Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editor at the annual national meeting, Mentoring in IBD XVIII: The Master Class, held November 3, 2017 in Toronto, Ontario.
The treatment landscape for inflammatory bowel disease (IBD) is evolving rapidly, with the recent approval of novel biologics and multiple agents in late-phase development. In the past 20 years, tumor necrosis factor (TNF) antagonists have provided clinicians and patients with better options. However, approximately one-third of biologic naïve patients fail to respond to induction therapy, and of those initially responding, up to 40% ultimately fail treatment due to suboptimal drug exposure (due to immunogenicity or high drug clearance), side effects or other poorly characterized mechanisms.
New therapies such as vedolizumab, an integrin blocker that prevents T-cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and -23, have been introduced to the market. These therapies are effective in both TNF-antagonist-naïve patients and those who have failed these agents. Several other new drugs, including novel anti-trafficking therapies (e.g., anti-β7 and sphingosine-1-phosphate receptor modulators), antibodies against IL-23, and small molecules including Janus kinase inhibitors, are under investigation in phase II and III trials.
In addition to these new agents, multiple strategies have evolved that have great potential to optimize treatment in a given patient. Many of these approaches are based on the precepts of “precision medicine.” First, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. Second, this shift in thinking has been accompanied by a movement away from “step-care“ to the early use of highly effective therapy in poor-prognosis patients. Third, adoption of therapeutic drug monitoring (TDM) has helped to direct management in patients who lose response to biologics. Finally, we are beginning to see that matching specific drug therapies in IBD to patients is possible just as it is in oncology. Validation of this approach will be an integral component of reducing the high cost of medical therapy.
Current treatment options and optimization strategies will be discussed in this review, with an emphasis on practical suggestions for patient management.
The natural history of Crohn’s disease (CD) is such that while symptoms vary in severity over time (including periods of quiescence), inflammatory activity worsens over time and intestinal damage progressively accumulates.(1) Over the course of their disease, most patients with CD will require surgery(2) and evidence has also shown that overall survival is modestly reduced in individuals with CD.(3)
It is against this background that we develop treatment strategies in an effort to interfere with the downward trajectory of disease, through induction and maintenance of gastrointestinal healing; prevention of strictures and penetrating complications and prevention of extra-intestinal complications. Achieving these goals also leads to a decrease in hospitalization, surgery and mortality rates, as well as reduced long-term costs of care.
To optimize treatment efforts and better achieve the goals of therapy, models of precision medicine are being developed. The key aspects of this approach are: identifying the “right patient” to target with highly effective therapy early in the course of disease, prescribing the “right drug(s)” based on the individual patient characteristics and choosing the “right target.” Additionally, precision medicine also needs to incorporate strategies to use when patients have suboptimal response to their medications, including what to do in the event of low drug levels and/or the presence of anti-drug antibodies.
There are several clinical factors that have been identified to help predict long-term outcomes in CD. Current smoking, the presence of abdominal pain, nausea or vomiting, ileal localization and use of oral corticosteroids in the first six months are among the predictors that have been identified.(4) Perhaps more compelling are the data showing the association between baseline endoscopic lesions and long-term outcomes. Fistulizing disease and colectomy have been found to be significantly more common among patients with baseline endoscopic lesions than those without these characteristics.(5) Multiple positive anti-bacterial serologies also appear to be a compelling predictor of poor outcomes.(6)
In addition to keeping in mind the factors that identify patients as good candidates for early highly effective therapy, we should also consider that there are patients who would not be favorable candidates for such therapy. One important potential complicating factor to keep in mind is the possibility of C. difficile infection, which may be responsible for up to one-quarter of flares of CD.(6) In such cases, treatment of the infection is the primary course of action.
Thiopurine monotherapy (e.g., thiopurine) is not an optimal immunosuppressive option for the management of CD. Longitudinal data have shown that surgery rates did not markedly change over the duration of the azathioprine era from the late 1970s to the early 2000s,(8) and the prospective AZTEC and GETAID studies confirmed that early azathioprine use does not result in significant differences in sustained remission rates compared to placebo.(9,10)
These observations have led us to revisit and reject the traditional step-care model of first-line 5-ASA and/or corticosteroids, followed by traditional immunosuppressives, followed in turn by biologic therapy. Notably, the Top-Down study showed that a strategy of early biologic therapy was associated with significantly higher rates of clinical remission during the first year.(11) While these differences were no longer significant in the second year after initiation, long-term follow-up showed that the proportion of patients with complete ulcer disappearance was 73% for the top-down approach and 30% for the step-up approach (P=0.003; Figure 1). This clinically relevant benefit was obtained despite the fact that the top-down approach used in that study featured intermittent dosing of infliximab – which is now known to be suboptimal with increased rates of sensitization.
Important RCTs that underscore the value of biologic therapy with or without concomitant use of a traditional immunosuppressant, include the SONIC trial with infliximab + azathioprine vs. either monotherapy,(12) and the CHARM and EXTEND studies with adalimumab vs. placebo (each in addition to usual care).(13,14)
The value of a treatment algorithm incorporating early initiation of highly effective therapy was validated in the REACT study, a cluster randomized controlled trial in which gastroenterology practices in Canada and Belgium were randomized to either implement a treatment algorithm or to continue with their usual care for the management of CD.(15) A total of 40 practices were randomized, in a 1:1 ratio, using a minimization procedure to balance treatment allocation for country and number of CD patients seen annually at the practice (<100 or ≥100). As shown in Figure 2, while there were no differences in symptomatic remission between those patients who received early combination treatment as directed by the algorithm and those who had conventional management, there was a significant difference in favor of the early combination group in time to first hospitalization, surgery or complication (the prespecified first secondary endpoint).(15)
Notably, there were no significant differences between these groups with respect to serious adverse events or overall mortality indicating that this strategy can be safely implemented in community practice .
Several unanswered questions remain with respect to the use of early, combined immunosuppression with a thiopurine and an anti-TNF agent, including: What would the benefit be in high risk patients? What would the impact be in treatment-naïve patients with very early disease? and what if decisions were made based upon on objective markers of inflammation rather than symptoms?
Clinicians and patients in Canada also have two other classes of biologic therapies approved for the treatment of CD: vedolizumab, an a4b7 integrin inhibitor with gut-specific immunosuppression; and ustekinumab, an anti IL-12/23 agent.(16,17) Each has demonstrated excellent efficacy and safety in induction and maintenance treatment for CD.(18,19)
Another class of biologic therapy has also been studied among patients with CD and has demonstrated excellent efficacy and safety. Risankizumab, a humanized mAb that targets the p19 subunit, specific to IL-23(20), has been evaluated in a dose-finding study in induction therapy for CD.(21) The investigators noted a dose-dependent effect on the primary outcome of clinical remission at week 12 in a patient population who, for the most part, had failed a TNF antagonist. Also encouraging in this study were the rates of endoscopic improvements with the active therapy compared to placebo (Figure 3). Deep remission was achieved by 12.2% of the higher-dose risankizumab patients, compared to none in the placebo group. This finding did not, however, reach statistical significance.
In IBD, it is clear that the goals of therapy need to go beyond clinical markers. Observational studies have demonstrated that patients who achieve mucosal healing are more likely to have a favorable disease course than those who do not. The Norwegian IBSEN study, for example, showed that the risk of future surgery was significantly reduced among people with complete mucosal healing in the first year of therapy compared to those without this outcome (hazard ratio 0.42, 95% CI 0.20=0.89, P=0.027).(22)
Prospective, randomized studies have supported these findings. The EXTEND study with adalimumab showed that patients who achieve an endoscopic response at week 12 are far more likely to achieve endoscopic remission at one year.(23)
The CALM study found that following a biomarker-based treat-to-target approach in CD is associated with higher rates of endoscopic remission (45% of patients with CDEIS <4 and no deep ulcers) compared to patients managed conventionally (30.3%, P=0.01).(24)
The STRIDE guidelines recommend that the target for treatment in CD is a combination of both clinical and endoscopic criteria.(25) For the former, the guidelines specify control of the cardinal symptoms of CD (i.e., abdominal pain, loose bowel habits); for the latter, the target is absence of ulceration on endoscopy.(25)
Long-term observational studies have noted an annual loss of response of 12–18% among patients with an initial response to the TNF antagonists infliximab or adalimumab in CD.(26,27) Research has shown that low drug concentrations at baseline is the most powerful predictor of this loss of response.(28) Trough drug concentrations have also been shown to correlate well with mucosal healing rates with TNF antagonist therapy in CD.(29)
The current treatment paradigm for patients with loss of response is to perform TDM for trough drug concentration and presence or absence of anti-drug antibodies. The recommended course of action based upon the results of testing is shown in Figure 4.(30)
Multiple effective new therapies have been identified for the treatment of IBD. However, better prognostic models are needed to identify high risk patients. More robust treatment targets incorporating endoscopy, together with the expanding array of medications available to clinicians and their patients have put us on the cusp of developing treatment algorithms that can truly change the course of IBD.
Charles is a 60-year-old steel worker with Crohn’s colitis. He is receiving adalimumab 40 mg SC weekly and methotrexate 12.5 mg PO weekly. Recent TDM has shown trough adalimumab concentration of 15.2 mcg/mL. A surveillance colonoscopy shows scarring and inflammatory polyps throughout the colon, multiple aphthous ulcers and several linear ulcers in the rectum. Magnetic resonance enterography (MRE) notes no small bowel disease but makes incidental note of an uncomplicated trans-sphincteric fistula.
The recommended maintenance dose for adalimumab is 40 mg every other week, so Charles’ regimen has already been optimized to 40 mg weekly.(31) In addition, he is already receiving combined therapy with methotrexate (12.5 mg weekly), albeit at a dose lower than the maximum of 25 mg weekly.
Charles’ adalimumab trough level is within the therapeutic range at 15.2 mcg/mL. In a study published in 2014, researchers determined that a cut-off drug level of 5.85 mcg/mL yielded optimal sensitivity, specificity and positive likelihood ratio for remission prediction.(32) While the target trough level for all biologics remains controversial, increasing the dose of adalimumab is unlikely to be helpful here.
Given that the current therapy is optimized, and anti-drug antibodies were demonstrated, switching to another biologic is probably the best option. Specifically, a medication with a different mechanism of action is preferred.(33)
Chantelle is a 19-year-old engineering student with left-sided ulcerative colitis. Four months ago, treatment with vedolizumab was initiated and she is currently receiving 300 mg IV every eight weeks. Her symptoms initially improved; however, they are now the same as when she started therapy. You repeat her sigmoidoscopy and find Mayo 2 endoscopic disease activity to at least 25 cm. You add budesonide MMX® 9 mg daily, arrange for an early dose of vedolizumab the next day, and dose-intensify her regimen to every four weeks. Four weeks later her symptoms are unchanged. Review of her biopsies returned, showing granulomas in the rectum.
In the US VICTORY consortium, vedolizumab dose intensification (q4wks instead of q8wks) in a mixed population of patients with CD and ulcerative colitis led to a successful recapture of response in 32% of patients who had lost response and in 19% of patients who did not have an initial response to q8wk dosing.(35)
Given that only 20 percent of such patients respond to dose optimization and that there has been no change in four weeks for Chantelle, another strategy will likely be necessary; however, additional time should be allowed to fully evaluate the potential benefit of dose intensification on the situation. It is also concerning that the presence of granuloma indicates that the patient likely has CD. In this setting, addition of either azathioprine or methotrexate might be an attractive option. There is limited evidence available to support the addition of azathioprine as a clinically effective strategy in the setting of primary vedolizumab failure.(37) Of note, concomitant thiopurine therapy has not been shown to impact vedolizumab pharmacokinetics.(38)
Minimal experience is available with the use of TDM for vedolizumab. A recent study demonstrated that patients with vedolizumab concentrations ≥5.1ug/mL were more likely to achieve deep remission.(36) While these results suggest that there may be a role for TDM and drug optimization in patients receiving VDZ for IBD, the patient’s dose has already been empirically intensified.
Switching to another biologic with a different mechanism of action (e.g., TNF antagonist therapy) is also a reasonable consideration, although there is limited evidence showing that this strategy is effective.
Surgical consultation is an option. However, one would probably consider a trial of a TNF antagonist (with or without thiopurine in combination) as the best course if the patient does not respond to empiric dose intensification.
Ahmed is a 29-year-old tattoo artist with extensive small-bowel Crohn’s disease, who began ustekinumab induction therapy nine months ago. He had considerable symptomatic improvement and continued ustekinumab maintenance therapy 90 mg SC every 8 weeks as monotherapy. He feels well, but is frustrated that he cannot gain weight. Re-evaluation with MRE shows persistent mid-jejunal ulceration. You take advantage of a new TDM program and find that his serum ustekinumab concentration is 9.1 mcg/mL
Pharmacokinetic data from the UNITI trials in CD demonstrated that higher ustekinumab serum concentrations were associated with greater rates of clinical remission at 1 year.(39) Although Battat et al reported that maintenance trough concentrations of ustekinumab above 4.5 mcg/mL at 26 weeks or later were associated with biomarker reduction and endoscopic response,(40) a comprehensive pharmacokinetic analysis of data from the pivotal UNITI trials indicated a much lower target trough concentration of approximately 1 mcg/mL.(41) The discrepancy between these results likely is due to the timing of the testing and route of administration with subcutaneous dosing being used exclusively in the former study and intravenous induction followed by subcutaneous maintenance in the latter.
In any case, Ahmed’s trough level (9.1 mcg/L) is above the threshold identified in both studies As such, there does not appear to be justification for dose intensification in this case.
There is limited evidence to support the addition of either methotrexate or azathioprine to ustekinumab in CD. Ustekinumab has a low rate of immunogenicity, so concomitant use of an immunosuppressive is unnecessary solely for of prevention of anti-drug antibodies.
A switch to a biologic with another mechanism of action (anti-TNF or vedolizumab) is a logical choice in this case, notwithstanding that there are no data showing the rates of response or other parameters among patients who fail to respond adequately to ustekinumab. Alternatively, addition of an immunosuppressive is also an option.
John K. Marshall, MD MSc FRCPC AGAF, Director, Division of Gastroenterology, Professor, Department of Medicine, McMaster University, Hamilton, ON
Richard N. Fedorak, MD FRCPC FRCP (London) FRCP (Edinburgh) FRCS, Dean, Faculty of Medicine and Dentistry, Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB
Brian G. Feagan, MD FRCPC, Professor of Medicine, Epidemiology and Biostatistics, Senior Scientific Director, Robarts Clinical Trials Inc., Robarts Research Institute, Western University, London, ON
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, NS
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
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