Refractory Crohn's Disease Research Articles

P0479USTEKINUMAB INDUCED PAUCI IMMUNE ANCA NEGATIVE VASCULITIS IN PATIENT WITH CHRON'S DISEASE

Abstract Background and Aims Crohns disease is a chronic transmural inflammation which can affect any segment of the gastrointestinal tract in a discontinuous fashion. Treatment for crohns include steroids, Immunosuppresants (thiopurines and methotrexate) and biological agents such as TNF antagonist (adalimumab, infliximab and certrolizumab pegol) and anti-integrin antibodies (natalizumab and vedolizumab). However in cases of refractory disease the management can become difficult. In such case, use of Ustekinumab is indicated. Tumour necrosis factor-alpha are first line biological agents for managing adult patients with moderate to severe disease . We present a rare case of Ustekinumab treatment and onset of renal disease secondary to crescentic glomerulonephritis in a 37-year-old female. We aim to discuss the presentation, diagnosis and management of the above condition. To the best of our knowledge, this type of presentation has not been described in existing literature. Method Patient’s hospital case records and GP correspondence were used to analyze this case. Results This is a case of a 37-year-old female with a four year history of refractory crohns disease affecting colon and terminal ileum. She was treated with numerous treatment modalities such as budesonide, mesalazine, azathioprine, mercaptopurine, adalimumab and vedolizumab over the years. However, these treatments were not successful as she had multiple hospital admissions every year with flare up of crohns requiring intravenous steroids. In January 2018, she was again admitted to hospital with a flare up of Crohns disease. Colonoscopy and imaging confirmed active disease with moderate severity. Further treatment strategies were discussed and Ustekinumab was decided as the best next treatment option. She had her first intravenous infusion in February 2018 and was planned for injections every 3 months. Her symptoms of Crohns disease improved with the Ustekinumab injections. After her second injection of Ustekinumab in May 2018, repeat blood tests showed acute kidney injury with creatinine of 127 umol/l from a baseline of 75 umol/l and a urea of 8.3 mmol/l from a baseline of 3 mmol/l. Urine dip in May was positive for protein and blood. She was referred to the renal team as an outpatient on the basis of these results for further management. Urea and creatinine had worsened to 10.4 mmol/l and 168 umol/l respectively. Urine protein creatinine ratio was 200. The initial impression was drug induced vasculitis versus Acute kidney injury (AKI) secondary to diarrhoea and poor intake. Considering the possibility of glomerulonephritis, serology testing for immunoglobulins, complements, blood and urine electrophoresis, ANA, ANCA, anti-GBM and viral serology tests were arranged, which all came back negative. ultrasound-guided percutaneous kidney biopsy was performed. Renal biopsy confirmed the diagnosis of pauci-immune glomerulonephritis with crescents (vasculitis). A diagnosis of Ustekinumab induced ANCA negative crescentic glomerulonephritis was established. Ustekinumab was discontinued and she was treated with prednisolone 60mg for four weeks, followed by tapering regime for 6-12 weeks in the community. Renal function improved with a creatinine of 120 umol/l, two months after stopping Ustekinumab. Repeated blood tests during these two months showed a steady and gradual decline in creatinine and eventually return back to normal level of 80 umol/l. Urinalysis showed proteinuria settling with no evidence of haematuria. Conclusion/learning points

Enfermedad de Crohn

Crohn's disease (CD) is a chronic inflammatory bowel disease (CIBD). Just like ulcerative colitis (UC), etiology of CD likely involves immunological factors acting on any section of the digestive tract, from the mouth to the anus (most often the distal ileum). The incidence and prevalence of CD are rising. Anus and adjacent structures are involved in perianal Crohn's disease. Diagnosis is based on clinical and imaging data, mainly endoscopy (colonoscopy with ileoscopy) and magnetic resonance enterography (or bowel ultrasound carried out by experts), and on anatomopathological findings. Topical corticosteroids (budesonide) are useful for mild-moderate ileal or ileocecal CD (they are delivered in the distal small intestine). In moderate-severe CD systemic corticosteroids are recommended. Immunomodulatory drugs (azathioprine and 6-mercaptopurine and cyclosporine) and biological drugs, such as anti-TNF (infliximab and adalimumab) are used for refractory CD. Recently, new drugs have been included: vedolizumab (anti-integrin molecule) and ustekinumab (interleukin-12 and interleukin-23 inhibitor).

Augmented ustekinumab dosing is needed to achieve clinical response in patients with anti-TNF refractory pediatric Crohn’s disease: a retrospective chart review

Background: Ustekinumab is a monoclonal antibody that inhibits interleukins 12 and 23. It is approved for treatment of Crohn's disease (CD) in adults; however, there is a paucity of data regarding its use in pediatric CD. We describe our experience using ustekinumab in anti-TNF refractory CD pediatric patients. Methods: We performed a retrospective chart review on pediatric patients with CD who were started on ustekinumab from January 2016 to November 2018. We collected patient's clinical history, previous treatment history, surgeries related to CD, disease severity, as measured by abbrPCDAI, and endoscopic severity as recorded by SES-CD before and after ustekinumab. Results: We identified 10 patients with CD who were started on ustekinumab due to non-response to currently approved agents. Seven patients needed augmented maintenance dosing every 4-6 weeks to achieve clinical response or remission. Six of these seven patients had therapeutic drug monitoring during the course of treatment, with five patients showing subtherapeutic drug levels of <4.5 μg/mL while on standard maintenance dosing every 8 weeks, and four patients showing therapeutic drug levels of >4.5 μg/mL on augmented dosing interval. The remaining three patients were on standard maintenance dosing for the duration of treatment. Conclusion: In this retrospective chart review, 7 out of 10 patients with anti-TNF refractory pediatric-onset CD required augmented maintenance doses of ustekinumab to achieve clinical response or remission. A prospective study is needed to define appropriate ustekinumab dosing and interval in management of pediatric CD.

Preoperative Exclusive Total Parental Nutrition is Associated with Clinical and Laboratory Remission in Severe Active Crohn's Disease-A Pilot Study.

Background: The effect of 1–3 months of preoperative exclusive total parental nutrition (TPN) in active Crohn’s disease (CD) patients is not well established. We investigated the efficacy of exclusive TPN in active CD patients. Methods: In a retrospective multi-visit study with data according to our standard care therapy, we assessed clinical and laboratory remission to refractory CD with exclusive preoperative TPN. Inclusion required exclusive preoperative home TPN without additional oral intake for 1–3 months prior to planning surgery. Results: Twenty preoperative CD patients (65% male; 35% female) were on exclusive TPN. The mean age of the cohort was 30.8 ± 11.6 years. Mean duration of preoperative TPN treatment was 73 days (range: 24–142 days). Most patients had terminal ileal (35%) or ileocolonic CD (30%), and with stricturing (B2) phenotype. All 20 patients had significant clinical improvement in all disease activity indices at the end of preoperative TPN (baseline vs. post TPN): HBI 14.5 vs. 4.0 (p = 0.001); BMI 19.2 vs. 19.7 kg/m2 (p = 0.017); CRP 57.2 vs. 10.3 mg/L (p = 0.001); Fecal calprotectin (FC) 672 vs. 200 (μg/g); albumin 2.7 vs. 3.6 g/dL (p = 0.001). Two patients (10%) no longer required surgery after completion of exclusive TPN. Conclusion: Exclusive preoperative TPN was found to provide significant improvement in nutritional status, and clinical and laboratory remission in severe active Crohn’s patients.

Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn's disease.

Biologic therapies in patients with Crohn's disease often yield low clinical and endoscopic remission rates. After multiple failed therapies, combining two biologic therapies is possibly the sole medical alternative to recurrent surgery. However, data on this approach are limited. To assess the efficacy and safety of concomitant use of two biologic therapies in the largest cohort to date of refractory Crohn's disease patients. Data were extracted from Crohn's disease patients started on dual biologic therapy at two referral centres. Biologics utilised include infliximab, adalimumab, vedolizumab, ustekinumab, certolizumab and golimumab. The primary outcome was endoscopic improvement (>50% reduction in Simplified Endoscopic Score-Crohn's disease [SES-CD] or explicitly stated). Endoscopic remission (SES-CD<3 or stated), clinical response (Crohn's disease-patient-reported outcome-2 score [PRO2] reduced by 8), clinical remission (PRO2<8), and C-reactive protein (CRP) were also assessed. A total of 22 patients with 24 therapeutic trials of dual biologic therapy were identified. The majority of patients had prior surgical resections (91%), stricturing (59%) or penetrating (36%) phenotype, and perianal fistulas (50%). Median number of prior failed biologics was 4. Endoscopic improvement occurred in 43% of trials and 26% achieved endoscopic remission. Fifty per cent had clinical response and 41% achieved clinical remission. There were significant post-treatment reductions in median SES-CD (14.0 [12.0-17.5] to 6.0 [2.5-8.0], P=0.0005], PRO-2 (24.1 [20.3-27.0] to 13.4 [4.6-21.8], P=0.002] and CRP (17.0 [11.0-24.0] to 9.0 [4.0-14.0], P=0.02). Presence of perianal fistulas decreased from 50% to 33%. Adverse events occurred in 13% of trials. Dual biologic therapy was associated with clinical, biomarker and endoscopic improvements in selected patients with refractory Crohn's disease who failed multiple biologics. Further studies are needed to validate this approach.

Efficacy and safety of ustekinumab in real clinical practice. Retrospective multicentre study. ARAINF cohort

Introduction Ustekinumab, a monoclonal antibody that blocks interleukins 12/23, has proven in clinical trials its efficacy in inducing and maintaining clinical remission of Crohn's disease (CD). Its effectiveness and safety in actual clinical practice is less known and may differ from trials. Objective To evaluate its effectiveness and safety in clinical practice (intravenous induction pattern essentially), such as induction and over the long term, in patients with CD refractory to biological treatment. Material and methods Multicentre retrospective analysis (6 hospitals in Aragon), which includes all patients (N=69) with CD undergoing treatment with ustekinumab (either with intravenous or subcutaneous induction), who had at least 16 weeks of follow-up. The clinical response or remission has been evaluated at weeks 16, 24, 32 and 48 using the Harvey-Bradshaw index. Results A total of 69 patients have been included, mean age 42 years, 54% men. A percentage of 89.86 (95% CI [0.805, 0.949]) of the patients presented clinical improvement at week 16 (15.95% remission, 73.92% response). In the subsequent follow-up, this response has been maintained. Age (OR 0.95, P=.028) and smoking habits (OR 0.19, P=.027) have been identified by an ordinal regression model as predictors of poor treatment response while the need for biological change due to adverse effect (OR 96, P=.00017) and due to loss of secondary response (OR 7.07, P=.034) have been predictors of good response. No serious adverse effects have been reported that forced them to stop taking ustekinumab. Conclusion Ustekinumab is effective and safe in real clinical practice to achieve induction and maintenance of the response in patients with refractory CD. Tobacco and age have been shown to be predictors of poor response, while the indication for adverse effect to previous biological and for loss of secondary response has been shown to be predictors of good response.

Exclusive enteral nutrition for induction of remission in anti-tumor necrosis factor refractory adult Crohn's disease: the Indian experience.

Background/AimsExclusive enteral nutrition (EEN) is recommended for induction of remission in pediatric Crohn’s disease (CD). However, it is not currently recommended for inducing remission in adults. This report describes the use of 12-week EEN for induction of remission in anti-tumor necrosis factor (anti-TNF) refractory adult CD.MethodsThis is a retrospective analysis of adults with moderate to severe active (Crohn’s Disease Activity Index [CDAI] >220) anti-TNF refractory CD, who received EEN for 12 weeks between April 2018 and March 2019 at Dayanand Medical College and Hospital, Ludhiana, India. Primary outcomes included achievement of clinical remission and fistula healing at 12 weeks. Improvement in inflammatory markers and nutritional status were the secondary end points.ResultsOut of 23 patients who received anti-TNF agents, 7 (30.4%) were refractory and were offered EEN as a salvage therapy. Six patients (66.7% females, mean age 25.6±6.5 years) consented. Four patients (66.6%) achieved clinical remission (CDAI <150). Mean CDAI of patients decreased significantly after 12 weeks of EEN (388.8±74.8 vs. 160.0±25.2, P<0.001). Perianal fistulas showed clinical response (drainage decreased by >50%), though none achieved remission. Entero-enteric fistulae showed complete healing. Mean body mass index improved from 15.6±3.1 to 18.9±1.9 kg/m2 at week 12 (P=0.003). Hemoglobin and serum albumin also improved from 8.2±1.1 g/dL and 2.8±0.3 g/dL at baseline to 12.6±0.6 g/dL and 3.6±0.5 g/dL post-EEN respectively (P<0.001 and P=0.006 respectively).ConclusionsEEN appears to be an effective and well tolerated therapy for induction of remission in anti-TNF refractory adult CD. More data from prospective trials with larger number of patients is required.

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

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.

P499 Objectively assessed disease activity during ustekinumab treatment in a nationwide real-life Crohn’s disease cohort

Abstract Background Real-life long-term evidence on ustekinumab treatment response in patients with Crohn’s disease (CD) is scarce. We performed a retrospective non-interventional nationwide chart review study of dosing and long-term clinical outcomes in Finnish CD patients treated with ustekinumab (FINUSTE2, EUPAS30920). Methods FINUSTE2 involved 17 Finnish centres. Eligible patients were adults with CD, receiving an intravenous first dose of ustekinumab during 2017 or 2018. Disease activity data, such as C-reactive protein (CRP), faecal calprotectin (fCal), and the Simple Endoscopic Score for Crohn’s disease (SES-CD) were collected at baseline, 16 weeks, and one year from treatment initiation. A local gastroenterologist at each centre collected the data from health records in an electronic standardised health questionnaire. Results One hundred and fofty-five patients (48% female) with a mean age of 44 and disease duration of 14 years initiated ustekinumab treatment for CD. Table 1 summarises patient characteristics at baseline. After induction consisting of one intravenous dose and one to two subcutaneous doses at 8 to 16 weeks, 140 patients (93%) continued to maintenance treatment with subcutaneous ustekinumab. Of 93 patients with a follow-up of at least one year, 77 were still on ustekinumab. During ustekinumab treatment, SES-CD (10 at baseline, 3 at 1 year, medians, p = 0.033) and CRP (7 mg/l at baseline, 5 mg/l at 1 year, medians, p &amp;lt; 0.001) and fCal (776 μg/g at baseline, 305 μg/g at 1 year, medians, p &amp;lt; 0.001) decreased significantly in those patients with data available. Figure 1 describes changes in fCal levels over time. Conclusion In this nationwide real-life long-term follow-up study, covering all major centres in Finland, ustekinumab treatment of patients with highly refractory and long-standing CD effectively reduced inflammatory activity, assessed by endoscopy, CRP, and fCal.

P415 The anti-IL-23/IL-12 agent Ustekinumab is an effective and safe induction therapy in patients with Crohn’s disease refractory or intolerant to anti-TNF: a multicentre Italian study

Abstract Background There are limited real-life studies in medical literature evaluating the efficacy and safety of Ustekinumab, an Anti-IL-23/Anti IL-12 agent, in patients with Crohn’s disease (CD) who required treatment because of refractoriness or intolerance to previous biological treatments. Thus, the aim of this study was to assess the effectiveness and tolerability of Ustekinumab in anti-TNF refractory or intolerant CD patients. Methods All CD patients who completed induction with Ustekinumab in three Italian IBD Units (Padua, Santorso, and Pisa) were enrolled. Patients were evaluated after induction (first intravenous dose followed by a subcutaneous dose at 8 weeks) and clinical (Harvey- Bradshaw-Index) and biochemical data, including faecal calprotectin (FC) and C-reactive protein (CRP) were collected. Information on the need of optimisation (every 12 or 8 weeks) and adverse events were also collected. Continuous and categorical variables were expressed as mean with standard deviation (sd) and frequency with percentages, respectively. Comparisons between variables were conducted using paired t-test and chi-square test. Data were analysed using STATA11.1 software. Results Sixty-three patients were included (41 males, mean age 43 ± sd 13.2 years). All of them had previously been treated with at least one biologic agent and 95.2% with oral steroids. The main indications for starting therapy were: previous treatment failure (77.2%) and pharmacological intolerance (17.5%). At the time of the induction, 28.6% patients were under steroid treatment. Post induction, clinical remission was obtained in 63.5% patients, while steroid-free clinical remission in 52.4%. Moreover, a statistically significant reduction of FC (from 916 μg/l to 444 μ/l, p &amp;lt; 0.001) and normalisation of CRP (n = 14, 33.3%; p &amp;lt; 0.001) were observed. After induction, 3 adverse effects were reported, and in two treatment discontinuations was necessary (i.e. 1 case of pyelonephritis and 1 case of a re-activation of entero-cutaneous fistula). Finally, among 63 patients enrolled, 51 (80.9%) were optimised with a maintenance regimen of 8 weeks sub-cutaneous doses. Conclusion Our study shows that Ustekinumab seemed is effective in achieving clinical remission and steroid-free clinical remission after induction in the majority of CD patient despite the refractoriness to anti-TNF treatment. Moreover, the drug appeared safe and well tolerated. On the other hand, treatment optimisation to 8 weeks was adopted in most of the patients, in order to guarantee a better outcome.

P537 Real-world long-term effectiveness of ustekinumab in Crohn’s disease: Results from the ENEIDA registry

Abstract Background There are limited data of long-term ustekinumab administered according to the doses recommended in the UNITI studies. The objective of this study was to assess the real-world, long-term effectiveness of ustekinumab in refractory Crohn’s disease (CD) (LONG-CROHNUSK Study). Methods Multicentre study of CD patients starting ustekinumab at the recommended dose based on weight ~6 mg/kg IV week 0, 90 mg SC week 8 and maintenance 90 mg SC every 8 or 12 weeks and with 1 year of follow-up. Values for Harvey-Bradshaw Index (HBI), endoscopic activity, C reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 26 and 52. Demographic and clinical data, previous treatments, adverse events (AEs), surgeries and hospitalisations were documented. Potential predictors of clinical and endoscopic remission were examined. Results Four hundred and seven patients were analysed (Table 1). For the maintenance dose, ustekinumab 90 mg was administered SC every 12, 8 and 4 weeks in 56 (14%), 318 (84.5%) and 7 (1.5%) patients, respectively. An interval reduction was applied for 118 patients (29%). Before 52 weeks, treatment discontinuation occurred in 71 patients (17%). At baseline, 295 (72%) had an HBI &amp;gt;4 points. Of these, 169 (57%) and 190 (64%) achieved clinical remission at weeks 26 and 52, respectively. FC levels returned to normal (&amp;lt;250 μg/g) in the 44% and 54% of the patients at weeks 26 and 52, respectively. CRP returned to normal (&amp;lt;3 mg/l) in 36% and 37% of the patients at weeks 26 and 52 respectively. HBI, FC, and CRP values over time are shown in Figure 1. Of the 159 patients with endoscopy at 52 weeks, 25 (16%) were in remission and 58 (36%) presented mild activity. Thirty-eight (9.3%) patients worsened extra-intestinal manifestations and 33 (8%) their perianal disease. AEs were recorded in 54 patients, 73 were hospitalised and 53 had surgery. An association was shown for fewer previous anti-TNF agents and ileal localisation with clinical remission, and for endoscopic severity at baseline with poor response. No factors correlated with endoscopic remission. Conclusion This is the first study to show the real-world long-term effectiveness, endoscopic improvement and safety of ustekinumab administered according to the recommended induction regimen in a cohort of highly refractory CD patients.

P545 Deep remission assessed by endoscopy, magnetic resonance or intestinal ultrasound, in refractory Crohn’s disease patients in clinical remission with ustekinumab: a real-life single-centre experience

Abstract Background Current therapeutic goals in Crohn’s disease (CD) include not only the mere absence of symptoms but also the objective resolution of macroscopic lesions, so-called deep remission (DR), which has been related to better outcomes. DR is usually acknowledged by endoscopy, although magnetic resonance (MR) or intestinal ultrasound (IUS) are also reliable, provide extramucosal information and may be more appropriate in certain clinical scenarios. Data regarding the achievement of DR with ustekinumab in real-life clinical practice is still scarce. Methods Retrospective cohort study carried out in a tertiary hospital between April 2017 and April 2019 including patients who had clinically active CD (Harvey–Bradshaw index [HBI] ≥ 4) objectively assessed by either endoscopy, MR or IUS; received intravenous induction with ustekinumab, had achieved clinical remission and had treatment response assessed by either endoscopy, MR or IUS. DR was defined by SES-CD 0–3 or Rutgeerts index i0 if endoscopically assessed, or by complete normalisation of inflammatory parameters on cross-sectional imaging. Endoscopic response was defined by the decrease of SES-CD of 50% compared with baseline. Radiographic response was defined by improvement in bowel wall thickness, inflammatory fat, mural blood flow and hyperenhancement compared with baseline imaging by physician global assessment. Demographics, clinical data and information regarding ustekinumab treatment were collected. Results 90 patients treated with ustekinumab at our centre were analyzed, but only 28 met inclusion criteria (14(50%) female; median age 45 (43–50)) with a median follow-up of 19 (IQR: 15–23) months. All of them had previously failed to antiTNFα and 20 (71%) failed to ≥2 biologics. Treatment response assessment was made by endoscopy (22 cases; 79%) or cross-sectional imaging technique (6 cases; 21%) in a median time of 10 months (IQR: 7–13) from the start of treatment. Deep remission was achieved in 18 (64%) patients. Endoscopic response was achieved in 5 (18%) additional patients. Five (18%) remaining patients obtained no objective response to ustekinumab despite being in clinical remission. Patients who had received prior treatment with ≥2 biologics or those classified as B2 or B3 according to Montreal Classification were less likely to achieve deep remission, although those associations did not reach statistical significance. Conclusion In our experience, a majority of refractory CD patients who achieved clinical remission with ustekinumab also reached deep remission assessed by either endoscopy, MR or IUS.

P344 Effectiveness of ustekinumab in refractory Crohn’s disease: A real-life experience in a tertiary referral centre

Abstract Background Ustekinumab (UST) is increasingly used in Belgium for moderate to severe Crohn’s disease (CD). The aim of the current study was to describe the real-life experience with UST in our tertiary centre. Methods A retrospective study was performed in patients with CD who were started on UST between December 2017 and August 2019. All patients received an initial intravenous (IV) dose of 6 mg/kg body-weight, followed by 8-weekly 90 mg subcutaneous UST. The clinical and endoscopic response was assessed by the physician after induction and during the maintenance phase. Results In total, 67 patients were included, of which the majority was refractory to anti-TNF and/or vedolizumab (Table 1). The median duration of treatment was 15 months (IQR 7–25). The clinical and endoscopic response is shown in Table 2. UST was discontinued in 16 patients (23.9%) after a median of 27.5 weeks (IQR 12.3–52.8). Reasons for discontinuation were a loss of response (LOR), including 5 patients who were in need of surgery (n = 10), primary non response (n = 3), malignancy (n = 1), adverse event (n = 1) and patients’ wish (n = 1). In 29 patients (43.3%) optimisation of UST was necessary due to partial response (n = 13) or due to LOR (n = 16). The optimisation consisted of an IV re-induction in 2 patients, shortening of the dosage interval in 16 patients and a combination of both in 11 patients. The effect of optimisation could be assessed in 22 patients: 10 patients regained a good clinical response and 5 patients attained clinical remission after optimisation. In 7 patients UST was stopped despite optimisation, most often due to persistent LOR. Conclusion In this tertiary population of refractory CD patients, treatment with UST resulted in a clinical response in more than 70% of patients. Of note, 43.3% needed optimisation, with a good clinical response in almost half of the cases. The endoscopic response in this preliminary analysis was modest.

Ustekinumab dose escalation improves clinical responses in refractory Crohn's disease.

Background:Clinicians often utilize off-label dose escalation of ustekinumab (UST) in Crohn’s disease (CD) patients with disease refractory to standard dosing. Previous studies report mixed results with dose escalation of UST.Methods:A retrospective observational study of 143 adult patients with CD receiving UST over a 33-month time period was conducted. Patients receiving UST at standard dosage for a minimum of 16 weeks were included in the analysis. Primary outcomes collected were clinical response [Physician Global Assessment Score (PGA) by >1] and remission (PGA = 0). Changes in clinical parameters were calculated for dose-escalated patients beginning with the time of dose switch (~42 weeks) and compared with a group of patients who were classified as “failing” standard dosing at 42 weeks who were not dose escalated.Results:Dose escalation improved PGA by 0.47 ± 0.19 compared with patients remaining on every 8 weeks dosing (Q8 week), who worsened by 0.23 ± 0.23 (p < 0.05). Dose escalation decreased CRP 0.33 ± 0.19 mg/L and increased serum albumin 0.23 ± 0.06 g/dL (p < 0.05). Surprisingly, disease duration and prior CD surgeries inversely correlated with the need for dose escalation.Conclusion:Our results support UST Q4 week dose escalation for selected CD patients who fail to achieve remission on standard Q8 week dosing. Dose escalation improves clinical outcomes, prevents worsening disease severity, and positively impacts CRP and albumin levels. Together these data indicate that clinicians should attempt Q4 week UST dosing in refractory CD patients before switching to an alternative class of biologic therapy.

A Single Center Experience With Long-Term Ustekinumab Use and Reinduction in Patients With Refractory Crohn Disease.

BackgroundUstekinumab was approved for moderate and severe Crohn’s disease (CD) in 2016, but little is known about long-term outcomes.MethodsA retrospective study evaluated all patients with CD treated with ustekinumab, including patients with reinduction. C-reactive protein (CRP), Harvey-Bradshaw Index (HBI), Short Inflammatory Bowel Disease (SIBDQ), and endoscopy outcomes were collected prospectively.ResultsNinety-six patients received ustekinumab, resulting in improvement in CRP, HBI, and SIBDQ scores with 68% endoscopic improvement/remission. Thirty-four patients underwent reinduction, resulting in improved HBI and CRP.ConclusionsUstekinumab in refractory CD results in significant clinical and endoscopic improvement and reinduction may be a viable option to recapture response.

Biomarkers are associated with clinical and endoscopic outcomes with vedolizumab treatment in Crohn's disease.

Background:Vedolizumab, an α4β7 integrin antagonist, is an effective therapy for Crohn’s disease (CD). Biomarkers are needed to guide therapy and predict outcomes. This study evaluated biomarker concentrations and outcomes in patients with CD undergoing vedolizumab treatment.Methods:Sera at weeks 0, 2, 6, 14, and ⩾26 were collected from vedolizumab-treated, refractory CD patients. Concentrations of soluble (s)-Vascular Cell Adhesion Molecule (VCAM)-1, s-Intercellular Cell Adhesion Molecule (ICAM)-1, s-Mucosal Addressin Cell Adhesion Molecule (MAdCAM)-1, and s-α4β7 integrin were evaluated for associations with achieving endoscopic remission.Results:A total of 22 patients with CD were included. In all patients, s-MAdCAM-1 decreased significantly and s-α4β7 increased compared with baseline. s-VCAM-1 and s-ICAM-1 changed differentially in patients who achieved remission. At week 6, median s-VCAM-1 (859.6 ng/ml versus 460.3 ng/ml, p = 0.03) and s-ICAM-1 (545.7 ng/ml versus 286.2 ng/ml, p = 0.03) concentrations were higher in patients who achieved endoscopic remission compared with those who did not, and similar differences were observed for s-ICAM-1 concentrations in patients who achieved clinical remission, compared with those who did not (669.1 ng/ml versus 291.0 ng/ml, p = 0.04). Week 14 s-α4β7 concentrations were lower in patients who achieved endoscopic remission, compared with those who did not (7.5 ng/ml versus 17.6 ng/ml, p = 0.020).Conclusion:In all vedolizumab-treated CD patients, s-MAdCAM-1 decreased significantly and s-α4β7 increased. However, higher concentrations of s-ICAM-1 and s-VCAM-1 at week 6 and lower concentrations of s-α4β7 at week 14 differentiated patients who achieved endoscopic remission. These findings may help identify early predictors of response to vedolizumab treatment in patients with CD. Further validation in less refractory CD patients is needed.

Eficacia y seguridad de ustekinumab en la práctica clínica real. Estudio multicéntrico retrospectivo. Cohorte ARAINF

IntroductionUstekinumab, a monoclonal antibody that blocks interleukins 12/23, has proven in clinical trials its efficacy in inducing and maintaining clinical remission of Crohn's disease (CD). Its effectiveness and safety in actual clinical practice is less known and may differ from trials. ObjectiveTo evaluate its effectiveness and safety in clinical practice (intravenous induction pattern essentially), such as induction and over the long term, in patients with CD refractory to biological treatment. Material and methodsMulticentre retrospective analysis (6 hospitals in Aragón), which includes all patients (N=69) with CD undergoing treatment with ustekinumab (either with intravenous or subcutaneous induction), who had at least 16 weeks of follow-up. The clinical response or remission has been evaluated at weeks 16, 24, 32 and 48 using the Harvey-Bradshaw index. ResultsA total of 69 patients have been included, mean age 42 years, 54% men. A percentage of 89.86 (95% CI [0.805, 0.949]) of the patients presented clinical improvement at week 16 (15.95% remission, 73.92% response). In the subsequent follow-up, this response has been maintained. Age (OR 0.95, P=.028) and smoking habits (OR 0.19, P=.027) have been identified by an ordinal regression model as predictors of poor treatment response while the need for biological change due to adverse effect (OR 96, P=.00017) and due to loss of secondary response (OR 7.07, P=.034) have been predictors of good response. No serious adverse effects have been reported that forced them to stop taking ustekinumab. ConclusionUstekinumab is effective and safe in real clinical practice to achieve induction and maintenance of the response in patients with refractory CD. Tobacco and age have been shown to be predictors of poor response, while the indication for adverse effect to previous biological and for loss of secondary response has been shown to be predictors of good response.

P073 Double Balloon Enteroscopy in Refractory Crohn's Disease: Jejunal Findings and Clinical Impact After 10 Years of Follow-Up

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory disease that can affect all segments of the gastrointestinal tract. With various phenotypes and progressive course, it can be complicated with fistulas, abscesses or stenosis. Treatment targets includes clinical remission and mucosal healing in order to avoid complicated outcomes. Double balloon enteroscopy (DBE) allows complete evaluation of the small intestine, providing diagnoses and the possibility of interventions such as biopsies, with low complication rates. Some authors suggest that involvement of the proximal small bowel may indicate worse long-term therapeutic outcomes. This study aims to correlate jejunal endoscopic findings observed in baseline DBE with the activity of CD after 10 years of follow-up. METHODS: Twenty paediatric refractory CD patients (2–17 years old) performed DBE by a single experienced specialist after radiological evaluation for stenosis exclusion between 2007 and 2010. After 10 years, the degree of CD activity was assessed by the Harvey-Bradshaw Index (HBI), C-Reactive Protein (CRP) serum dosage, and current therapy through collection of electronic medical records and personal communication. RESULTS: Sixteen 16/20 patients (80%) completed the 10 years follow up period. Two patients (2/16) changed diagnosis (1- monogenic disease, IL-10 and / or IL10R gene mutation; 1 - ulcerative colitis). Previous findings of DBE of the 14 patients corresponded to: 2 active duodenojejunal ulcers, 4 duodenojejunal scar retractions, 1 retraction and pseudopolyps in the proximal ileum, 6 hyperemia and / or edema and / or granularity of the jejunal mucosa, and 1 without alteration. After 10 years, 6/14 patients have abnormal CRP (>5 mg/L), with 3 of them having HBI between 5 and 7, 2 between 8 and 16 and 1 of 4. All of them presented previous jejunal alterations, 5/6 are currently in use of biologic and 3/6 are steroid dependent. The 2 patients who had active ulcers in baseline DBE remain steroid dependent and with higher rates of HBI activity. Eight patients (8/14) have normal CRP, all presenting HBI lower than 5. Of these, 3 are using combined therapy with immunosuppressant and biologic, 1 with biologic monotherapy, 2 with immunosuppressant, and 2 without medication. CONCLUSION(S): Active jejunal disease, observed through DBE, may indicate a more severe phenotype in CD after long-term follow-up, suggesting a distinct phenotype. Evaluation of the proximal small intestine should be considered in refractory paediatric CD patients or those with diagnostic uncertainty.

Imatinib in Refractory Crohn Disease: A Series of 6 Cases

Abstract Biologics have revolutionized Crohn disease (CD) treatment. Nevertheless, absence or loss of response is frequent and alternative therapeutic options may be necessary. Imatinib is a tyrosine kinase inhibitor that is used in chronic myeloid leukemia. A positive impact on CD in 2 patients with chronic myeloid leukemia treated with imatinib led us to propose the drug in 4 additional patients with refractory CD. Four out of these 6 patients reached clinical and endoscopic remission at a median time of 3 months. Remission was maintained for 9 months to 7 years. Imatinib may thus be considered as new therapeutic options for refractory CD. We report 6 CD patients treated with imatinib. Two of them because of a leukemia and 4 because of a disease refractory to all medical options. Four patients experienced full and sometimes prolonged remission of their digestive disease.

Cost of Refractory Crohn's Disease Before and After Ustekinumab Utilization.

BackgroundCrohn’s disease (CD) is associated with major health services utilization and costs. Between 2012 and 2015, ustekinumab was used off-label in Quebec, Canada for treatment of refractory CD.AimsWe assessed the direct medical cost of adult CD patients in the 1-year pre- and 1-year postustekinumab initiation.MethodsData were obtained from the provincial administrative databases. CD patients dispensed subcutaneous ustekinumab in 2012 to 2014 were followed for 1 year from the date of initiation (index-date). Kaplan Meier plots were used to display time to ustekinumab discontinuation and factors associated with discontinuation were identified using multivariate Cox regression models. Direct medical costs and 95% confidence interval (CI) of gastrointestinal-related health services were calculated for the 1-year pre- and 1-year post-index-date.ResultsThirty-four CD patients (mean age ± standard deviation, 44 ± 14 years, 59% women and 41% with low income) were included. Of these, 14 (41%) discontinued ustekinumab during the postperiod. Discontinuation was less likely among older patients: hazard ratio (95% CI) per 5-year age increase, 0.77 (0.61 to 0.96). The total $CAN direct medical cost (mean, 95% CI) was higher in the post- versus preperiod: $1,681,239 ($49,448; $42,265 to $57,160) versus $880,060 ($25,884; $20,391 to 31,596), while the total costs of GI-related health services were similar: $250,206 ($7359, $3536 to $11,674), versus $213,446 ($6278, $3609 to $9423).ConclusionIn patients with severe refractory CD on off-label ustekinumab, approximately 60% remained on treatment beyond 1 year. The cost of gastrointestinal services did not increase during that year as compared to that of the year preceding ustekinumab use.