Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that now includes an annual national meeting, regional satellites in both official languages, a website, 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 issue editor at the annual national meeting, Mentoring in IBD XVII: The Master Class, held November 4, 2016 in Toronto, Ontario.
Recent decades have seen important advances in the management of inflammatory bowel diseases (IBD). The development of tumour necrosis factor-α (TNF-α) inhibitor therapy completely changed both treatment of IBD and its expected outcomes. New paradigms include concepts of early diagnosis and treatment, the use of combination therapy, a treat-to-target approach, and tight control through objective monitoring, including for asymptomatic patients.
Despite approval of newer TNF-α inhibitors, overall efficacy of these agents in induction of remission in randomized controlled trials is no better than 50%; in maintenance of remission, efficacy is lost in 30–50% of patients; and in Crohn’s disease (CD), patients with stricturing, or penetrating disease have an increased risk of treatment failure.(1,2) Therefore a therapeutic gap exists and there is a need for new approaches to IBD therapy.
A better understanding of the immunopathogenesis of IBD has led to the identification of a variety of new therapeutic targets. The inflammatory reaction in the gut relies upon an interaction between the intestinal epithelium and integrins (adhesion molecules) that mediates leukocyte recruitment (Figure 1).(3) Increased epithelial barrier permeability allows gut microbial antigens to penetrate the mucosa, stimulating an immune response, with production of interleukin (IL)-7, -12, and -15, and activation of immune cells, including dendritic cells and macrophages. Activation of T helper 1 (Th1) cells results in release of inflammatory cytokines, such as TNF-α and interferon-γ (IFN-γ). The adaptive immune response builds on this initial inflammatory response and results in high levels of IL-6 and -23 and in Th17-mediated production of IL-17A, -21, and -22. The abundance of numerous inflammatory cytokines stimulates accumulation of myofibroblasts and disturbs the normal epithelial healing process, potentially leading to fibrosis and fistula formation.
An increased understanding of the immunopathogenesis of IBD has allowed the targeted development of novel therapeutic classes that are launching a new era of IBD therapeutics, beyond TNF-α inhibitors, some which will be discussed in this issue (Table 1).(4)
Lymphocytes, a vital part of the adaptive immune response, imprint for migration to areas of inflammation in the lymphoid tissues in which they first encounter antigen. They preferentially leave the circulation in the target tissue for which they were activated.(5) In ulcerative colitis (UC) and CD, an excess of lymphocytes accumulates in gastrointestinal tissue as a result of the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) (Figure 2).(6) This interaction contributes importantly to the chronicity of inflammation.
Vedolizumab is a novel gut-selective anti-inflammatory monoclonal antibody (mAb) that binds exclusively to the α4β7 integrin heterodimer, inhibiting adhesion to MAdCAM-1 and fibronectin and preventing leukocyte migration to the intestinal tract.(7) The GEMINI I trial of vedolizumab, 300 mg, assessed induction and maintenance after failure of at least one prior therapy in patients with moderate-to-severe UC (N=374).(8) Vedolizumab was significantly more effective than placebo in induction and maintenance of clinical remission and mucosal healing at 6 and 52 weeks. The GEMINI II trial of vedolizumab, 300 mg, induction and maintenance in patients with active CD, found vedolizumab to have a modest benefit compared with placebo.(9) Additional data analyses are attempting to define optimal induction approaches with vedolizumab in CD, such as coinduction with a corticosteroid and timelines for response.
In moderate-to-severe UC, phase II results of etrolizumab, a gut-specific, humanized mAb that blocks both αEβ7 and α4β7, and of PF-00547659, an anti-MAdCAM-1 mAb, are promising.(10,11)
The Janus kinase (JAK) family of intracellular tyrosine kinases (TYKs) – JAK1, JAK2, JAK3, and TYK2 – plays an important role in cytokine signaling pathways, which operate through paired JAKs.(3) Different cytokine receptors link to different JAK pairs. In IBD, JAK signal transducers and activators of transcription (JAK-STAT) pathways are integral to both innate and adaptive immune responses. Cytokine receptor binding activates JAKs, which is followed by phosphorylation and activation of STATs. Activated STATs enter the cell nucleus to modulate gene transcription, which may alter cellular inflammatory and immune responses. Because numerous cytokines activate JAK-STAT pathways, JAK inhibition is a promising approach to blocking multiple cytokines by inhibiting a single pathway.
Tofacitinib is a reversible oral JAK inhibitor under investigation as a targeted immunomodulator for UC and other inflammatory diseases.(3) Tofacitinib demonstrates functional cellular specificity for JAK1 and JAK3 and modulates signaling for several inflammatory cytokines, including IL-2, -4, -7, -9, -15, and -21 (Table 2).
The Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE) induction trials involved a total of 1139 patients with moderate-to-severe UC and demonstrated significantly greater remission and mucosal healing rates with tofacitinib, 10 mg, than placebo at 8 weeks, with similar efficacy in both TNF-α–naïve and TNF-α–experienced patients.(12) Rapid improvement was seen, with improvements in the partial Mayo score at 2 weeks. No new or unexpected safety signals were seen. The follow-up maintenance trial, OCTAVE Sustain (N=593), found a significantly greater proportion of patients in remission at 52 weeks with tofacitinib than with placebo.
IL-12 and -23 are inflammatory cytokines with a central role in immune regulation through their influence on Th1 and Th17 cellular responses. These cytokines, which are involved in promoting various immune-mediated diseases, signal through the JAK-2/TYK-2 combination (Figure 3).(13)
Fully human immunoglobulin (IgG)1 mAbs, such as ustekinumab and risankizumab, are being evaluated in CD. Ustekinumab binds the p40 subunit of IL-12 and- 23, whereas risankizumab selectively blocks the IL-23 p19 subunit.
In patients with moderate-to-severe CD, ustekinumab induction and maintenance studies UNITI-1 (refractory to TNF-α inhibitors) and UNITI-2 (naïve or not refractory to TNF-α inhibitors) have demonstrated statistically significant efficacy in achieving and maintaining remission.(14) A phase IIb study of risankizumab in patients with moderate-to-severe CD found risankizumab to be well tolerated and significantly more effective than placebo in inducing clinical and endoscopic remission at 12 weeks.(15)
IL-6, an inflammatory cytokine, is involved in inflammatory pathways in several chronic inflammatory diseases. In CD, CD4+ T-cells and macrophages produce increased amounts of IL-6 and soluble IL-6 receptor, which are linked to disease activity and elevated C-reactive protein (CRP) levels.(16)
PF-04236921, a fully human IgG2 mAb, binds to and neutralizes the IL-6 ligand.(16) ANDANTE, a phase II dose-ranging (10, 50, and 200 mg) study of PF-04236921, enrolled 247 patients with moderate-to-severe CD and failure of, or intolerance to, TNF-α inhibitor therapy. The 50-mg dose achieved the primary endpoint of a Crohn’s Disease Activity Index-70 (CDAI-70) response at 8 and 12 weeks, with a 12-week Δ of 18.8% over placebo (P=0.04). Treatment suppressed CRP levels in a dose-response manner. Safety was acceptable for this population with refractory disease.
The signaling molecule sphingosine 1-phosphate (S1P), which is involved in lymphocyte trafficking, binds to the S1P receptor family, which includes 5 receptors (S1P1–S1P5) that regulate numerous immunologic effects.(17) Binding of receptor agonists to cell membrane-associated S1P1 prevents lymphocyte migration out of lymph nodes to sites of inflammation, reducing immune-mediated pathology. S1P1 modulators in development include ozanimod, an oral agent that modulates S1P1 and S1P5.
A phase II trial evaluating ozanimod in patients with moderately to severely active UC (N=197) found the 1-mg dose to be associated with slightly greater clinical remission rates than placebo.(17) Additional assessment of efficacy in larger trials is needed, as the trial was inadequate in both size and length to assess safety.
Among other physiologic roles, transforming growth factor-β (TGF-β) functions as the principal immune system regulator, through activation of SMADs.(18) (The name SMAD is an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad proteins.) SMADs are a family of intracellular proteins divided into 3 functional classes (Table 3). SMADs transduce extracellular signals from TGF-β ligands (which include bone morphogenic protein, activin, and nodal) to the nucleus and are also involved with integrating TGF-β signalling with several additional pathways. Binding of TGF-β ligands to type I and II receptors results in phosphorylation of receptor-activated SMADs (R-SMADs) (Figure 4).(18,19) Common-mediator SMAD (Co-SMAD) then complexes with phosphorylated R-SMADs, allowing their translocation to the nucleus, where they regulate genes for cellular proliferation, differentiation, and survival.(18) The inhibitory SMADs (I-SMADs) competitively inhibit R-SMAD activation at their receptor and prevent R-SMAD phosphorylation and complexing with Co-SMAD.
In IBD, upregulation of SMAD7 and its induction by TNF-α and IFN-γ prevent SMAD3 phosphorylation. This action interferes with the immunosuppressive function of TGF-β1 at the mucosal level and eventually allows the development of fibrosis.(20) SMAD7 knock-down using an antisense oligonucleotide restores endogenous TGF-β1signaling, suppressing production of inflammatory cytokines, inhibiting inflammatory pathways, and preventing tissue injury.
Mongersen is an oral, topically active SMAD7 antisense DNA oligonucleotide that inhibits SMAD7 by targeting SMAD7 mRNA, restoring SMAD2 and SMAD3 activity and TGF-β-mediated signaling, and suppressing inflammatory cytokine production.(21)
A 14-day phase IIa trial of mongersen induction in 126 patients with steroid-dependent or steroid-resistant active CD was designed with primary outcomes of clinical remission at 15 days maintained for 14 days; clinical response at 28 days; and safety at 3-month follow-up.(21) A significantly greater proportion of patients receiving mongersen (40 mg: 55.0%, 160 mg: 65.1%) achieved clinical remission than did patients receiving placebo (9.5%, P<.0001 for both). A 12-week phase Ib endoscopic and clinical outcomes study with a 52-week follow-up evaluated mongersen, 160 mg, given every 4, 8 or 12 weeks in 63 patients with active CD.(22) All treatment groups experienced a significant drop in CDAI at all assessment points (2, 4, 8, and 12 weeks; P<.0001) and meaningful endoscopic improvement in a difficult-to-treat population by 12 weeks. Negligible systemic exposure was seen, and clinical development is ongoing.
Recognition of the interruption of lymphocyte trafficking as an effective treatment strategy, knowledge of the importance of blocking the IL-12/23 pathway, greater understanding of intracellular signaling pathways, and new oral molecules will redefine the next generation of IBD treatment algorithms. Furthermore, emerging concepts and new therapeutic classes will continue to evolve and shape the field.
Your 34-year-old male patient with colonic and perianal CD has been on TNF-α inhibitor monotherapy for the last 6 years and has been in excellent clinical remission with confirmed endoscopic mucosal healing. Over the past year he has experienced occasional diarrhea and some discharge from an old perianal fistula. These symptoms are more pronounced shortly before his next TNF-α inhibitor treatment.
In general, in the IBD population, physicians too quickly abandon treatment optimization in the face of loss of response. In many cases, significant opportunities for treatment optimization still exist before changing therapies.
It is first critical to determine whether the symptoms are due to inflammation resulting from active disease or to another cause. Because symptoms of C. difficile infection are generally indistinguishable from those of CD, measurement of C. difficile toxin is essential. Stool culture should be performed to rule out other enteric infections.
CRP and fecal calprotectin (FCP) are biomarkers of inflammation that can indicate active disease. FCP can be used alone, without performing endoscopy, to confirm disease if there are baseline FCP results correlated with endoscopy results. These biomarkers, however, remain surrogates, and endoscopy is required for absolute confirmation of the presence of active disease. Diagnostic imaging (computed tomography enterography and/or magnetic resonance enterography) can also be used to define active small-bowel disease. After confirmation of disease activity, it is appropriate to determine whether the patient is adherent to the treatment schedule and to utilize therapeutic drug monitoring (TDM) to measure trough drug concentrations and antidrug antibody (ADA) levels to guide optimization. In patients such as this a referral to a colorectal surgeon for an examination under anaesthesia may be appropriate.
His stool cultures are negative. He has delayed a few doses of his TNF-α inhibitor by no more than a week, but otherwise adheres to his therapy, confirmed by the company’s patient support program. Laboratory investigation reveals FCP of 874 µg/g and a sub-therapeutic trough level with no ADAs. Magnetic resonance imaging of the pelvis shows a left-sided trans-sphincteric fistula tract but no abscess. He does not want to change his biologic.
In this case, in the absence of ADA and low trough levels, dose optimization is appropriate. This may include increasing the dose, shortening the interval and/or adding an immunosuppressive. It should be noted that emerging data suggests that different trough levels of drug may be needed to achieve different outcomes. Therefore, trough levels needed to achieve mucosal healing or fistula closure may need to be much higher than previously thought. The IBD literature indicates that one-third to two-thirds of patients can achieve mucosal healing with early introduction of intensive highly effective therapy accompanied by careful routine monitoring. Experience with TDM has demonstrated the importance of trough levels in loss of response but also broad range of normal trough levels.
You add methotrexate 15 mg PO weekly, prescribe a 2-week course of ciprofloxacin plus metronidazole, and increase his TNF-α inhibitor dose. He returns in 16 weeks to report no improvement.
Confirming response 12–16 weeks after dose adjustment is critical to determining the success of optimization and the need for continuing current therapy. Lack of response suggests a need to change the therapy.
Confirming the response to optimization should include objective parameters. Using FCP, and comparing it to the pre-optimization value as a surrogate, is good practice, as it helps to avoid frequent endoscopy. It may also be useful to measure CRP if previously elevated.(23) Re-measuring TDM is appropriate. It is important to ensure that the TNF-α inhibitor trough level is “adequate” before determining that the TNF-α inhibitor is ineffective.
Before calling this loss of response, you again arrange objective monitoring with TDM and FCP (based on the elevated baseline level). His TNF-α inhibitor trough level is now 17 µg/mL (you recognize the individuality in drug levels required for remission) and his FCP remains elevated at 980 µg/g.
The adequate trough levels and persistently elevated FCP indicate loss of response that optimization has been unable to overcome. Attempting re-induction of the biologic or a tapering course of steroids may rescue the response; these strategies, however, are unsupported by evidence. It is time for a change in therapy. This would be considered a mechanistic escape and the need to consider an alternative class of therapy. Limited options exist at this point. There is limited evidence from sub-group analysis of fistula patients receiving either vedolizumab or ustekinumab.
John K. Marshall, MD MSc FRCPC AGAF, Chief of Gastroenterology Clinical Service, Hamilton Health Sciences; Professor of Medicine, Division of Gastroenterology, McMaster University, Hamilton, ON
Richard N. Fedorak, MD FRCPC FRCP (London) FRCS, Dean, Faculty of Medicine and Dentistry; Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB
Remo Panaccione, MD FRCPC, Director, Inflammatory Bowel Disease Clinic, Director, Gastroenterology Research; Professor of Medicine, University of Calgary, Calgary, AB
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, ON
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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