P084 DEEP REMISSION WITH DOUBLE BIOLOGIC THERAPY: A SUCCESSFUL CASE OF COMBINATION USTEKINUMAB AND VEDOLIZUMAB FOR SEVERE REFRACTORY CROHN’S DISEASE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S72-S72
Author(s):  
Ahmed Elmoursi ◽  
Courtney Perry ◽  
Terrence Barrett

Abstract Background Stricturing Crohn’s disease (CD) constitutes a severe phenotype often associated with a high degree of morbidity (3). Surgical resection is first-line therapy for symptomatic strictures, but most patients relapse without subsequent medical therapy (4–5). Biologics are the mainstay for inducing and maintaining remission, but some cases are refractory despite maximum dosage of therapy. Reports of dual biological therapy (DBT) in refractory, stricturing CD are sparse, and prior case reports document only clinical remission (1). To contribute further knowledge regarding the use of DBT in stricturing CD, we present the case of a refractory CD patient who achieved deep remission with ustekinumab and vedolizumab. Case Presentation A 35 year old non-smoking, Caucasian male was referred to our clinic in 2014 for refractory CD complicated by multiple strictures. Prior to establishing care with us, he received two jejunal resections and a sigmoid resection. Previously failed therapies included azathioprine with infliximab, adalimumab, and certolizumab. He continued to progress under our care despite combination methotrexate/certolizumab, as well as methotrexate/golimumab. He underwent proctocolectomy with end ileostomy in 2015 and initiated vedolizumab q8weeks post-operatively. He reoccurred in 2018, when he presented with an ulcerated ileal stricture. He was switched from vedolizumab to ustekinumab q8weeks and placed on prednisone, but continued to progress, developing significant hematochezia requiring hospitalization and blood transfusions. Ileoscopy performed during hospital admission confirmed severe, ulcerating disease in the ileum with stricture. Ustekinumab dosing was increased to q4weeks, azathioprine was initiated, and he underwent stricturoplasty. Follow-up ileoscopy three months later revealed two ulcers in the neo- TI (Figure 1). Vedolizumab q8weeks was initiated in addition to ustekinumab q4weeks and azathioprine 125mg. After four months on this regimen the patient felt better, but follow-up ileoscopy showed two persistent ulcers in the neo-TI. Vedolizumab dosing interval was increased to q4weeks. After four months, subsequent ileoscopy demonstrated normal neo-TI (Figure 2). Histologic evaluation of biopsies confirmed deep remission of crohn’s disease. No adverse side effects have occurred with maximum doses of both ustekinumab and vedolizumab combination therapy. Discussion This case supports both the safety and efficacy of ustekinumab and vedolizumab dual biologic therapy for treatment of severe, refractory Crohn’s disease. While there are reports of DBT inducing clinical remission, this case supports efficacy for vedolizumab and ustekinumab combination therapy to induce deep histologic remission. Large practical clinical trials are needed to better investigate the safety and efficacy of DBT with vedolizumab and ustekinumab, but our case suggests this combination may be a safe and efficacious therapy for refractory CD patients.

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S491-S492
Author(s):  
S Lawrence ◽  
H Huynh ◽  
W El-Matary ◽  
J DeBruyn ◽  
M Carroll ◽  
...  

Abstract Background There is a paucity of data regarding long-term outcomes for adalimumab (ADA) in pediatric Crohn’s disease (CD). We describe the long-term effectiveness of ADA, in achieving clinical and biochemical remission in a Canadian multi-centre pediatric CD cohort. Moreover, we report the effects of prior anti-TNF exposure and use of a concomitant immunomodulator (IM) on durability of clinical and biochemical response. The primary outcome was 24-month corticosteroid (CS) free remission. Secondary objectives included biochemical and faecal calprotectin response over the study period. Methods Retrospective review of electronic records of all children aged 3–18 years with CD requiring ADA at 4 centres across Canada (Vancouver, Edmonton, Winnipeg and Calgary) between January 2005 and December 2017. Results One hundred and nine children (68% male; median age 13.07 [IQR 10.6–15.1]) with CD (L1 21.7%, L2 28.3%, L3 50%) were included with a median follow-up of 15.9 months [IQR 7.6–24]. Seventy-four patients (67.9%) were anti-tumour necrosis factor (TNF) naïve. Concomitant IM therapy was used in 51 (46.8%). CS free clinical remission at 24 months was observed in 45/66 (68%). Over time, the median PCDAI, CRP, ESR and faecal calprotectin significantly improved (Table 1). During follow-up, 36 (33%) patients discontinued ADA; 6 (5.5%) had primary non-response, 28 (25.7%) had secondary LOR and 2 (1.8%) had intolerance. At 24 months, clinical remission was achieved more frequently in patients who were Anti-TNF naïve (81% vs. 43.5% p 0.002). There was no significant difference in biochemical or faecal calprotectin outcomes between those who were bio-naive or experienced. There was no significant difference in the time to loss of response between those on monotherapy and combination therapy with an IM and ADA (HR 0.64 [95% CI 0.33–1.26] p0.2). Conclusion This study demonstrates that ADA is effective and durable in pediatric CD. Over 24 months, clinical, biochemical and faecal calprotectin improvement was seen. In our cohort, clinical response to ADA was greater in anti-TNF naïve compared with anti-TNF experienced patients; however,, biochemical and faecal calprotectin outcomes did not differ. ADA response appears durable with no significant difference in patients on monotherapy or combination therapy.


2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S522-S523
Author(s):  
A Miranda ◽  
A Cuomo ◽  
S Camera ◽  
C Ciacci ◽  
F R De Filippo ◽  
...  

Abstract Background Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, was approved by FDA and EMA for the treatment of moderate to severe Crohn’s disease (CD). Whether UST is effective in inducing deep remission, including mucosal healing and transmural healing, in patients with CD in a real life setting is not completely clear. Methods The study was performed on 92 subjects (47 males; 45 females; mean age: 42 (17–78) from six medical centers in Campania, Italy, with confirmed diagnosis of moderate to severe Crohn’s disease and no neoplasia. In all patients diagnosis of CD had been reached to years earlier. Before inclusion, all patients had been exposed and had failed to respond to conventional and/or at least one biological therapy.The administration of UST was as follows: IV infusion at week 0 (3 vials of 130 mg each if body weight of 55–85 kg; 2 vials of130 mg each if body weight < 55 kg) and subsequent SC injections (90 mg) q8w thereafter. At enrollment, all subjects underwent colonoscopy and were divided into groups according to endoscopic evaluation: 5 (5.4%) patients had erosions; 24 (26.1%) inflammation; 63 (68.5%) ulcers. Based on the CDAI value, 52 (56.5%) patients had a CDAI of 180–220, 35 (38%) had a CDAI of 220–450, and 5 (5.4%) had a CDAI >450. All patients underwent endoscopic examination and bowel MRI or ultrasonography at baseline and at week 52 to evaluate mucosal and transmural healing. Clinical response was defined as a reduction of CDAI by at least 100 points; clinical remission when CDAI was lower than 150. Clinical response and remission were evaluated at baseline and on 5 different occasions throughout a 12 months follow-up. Incidence of treatment-related adverse events (TRAEs) was recorded during the study period. Results Seventeen patients interrupted therapy while 75 patients continued follow-up until the fifth visit. Clinical response at week 52 was achieved in 38 (50,5%) patients and clinical remission in 29 (39%). Twenty-six (34%) patients showed mucosal healing, 34 (45%) showed partial endoscopic response. Fifteen patients (20%) did not show any change during endoscopic evaluation at follow-up. All patients showing mucosal healing also showed transmural healing, as assessed by ultrasonography or MRI. No major TRAEs were observed during treatment. Conclusion In this multi-center, real life study, we show that UST was well tolerated and effective in inducing clinical response and clinical remission in patients with moderate to severe CD who had previously failed to respond to conventional or biologic therapy. UST showed limited efficacy in inducing deep remission (i.e. mucosal+transmural healing).


2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S75-S75
Author(s):  
Scott D Lee ◽  
Anand Singla ◽  
Caitlin Kerwin ◽  
Kindra Clark-Snustad

Abstract Background Vedolizumab (VDZ) is an effective treatment for Crohn’s disease (CD); however, inadequate and loss of response is common. Pivotal VDZ trials evaluated alternative dosing intervals, demonstrating numeric but not statistical superiority in efficacy as compared to FDA-approved dosing. The safety and effectiveness of FDA-approved and modified-dosing schedules in a real-world population are unknown. We aimed to evaluate clinical and endoscopic effectiveness & safety of standard and modified maintenance VDZ dosing in a real world cohort. Methods We retrospectively reviewed CD patients (pts) treated with >3 months VDZ, assessing Harvey Bradshaw Index (HBI), Simple Endoscopic Score for Crohn’s disease (SESCD), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), C-reactive protein (CRP), albumin and hematocrit prior to and following standard VDZ dosing, and prior to and following modified VDZ maintenance dosing. We measured duration on therapy and adverse events. Results We identified 226 eligible pts, mean age 41.5 years, 55.3% female, median disease duration 10 years, 88.9% with prior biologic exposure. Mean duration on VDZ was 28.3 months. Standard VDZ dosing: 61.5% of pts with active clinical disease and adequate follow up data achieved clinical response after 3–12 months; 41.0% had clinical remission. 51.9% of pts with active endoscopic disease and adequate follow up data achieved mucosal improvement; 42.3% had endoscopic remission; 26.0% had mucosal healing after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized CRP after 3–12 months. Modified maintenance dosing: 72 non-remitters to standard VDZ dosing received modified VDZ maintenance dosing. 51.5% of pts with active clinical disease prior to starting dose modification and adequate follow up data achieved clinical response after 3–12 months of modified maintenance dosing; 42.4% had clinical remission. 22.2% of pts with SESCD ≥3 prior to starting dose modification achieved mucosal improvement after 3–24 months; 22.2% had mucosal healing. 26.7% of pts with SESCD ≥4 prior to starting modified dosing had endoscopic remission after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized their CRP after 3–12 months. Safety: 82.7% of pts reported ≥1 adverse events, most commonly infection and worsening CD symptoms. Discussion Standard VDZ dosing resulted in clinical and endoscopic improvement in pts with moderate-severe CD, with prior exposure to multiple advanced therapies. For non-remitters to standard dosing, modified VDZ maintenance dosing improved clinical disease activity in ∼50% of pts and improved endoscopic disease activity in ∼20% of pts, suggesting that for pts who did not achieve remission with standard VDZ dosing, modified VDZ dosing may result in clinical and endoscopic improvement.


2018 ◽  
Vol 24 (10) ◽  
pp. 2135-2141 ◽  
Author(s):  
Ruben J Colman ◽  
Rachel C Lawton ◽  
Marla C Dubinsky ◽  
David T Rubin

Abstract Background Methotrexate (MTX) is an immunomodulator used for the treatment of pediatric inflammatory bowel disease (IBD). There are currently no RCTs that assess the treatment efficacy of methotrexate within the pediatric IBD patient population. This systematic review and meta-analysis assesses the efficacy of MTX therapy among the existing pediatric literature. Methods A systematic literature search was performed using MEDLINE and the Cochrane library from inception until March 2016. Synonyms for ‘pediatric’, ‘methotrexate’ and ‘IBD’ were utilized as both free text and MESH search terms. The studies included contained clinical remission (CR) rates for MTX treatment of pediatric IBD patients 18 yrs old, as mono- or combination therapy. Case studies with <10 patients were excluded. Quality assessment was performed with the Newcastle-Ottawa Scale. Meta-analysis calculated pooled CR rates. A random-effects meta-analysis with forest plots was performed using R. Results Fourteen (11 monotherapy, 1 combination therapy, 2 both; n = 886 patients) observational studies were eligible out of 202 studies. No interventional studies were identified. The pooled achieved CR rate for pediatric CD patients on monotherapy within 3-6 months was 57.7% (95% CI 48.2-66.6%), (P =0.22; I2 = 29.8%). The CR was 37.1% (95% CI 29.5-45.5%), (P = 0.20; I2 = 37.4%) for maintenance therapy at 12 months. Sub-analysis could not identify CR differences between MTX administration types, thiopurine exposure. Conclusions This meta-analysis demonstrated that, over 50% of pediatric Crohn’s disease patients induced with methotrexate achieved clinical remission, while 12-month remission rate was only 37%. Prospective controlled interventional trials should assess treatment efficacy among patient subgroups.


2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S319-S320
Author(s):  
T Straatmijer ◽  
V B C Biemans ◽  
F Hoentjen ◽  
N K H de Boer ◽  
A G Bodelier ◽  
...  

Abstract Background Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin (IL)-12 and IL-23. It is registered for the treatment of Crohn’s disease (CD) and ulcerative colitis. We assessed the two-year efficacy and safety of ustekinumab in a real world, prospective cohort of CD patients. Methods CD patients who started ustekinumab in regular care were prospectively enrolled in the nationwide Initiative on Crohn and Colitis Registry. At week 0, 12, 24, 52 and 104, clinical remission (HBI ≤ 4 points), biochemical remission (fecal calprotectin (FC) ≤200 μg/g and/or CRP ≤5 mg/L), peri-anal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. Patients starting therapy less than two years ago were excluded for the current evaluation. The primary outcome was corticosteroid-free clinical remission at week 104. Results In total, 252 CD patient with at least two years of follow up were included. Of all included patients, the proportion of patients in corticosteroid-free clinical remission at week 12, 24, 52 and 104 was 32.3% (81/251), 41.4% (104/251), 39% (97/249) and 34.0% (84/247), respectively. Of the 97 patients in corticosteroid free clinical remission at week 52, 58 (59.8%) were still in corticosteroid-free clinical remission at week 104. In patients with combined clinical and biochemical disease activity at baseline (n=122), the corticosteroid-free clinical remission rates were 23.8% (29/122), 35.2% (43/122), 40.0% (48/120) and 32.8% (39/119) at week 12, 24, 52 and 104, respectively. The probability of remaining on ustekinumab treatment after 52 and 104 weeks was 64.3% and 54.8%, respectively. There were no predictive factors associated with corticosteroid-free clinical remission at week 104 on univariate and multivariate analysis. Most common adverse events were headache, skin reaction and musculoskeletal complaints. Two patients stopped ustekinumab due to an infection after 8 and 30 weeks of treatment (mild fever syndrome and moderate upper airway infection, respectively). The main reason for discontinuing treatment after 52 weeks was loss of response (66.7%). Conclusion Ustekinumab was effective and relatively safe in our real world, prospective cohort of CD patients. After 104 weeks of ustekinumab treatment, one third of patients were in corticosteroid-free clinical remission.


2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S528-S528
Author(s):  
N Dussias ◽  
F Rizzello ◽  
C Calabrese ◽  
A Sanna Passino ◽  
L Melotti ◽  
...  

Abstract Background Both vedolizumab (VDZ) and ustekinumab (UST) are indicated in the treatment of Crohn’s disease (CD) when anti-TNF treatment fails. While there are some studies regarding the efficacy of these two drugs in this setting, data are lacking regarding the effectiveness of UST in the treatment of VDZ-refractory disease. We aim to address this particularly challenging clinical picture in a real-world single-centre study. Methods CD patients from a single tertiary IBD referral centre receiving treatment with UST after failure to VDZ with a minimum follow-up period of 6 months were included. All patients had previously failed anti-TNF treatment. The primary outcome measure was achievement of steroid-free clinical remission, defined as HBI &lt; 5 at 6 months. We also assessed rates of partial response, defined as a reduction in HBI by ≥ 3 points and/or cessation of steroid treatment in patients who required corticosteroids at baseline for symptom control. Results A total of 32 patients (20 male, mean age ± SD 40.7 ± 14.2, range 21–75) receiving UST treatment after VDZ failure were analysed. Complete steroid-free clinical remission at 6 months from starting UST therapy was achieved in 19 patients (59.4%). Nine patients (28.1%) had partial response, while in the remaining 4 patients (12.5%) no response was achieved. No adverse events were recorded during the follow-up period. Conclusion Preliminary results suggest that UST is effective and safe in the treatment of VDZ-refractory CD.


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