Introduction: While ustekinumab is not yet approved to treat Crohn's disease (CD), clinicians have begun to prescribe it off-label due to promising clinical trials. We assess the real-world efficacy of ustekinumab for induction of clinical response in CD patients. We also evaluate the proportion of ustekinumab primary responders who develop secondary loss of response during maintenance therapy. Methods: A retrospective multicenter cohort study was performed at two academic institutions on patients with CD who received ustekinumab between 2011-2016. The primary outcome was induction of clinical response at 3 months, defined by reduction in Harvey Bradshaw Index of >2 points and tapering off corticosteroids. Secondary loss of response was defined by clinical, endoscopic, or radiographic disease activity requiring dose escalation, rescue steroids/immunomodulators, surgical resection, or ustekinumab discontinuation. Patients were stratified by weight-adjusted induction dose (3 vs. 6mg/kg), method of induction (intravenous vs. subcutaneous), and initial maintenance regimen (q8 vs. 12 weeks). The proportion of patients on ustekinumab with clinical response was determined at 3, 6, and 12 months. Results: 82 CD patients met inclusion criteria. Median follow-up was 45.6 weeks (IQR 33.0-66.6). 75 patients (91.4%) had previously failed anti-TNF therapy and 61 patients (74.4%) had failed more than one biologic. 55 patients (67.1%) had clinical response to induction therapy at 3 months. Among 78 CD patients who were followed for or discontinued drug prior to 6 months, 67.9% (53/78) were still on treatment and in clinical response. 49.3% (33/67) of patients followed for 12 months or discontinuing drug prior to 12 months were on drugt and responding at 1 year. There were no differences in proportion of patients achieving response at 3, 6, or 12 months when stratified by induction dose (p=0.40-0.94), maintenance dose (p=0.30-0.75), or induction method (p=0.12-0.58). Among 55 primary induction responders, 60.0% (33/55) maintained response to end of follow-up. Median time to secondary loss of response was 45.6 weeks (IQR 33.0-66.6 weeks). Twenty-six patients (31.7%) experienced an adverse effect, predominantly arthralgias (11.0%) and infections (13.4%). Conclusion: In this cohort of CD outpatients, the majority of whom had previously failed multiple biologic agents, ustekinumab was effective for inducing clinical response and this response was maintained over long-term follow-up.Table 1: Baseline patient demographic and clinical characteristics of 82 patients treated with ustekinumab between 2011 and 2015
Ultrasound (US) is safe and accurate for detecting activity and therapeutic response in Crohn’s disease (CD). Early objective assessment may better guide treatment in a treat to target paradigm. The aim of this study is to evaluate 12-week US response to adalimumab (ADA) induction, as a predictor of US, serologic and endoscopic response at 6 months. Patients with known CD were prospectively recruited from January 1, 2011 to December 31, 2014. Patients with active CD had induction and maintenance therapy with ADA with US and C-reactive protein (CRP) levels measured pre-treatment, at 12 weeks and 6 months. Patients underwent ileocolonoscopy (IC) at baseline. A subset had repeat IC at 6 months. The Simple Ultrasound Score (SUS) was calculated (bowel wall thickness and hyperaemia) at each interval and a Simple Endoscopic Score (SES)/Rutgeert’s score for IC when available. Response at 12 weeks was defined by a reduction in SUS or length of disease. Differences between variables at baseline and 6 months were compared using paired sample t test. Features for non-response including presence of strictures or penetrating complications were recorded at baseline. Forty-four patients were included: 64% (28 of 44) females, 36% (16 of 44) male, with mean age of 42 years. Disease distribution was ileal 38% (17 of 44), 55% (24 of 44) ileocolonic and 7% (3 of 44) limited to the colon. All patients exhibited activity on US at baseline, with a mean SUS of 3.14 (out of 4.63). SES was completed for 22 of 44 patients (50%), mean 6.82, Rutgeert’s score was completed for 11 of 44 patients (25%), mean 3.27, while 18% (8 of 44) were not amenable to endoscopic scoring and 7% (3 of 44) had no baseline IC. The median baseline CRP was 5.7 mg/l. At 12 weeks, 70% (31 of 44) improved while 30% (13 of 44) had no change or worsened. Responders were evaluated at 6 months for response compared with baseline: SUS and SES were significantly improved, SUS was 3.45 at baseline and 1.84 at 6 months (p < 0.001) and SES was 6.77 at baseline and 2.50 at 6 months (p = 0.002). Change in CRP was significant (p = 0.044); but the change in Rutgeert’s score was not (p = 0.178). No significant difference for any comparison amongst the non-responders was detected. Of the responders, 9 of 31 (29%) exhibited high-risk features at baseline, compared with 5 of 13 (38%) in the non-responders. Sonographic response to ADA induction at 12 weeks significantly increases the likelihood of further response at 6 months. Responders also exhibited a significant reduction in CRP. High-risk features on baseline US may indicate increased likelihood for non-response. Measurement of 12-week US response may help guide early treatment optimisation.
Purpose: Comparative effectiveness research (CER) is an emerging field that compares the relative effectiveness of alternative strategies to prevent, diagnose, or treat patients that are typical of day-to-day clinical practice. To focus goals for CER in inflammatory bowel disease (IBD) it is important to identify research questions that practitioners and patients believe are important. We sought to develop a priority list of CER studies (CERs) for IBD. Methods: Following the Institute of Medicine's approach for developing CER priorities, we developed and administered a survey to gastroenterologists (GIs) asking them to suggest important CERs in IBD. The survey was electronically distributed to an international sample of GIs from North America, UK and Australia. In addition, an international panel of 13 IBD experts (BRIDGe group) independently proposed CERs. Two patient focus groups were also convened to solicit their opinions of priority IBD research topics. All CERs were compiled and divided into 21 topic categories. The candidate CERs were then presented to the expert panel using the validated RAND/UCLA method. The panel rated the proposed CERs using a standard 1-9 point scale (1=lowest priority; 9=highest; >7=high priority). Following the initial ratings the panel met in person to discuss and re-rate priorities. Disagreement was assessed using a validated index accounting for response distributions over the 9-point scale. Results: Responses were collated into 234 unique CERs proposed by the GIs, experts and patients. Based on the initial round of rating, the RAND panel selected 87 CERs to re-rate, of which 40 were rated as high priority. Disagreement was observed in only 5 of 87 CERs. The highest priority CERs (scores >7.7) related to comparing the effectiveness of: withdrawal of biologic or immunomodulator agents for Crohn's patients in remission; anti-TNF monotherapy versus combination therapy in patients failing thiopurines; biologics vs. thiopurines for prevention of post-operative recurrence; the utility of colonoscopy in guiding post-operative management; the use of infliximab levels vs. standard infliximab dosing to guide therapy; the use of biomarkers to predict outcomes and response to therapy; the use of biologics in inducing remission and mucosal healing in Crohn's disease; and cyclosporine vs. infliximab vs. surgery in steroid refractory UC. Conclusion: We systematically developed a list of high priority CERs for IBD based on a survey of GIs, expert review, and patient input. This list may guide IBD researchers and funding agencies towards the most important CERs that would impact day-to-day clinical practice. Disclosure: GYM: Consultant and/or Research Support (Centocor, Setpoint, Amgen, Celgene), Speaker's Bureau (Abbott, P&G, Shire), Advisory Board (UCB). CAS: Advisory board (Abbott, UCB, P&G), Consultant and research support (Elan, P&G), CME activities (Abbott, UCB). BMS: Research (Takeda, Rose Pharma A/S, Prometheus, Novartis), Advisory Board (Prometheus, Takeda, Ironwood, Procter & Gamble, AstraZeneca). BB: Advisory Board (Abbott, Schering-Plough Canada, Shire, Ferring,), Speaker's Bureau (Abbott, Schering-Plough Canada, Shire, Takeda). AC: Speaker's bureau (UCB, P&G, Shire, and Abbott), Advisory board (Abbott, UCB, Schering-Plough Canada). JJ: Consulting, speaker's Bureau and educational funding (Schering-Plough Canada, UCB Pharma, Shire, P&G and Abbott). MS: Research Support (Ferring Pharmaceuticals, Abbott Pharmaceuticals), Advisory Board (Schering-Plough Pharmaceuticals). FV: Research support (P&G). PI: Advisory Board (Abbott, Shire, Falk), Speaker's Bureau (Shire, Abbott, MSD, Merck). SD: Speaker's Bureau (Scheringing-Plough, Abbott, Merck, Shire), Advisory Board (Abbott, UCB, Merck). GK: Advisory Board (Schering-Plough, Abbott, UCB, Shire). LH: Consultant (Abbott, Salix), Research support (Glycominds). LB: Advisory board (UCB), Speaker's bureau (Centocor, Salix). PK: None. Funding Source: Unrestricted funding for the in-person Scottsdale RAND Appropriateness Panel meeting was generously provided by Proctor and Gamble Pharmaceuticals, Abbott, and Shire. Unrestricted funding for the BRIDGe group is provided by Abbott, Shire, UCB, and Proctor and Gamble Pharmaceuticals.
Therapy with adalimumab has been shown to be effective in Crohn's disease (CD) patients who have lost response or are intolerant to infliximab.To determine the efficacy of adalimumab in CD patients who discontinued infliximab through a systematic review.Electronic searches of EMBASE and MEDLINE databases up to May 1, 2009, as well as abstracts from the AGA (2006-2008), ACG (2006-2007), UEGW (2006-2008) and CDDW (2006-2009) identified randomized-controlled trials (RCT) or open-labelled cohorts (OLC) evaluating the short-term and/or long-term efficacy of adalimumab in infliximab failures. The response rates for short-term (clinical response and remission at 4 weeks) and long-term (remission at 6 and 12 months) efficacy were considered.A total of 1810 CD patients were identified among the 15 studies (2 RCT and 13 OLC). The majority of studies evaluated CD patients who either lost response or were intolerable to infliximab, although five OLCs permitted patients refractory to infliximab. Short-term clinical response (n = 9 articles) ranged from 41% to 83%. Long-term clinical remission at 12 months (n = 8 articles) ranged from 19% to 68%. The occurrence of severe adverse events ranged from 0% to 19% and four patients died.Current RCT and OLC evidence suggest that adalimumab is an efficacious therapy for CD patients who discontinue infliximab.
There are limited therapeutic options available for patients with autoimmune hepatitis in whom conventional treatment fails. A case series of five patients unresponsive to or unable to take azathioprine, 6-mercaptopurine or corticosteroids who were treated with mycophenolate mofetil (MMF) is reported. While on MMF, alanine aminotransferase normalized or remained normal in all patients. MMF had a steroid-sparing effect and histological remission was demonstrated in one patient after seven months of MMF. One patient experienced an uncomplicated episode of pyelonephritis. In conclusion, MMF can effectively induce and maintain remission in refractory autoimmune hepatitis patients.
The advent of biologic molecules is one of the most important therapeutic advances to have occurred in the medical management of inflammatory bowel disease (IBD). From a Canadian perspective, the monoclonal antibodies directed against tumour necrosis factor-alpha (TNF-α), namely infliximab (Remicade, Johnson & Johnson, USA) and adalimumab (Humira, AbbVie Corporation, USA), are the only approved and commercially available biologics for the treatment of either Crohn disease (CD) or ulcerative colitis (UC) in Canada.
These molecules have a large and complex structure and are generated with the aid of DNA recombination technology. This complexity makes the development of biologically similar substitutes – as is common with smaller, less complex molecules – a challenge. However, following the expiry of the patent on Remicade, a biosimilar infliximab has been developed (CT-P13, Remsima [Celltrion, South Korea], Inflectra [Hospira Inc, USA]). In addition, another biosimilar infliximab has been developed by an Indian pharmaceutical company, Reliance Life Sciences.
Standard, small-molecule pharmaceuticals are significantly different from their complex biological counterparts (Figure 1). Most synthesized pharmaceuticals have a molecular size of only a few hundred Daltons (Da) (eg, omeprazole is 345 Da). In comparison, infliximab is 149,000 Da. Moreover, monoclonal antibodies have a complex structure that is influenced by the vector and post-translational modification, among other factors (1–3). In addition, although the overall structure of a monoclonal antibody may be known, the manufacturing platform used by the manufacturer of the reference biologic drug (RBD) is not, due to the proprietary nature of the information. As such, a different biological system that is used to produce a biosimilar agent will likely translate into subtle differences that could be difficult to characterize. Such differences have the potential to translate into clinically relevant differences in efficacy, safety and immunogenicity. Therefore, it will be extremely challenging to ensure that a subsequent entry biologic (SEB) is, in fact, ‘equivalent’ to the RBD. Clinical equivalence can only be proven in clinical trials.
Figure 1)
Comparison between a biologic monoclonal antibody and an acetylsalicylic acid molecule. From Kozlowski S, Woodcock J, Midthun K, Behrman Sherman R. Developing the Nation’s Biosimilars Program. N Engl J Med 2011;365:385–8. Reprinted with ...
It is important for the Canadian gastroenterology community to gain a full understanding of the important issues in the context of the development and entry into the marketplace of such biologic agents.
The objectives of the present document are to:
Provide a brief primer on the terminology germane to this issue.
Describe the current state of SEBs and the existing guidelines from Health Canada and other jurisdictions.
Provide perspective on the potential opportunity in the Canadian marketplace for SEBs in the arena of IBD.
Provide a brief overview of the existing data, generated from two trials conducted in rheumatoid arthritis and ankylosing spondylitis, for infliximab-Celltrion (Remsima).
Identify areas that will require careful thought and attention moving forward.
Provide a current position statement from the Canadian Association of Gastroenterology (CAG) regarding SEBs.
Mutations in the nucleotide oligomerization domain-2 (NOD2) gene and positive antibodies to microbial antigens have been found to be associated with the Crohn's disease (CD) phenotype, fibrostenosis. The aim of this study was to confirm these relationships in a large cohort of CD patients and to determine the correlation between the presence of NOD2 variants and antibodies to oligomannan, CBir, outer membrane porin-C (OmpC), and I2 in CD patients with fibrostenosis.Sera and DNA from 731 unrelated CD patients were tested for NOD2 variants (SNP 8, 12, and 13) and the antibodies. The results were correlated with CD phenotypes, fibrostenosis, internal penetrating, perianal penetrating, and ulcerative colitis (UC)-like as well as other clinical features.The presence of NOD2 allelic variants was primarily associated with fibrostenosis, secondarily with small bowel disease and small bowel surgery, and was inversely associated with UC-like disease. This association was present in patients with a fibrostenosis only (Vienna B2) and those with both stricturing and penetrating disease. The presence and level of antibodies to microbial antigens was also associated with the fibrostenosis phenotype. In the 316 patients with fibrostenosis the prevalence of NOD2 variants was significantly correlated with the antibody titer by quartile sum score. Further, when these patients with fibrostenosis were clustered by quartile sum score, the odds ratio for fibrostenosis was significantly higher in the patients with NOD2 variant alleles within each cluster, indicating synergy.Defects of innate (NOD2 variants) and adaptive (antibodies to microbial antigens) immunity act synergistically to increase the risk of the fibrostenosis phenotype.
