014; 28: 325-329Crossref PubMed Scopus (19) Google ScholarB.After reinduction: (1) clinical response: ≥50% reduction in CD symptoms or severity; (2) clinical remission: complete resolution in CD symptoms or severity.7Narula N. Peerani F. Meserve J. et al.Vedolizumab for ulcerative colitis: treatment outcomes from the VICTORY consoritum.Am J Gastroenterol. 2018; 113: 1345Crossref PubMed Scopus (87) Google Scholar A.Before reinduction: (1) remission: ≤4 points; (2) mild activity: 5–7 points; (3) moderate-to-severe activity: >7 points.B.After reinduction: (1) response: reduction in HBI >3 points; (2) remission: HBI ≤4 points. A.Endoscopic: (1) active disease: presence of ulcers; (2) response: Improvement from previous study; (3) remission: absence of ulcers.B.Imaging: (1) active disease: mucosal inflammation. (2) response: improvement from previous study; (3) remission: absence of mucosal inflammation. A.Active disease: >5 mg/dLB.Inactive disease: <5 mg/dL. Fifteen patients, with a median age of 52 (range, 33–66) years, comprising 66.7% (n = 10 of 15) women, with 80% (n = 12 of 15) being bio-exposed, and 40% (n = 6 of 15) having failed 2 prior biologics (Table 1), underwent UST weight-based dosing IV reinduction (260 mg [weight ≤55 kg], 390 mg [>55 kg to 85 kg], and 520 mg [>85 kg]) between May 2018 and February 2020, with 8 of 15 (53.3%) patients using corticosteroids at reinduction. Reasons for reinduction were active disease according to PGA (n = 15 of 15, 100%), HBI (n = 9 of 15, 60%), endoscopy and imaging (n = 15 of 15, 100%), and elevated CRP (n = 5 of 15, 33.3%). Mean time to IV reinduction since UST was started was 60.1 (range, 19–138) weeks. Mean time to assessment after reinduction was 14.9 (range, 4–29) weeks for PGA and HBI, 30.9 (range, 4–58) weeks for endoscopy and imaging, and 28.4 (range, 5–50) weeks for CRP. According to PGA, after reinduction, 10 of 15 (66.7%) patients had response and 8 of 15 (53.3%) achieved remission. According to HBI, 11 of 14 (78.6%) patients achieved response, and 8 of 14 (57.1%) achieved remission. On paired t test, HBI showed a statistically significant mean decrease of 2.4 points after reinduction (95% confidence interval, –3.8 to –0.9; P = .0034). Overall, 2 patients did not respond to reinduction, and 1 patient experienced LOR at month 14, after achieving remission initially after reinduction. Eleven patients had paired CRP values before and after reinduction, with mean values of 10.1 (range, 0.6–43.1) mg/dL and 8.1 (range, 0.6–31.1) mg/dL, respectively. On paired t test, the mean CRP dropped 2.1 mg/dL on average (95% confidence interval, –5.8 to 1.6 mg/dL; P = .24). Eight patients had paired endoscopy and imaging before and after reinduction, with 7 of 8 (87.5%) patients achieving response and 5 of 8 (62.5%) achieving remission (Supplementary Table 1). To assess durability of initial clinical response, patients were followed up to July 2020 (mean time to assessment 49 [range, 8–114] weeks). According to PGA, 12 of 15 (80%) patients had clinical response and 9 of 15 (60%) achieved remission. According to HBI, 11 of 14 (78.6%) patients achieved clinical response, and 8 of 14 (57%) achieved remission. No adverse reactions were seen, and 1 (6.7%) patient reported headache, not associated with UST.Table 1Patient Characteristics (N = 15)Female10 (66.7)Median age, y52 (33–66)Mean disease duration, y18.13 (0–40)Disease locationaSome patients had more than 1 disease location. Colonic2 (13.3) Ileocolonic11 (73.3) Upper gastrointestinal tract2 (13.3) Perianal3 (20)Disease phenotype Inflammatory7 (46.7) Stricturing3 (20) Penetrating5 (33.3)Previous surgery None7 (46.7) Colectomy2 (13.3) Ileocolonic resection5 (33.3) Small bowel resection1 (6.7)Previous therapies Mesalamine4 (26.7) Immunosuppressants7 (46.7) Steroids11 (73.3)Biologics (previous to UST) Bio-naïve3 (20) Infliximab9 (60) Adalimumab7 (46.7) Vedolizumab2 (13.3)Number of previous biologics 16 (40) 26 (40)Concomitant corticosteroid use at reinduction Prednisone4 (26.7) Budesonide4 (26.7) None7 (46.7)NOTE. Values are n (%) or median (range).a Some patients had more than 1 disease location. Open table in a new tab NOTE. Values are n (%) or median (range). In this real-world setting, in a prior biologic failure CD population who had already been escalated to Q4 SC maintenance UST, IV reinduction with UST led to a statistically significant recapture of clinical response and induced remission in over half of patients. Moreover, a durable response was observed in a mean follow-up of 49 weeks. Furthermore, the objective measurement of treatment response through endoscopy and imaging found response in >80% cases and reduction in CRP. No safety signals were observed. A limitation of this study is that we did not measure drug levels in a standardized manner, given the real-world nature of the study, accepting the role of drug-level monitoring, and the optimal level is unknown. Despite the small sample size, these data are useful to guide clinical practice, as it indicates that IV reinduction in patients already on maximal SC maintenance dosing is effective and safe and should be routinely attempted before prematurely switching out of class. Supplemental Table 1Endoscopic/Imaging Findings Before and After Reinduction With UstekinumabIDEndoscopy/imaging before reinduction (n =15)Endoscopy/imaging after reinduction (n = 8)Endoscopy/imaging response (n = 7)a0 = no, 1 = yes.Endoscopy/imaging remission (n = 5)a0 = no, 1 = yes.Time to endoscopy/imaging assessment after reinduction (wk)bMean 30.9 (range, 4–58) wk.1Colonoscopy: Anal ulceration and stenosis. Deep ulcers and evidence of sinus tracts in the pouch body. Deep ulcer in the prepouch, stricture 10 cm upstream from the pouch, and multiple ulcers up to 20 cm from the pouch.2Colonoscopy: 2 long and deep ulcers in the ileum. Colon normal.3Colonoscopy: Ileocecal valve with stenosis and 1 superficial ulcer.MRE: 2 Inflammatory strictures, 3 and 10 cm in distal-terminal ileum.0044Colonoscopy: Pancolonic patchy loss of vascular pattern and erythema.5Colonoscopy: Pouch. Stricturing of the ileum and multiple ulcers throughout the ileum.Colonoscopy: Complete mucosal healing, just scar tissue, no ulcerations.11586Colonoscopy: 50% of pouch body is covered with ulcers, some over 1 cm.7Colonoscopy: Deep ulcers in rectum, patchy colonic disease. Multiple ulcers in the anastomosis. Narrowed and edematous terminal ileum.Colonoscopy: Normal terminal ileum. Small superficial ulcers in rectosigmoid.10188Colonoscopy: Multiple ulcers in the terminal ileum.CTE: Chronic changes. Mild inflammation.10399Colonoscopy: Not able to reach the terminal ileum. Ileocecal valve deformed and inflamed. Small area with inflammatory aspect in the low rectum–fistula.10Colonoscopy: Large ulcer in the terminal ileum. Erythema in the ileocecal valve.11Colonoscopy: Normal neoterminal ileum, perianal fistula tracts.12Colonoscopy: Erythema loss of vascular pattern and ulcers in the sigmoid colon. Right colon with ulcers. Large ulcers in the terminal ileum.Colonoscopy: Complete mucosal healing, just scar tissue, no ulcerations in the ileum.112113Colonoscopy: Ulcerations and narrowing of the terminal ileum.Colonoscopy: No ulcers at terminal ileum.114414MRE: Several loops of duodenum and proximal jejunum focally tethered and strictured with probable enteroenteric fistulas. Predominately fibrostenotic and inflammatory.Push enteroscopy: No evidence of underlying Crohn's disease in terms of the mucosa.114015Colonoscopy: Ileocolonic anastomosis stricture with erosions.Colonoscopy: Mucosal healing.1123CTE, computed tomography enterography; MRE, magnetic resonance enterography.a 0 = no, 1 = yes.b Mean 30.9 (range, 4–58) wk. Open table in a new tab CTE, computed tomography enterography; MRE, magnetic resonance enterography.